Treatment of schwannomas with an oncolytic recombinant herpes simplex virus in murine models of neurofibromatosis type 2

Gene therapy for schwannomas was evaluated in two mouse models of neurofibromatosis type 2 (NF2): (1) a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas, and (2) a xenograft model in which human schwannoma tissue is implanted subcutaneously into immune- compromised mice. In both models, schwannoma volumes were monitored by magnetic resonance imaging (MRI) and showed strong gadolinium enhancement typical of these tumors in humans. Both types of tumor were positive for the Schwann cell marker S100, and highly infectable with herpes simplex virus (HSV) vectors. Schwannomas were injected with an oncolytic HSV-1 recombinant virus vector, G47Delta, which has deletions in genes for ribonucleotide reductase (ICP6), gamma34.5, and ICP47. In the NF2 transgenic model, schwannomas were reduced by more than half their original size by 10 days after infection. In the case of subcutaneous schwannoma xenografts, reduction in size after infection occurred more slowly, with a mean reduction of onethird by 42 days after treatment. Schwannomas injected with control vehicles continued to grow slowly over time in both schwannoma models. These studies demonstrate the ability of an oncolytic recombinant HSV vector to reduce the volume of schwannoma tumors in NF2 tumor models in mice and extend the possible therapeutic applications of oncolytic vectors for benign tumors to reduce mass while minimizing nerve damage.     

Beta-blockers for primary prevention in hypertension: era bygone?

Beta-blockers are used commonly worldwide in clinical practice for lowering blood pressure. Most of the agents in this class are efficacious in reducing blood pressure, although they vary widely in their pharmacokinetic and pharmacodynamic properties. This variability may confer significant differences in clinical benefits associated with use of specific agents. Although commonly used in managing hypertension, the role of beta-blockers for primary prevention in uncomplicated hypertension has been controversial. Evidence from recent trials suggest relatively poor efficacy toward primary prevention and worse outcomes for certain end points, when compared with other blood pressure-lowering agents, Recently updated National Institute for Health and Clinical Excellence guidelines for England and Wales reflect this concern and have changed the indication for beta-blockers for blood pressure control from primary agents to use as an add-on agent in patients requiring multiple therapy. In this review, considering the extended debate on this topic, we discuss the general properties of beta-blockers and evidence from clinical trials supporting or refuting their use in various clinical scenarios. Newer beta-blockers have additional properties which may be beneficial. Although, whether these additional benefits will help in primary prevention is not clear.     

Sex differences in the long-term prognostic value of <Superscript>13</Superscript>N-ammonia myocardial perfusion positron emission tomography

Purpose

Evidence to date on the unique female determinants of cardiovascular risk is inadequate. Positron Emission Tomography (PET) is considered to have the highest accuracy for the assessment of myocardial perfusion in patients with suspected coronary artery disease (CAD), but its long-term prognostic accuracy in women has not been established.

Methods

A total of 619 consecutive patients (138 women, mean age 60.0?±?11.8 years) underwent clinically indicated ¹³N-ammonia PET at our institution and were followed up (median 5.7 years) for major adverse cardiovascular events (MACE) including cardiac death, nonfatal myocardial infarction, hospitalization for any cardiac reason and late revascularization.

Results

During follow-up, 271 patients had at least one cardiac event, including 64 cardiac deaths and 33 nonfatal myocardial infarctions. In both women and men, abnormal myocardial perfusion was associated with reduced event-free survival (log rank p <?0.001). In women, abnormal myocardial perfusion was associated with a higher risk of a worse outcome than in men (adjusted HR 4.1, 95% CI 1.8–9.0 in women; HR 2.4, 95% CI 1.5–3.8 in men; p_interaction <?0.001). In contrast, abnormal coronary flow reserve (CFR) was a significant predictor of 10-year MACE in men (p =?0.006) but not in women (p =?NS). Accordingly, an interaction term of sex and abnormal myocardial perfusion or CFR was significant (p <?0.001).

Conclusion

While perfusion findings in ¹³N-ammonia PET provide effective risk stratification in women and men, CFR adds incremental prognostic value for long-term cardiac outcomes only in men. Refined strategies in noninvasive imaging are needed in women to improve CAD risk prediction.