This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials.We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.In most epithelial tissues, accumulating mutations (i.e., genetic progression) and loss of cellular control functions cause progressive phenotypic changes from normal histology to early precancer [intraepithelial neoplasia (IEN)] to increasingly severe IEN to superficial cancer and finally to invasive disease. This process can be relatively aggressive in some settings (e.g., in the presence of a DNA repair -deficient genotype) but generally occurs relatively slowly over years and decades. Cancer chemoprevention can be defined as the prevention of cancer or treatment of identifiable precancers (defined as histopathologic or molecular IEN). The long latency to invasive cancer is a major scientific opportunity but also an economic obstacle to showing the clinical benefit of candidate chemopreventive drugs. Therefore, an important component of chemopreventive agent development research in recent years has been to identify earlier (than cancer) end points or biomarkers that accurately predict an agent's clinical benefit or cancer incidence -reducing effect. In many cancers, IEN is an early end point. In 2002, the AACR IEN Task Force recommended focusing chemopreventive drug development on IEN because of the close association between IEN and invasive cancer and because reducing IEN burden can benefit patients by reducing cancer risk and/or the need for invasive interventions (1). The IEN Task Force proposed several practical and feasible clinical trial designs for developing new agents to treat and prevent precancer in nine cancer target organs.

Objective Cervical adenocarcinoma in situ (AIS) is increasing in incidence among reproductive-age women. Cervical conization is an alternative to hysterectomy that allows future fertility, however reports regarding the risk of residual AIS and underlying adenocarcinoma are conflicting. The purpose of this study was to determine the outcomes of a large cohort of women treated for AIS. Methods The medical records of 180 women with cervical AIS evaluated at the University of Texas MD Anderson Cancer Center and its outlying clinics between 1983 and 2011 were reviewed for demographic information, treatment history, pathologic findings and outcomes. Results The mean age at diagnosis was 33.8 years (range 17.6-76.1 years). 172 of the 180 women had at least one cone biopsy performed, with 110 (64.0%) undergoing a cold knife cone (CKC), and 62 (36.0%) undergoing a loop electrosurgical excision procedure (LEEP) as their initial method of treatment. Positive margins were noted in 35.0% of patients undergoing CKC compared with 55.6% undergoing LEEP (p=0.017). 71 patients ultimately underwent hysterectomy with residual disease noted in 10 patients (14.1%), 8 patients (11.3%) with residual AIS and 2 patients (2.8%) with invasive carcinoma. Of the 101 patients who did not undergo hysterectomy, 2 patients (2.0%) developed recurrent AIS at a median of 27.5 months (range 18- 37 months) from the last cone, and none developed invasive carcinoma. Conclusion Patients undergoing conservative management for AIS with cervical conization alone should be monitored closely and counseled regarding the potential risks of residual and recurrent disease, even when negative cone margins are obtained.

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We conclude that acute exposure temporarily affected endothelial function as measured by a change in vascular tone but this did not predict the development of AMS. The rise in arterial BP was not related to changes in arterial stiffness or tone.

Digital colposcopy is a promising technology for the detection of cervical intraepithelial neoplasia. Automated analysis of colposcopic images could provide an inexpensive alternative to existing screening tools. Our goal is to develop a diagnostic tool that can automatically identify neoplastic tissue from digital images. A multispectral digital colposcope (MDC) is used to acquire reflectance images of the cervix with white light before and after acetic-acid application in 29 patients. A diagnostic image analysis tool is developed to identify neoplasia in the digital images. The digital image analysis is performed in two steps. First, similar optical patterns are clustered together. Second, classification algorithms are used to determine the probability that these regions contain neoplastic tissue. The classification results of each patient's images are assessed relative to the gold standard of histopathology. Acetic acid induces changes in the intensity of reflected light as well as the ratio of green to red reflected light. These changes are used to differentiate high-grade squamous intraepithelial (HGSIL) and cancerous lesions from normal or low-grade squamous intraepithelial (LGSIL) tissue. We report diagnostic performance with a sensitivity of 79% and a specificity of 88%. We show that diagnostically useful digital images of the cervix can be obtained using a simple and inexpensive device, and that automated image analysis algorithms show a potential to identify histologically neoplastic tissue areas.