Italian Chapter of the International Society of Cardiovascular Ultrasound expert consensus document on coronary computed tomography angiography: overview and new insights

Coronary computed tomography angiography is a noninvasive heart imaging test currently undergoing rapid development and advancement. The high resolution of the three‐dimensional pictures of the moving heart and great vessels is performed during a coronary computed tomography to identify coronary artery disease and classify patient risk for atherosclerotic cardiovascular disease. The technique provides useful information about the coronary tree and atherosclerotic plaques beyond simple luminal narrowing and plaque type defined by calcium content. This application will improve image‐guided prevention, medical therapy, and coronary interventions. The ability to interpret coronary computed tomography images is of utmost importance as we develop personalized medical care to enable therapeutic interventions stratified on the bases of plaque characteristics. This overview provides available data and expert's recommendations in the utilization of coronary computed tomography findings. We focus on the use of coronary computed tomography to detect coronary artery disease and stratify patients at risk, illustrating the implications of this test on patient management. We describe its diagnostic power in identifying patients at higher risk to develop acute coronary syndrome and its prognostic significance. Finally, we highlight the features of the vulnerable plaques imaged by coronary computed tomography angiography.     

Resting Echocardiography for the Early Detection of Acute Coronary Syndromes in Chest Pain Unit Patients

Aim: The purpose of this study is to assess the ability of resting echocardiography to detect an acute coronary syndrome (ACS) before the occurrence of ischemic electrocardiogram (ECG) changes or troponin‐T elevations. Methods: Four hundred and three patients who presented to the emergency room (ER) with chest pain, normal ECGs, and normal troponin‐T levels were admitted to the cardiologist‐run Chest Pain Unit (CPU) for further monitoring. They underwent serial resting echocardiography for monitoring of left ventricle wall motion (LVWM), ECG telemetry monitoring, and serial troponin‐T measurements. Results: An ACS was detected in 49 patients (12.1%). These 49 patients were then subdivided into three different groups based on the initial mode of detection of their ACS. In group A, 16 of 49 (32.6%) patients had ACS shown by echocardiographic detection of LVWM abnormalities. In group B, 24 of 49 (48.9%) patients had an ACS detected by ischemic ECG changes. In group C, 9 of 49 (18.3%) patients had an ACS detected by troponin‐T elevations. The shortest time interval between CPU‐admission and ACS‐detection occurred in group A (A vs. B, P < 0.003; A vs. C, P < 0.0001). In group A, cardiac angiogram showed that the culprit coronary lesion was more frequent in the circumflex artery (11 out of 16; 68.7%) (LCx vs. LAD, P < 0.02; LCx vs. RCA, P < 0.001) and of these 11 patients with circumflex lesions, the ECG was normal in eight (72.7%) patients. Conclusion: This study demonstrates the utility of LVWM monitoring by serial echocardiography as part of a diagnostic protocol that can be implemented in a CPU. Furthermore, echocardiography could become an essential tool used in the diagnosis of ACS secondary to circumflex lesions. (Echocardiography 2010;27:597‐602)     

A Mechanistic Proof-of-concept Clinical Trial With JX-594, a Targeted Multi-mechanistic Oncolytic Poxvirus,in Patients With Metastatic Melanoma

JX-594 is a targeted and granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In order to study the mechanisms-of-action (MOA) of JX-594 in humans, a mechanistic proof-of-concept clinical trial was performed at a low dose equivalent to ≤10% of the maximum-tolerated dose (MTD) in other clinical trials. Ten patients with previously treated stage IV melanoma were enrolled. Tumors were injected weekly for up to nine total treatments. Blood samples and tumor biopsies were analyzed for evidence of transgene activity, virus replication, and immune stimulation. The β-galactosidase (β-gal) transgene was expressed in all patients as evidenced by antibody induction. Six patients had significant induction of GM-CSF-responsive white blood cell (WBC) subsets such as neutrophils (25–300% increase). JX-594 replication and subsequent shedding into blood was detectable in five patients after cycles 1–9. Tumor biopsies demonstrated JX-594 replication, perivascular lymphocytic infiltration, and diffuse tumor necrosis. Mild flu-like symptoms were the most common adverse events. In sum, JX-594 replication, oncolysis, and expression of both transgenes were demonstrated; replication was still evident after multiple cycles. These findings have implications for further clinical development of JX-594 and other transgene-armed oncolytic viruses.     

Complement Inhibition Prevents Oncolytic Vaccinia Virus Neutralization in Immune Humans and Cynomolgus Macaques

Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.     

Synergistic Interaction Between Oncolytic Viruses Augments Tumor Killing

A major barrier to all oncolytic viruses (OVs) in clinical development is cellular innate immunity, which is variably active in a spectrum of human malignancies. To overcome the heterogeneity of tumor response, we combined complementary OVs that attack cancers in distinct ways to improve therapeutic outcome. Two genetically distinct viruses, vesicular stomatitis virus (VSV) and vaccinia virus (VV), were used to eliminate the risk of recombination. The combination was tested in a variety of tumor types in vitro, in immunodeficient and immunocompetent mouse tumor models, and ex vivo, in a panel of primary human cancer samples. We found that VV synergistically enhanced VSV antitumor activity, dependent in large part on the activity of the VV B18R gene product. A recombinant version of VSV expressing the fusion-associated small-transmembrane (p14FAST) protein also further enhanced the ability of VV to spread through an infected monolayer, resulting in a “ping pong” oncolytic effect wherein each virus enhanced the ability of the other to replicate and/or spread in tumor cells. Our strategy is the first example where OVs are rationally combined to utilize attributes of different OVs to overcome the heterogeneity of malignancies and demonstrates the feasibility of combining complementary OVs to improve therapeutic outcome.     

Sustained suppression of plasma HIV RNA is associated with an increase in the production of mitogen-induced MIP-1alpha and MIP-1beta.

The chemokine receptor CCR5 has been shown to be a major coreceptor for HIV-1. The chemokines that bind to this receptor (MIP-1alpha, MIP-1beta, and RANTES) are potent inhibitors of HIV replication and may play an important role in the pathophysiology of HIV disease. We investigated the effect of potent antiretroviral therapy (ritonavir and saquinavir) on the production of MIP-1alpha, MIP-1beta, and RANTES in 19 HIV-infected patients who had sustained decreases in plasma HIV RNA levels (<200 copies/ml). Chemokine concentrations were measured in serum, plasma, and PHA-stimulated PBMCs at baseline and 24 and 48 weeks after initiating therapy. MIP-1alpha, MIP-1beta, and RANTES levels in serum and plasma did not significantly change in the 48-week period. In contrast, MIP-1alpha and MIP-1beta secreted by PHA-stimulated PBMCs increased at 24 weeks, with this increase sustained at 48 weeks, whereas no significant change was observed in PHA-induced RANTES production. A significant positive correlation was found between the changes in PHA-induced chemokine production and baseline CD4+ T cell counts. These data demonstrate that sustained suppression of viral replication by potent antiretroviral therapy has a potentially beneficial effect on chemokine production and early initiation of this therapy appears to confer a more favorable chemokine profile.     

Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10

OBJECTIVES: Natural killer (NK) cell function is likely to be important in controlling HIV infection and opportunistic pathogens. We therefore evaluated NK function and phenotype over the course of antiretroviral therapy (ART) and examined the potential mechanisms of altered NK activity in HIV infection. METHODS: We measured NK cell percentage, NK cytolytic activity (both by flow cytometry) and plasma IL-10 concentrations (by enzyme-linked immunosorbent assay) in 10 HIV-seropositive patients before and over one year of effective ART. To examine potential mechanisms of altered NK activity, we measured NK receptor expression in ART treated and untreated HIV-positive individuals by flow cytometry. As IL-10 enhances NK activity, we studied the effect of IL-10 on NK receptor expression and activity in peripheral blood mononuclear cells (PBMC) from HIV-seronegative individuals. RESULTS: NK cytolytic activity was elevated in HIV infection and decreased with ART to levels observed in HIV-negative individuals. A greater proportion of NK cells from untreated HIV-positive individuals expressed the NK receptors CD158a and CD161 than either HIV-negative volunteers or effectively treated HIV-positive patients. NK cells from PBMC incubated with IL-10 demonstrated increases in CD158a, CD161 and CD94 expression and increases in cytolytic activity. The treatment-associated decrease in NK activity paralleled a decrease in IL-10 production. CONCLUSION: The observation that IL-10 alters NK receptor expression similar to that observed in HIV infection, and the fact that NK receptor expression and activity normalize in parallel with ART-induced reduction of circulating IL-10 levels supports a role for IL-10 in NK cell activity and HIV immunopathogenesis.     

Recent progress in the battle between oncolytic viruses and tumours

In the past 5 years, the field of oncolytic virus research has matured significantly and is moving past the stage of being a laboratory novelty into a new era of preclinical and clinical trials. What have recent anticancer trials of oncolytic viruses taught us about this exciting new line of therapeutics?