A phase II study of Hsp-7 (SGN-00101) in women with high-grade cervical intraepithelial neoplasia.

OBJECTIVE: Approximately 2 million women worldwide are infected with high-risk human papillomaviruses (HPV), resulting in a substantial risk for the development of invasive lower genital malignancies. This study was undertaken to determine the effects of vaccination with a protein encoding a bacterial heat shock protein fused to sequences from the oncogenic E7 protein of HPV-16 in women with high-grade cervical intraepithelial neoplasia. Endpoints included lesion regression, immune response, and viral clearance. METHODS: Twenty-one women were prospectively entered into an IRB-approved Phase II study. All women had biopsy-proven high-grade cervical intraepithelial neoplasia and persistent post-biopsy lesions visible by colposcopy. Four injections of HPV-16 Hsp E7 fusion protein at a dose of 500 mug were given 3 weeks apart after which Loop Electrosurgical Excision of the Transformation Zone (LLETZ) was performed. Immune parameters were evaluated pre-vaccine and at the time of LLETZ, and HPV testing was performed at intervals before and after LLETZ. Study subjects were followed for 1 year after LLETZ. RESULTS: Seven of 20 women (35%) evaluable for response had complete regression of their intraepithelial neoplasia at the time of LLETZ, 1 (5%) had regression to CIN I, 11 (55%) had stable disease and 1 (5%) had progression due to enlargement of her lesion. Immune responses were seen in 9 of the 17 women tested; 5 of the 7 complete responders had an immune response. Only 5 of 21 women had HPV-16 or -18. HPV clearance was not associated with lesion regression. CONCLUSION: Hsp-7 (SGN-00101), at this dose and schedule induced lesion regression in women with high-grade intraepithelial neoplasia. The fact that regression was correlated with immune response suggests that enhancing the immunogenicity of this vaccine may lead to improvement in the rate of lesion eradication.

The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management.

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.

Verbal protocol accuracy in fault diagnosis.

The study examined whether concurrent and retrospective verbal protocols possess the potential to provide a non-reactive and valid account of the cognitive processes involved in fault diagnosis. With this goal in mind, a group of subjects performed a fault diagnosis task under concurrent and retrospective verbalization and in a silent control condition as well. In the task, concurrent verbalization led to a considerable increase in time to completion, but exerted no effect on overall accuracy and the adopted strategy. Retrospective verbalization did not have any effect on performance. The strategy-related data obtained under concurrent verbalization proved to be more valid than those obtained under retrospective verbalization. On the basis of the results it is suggested that, where possible, concurrent verbal reports should be collected when trying to get a better understanding of the nature of the fault diagnostic process.

Dynamic vs static stimuli in their effect on visual vigilance performance.

This report describes a test of the prediction, made by Teichner in 1974, that on visual vigilance tasks dynamic stimuli result in greater performance decrements than do static stimuli. For correct detections and sensitivity there was only a nonsignificant trend in the predicted direction, but for response latency (RT) the prediction was supported. Positional uncertainty within displays did not affect vigilance performance. Teichner's assumption that ocular demand is responsible for the impairing effect of dynamic stimuli is questioned. Depletion of central capacity rather than an ocular effect may explain deteriorating performance. Just as in studies of visual fatigue, the contributions of central and modality-specific impairing effects are difficult to separate.

Processing demands, effort, and individual differences in four different vigilance tasks.

In an attempt to specify the limiting conditions of the taxonomy of vigilance tasks, four tasks differing in memory load and in stimuli employed (sensory or cognitive) were compared. Electrodermal activity and subjective measures were used to determine the investment of effort. The data show that vigilance level and vigilance decrement dissociate. The level seems to relate to effort demand and investment; the decrement seems to be task driven, determined mainly by the type of stimuli used. Tasks employing unfamiliar stimuli showed a decline in sensitivity; "cognitive" tasks employing alphanumeric stimuli did not. Principal components analyses suggest that measures of speed and accuracy may reflect relatively independent systems. Subjective data showed that good performers expand more effort in difficult and complex tasks. Effortful processing seems to prevent rather than induce a decline in efficiency.