Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.     

Herpesvirus Replication Compartments: Dynamic Biomolecular Condensates?

Recent progress has provided clear evidence that many RNA-viruses form cytoplasmic biomolecular condensates mediated by liquid–liquid phase separation to facilitate their replication. In contrast, seemingly contradictory data exist for herpesviruses, which replicate their DNA genomes in nuclear membrane-less replication compartments (RCs). Here, we review the current literature and comment on nuclear condensate formation by herpesviruses, specifically with regard to RC formation. Based on data obtained with human cytomegalovirus (human herpesvirus 5), we propose that liquid and homogenous early RCs convert into more heterogeneous RCs with complex properties over the course of infection. We highlight how the advent of DNA replication leads to the maturation of these biomolecular condensates, likely by adding an additional DNA scaffold.     

Functional implications of short‐term retinal detachment in porcine eyes: study by multifocal electroretinography

Purpose: The aim of the study was to determine the type and magnitude of detectable changes in pig multifocal electroretinography (mfERG) induced by the vitreoretinal surgical procedures necessary to gain access to the subretinal space. Methods: Twenty pigs underwent posterior segment surgery. Six animals had a vitrectomy (V), six had in addition a retinal bleb detachment (V + B); five had in addition a retinal diathermia on the bleb (V + B + D) and three received a retinotomy in the diathermized retinal area (V + B + D + R). mfERG evaluation was performed at baseline and 1 and 6 weeks postoperatively. Selected eyes were enucleated for histological evaluation. Results: The retinal detachments blebs all reattached spontaneously. All four surgical sequences resulted in slight, non‐significant changes in the mfERG peaks. A trend towards an amplitude reduction of the mfERG peaks N1, P1 and N2 were observed within the first postoperative week. After 6 weeks, all amplitudes had normalized. Of the implicit times only that of peak N1 (after retinal diathermia) was prolonged significantly at 1 week (P = 0.037). However, it returned to the preoperative level after 6 weeks. Histologically, the retinal detachment bleb was characterized by transient double layering of the retinal pigment epithelium (RPE) and loss photoreceptor outer segments. Conclusion: Access to the subretinal space in pigs can be gained without permanent detectable changes in the mfERG. A short‐term retinal detachment was found to cause only reversible electrophysiological and histological changes in the outer retina, which suggests that this procedure is tolerated well in the porcine retina. The size of the known destructive lesion (retinotomy) was too small to be detected, given the spatial resolution of the mfERG method applied. In the future, the presented protocol can be used to assess the functional outcome of surgery and transplantation in the subretinal space in pigs.     

A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).