Barro, Oumar

Background: Morreton virus (MORV) is an oncolytic Vesiculovirus , genetically distinct from vesicular stomatitis virus (VSV). Aim: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models. Approach and Results: In preliminary safety analyses, high intranasal doses (up to 10 10 50% tissue culture infectious dose [TCID 50 ]) of MORV were not associated with significant adverse effects in immune competent, non–tumor‐bearing mice. MORV was shown to be efficacious in a Hep3B hepatocellular cancer xenograft model but not in a CCA xenograft HuCCT1 model. In an immune competent, syngeneic murine CCA model, single intratumoral treatments with MORV (1 × 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control at a dose 10‐fold lower than VSV (1 × 10 8 TCID 50 ). MORV led to increased CD8 + cytotoxic T cells without compensatory increases in tumor‐associated macrophages and granulocytic or monocytic myeloid‐derived suppressor cells. Conclusions: Our findings indicate that wild‐type MORV is safe and can induce potent tumor regression via immune‐mediated and immune‐independent mechanisms in HCC and CCA animal models without dose limiting adverse events. These data warrant further development and clinical translation of MORV as an oncolytic virotherapy platform.

PURPOSE This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

ABSTRACTThere is a high prevalence of blood-borne infections in West Africa. This study sought to determine the seroprevalence of blood-borne infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and syphilis, in blood donors in Burkina Faso. Blood donors were recruited from 2009 to 2013 in four major cities in Burkina Faso of urban area (Ouagadougou) and rural area (Bobo Dioulasso, Fada N’Gourma, and Ouahigouya). Serology tests including hepatitis B surface antigen, anti-HCV, anti-HIV, and rapid plasma reagin test were used for screening and were confirmed with ELISA. Disease prevalence was calculated among first-time donors. Incidence and residual risk were calculated from repeat donors. There were 166,681 donors; 43,084 had ≥ 2 donations. The overall seroprevalence of HBV, HCV, HIV, and syphilis were 13.4%, 6.9%, 2.1%, and 2.4%, respectively. The incidence rates (IRs) of HBV, HCV, HIV, and syphilis infection were 2,433, 3,056, 1,121, and 1,287 per 100,000 person-years. There was lower seroprevalence of HBV and HCV in urban area than in rural area (12.9% versus 14.0%, P < 0.001; and 5.9% versus 8.0%, P < 0.001), and no difference in HIV (2.1% versus 2.1%, P = 0.25). The IRs of new HBV, HCV, HIV, and syphilis were 2.43, 3.06, 1.12, and 1.29 per 100,000 person-years, respectively. The residual risk was one per 268 donations for HBV, one per 181 donations for HCV, and one per 1,480 donations for HIV, respectively. In conclusion, this comprehensive study from four blood donation sites in Burkina Faso showed high HBV and HCV seroprevalence and incidence with high residual risk from blood donation.