Viral replication of thymidine kinase deleted (tk-) vaccinia virus (VV) is attenuated in resting normal cells, enabling cancer selectivity, however, replication potency of VV-tk- appears to be diminished in cancer cells. Previously, we found that wild-type herpes simplex virus (HSV)-tk (HSV-tk) disappeared in most of the recombinant VV after multiple screenings, and only a few recombinant VV containing naturally mutated HSV-tk remained stable. In this study, VV-tk of western reserve (WR) VV was replaced by A167Y mutated HSV-tk (HSV-tk418m), to alter nucleoside selectivity from broad spectrum to purine exclusive selectivity. WOTS-418 remained stable after numerous passages. WOTS-418 replication was significantly attenuated in normal cells, but cytotoxicity was almost similar to that of wild type WR VV in cancer cells. WOTS-418 showed no lethality following a 5 × 108 PFU intranasal injection, contrasting WR VV, which showed 100% lethality at 1 × 105 PFU. Additionally, ganciclovir (GCV) but not BvdU inhibited WOTS-418 replication, confirming specificity to purine nucleoside analogs. The potency of WOTS-418 replication inhibition by GCV was > 10-fold higher than that of our previous truncated HSV-tk recombinant OTS-412. Overall, WOTS-418 demonstrated robust oncolytic efficacy and pharmacological safety which may delegate it as a candidate for future clinical use in OV therapy.

Background: Regorafenib has shown promising results as a second-line therapy for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib. Although several data regarding the efficacy of sequential therapy with sorafenib and that of regorafenib in real-life, specific inflammation markers for predicting the prognosis have not been studied. This study aimed to investigate prognostic value of systemic inflammatory markers in patients with HCC who received sorafenib-regorafenib sequential therapy. Methods: We retrospectively analyzed medical data of patients who received regorafenib for the treatment of HCC after sorafenib failure. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier survival curves. Univariate and multivariate analyses were performed to analyze the factors associated with survival.Results: A total of 58 patients who received at least one dose of regroafenib and fulfilled the eligibility criteria, good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1) and preserved liver function (Child-Pugh-A), were included in the analysis. The median PFS was 3 months (95% confidence interval [CI] = 0.981-5.019) and the median OS was 8 months (95% CI=5.761–10.239). Elevated systemic immune-inflammation index (SII ≥340) was independently associated with poor OS. In multivariate analysis, the SII (hazard ratio [HR] = 2.211, 95% CI = 1.089-4.489, P = 0.028) and alpha-fetoprotein (AFP) (HR = 2.750, 95% CI = 1.259-6.010, P = 0.011) were independent predictors of OS.Conclusion: Elevated SII is associated with poor OS in patients with HCC who received sequential therapy with sorafenib and regorafenib. In addition, when selecting a treatment strategy, the SII can be used in combination with the AFP level as a promising prognostic tool for HCC.

No abstract

Primary biliary cholangitis is a chronic inflammatory autoimmune liver disease that is characterized by a positive antimitochondrial antibodies test and progressive destruction of the small intrahepatic bile duct. Ankylosing spondylitis is a chronic, systemic, inflammatory disease of the spine and the sacroiliac joints. The association between these two is very low. This paper reports a rare case who had ankylosing spondylitis and developed primary biliary cholangitis.