This quadrivalent human papillomavirus (qHPV) (HPV6, -11, -16, and -18) vaccine long-term follow-up (LTFU) study is an ongoing extension of a pivotal clinical study (FUTURE II) taking place in the Nordic region. The LTFU study was designed to evaluate the effectiveness, immunogenicity, and safety of the qHPV vaccine (Gardasil) for at least 10 years following completion of the base study. The current report presents immunogenicity data from testing samples of the year 5 LTFU visit (approximately 9 years after vaccination). FUTURE II vaccination arm subjects, who consented to being followed in the LTFU, donated serum at regular intervals and in 2012. Anti-HPV6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA), and in addition, serum samples from 2012 were analyzed by the total IgG Luminex immunoassay (LIA) (n = 1,598). cLIA geometric mean titers (GMTs) remained between 70% and 93% of their month 48 value depending on HPV type. For all HPV types, the lower bound of the 95% confidence interval (CI) for the year 9 GMTs remained above the serostatus cutoff value. The proportion of subjects who remained seropositive based on the IgG LIA was higher than the proportion based on cLIA, especially for anti-HPV18. As expected, the anti-HPV serum IgG and cLIA responses were strongly correlated for all HPV types. Anti-HPV GMTs and the proportion of vaccinated individuals who are seropositive remain high for up to 9 years of follow-up after vaccination.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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In recent years, various outcome adaptive randomization (AR) methods have been used to conduct comparative clinical trials. Rather than randomizing patients equally between treatments, outcome AR uses the accumulating data to unbalance the randomization probabilities in favor of the treatment arm that currently is superior empirically. This is motivated by the idea that, on average, more patients in the trial will be given the treatment that is truly superior, so AR is ethically more desirable than equal randomization. AR remains controversial, however, and some of its properties are not well understood by the clinical trials community.
Computer simulation was used to evaluate properties of a 200-patient clinical trial conducted using one of four Bayesian AR methods and compare them to an equally randomized group sequential design.
Outcome AR has several undesirable properties. These include a high probability of a sample size imbalance in the wrong direction, which might be surprising to nonstatisticians, wherein many more patients are assigned to the inferior treatment arm, the opposite of the intended effect. Compared with an equally randomized design, outcome AR produces less reliable final inferences, including a greatly overestimated actual treatment effect difference and smaller power to detect a treatment difference. This estimation bias becomes much larger if the prognosis of the accrued patients either improves or worsens systematically during the trial.
AR produces inferential problems that decrease potential benefit to future patients, and may decrease benefit to patients enrolled in the trial. These problems should be weighed against its putative ethical benefit. For randomized comparative trials to obtain confirmatory comparisons, designs with fixed randomization probabilities and group sequential decision rules appear to be preferable to AR, scientifically, and ethically.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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Skin allergy, in particular, allergic contact dermatitis and irritant contact dermatitis, are common occupational and environmental health problems affecting the quality of life of a significant proportion of the world population. Since all new ingredients to be incorporated into a product are potential skin allergens, it is essential that these ingredients be first tested for their allergenic potential. However, despite the considerable effort using animal models to understand the underlying mechanism of skin sensitization, to date, the molecular and cellular responses due to skin contact with sensitizers are still not fully understood. To replace animal testing and to improve the prediction of skin sensitization, significant attention has been directed to the use of reconstructed organotypic in vitro models of human skin. Here we describe a miniaturized immune competent in vitro model of human skin based on 3D co-culture of immortalized human keratinocytes (HaCaT) as a model of the epidermis barrier and human leukemic monocyte lymphoma cell line (U937) as a model of human dendritic cells. The biological model was fitted in a microfluidic-based cell culture system that provides a dynamic cellular environment that mimics the in vivo environment of skin. The dynamic perfusion of culture media significantly improved the tight junction formation as evidenced by measuring higher values of TEER compared to static culture. This setting also maintained the high viability of cells over extended periods of time up to 17 days. The perfusion-based culture also allows growth of the cells at the air-liquid interface by exposing the apical side of the cells to air while providing the cell nutrients through a basolateral fluidic compartment. The microsystem has been evaluated to investigate the effect of the chemical and physical (UV irradiation) stimulation on the skin barrier (i.e. the TJ integrity). Three-tiered culture differential stimulation allowed the investigation of the role of the keratinocyte layer as a protection barrier to chemical/biological hazards.

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On April 22, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "The Company"), reported that researchers from Moffitt Cancer Center in Tampa, Florida, presented a poster titled, "T cell Mediated Immunity After Combination Therapy with Intralesional PV-10 and Co-Inhibitory Blockade in a Melanoma Model," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, held at the Ernest N. Morial Convention Center in New Orleans, Louisiana (Filing, 8-K, Provectus Pharmaceuticals, APR 22, 2016, View Source [SID:1234511259]).

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In the poster, authors Amy M Weber, Hao Liu, Krithika Kodumudi, Amod A Sarnaik and Shari Pilon-Thomas state that "treatment with IL PV-10 and anti-PD-1 antibody results in a delay in tumor growth and enhanced T cell activation in the M05 tumor model." They also conclude that "the effect of combination therapy with IL PV-10 and PD-1 blockade is mediated by CD8+ T cells, and depletion of either CD4+ T cells or CD25+ Tregs enhances anti-tumor immunity in the M05 melanoma model." The abstract of the poster (number 4978) may be viewed at: View Source

Shari Pilon-Thomas, Ph.D., who leads the research team at Moffitt, noted, "Our results show that combining intralesional PV-10 with anti-PD-1 co-inhibitory blockade not only suppresses tumor growth vs. either agent alone but also yields marked increases in tumor-specific T cell activation against injected tumor."

Eric Wachter, Ph.D., Chief Technology Officer of Provectus, observed, "The nonclinical data reported by our collaborators at Moffitt reaffirm the crucial role T cells play in response to tumor ablation with intralesional PV-10, and further demonstrate the potential value of combining PV-10 with T cell directed checkpoint inhibition, such as the anti-PD-1 agent pembrolizumab. Intriguingly, these data also highlight possible strategies for augmenting this paradigm by harnessing additional targets in T cell signaling."

Provectus is currently enrolling patients in a phase 3 study of PV-10 as a single agent therapy for patients with locally advanced cutaneous melanoma (Clinical Trials ID NCT02288897) and in a phase 1b study of PV-10 in combination with the immune checkpoint inhibitor pembrolizumab in patients with metastatic melanoma (Clinical Trials ID NCT02557321).

Cell clusters were observed in the seminiferous tubules of C57BL/6J mice as a spontaneous lesion in a 2-week toxicity study, and they were demonstrated to be basically composed of Sertoli cells by immunohistochemistry for claudin-11 and GATA-4 (GATA-binding protein 4), which are both Sertoli cell markers. The clusters were composed of about 5 to 50 cells, which had eosinophilic and occasionally vacuolated cytoplasm with an unclear cell boundary. The cell clusters involved some sperm. No mitotic figures were observed and no immunoreactivity for proliferating cell nuclear antigen (PCNA) was detected in the clusters. In most cases, the cell clusters were observed in seminiferous tubules that also showed degenerative changes. In rare instances, cell aggregates immunohistochemically positive for claudin-11 were observed in the lumen of the epididymis, suggesting that some of the Sertoli cell clusters were sloughed off from the seminiferous epithelium into the epididymal ducts. To our knowledge, this is the first report of Sertoli cell clusters in any animal species except for transgenic or surgically altered animals.
© 2015 by The Author(s).

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