Oncolytic virotherapy augments self-maintaining natural killer cell line cytotoxicity against neuroblastoma.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death. METHODS: We utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo. RESULTS: NK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression. CONCLUSIONS: To the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma.

The Application of Artificial Intelligence to Investigate Long-Term Outcomes and Assess Optimal Margin Width in Hepatectomy for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is associated with poor long-term outcomes, and limited evidence exists on optimal resection margin width. This study used artificial intelligence to investigate long-term outcomes and optimal margin width in hepatectomy for ICC. METHODS: The study enrolled patients who underwent curative-intent resection for ICC between 1990 and 2020. The optimal survival tree (OST) was used to investigate overall (OS) and recurrence-free survival (RFS). An optimal policy tree (OPT) assigned treatment recommendations based on random forest (RF) counterfactual survival probabilities associated with each possible margin width between 0 and 20 mm. RESULTS: Among 600 patients, the median resection margin was 4 mm (interquartile range [IQR], 2-10). Overall, 379 (63.2 %) patients experienced recurrence with a 5-year RFS of 28.3 % and a 5-year OS of 38.7 %. The OST identified five subgroups of patients with different OS rates based on tumor size, a carbohydrate antigen 19-9 [CA19-9] level higher than 200 U/mL, nodal status, margin width, and age (area under the curve [AUC]: training, 0.81; testing, 0.69). The patients with tumors smaller than 4.8 cm and a margin width of 2.5 mm or greater had a relative increase in 5-year OS of 37 % compared with the entire cohort. The OST for RFS estimated a 46 % improvement in the 5-year RFS for the patients younger than 60 years who had small (<4.8 cm) well- or moderately differentiated tumors without microvascular invasion. The OPT suggested five optimal margin widths to maximize the 5-year OS for the subgroups of patients based on age, tumor size, extent of hepatectomy, and CA19-9 levels. CONCLUSIONS: Artificial intelligence OST identified subgroups within ICC relative to long-term outcomes. Although tumor biology dictated prognosis, the OPT suggested that different margin widths based on patient and disease characteristics may optimize ICC long-term survival.

PIM Kinase Inhibition Attenuates the Malignant Progression of Metastatic Hepatoblastoma.

Hepatoblastoma is the most common primary pediatric liver tumor. Children with pulmonary metastases at diagnosis experience survival rates as low as 25%. We have shown PIM kinases play a role in hepatoblastoma tumorigenesis. In this study, we assessed the role of PIM kinases in metastatic hepatoblastoma. We employed the metastatic hepatoblastoma cell line, HLM_2. PIM kinase inhibition was attained using PIM3 siRNA and the pan-PIM inhibitor, AZD1208. Effects of PIM inhibition on proliferation were evaluated via growth curve. Flow cytometry determined changes in cell cycle. AlamarBlue assay assessed effects of PIM kinase inhibition and cisplatin treatment on viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. PIM kinase inhibition resulted in decreased HLM_2 proliferation, likely through cell cycle arrest mediated by p21. Combination therapy with AZD1208 and cisplatin resulted in synergy, potentially through downregulation of the ataxia-telangiectasia mutated (ATM) kinase DNA damage response pathway. When assessing the combined effects of pharmacologic PIM kinase inhibition with cisplatin on HLM_2 cells, we found the agents to be synergistic, potentially through inhibition of the ATM pathway. These findings support further exploration of PIM kinase inhibition as a therapeutic strategy for metastatic hepatoblastoma.

Racial Disparity Among the Clinical Outcomes Post-Myocardial Infarction Patients: A Systematic Review and Meta-analysis.

The clinical outcomes post-Myocardial Infarction (MI) between Black and White patients have not been well studied, with limited literature available. We conducted a meta-analysis to estimate the clinical outcomes between Black and White patients post-MI.We systematically searched the PubMed, Embase, and Scopus databases from inception until September 26, 2022. A total of 6 studies with 220,984 patients have been included in the analysis. The mean age of patients with White and Black race was 68.46 and 65.14 years, respectively. The most common comorbidity among White and Black patients was hypertension (53% vs 87.73%). Our analysis showed that the likelihood of all-cause mortality (OR, 0.71[95%CI: 0.56-0.91]), P=0.01] and stroke (OR, 0.74[95%CI: 0.67-0.81]), P<0.001] were significantly lower in white patients compared with black patients. However, Black patients had fewer utilization of CABG (OR, 1.38[95%CI: 1.19-1.62], P<0.001]) and PCI (OR, 1.31[95%CI: 1.101-1.68]), P=0.04] compared with White patients, while 30-day mortality was comparable between both the groups. To our knowledge, this is the first meta-analysis with the largest sample size thus far, highlighting that Black patients are at increased risk for all-cause mortality and stroke but have lower utilization of revascularization among MI patients than White patients.

Inflammatory bowel disease and associated cardiovascular disease outcomes: A systematic review.

BACKGROUND: There is limited and conflicting data available regarding the cardiovascular disease outcomes associated with inflammatory bowel disease (IBD). OBJECTIVE: We aim to perform a systematic review to evaluate the cardiovascular outcomes and mortality associated with IBD patients. METHODS: A systematic literature search has been performed on PubMed, Embase, Cochrane, and Scopus from inception till May 2022 without any language restrictions. RESULTS: A total of 2,029,941 patients were included in the analysis from 16 studies. The mean age of the patients was 45.6 years. More females were found compared with males (57% vs 43%). The most common risk factors for cardiovascular disease (CVD) included smoking (24.19%) and alcohol (4.60%). The most common comorbidities includes hypertension (30%), diabetes mellitus (14.41%), dyslipidemia (18.42%), previous CVD (22%), and renal disease (10%). Among outcomes, all-cause mortality among IBD patients was 1.66%; ulcerative colitis (UC): 15.92%; and Crohn disease (CD): 0.30%. Myocardial Infarction (MI) among IBD patients were 1.47%, UC: 30.96%; and CD: 34.14%. CVD events among IBD patients were 1.95%. Heart failure events among IBD patients were 5.49%, stroke events among IBD patients were 0.95%, UC: 2.63%, and CD: 2.41%, respectively. CONCLUSION: IBD patients are at higher risk for adverse cardiovascular outcomes, especially in women. Although there remains a lack of concrete treatment algorithms and assessment parameters that better characterize IBD risk factors, nutritional modifications and physical activity should be at the forefront of CVD prevention in IBD.

Association between sarcoidosis and cardiovascular Outcomes: A systematic review and Meta-analysis.

Background: Sarcoidosis is a chronic inflammatory disorder of unknown etiology associated with high morbidity and mortality. Its association with cardiovascular outcomes is under-documented. Aim: The aim of this study was to assess the adverse cardiovascular outcomes in patients with sarcoidosis compared with that of non-sarcoidosis. Methodology: Online databases including PubMed, Embase and Scopus were queried from inception until March 2022. The outcomes assessed included all-cause mortality (ACM) and incidence of ventricular tachycardia (VT), heart failure (HF) and atrial arrhythmias (AA). Result: A total of 6 studies with 22,539,096 participants (42,763 Sarcoidosis, 22,496,354 Non-Sarcoidosis) were included in this analysis. The pooled prevalence of sarcoidosis was 13.1% (95% CI 1% to 70%). The overall mean age was 47 years. The most common comorbidities were hypertension (12.7% vs 12.5%), and diabetes mellitus (5.5% vs 4%) respectively. The pooled analysis of primary endpoints showed that all-cause mortality (RR, 2.08; 95% CI: 1.17 to 3.08; p = 0.01) was significantly increased in sarcoidosis patients. The pooled analysis of secondary endpoints showed that the incidence of VT (RR, 15.3; 95% CI: 5.39 to 43.42); p < 0.001), HF (RR, 4.96; 95% CI: 2.02 to 12.14; p < 0.001) and AA (RR, 2.55; 95% CI: 1.47 to 4.44); p = 0.01) were significantly higher with sarcoidosis respectively compared to non-sarcoidosis. Conclusion: Incidence of VT, HF and AA was significantly higher in patients with CS. Clinicians should be aware of these adverse cardiovascular events associated with sarcoidosis.

Retraction notice to "Association between sarcoidosis and cardiovascular Outcomes: A systematic review and meta-analysis" [IJC Heart Vasculat. 41 (2022) 101073].

[This corrects the article DOI: 10.1016/j.ijcha.2022.101073.].