Biomedical subjects

Allan Hildesheim

Publications and source records attributed to Allan Hildesheim.

At least 37 records · Page 2Linked to original sources

PubMed2005

A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica.

BACKGROUND: Cross-sectional human papillomavirus (HPV) DNA prevalence peaks at young ages, reflecting sexual acquisition and typically rapid clearance. In some populations, HPV prevalence demonstrates a second peak in older women. Longitudinal data may help to explain this second peak. METHODS: We followed a population-based cohort of 7237 women in Guanacaste, Costa Rica, in which we had previously observed a second peak in the baseline HPV prevalence in older women. We tested for >40 HPV types by polymerase chain reaction. We analyzed age-specific patterns of acquisition and persistence 5-7 years after enrollment for individual HPV types. RESULTS: At enrollment and follow-up, cross-sectional data revealed U-shaped age-specific HPV prevalence curves for virtually every type, with higher prevalences in the younger and older women than in the middle-aged women. Prospectively, acquisition of types decreased significantly as women aged (PTrend<.05, for both), with the highest peak in young women and a secondary minor peak in older women. Type-specific persistence of HPV increased with age (PTrend<.0001). Overall, HPV acquisition predominated at younger ages, whereas persistent infections gradually became more prominent with age (PTrend<.0001). CONCLUSIONS: Newly apparent infections decreased, whereas persistence increased, with age; this latter tendency supports the utility of HPV screening in older women.

Adult↗

PubMed2005

Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica.

BACKGROUND: Detailed epidemiologic studies of cervical type-specific human papillomavirus (HPV) infection in large populations are scarce. METHODS: We recruited a population-based cohort in Guanacaste, Costa Rica. Participants were interviewed, screened for cervical neoplasia, and tested for >40 HPV types by use of MY09/11 L1 consensus primer polymerase chain reaction. We estimated the risk factors for infection and the associations between type-specific HPV infections and cervical intraepithelial neoplasia (CIN) and cancer in 8514 sexually active women who had not undergone a hysterectomy. RESULTS: The overall HPV prevalence was 26.5%. The most common type was HPV-16 (3.6% of the population). HPV prevalence showed a U-shaped age-specific curve. Sexual behaviors were the main determinants of oncogenic and nononcogenic infections; age at first sexual intercourse was not independently associated with infection. Barrier contraceptive use was somewhat protective against infection. Oncogenic infections were strongly associated with risk of all grades of CIN and of cancer. Types 16, 18, and 58 were the most common in women diagnosed with CIN3 and cancer. Except for those that included HPV-16, multiple-type infections were associated with an increased risk (compared with that for single-type infections) of all grades of CIN and of cancer. CONCLUSIONS: We confirmed the bimodal age pattern of HPV infection in Guanacaste and the sexually transmitted nature of both oncogenic and nononcogenic HPV types.

Adult↗

PubMed2005

Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor-ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.

Case-Control Studies↗

PubMed2005

A study of the impact of adding HPV types to cervical cancer screening and triage tests.

Use of human papillomavirus (HPV) testing in cervical cancer prevention is increasing rapidly. A DNA test for 13 HPV types that can cause cervical cancer is approved in the United States for co-screening with cytology of women >or=30 years old and for triage of women of all ages with equivocal cytology. However, most infections with HPV are benign. We evaluated trade-offs between specificity and sensitivity for approximately 40 HPV types in predicting cervical intraepithelial neoplasia 3 and cancer in two prospective studies: a population-based screening study that followed 6196 women aged 30-94 years from Costa Rica for 7 years and a triage study that followed 3363 women aged 18-90 years with equivocal cytology in four U.S. centers for 2 years. For both screening and triage, testing for more than about 10 HPV types decreased specificity more than it increased sensitivity. The minimal increases in sensitivity and in negative predictive value achieved by adding HPV types to DNA tests must be weighed against the projected burden to thousands of women falsely labeled as being at high risk of cervical cancer.

Adult↗

PubMed2005

Fixation and cryopreservation of whole blood and isolated mononuclear cells: Influence of different procedures on lymphocyte subset analysis by flow cytometry.

BACKGROUND: Immunophenotyping of whole blood (WB) and isolated peripheral blood mononuclear cells (PBMCs) is a common tool used to evaluate immune system changes in clinical studies. The development of methods that would allow preservation of samples for flow cytometric analysis is important for the extension of this technology to field testing in settings where the equipment might be not readily accessible. METHODS: Three-color flow cytometric analysis was used to determine percentages of T cells and their subsets (CD3(+), CD4(+), CD8(+)), B cells (CD19(+)), and natural killer cells (CD16(+)/56(+)) in WB and PBMCs using variations of a standard stain/fix WB staining procedure (Optilyse) that included staining following fixation and freezing of fixed samples before or after staining. RESULTS: Comparable lymphocyte subset percentages in WB or PBMCs were observed regardless of Optliyse method used (all Ps >/= 0.8). However, differences in fluorescence intensity for several markers were observed across procedures. Compared with the standard stain/fix procedures, fix/stain decreased the mean fluorescence intensities for CD4, CD8, CD19 and CD16/56 in WB and PBMCs (P </= 0.03 for these markers P = 0.105 for CD8 in PBMCs). Further decreases in mean fluorescence intensity were seen with the fix/stain/freeze procedure. The stain/fix/freeze yielded intensities largely comparable to those seen with standard stain/fix procedure (P >/= 0.13), suggesting that, when the markers of interest are known at the time of field collection, implementation of this procedure might be desirable. Fix/freeze/stain resulted in diminution of intensity in general, but they tended to be more modest than those seen for fix/stain/freeze and therefore might be applicable to field studies in instances when the specific markers of interest cannot be defined upfront. CONCLUSIONS: Freezing of fixed WB and PBMCs before or after cell surface staining is a reliable method for preserving specimens in field sites for later determination of lymphocyte subset percentages, which are commonly assessed in immunodeficient and cancer patients.

Blood Preservation↗

PubMed2005

Evaluation of risk factors for nasopharyngeal carcinoma in high-risk nasopharyngeal carcinoma families in Taiwan.

A study of nasopharyngeal carcinoma (NPC) families with two or more affected members was conducted in Taiwan (265 families with 2,444 individuals, 502 affected and 1,942 unaffected) to determine the association between NPC and potential etiologic factors in NPC high-risk families. Similar to results from a previous case-control study in Taiwan, Guangdong salted fish consumption during childhood, exposure to wood, and betel nut consumption were all associated with elevated NPC risk using conditional logistic regression, although these associations were not as strong as in the case-control study possibly due to shared environment among family members. Risk associated with cumulative wood exposure and salted fish consumption before age 10 was stronger in families with early NPC age-onset [odds ratio (OR(wood)), 5.10; 95% confidence interval (95% CI), 1.50-17.34; OR(fish), 3.94; 95% CI, 1.47-10.55] or three or more affected members (OR(wood), 4.41; 95% CI, 1.58-12.30; OR(fish), 4.27; 95% CI, 1.10-16.47). In contrast, a tendency for elevated risk was noted for betel nut use in late age-onset families (OR, 2.44; 95% CI, 1.16-5.13) and the CYP2E1 c2 allele in families with less than three affected members (OR, 2.06; 95% CI, 1.04-3.35). Risk estimates associated with these exposures were similar when the analyses were restricted to EBV-seropositive subjects. To better adjust for degree of relationship among family members and residual genetic correlations, we also calculated ORs using a variance components model. The results from the two methods were similar indicating that the risk estimates from conditional logistic regression were unbiased.

Adolescent↗

PubMed2005

Variation of the killer cell immunoglobulin-like receptors and HLA-C genes in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barrvirus (EBV)-associated malignancy. Previous studies have shown that NPC is associated with specific human leukocyte antigen (HLA) alleles which function in adaptive immunity to present viral and other antigens to the immune system. The role of innate immunity in NPC development is unknown. To determine whether innate immunity is associated with NPC, a case-control study was conducted among 295 Taiwanese NPC cases (99% EBV seropositive) and 252 community controls (29% EBV seropositive). Using high-resolution genotyping, we evaluated the variation of HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) alleles. Located on the surface of natural killer (NK) cells and a subset of T cells, inhibitory KIRs diminish NK cytolysis of target cells upon binding to their HLA class I ligands and activating KIRs are thought to stimulate NK destruction of target cells. Our results suggest that an increasing number of activating KIRs may be associated with increasing NPC risk, particularly in individuals seropositive for anti-EBV antibodies known to be linked to NPC susceptibility (P(trend) = 0.07). Among EBV-seropositive individuals, carriers of > or =5 activating KIRs had a 3.4-fold increased risk of disease (95% confidence interval, 0.74-15.7) compared with individuals with no functional activating KIRs. In contrast, there was no clear evidence of risk associated with increasing numbers of inhibitory KIRs. When evaluating HLA-Cw alleles, we observed that carriers of HLA-Cw*0401 alleles were at a significantly reduced NPC risk (odds ratio, 0.46; 95% confidence intervals, 0.23-0.92), an effect that could not be explained by linkage disequilibrium with other NPC-associated HLA alleles. Our results suggest that KIR-mediated activation may be associated with NPC risk. As this finding is consistent with a recent report examining cervical cancer, a malignancy caused by human papillomavirus, the data raises the possibility that KIRs, and more generally innate immunity, may be involved in the pathogenesis of viral-associated cancers.

Adult↗

PubMed2005

PCR testing of pooled longitudinally collected cervical specimens of women to increase the efficiency of studying human papillomavirus infection.

In large active cohort studies of women investigating human papillomavirus (HPV) and cervical neoplasia, many women will be HPV-negative at all time points and testing of all their cervical specimens is an inefficient use of laboratory resources. The aim of this pilot study was to evaluate whether pooling cervical specimens from the same woman might provide a useful pretest of specimens from women unlikely to have high-grade cervical neoplasia or significant HPV exposure. We selected women (n = 187) participating in the Guanacaste Project for whom we already had HPV testing data on all their specimens from multiple visits (median = 8 visits), who were HPV DNA-negative at enrollment and at their 5- to 7-year exit from the cohort, and had no evidence of high-grade cervical neoplasia. Equal aliquots of cervical specimens from these women were pooled to create a proportional pooled specimen. Aliquots of pooled specimens were tested in a masked fashion by MY09/11 L1 consensus primer PCR. Second aliquots of some pooled specimens (n = 83) were included to assess the reliability of pooled testing. Results were compared with the predicted (expected) results based on the obtained test results of the individual specimens collected at interim visits. There was good overall agreement between observed and expected HPV DNA positivity, with a kappa of 0.63 [95% confidence interval (95% CI), 0.51-0.75] and a percent agreement of 83.4% (95% CI, 77.3-88.5%) although the HPV DNA positivity in the pooled specimen was less than expected (P = 0.001). The agreement between observed and expected HPV DNA positivity was related to the number of aliquots pooled, suggesting that positivity was related to viral genome concentrations. The kappa and percent agreement for intra-batch reliability of testing pooled specimens were 0.68 (95% CI, 0.53-0.84) and 84.3% (95% CI, 74.7-91.4%), respectively. We conclude that pooling specimens and testing by PCR may be useful for discriminating HPV DNA-positive from completely negative specimen sets in women who are likely to have been HPV DNA-negative.>

Female↗

PubMed2004

Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan.

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.

Adolescent↗

PubMed2004

A population-based study of vaginal human papillomavirus infection in hysterectomized women.

We compared point prevalences and determinants of human papillomavirus (HPV) DNA detection by testing enrollment vaginal specimens from hysterectomized women (n=569) and enrollment cervical specimens from nonhysterectomized women (n=6098) >or=30 years old, using MY09/MY11 L1 consensus-primer polymerase chain reaction. The subjects were participating in a population-based cohort study (n=10,049) in Guanacaste, Costa Rica, that was initiated in 1993. Non-cancer-associated HPV types, especially types 61, 71, and 72, were detected more frequently in the vaginal specimens from hysterectomized women (23.7% [95% confidence interval [CI], 20.3%-27.4%]) than in the cervical specimens from nonhysterectomized women (16.7% [95% CI, 15.7%-17.6%]) (P=.0001). There was no difference between the prevalences of cancer-associated HPV types in hysterectomized women and those in nonhysterectomized women; in both groups, the prevalence of HPV DNA was greater in women with multiple lifetime sex partners. We infer from our data that the cervical transformation zone may not be needed for cancer-associated HPV infection but may be uniquely susceptible to HPV-induced carcinogenesis; we also infer that specific phylogenetic groups of HPV (i.e., A3/A4/A15) may have a predilection for vaginal epithelium.

Adult↗

PubMed2004

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Arylamine N-Acetyltransferase↗

PubMed2004

Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000.

BACKGROUND: Although cervical carcinoma incidence and mortality rates have declined in the U.S. greatly since the introduction of the Papanicolaou smear, this decline has not been uniform for all histologic subtypes. Therefore, the authors assessed the differential incidence rates of squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the cervix by race and disease stage for the past 25 years. METHODS: Data from nine population-based cancer registries participating in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program were used to compute incidence rates for cervical carcinoma diagnosed during 1976-2000 by histologic subtype (SCC and AC), race (black and white), age, and disease stage (in situ, localized, regional, or distant). RESULTS: In black women and white women, the overall incidence of invasive SCC declined over time, and the majority of tumors that are detected currently are in situ and localized carcinomas in young women. The incidence of in situ SCC increased sharply in the early 1990s. AC in situ (AIS) incidence rates increased, especially among young women. In black women, invasive AC incidence rose linearly with age. CONCLUSIONS: Changes in screening, endocervical sampling, nomenclature, and improvements in treatment likely explain the increased in situ cervical SCC incidence in white women and black women. Increasing AIS incidence over the past 20 years in white women has not yet translated into a decrease in invasive AC incidence. Etiologic factors may explain the rising invasive cervical AC incidence in young white women; rising cervical AC incidence with age in black women may reflect either lack of effective screening or a differential disease etiology.

Adenocarcinoma↗

PubMed2004

Opportunities for cancer epidemiology in developing countries.

Most cancer epidemiology studies involve people living in North America and Europe, which represent only a fraction of the global population. The wide variety of dietary, lifestyle and environmental exposures, as well as the genetic variation among people in developing countries can provide valuable new information on factors that contribute to cancer or that protect against it. What are the challenges and advantages to performing large epidemiological studies in developing nations?

Data Collection↗

PubMed2004

Performance of direct visual inspection of the cervix with acetic acid and magnification in a previously screened population.

OBJECTIVE: To assess the screening performance of direct visual inspection with acetic acid and x2 magnification (VIAM) in a previously screened population, as performed by experienced gynecologic nurses with minimal training in VIAM. PATIENTS AND METHODS: Performance of VIAM was evaluated in 2,080 women from a population-based cohort in Guanacaste, Costa Rica, 5 years after they had negative enrollment results of conventional and liquid-based cytologic analysis, cervigram, and human papillomavirus DNA by Hybrid Capture Tube Test (Digene Corporation, Gaithersburg, MD). The VIAM results were compared with repeat conventional Pap smears, liquid-based cytologic examinations, and cervicography, with adjudication of differences by reference to MY09/MY11 L1 consensus primer polymerase chain reaction detection of oncogenic human papillomavirus DNA. RESULTS: Less than 5% of women were classified as having positive results using VIAM. The VIAM positivity was also very low among women with high-grade squamous intraepithelial lesion conventional Pap smear results (8.3%), high-grade squamous intraepithelial lesion liquid-based cytologic results (6.3%), or cervigrams suggesting cervical intraepithelial neoplasia 2,3 or cancer (30%). The VIAM positivity was not associated with human papillomavirus DNA positivity. CONCLUSIONS: As we practiced it, VIAM was not sensitive for detection of possibly serious incident cervical lesions in this previously screened population where cytologic screening is in place.

Journal Article↗

PubMed2004

Comparison of benchtop microplate beta counters with the traditional gamma counting method for measurement of chromium-51 release in cytotoxic assays.

The most traditional method used to measure the lytic activity of cytotoxic T lymphocytes or natural killer (NK) cells is the chromium release assay (CRA). No study has been reported that systematically compares the traditional gamma counting method with various benchtop microplate scintillation formats to measure chromium release. Here we investigated the utilization of microplate beta counters in comparison with the traditional gamma counting method to quantitate antigen-specific cytolysis, lymphokine-activated killer (LAK) activity, and NK activity in the CRA. Supernatants from standard CRA (n = 7) were directly transferred to a 96-well microplate containing either a solid scintillant (Lumaplate) or a liquid scintillant (flexible beta plate). Samples were quantified by using two benchtop microplate beta counters, Wallac Microbeta Trilux (Lumalux and Trilux methods, respectively) and Packard TopCount instruments (TopCount method). These results were then compared with data from an identical assay run in parallel using the traditional gamma counting method (LKB). The lytic activity for influenza virus-stimulated effectors measured in the benchtop microplate beta counters using Lumalux and Trilux methods exhibited excellent correlations with the one measured in the traditional LKB (r = 0.967 and 0.968, respectively). The TopCount method demonstrated a similar correlation (r = 0.966). Similar findings were observed for LAK and NK activity. The 96-well microplate format, specifically the dry-scintillant Lumaplates, offers several advantages over the traditional gamma counting format. Most notable are the reductions in sample volume needed and in the total sample preparation and counting time. Furthermore, this system reduces the amount of dry and mixed radioactive waste generated while using the same instrument for gamma- and beta-emitting isotopes.

CD8-Positive T-Lymphocytes↗

PubMed2004

Comparison of ophthalmic sponges for measurements of immune markers from cervical secretions.

Measurements of cervical immunity are important for evaluating immune responses to infections of the cervix and to vaccines for preventing those infections. Three ophthalmic sponges, Weck-Cel, Ultracell, and Merocel, were loaded in vitro with interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18, gamma interferon (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), immunoglobulin A (IgA), or IgG, and sponges were extracted and evaluated for total recovery by enzyme-linked immunosorbent assay (ELISA). There was excellent (>75%) recovery for all immune markers from all three devices except for IL-6, which was poorly recovered (<60%) for all sponge types, IFN-gamma, which was poorly recovered from both Weck-Cel and Ultracell sponges but was completely recovered from Merocel sponges, and IL-4, which was poorly recovered from Weck-Cel sponges but was completely recovered from Ultracell or Merocel sponges. We then compared the absolute recovery of selected markers (IL-10, IL-12, IgG, and IgA) from cervical secretion specimens collected from women using each type of sponge. There were no significant differences in the recoveries of IL-10, IL-12, and IgG from cervical specimens collected by any type of ophthalmic sponge, but there was reduced IgA recovery from Merocel sponges. However, the variability in these measurements attributable to sponge types (1 to 3%) was much less than was attributable to individuals (45 to 72%), suggesting that differences in sponge type contribute only in a minor way to these measurements. We infer from our data that the three collection devices are adequate for the measurements of IL-1 beta, IL-2, IL-5, IL-12, IL-15, IL-18, and IgG. Merocel may be a better ophthalmic sponge for the collection of cervical secretions and measurements of IL-4, IL-8, IL-10, GM-CSF, and IFN-gamma, but our data from clinical specimens, not in vitro-loaded sponges, suggested the possibility of reduced recovery of IgA. These findings require confirmation.

Adult↗

PubMed2004

Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica.

Whether antibodies to human papillomavirus (HPV) capsids, elicited by natural infection, are protective is unknown. This question was addressed in a population-based cohort of 7046 women in Costa Rica by examining the association between baseline seroreactivity to HPV-16, HPV-18, or HPV-31 virus-like particles and the risk of subsequent HPV infection at a follow-up visit 5-7 years after enrollment. Seropositivity to HPV-16, HPV-18, or HPV-31 was not associated with a statistically significant decreased risk of infection with the homologous HPV type [relative risk (RR) and [95% confidence interval (CI)], 0.74 (0.45-1.2), 1.5 (0.83-2.7), and 0.94 (0.48-1.8), respectively]. Seropositivity to HPV-16 or HPV-31 was not associated with a decreased risk of infection with HPV-16 or its genetically related types [RR (95% CI), 0.82 (0.61-1.1) and 0.93 (0.68-1.2), respectively]. Seropositivity to HPV-18 was not associated with a decreased risk of infection with HPV-18 or its genetically related types (RR 1.3; 95% CI 1.0-1.8). Thus, we did not observe immunity, although a protective effect from natural infection cannot be excluded because of the limits of available assays and study designs.

Adult↗

PubMed2004

Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10000 women in Guanacaste, Costa Rica,.

OBJECTIVE: The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as > or = CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia. METHODS: A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993-1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing > or = CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop >or = CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions >or = CIN 2 served as both the censoring outcome and our surrogate for cancer risk. RESULTS: Participation during follow-up was high (near 90%). Suspected > or = CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected > or = CIN 2 came from the large group perceived at entry as being at low risk of developing > or = CIN 2, but the greatest rates of progression to > or = CIN 2 were observed among women perceived at entry to be at highest risk of > or = CIN 2, based on their cytology, virology, or sexual behavior. CONCLUSIONS: The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed to building knowledge for the search for vaccines against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide.

Adolescent↗