Guillermo Tortolero-Luna

Epidemiology and Natural History of Human Papillomavirus Infections and Type-Specific Implications in Cervical Neoplasia

Worldwide human papillomavirus (HPV) prevalence in women with normal cytology at any given point in time is approximately 10% indicating that HPV is one of the most common sexually transmitted infections. HPV-16 is consistently the most common type and HPV-18 the second with some minor regional differences. Furthermore, across the spectrum of cervical lesions, HPV-16 is consistently the most common HPV type contributing to 50-55% of invasive cervical cancer cases strongly suggesting that this viral type has a biological advantage for transmission, persistency and transformation. The same phenomenon is observed albeit at a lower level for HPV-18 and HPV-45. Sexual behavioral patterns across age groups and populations are central to the description of the HPV circulation and of the risk of infection. The concept of group sexual behavior (in addition to individual sexual behavior) is important in exploring HPV transmission and has implications for defining and monitoring HPV and cancer prevention strategies. In natural history studies, the pattern of HPV DNA prevalence by age groups is similar to the patterns of HPV incidence. Rates of exposure in young women are high and often include multiple types. There is a spontaneous and rapid decrease of the HPV DNA detection rates in the middle-age groups followed by a second rise in the post-menopausal years. This article reviews: 1) the evidence in relation to the burden of HPV infections in the world and the contributions of each HPV type to the spectrum of cervical cellular changes spanning from normal cytology to invasive cervical cancer; 2) the critical role of the patterns of sexual behavior in the populations; and 3) selected aspects of the technical and methodological complexity of natural history studies of HPV and cervical neoplasia.

Colposcopy For The Diagnosis of Squamous Intraepithelial Lesions: A Meta-Analysis

Objective To quantify by meta-analysis the performance of colposcopy to set a standard against which new technologies can be compared. Data Sources MEDLINE was searched for articles on colposcopy for diagnosis of squamous intraepithelial lesions (SIL). The search selected articles from 1960 to 1996 combining the key word “colposcopy” with key words “diagnosis,” “positive predictive value,” “negative predictive value,” “likelihood ratio,” and “receiver operating characteristic (ROC) curve.” Methods of Study Selection Articles were selected if the authors studied a population of patients with abnormal screening Papanicolaou smears and presented raw data showing for each cervical lesion type the number of patients judged positive and negative by colposcopic impression versus the standard of colposcopic biopsy results. Nine of 86 studies met these criteria. Tabulation, Integration, and Results Biopsies had been categorized as normal, atypia, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, carcinoma in situ, and invasive cancer; we recalculated performance measures using the Bethesda system. Overall sensitivity, specificity, likelihood ratios, ROC curves, and the corresponding areas under the curves were calculated. The average weighted sensitivity of diagnostic colposcopy for the threshold normal compared with all cervix abnormalities (atypia, low-grade SIL, high-grade SIL, cancer) was 96% and the average weighted specificity 48%. For the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer, average weighted sensitivity was 85% and average weighted specificity 69%. Likelihood ratios generated small but important changes in probability for distinguishing normal cervix and low-grade SIL from high-grade SIL and cancer. Areas under the ROC curve were 0.80 for the threshold normal cervix compared with all abnormalities and 0.82 for the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer. Conclusion Colposcopy compares favorably with other medical diagnostic tests in terms of sensitivity, specificity, and area under the ROC curve. New diagnostic methods for the cervix can be compared with colposcopy using these quantified values.

Epidemiology of human papillomavirus infection in men, cancers other than cervical and benign conditions.

Human papillomavirus (HPV) infection is commonly found in the genital tract of men and women with or without any clinical lesion. The association of HPV DNA with several different ano-genital cancers other than cervical has been reported for the vulva, vagina, anus and penis. HPV DNA has also been identified in head and neck cancers in the oral cavity, the oropharynx and the larynx in both sexes. In men, 80-85% of anal cancers and close to 50% of penile cancers are associated with HPV infection. In women, HPV DNA is prevalent in 36-40% vulvar cancer cases and close to 90% of vaginal cancers. There is limited data available on the natural history and HPV-related diseases in the genital tract in men, although studies are ongoing. Efficacy of HPV vaccines in the prevention of HPV infection and disease among men also remains unknown. Among HPV DNA positive ano-genital cancer cases, HPV-16 is the most frequently found followed distantly by HPV-18. In benign HPV-related diseases such as genital warts or recurrent respiratory papillomatosis HPV-6 and 11, the two most frequent non-oncogenic types, are the predominant types detected. Oncogenic types are rarely detected. In this article we summarize and review studies describing the natural history of HPV infections among men and its impact on HPV related disease in women. We summarize the evidence linking HPV in the epidemiology and etiology of cancers of the vulva, vagina, anus and oropharynx and present recent estimates of the burden of and HPV type distribution in genital warts and in cases of HPV infection of the airways.

Participation of Minorities in Cancer Research

Overall, participation rates in cancer clinical trials are very low, ranging from 3 to 20% of eligible participants. However, participation rates are especially low among the socially disadvantaged and racial/ethnic minority groups that have been historically underrepresented in clinical research. Structural factors such as study duration, treatment or intervention schedule, cost, time, followup visits, and side effects represent more of a barrier to participation among these groups compared with white, non-Hispanics. Attitudes, beliefs, perceptions, and knowledge regarding clinical research, and cultural characteristics of underrepresented minorities pose additional barriers to participation. This article focuses on the structural, cultural, and linguistic factors that affect participation in clinical cancer research for each major U.S. racial/ethnic group. Low socioeconomic status, speaking a primary language other than English, differences in communication styles, mistrust of research and the medical system, fear, embarrassment, and lack of knowledge about the origin of cancer appear to have a negative impact on clinical cancer research participation rates. Much of the information about these factors comes from studies of cancer screening because little data is available on the factors that prevent and facilitate participation of minorities in clinical cancer trials specifically. Such research is needed, and, given the heterogeneity within and between minority populations, should occur in several different geographic settings and with as many different minority subpopulations as possible.

A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix

Objective To compare cryotherapy, laser vaporization, and loop electrical excision for treatment of squamous intraepithelial lesions (SILs). Methods Women at least 18 years old with biopsy-proven SIL, negative pregnancy tests, negative findings on endocervical curettage, satisfactory colposcopy examinations, and congruent Papanicolaou smear and biopsy results were assigned randomly to treatment after stratification by SIL grade, endocervical gland involvement, and lesion size; they were evaluated 1, 4, 8, 12, 16, 20, and 24 months after treatment. Data were analyzed using χ2 statistics, logistic regression analysis, and the Cox proportional hazards model. Results Of 498 patients assigned, 108 were excluded (most because of inadequate follow-up), leaving 390 (139 cryotherapy, 121 laser vaporization, 130 loop excision) for analysis. All were followed 6–37 months (mean 16). There were no statistically significant differences in complications, persistence (disease present less than 6 months after treatment), or recurrence (disease present more than 6 months after treatment). Risk of persistent disease was higher among women with large lesions (risk ratio [RR], 18.9; 95% confidence interval [CI], 3.2, 110.6). Recurrence risk was higher among women aged 30 years and older (RR, 2.1; 95% CI, 1.2, 4.3), those with human papillomavirus type 16 or 18 (RR, 2.1; 95% CI, 1.1, 4.0), and those who had had prior treatment (RR, 2.1; 95% CI, 1.1, 3.9). Conclusion The data support a high success rate with all three modalities. No significant difference in success rates was observed between the three treatments in our population. Additional attention and research should be directed toward the higher risk patients identified above.

Recruitment and retention of minority women in cancer screening, prevention, and treatment trials.

Researchers are giving greater attention to the recruitment and retention of minority women in clinical studies because of their historical underrepresentation, despite their greater morbidity and mortality for many conditions. Using findings from four studies, this article examines documented barriers to the recruitment and retention of minority women to clinical cancer research and discusses effective recruitment strategies. Among the major barriers to recruitment were lack of awareness, lack of transportation, interference with work/family responsibilities, financial costs, negative side effects, and burdensome procedures. Effective recruitment strategies focused on using culturally targeted mass mailings and media presentations based on acquiring an understanding of the minority community. Recommendations are made for further study and implementation.

Ovarian and extraovarian endometriosis-associated cancer

OBJECTIVE To determine clinical characteristics of women with endometriosis‐associated intraperitoneal cancers, to assess differences based on the relationship of the cancer to the endometriosis, and to assess factors associated with survival. METHODS A search of medical records at The University of Texas M. D. Anderson Cancer Center from 1970 to 1999 identified patients who had synchronous endometriosis and intraperitoneal cancer. Demographic and clinicopathologic characteristics were evaluated for differences based on the relationship of the cancer to the endometriosis and for correlation with survival. RESULTS One hundred fifteen patients were identified: 25 patients with ovarian cancer arising in endometriosis, 21 with an extraovarian cancer arising in endometriosis, 33 patients with endometriosis and ovarian cancer in the same location but without a definite transition point, and 36 patients with ovarian cancer and incidental endometriosis. Women with extraovarian cancers arising in endometriosis were more likely to be postmenopausal (P < .001) and use hormone replacement (P < .001). The median age was 47 years, the most common histological tumor types were clear cell and endometrioid (23% each), and the most common stage was stage I (31%). The median survival was 35 months. Univariate survival analysis revealed that gravidity (P < .038), grade (P < .001), stage (P < .001), histology (P < .01), and type of chemotherapy (P < .011) correlated with survival. Multivariable analysis revealed that stage and gravidity independently predicted survival. CONCLUSION Women with endometriosis‐associated cancers are typically premenopausal, have a high incidence of endometrioid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival.

A Comparison of C/B Ratios from Studies Using Receiver Operating Characteristic Curve Analysis ☆

In receiver operating characteristic (ROC) curve analysis, the optimal cutoff value for a diagnostic test can be found on the ROC curve where the slope of the curve is equal to (C/B) x (1-p[D])/p[D], where p[D] is the disease prevalence and C/B is the ratio of net costs of treating nondiseased individuals to net benefits of treating diseased individuals. We conducted a structured review of the medical literature to examine C/B ratios found in ROC curve analysis. Only two studies were found in which a C/B ratio was explicitly calculated; in another 11 studies, a C/B ratio was based on a so-called holistic estimate, an all-encompassing educated estimate of the relative costs and benefits relevant to the clinical situation. The C/B ratios ranged from 0.0025 (tuberculosis screening) to 2.7 (teeth restoration for carious lesions). Clinical scenarios that are directly life threatening but curable had C/B ratios of less than 0.05. This analysis led us to construct a table of ordered C/B ratios that may be used by investigators to approximate C/B ratios for other clinical situations in order to establish cutpoints for new diagnostic tests.

Association between adiponectin, insulin resistance, and endometrial cancer

Obesity is a well known risk factor for the development of endometrial cancer; however, weight alone does not account for all cases. The authors hypothesized that insulin resistance also contributes to an increased risk for endometrial cancer. Adiponectin is a protein secreted by adipose cells and has been shown to be a surrogate marker for insulin resistance, with low levels of adiponectin correlated with hyperinsulinemia and degree of insulin resistance. The purpose of the current study was to determine whether there was an independent association between adiponectin level and endometrial cancer.

A RANDOMIZED CLINICAL TRIAL OF CRYOTHERAPY, LASER VAPORIZATION, AND LOOP ELECTROSURGICAL EXCISION FOR TREATMENT OF SQUAMOUS INTRAEPITHELIAL LESIONS OF THE CERVIX

: Women at least 18 years old with biopsy-provenSIL, negative pregnancy tests, negative findings on endocer-vical curettage, satisfactory colposcopy examinations, andcongruent Papanicolaou smear and biopsy results wereassigned randomly to treatment after stratification by SILgrade, endocervical gland involvement, and lesion size; theywere evaluated 1, 4, 8, 12, 16, 20, and 24 months aftertreatment. Data were analyzed using