High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy.

Salient studies have investigated the association between host inflammatory response and cancer. This study was conducted to test the hypothesis that peripheral absolute monocyte counts (AMC) could impart an increased risk of hepatocellular carcinoma (HCC) development in hepatitis C virus (HCV)-infected patients after a failed peginterferon/ribavirin (PR) combination therapy. A total of 723 chronic HCV-infected patients were treated with PR, of which 183 (25.3 %) patients did not achieve a sustained virological response (non-SVR). Post-treatment AMC values were measured at 6 months after end of PR treatment. Fifteen (2.8 %) of 540 patients with an SVR developed HCC during a median follow-up period of 41.4 months, and 14 (7.7 %) of 183 non-SVR patients developed HCC during a median follow-up of 36.8 months (log rank test for SVR vs. non-SVR, P = 0.002). Cox regression analysis revealed that post-treatment AFP level (HR 1.070; 95 % CI = 1.024-1.119, P = 0.003) and post-treatment aspartate aminotransferase (AST)-to-platelet ratio index (APRI) ≥0.5 (HR 4.401; 95 % CI = 1.463-13.233, P = 0.008) were independent variables associated with HCC development for SVR patients. For non-SVR patients, diabetes (HR 5.750; 95 % CI = 1.387-23.841, P = 0.016), post treatment AMC ≥370 mm(-3) (HR 5.805; 95 % CI = 1.268-26.573, P = 0.023), and post-treatment APRI ≥1.5 (HR 10.905; 95 % CI = 2.493-47.697, P = 0.002) were independent risks associated with HCC. In conclusion, post-treatment AMC has a role in prognostication of HCC development in HCV-infected patients who failed to achieve an SVR after PR combination therapy.

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

Feasibility of individualized treatment for hepatitis C patients in the real world.

BACKGROUND AND AIM: Individualized treatment with a combination of peg-interferon and ribavirin for patients with hepatitis C virus (HCV) infection has been validated in randomized controlled clinical trials, but its usefulness in the real world is unknown. The aim of the present study was to assess the feasibility of individualized treatment for HCV patients compared with standard therapy in a real-life clinical setting. METHODS: A total of 253 naïve patients with HCV infection who received peg-interferon and ribavirin combination treatment were analyzed and grouped into one of three clinical settings: (i) infection with genotype non-1 (HCV non-1) and treatment for standard 24 weeks (n = 105; none received an abbreviated therapy); (ii) genotype 1 (HCV-1) and standard therapy for either 24 weeks (n = 71) or 48 weeks (n = 21); and (iii) HCV-1 and individualized treatment (n = 56). The individualized therapy used was an abbreviated 24-week treatment for HCV-1 patients who achieved a rapid virological response, otherwise patients received a 48-week course of treatment. Early termination of treatment at week 16 was recommended for non-responders. RESULTS: A sustained virological response (SVR) was achieved in 83.8% of patients with HCV non-1 infection. Among the HCV-1-infected patients, 53.5% of patients who underwent standard 24-week treatment, 66.7% of patients who underwent standard 48-week treatment, and 64.3% of patients treated by individualized therapy achieved SVR. Patients infected with HCV-1 and treated by individualized therapy had a similar efficacy response compared with the standard 48-week therapy (adjusted odds ratio [OR] 0.765, 95% confidence interval [CI], 0.220-2.659, P = 0.673). Both individualized therapy (adjusted OR 2.855, 95% CI 1.189-6.855, P = 0.019) or standard 48-week treatment (adjusted OR 3.733, 95% CI 1.073-12.986, P = 0.038) had significantly higher odds of SVR compared with HCV-1 patients treated by standard 24-week course. CONCLUSION: Individualized therapy is feasible in the real world, especially for patients with HCV-1 infection.

Predictors of alpha-fetoprotein elevation in patients with chronic hepatitis C, but not hepatocellular carcinoma, and its normalization after pegylated interferon alfa 2a-ribavirin combination therapy.

BACKGROUND AND AIM: Elevated serum alpha-fetoprotein (AFP) levels are noted in patients with chronic hepatitis C (CHC) without hepatocellular carcinoma (HCC). The change in AFP levels after treatment with pegylated interferon and ribavirin (Peg-IFN/RBV) combination therapy is still unknown. The aim of this study was to investigate the predictors of elevated serum AFP in patients with CHC, and its change after Peg-IFN/RBV therapy. METHODS: A total of 123 patients, intended to receive pegylated interferon alfa-2a plus ribavirin therapy, were enrolled. Eighty-three patients had complete treatment and received follow up for and additional 24 weeks. The factors that may affect the elevation of pretreatment AFP and the normalization of post-treatment AFP were determined. RESULTS: The mean AFP level was 18.5 +/- 63.0 ng/mL (range, 1.3-676.0 ng/mL); 41 (33.3%) of the 123 patients had elevated serum AFP (more than 10 ng/mL) at baseline. A multivariate logistic regression analysis disclosed that older age (odds ratio [OR], 1.093; 95% confidence interval [CI], 1.015-1.177; P = 0.018), more advanced METAVIR fibrosis stage (OR, 5.237; 95% CI, 1.244-22.037; P = 0.024), a higher aspartate aminotransferase (AST) level (IU/L) (OR, 1.020; 95% CI, 1.008-1.033; P = 0.001), and lower platelet count (x10(9)/L, OR, 0.985; 95% CI, 0.968-0.994; P = 0.003) were independent determinants of pretreatment AFP elevation. After treatment, 72 of 83 (86.7%) cases were found to have normal post-treatment AFP levels (<10 ng/mL) at the end of follow up (EOF). Post-treatment negativity of the chronic hepatitis C virus (HCV)-RNA (OR, 10.014; 95% CI, 1.000-100.329; P = 0.050) and the post-treatment platelet count (x10(9)/L) (OR, 1.025; 95% CI, 1.001-1.050; P = 0.040) were associated with normal AFP at EOF. AFP progressively decreased with significant differences starting from the 12th week after treatment to the end of treatment, and was lowest at the EOF date for the sustained viral response (SVR) group. On the contrary, the non-SVR group did not have an AFP change during and after treatment. CONCLUSION: Older age, low platelet count, higher AST levels, and advanced fibrosis predisposed chronic hepatitis C patients without HCC to have elevated serum AFP levels. After Peg-IFN/RBV combination therapy, a higher platelet count and HCV viral eradication were determinants of normal AFP at EOF. Serial AFP levels decreased after treatment, presenting in a time-dependent manner, specifically for the SVR group.