We describe a sample of skulls, mandibles and isolated dentitions of Machairodus aphanistus from ... more We describe a sample of skulls, mandibles and isolated dentitions of Machairodus aphanistus from the Spanish late Vallesian (late Miocene) site of Batallones-1, near Madrid. This is the first time that the cranial morphology of this species has been seen in detail, and shows that late Vallesian M. aphanistus combined a relatively primitive cranial and mandibular morphology with very specialized upper canines, as flattened as in the later, cranially derived species M. giganteus. Cranio-mandibular adaptations for the canine shear-bite are incipient or non-existent, suggesting that the specialized canines of M. aphanistus were used within the context of a biting mechanism more similar to the canine bite of modern felids. Evolution of more extreme machairodont craniodental features in later members of the homotherin lineage converged with smilodontins but occurred independently of the initial development of derived saber-like canines. The high number of specimens, at least 14 individuals represented, reveals considerable variation in size within the population, with indications of sexual dimorphism in the size of the upper canines. Differences in cranial morphology suggest separation at the generic level between M. aphanistus and M. giganteus.
International Journal of Gynecological Pathology, 2007
We wished to compare the relative reproducibility and validity of cervical intraepithelial neopla... more We wished to compare the relative reproducibility and validity of cervical intraepithelial neoplasia (CIN) 2 and CIN3 diagnoses. In a population-based cohort study (1993-2001) of human papillomavirus (HPV) and cervical neoplasia in Costa Rica, we compared community pathologists' diagnoses with those of the 2 independent reviewers from the United States (total, n = 357). As measures of validity, we correlated primary and review diagnoses with HPV positivity and cytological interpretations. Two review pathologists agreed with 84% and 81%, respectively, of initial diagnoses of CIN3 compared with 13% and 31% of CIN2. The CIN3 diagnoses made by review pathologists were 94% oncogenic HPV positive, compared with 72% of CIN2 diagnoses. Eighty-one percent of CIN3 diagnoses versus 61% of CIN2 were correlated with high-grade cytological interpretations. The CIN3 is a substantially more reproducible diagnosis that can be validated more frequently with HPV tests and cytological interpretations than CIN2.
Revista Panamericana De Salud Publica-pan American Journal of Public Health, 2004
Objective. The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the ro... more 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 ≥ 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 ≥ CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop ≥ 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 ABSTRACT Rev Panam Salud Publica/Pan Am J Public Health 15(2), 2004 75 Bratti MC, Rodríguez AC, Schiffman M, Hildesheim A, Morales J, Alfaro M, et al. Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10 000 women in Guanacaste, Costa Rica. Rev Panam Salud Publica. 2004;15(2):75-89.
American Journal of Obstetrics and Gynecology, 1999
Cervicography was evaluated as a primary screening method for cervical cancer. Cervigrams of 8460... more Cervicography was evaluated as a primary screening method for cervical cancer. Cervigrams of 8460 women were taken on enrollment into a population-based study of cervical neoplasia. Cervicography results were compared with a referent diagnosis determined by histologic analysis and 3 cytologic tests, and with the performance of conventional cytologic evaluation. Cervicography identified all 11 cancers, whereas cytologic testing missed 1. Cervicography yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 49.3% overall (specificity, 95.0%), 54.6% in women younger than 50 years of age, and 26.9% in women 50 years of age and older. Cytologic testing yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 77.2% overall (specificity, 94. 2%), 75.5% in women younger than 50 years of age, and 84.6% in women 50 years of age and older. Cytologic testing performed better than cervicography for the detection of high-grade squamous intraepithelial lesions. Cervicography performed marginally better than cytologic testing for the detection of invasive cervical cancer. Cervicography is not recommended for postmenopausal women.
In a study using a split-sample design, liquid-based cytology (ThinPrep Processor, Cytyc Corporat... more In a study using a split-sample design, liquid-based cytology (ThinPrep Processor, Cytyc Corporation, Boxborough, MA) was compared with the conventional Papanicolaou (Pap) smear in Guanacaste, Costa Rica. The study provides the first population-based comparison of the ThinPrep screening technology and includes "gold standard" measures of diagnostic accuracy. The population-based study was performed among over 8000 women residing in a Costa Rican province with a high incidence of cervical carcinoma. Conventional smears were prepared and diagnosed in Costa Rica, while the residual material on the sampling device was collected into a liquid preservative and shipped to the U.S., where ThinPrep cytologic slides were prepared and diagnosed. Cytologic diagnoses based on the two techniques, categorized according to the Bethesda System, were compared with a "gold standard" final case diagnosis for each patient, also based on Bethesda terminology, that reflected an integrated interpretation of all available data, including cytology, histology, and cervicography. Results were also compared with the results of HPV DNA detection (Hybrid Capture, Digene Corporation, Silver Spring, MD). ASCUS was the threshold for colposcopy referral. There were significantly more women referred according to this threshold with the ThinPrep slide (12.7%) than with the conventional smear (6.7%, P<0.001). Compared with the final case diagnosis, referral by ThinPrep slides detected 92.9% of cases with high grade squamous intraepithelial lesions (HSIL) and 100% of carcinoma cases. Smears detected 77.8% of HSIL and 90.9% of carcinomas. Thus, ThinPrep cytology was significantly more sensitive in the detection of HSIL and cancer (McNemar test, P<0.001). Adjudication of cases in which the ThinPrep and smear diagnoses disagreed, using the final case diagnoses and the HPV DNA test results as reference standards, suggested that the ThinPrep method was detecting additional true SIL as opposed to false-positives. In a population-based study of high risk women, ThinPrep cytology demonstrated significantly increased sensitivity for detecting HSIL and carcinoma, with a concurrent significant increase in colposcopy referrals.
Mark E. Sherman, MD 1,2 BACKGROUND. Several new techniques have been developed to improve the sen... more Mark E. Sherman, MD 1,2 BACKGROUND. Several new techniques have been developed to improve the sensi-Mark H. Schiffman, MD, MPH 2 tivity of cervical carcinoma screening and reduce equivocal cytologic diagnoses Attila T. Lorincz, Ph.D. 3 referred to as atypical ...
Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 1... more Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10 049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n ¼ 9949), HPV-18 (n ¼ 9928), HPV-31 (n ¼ 9932), and HPV-45 (n ¼ 3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n ¼ 573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA-and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.
Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all... more Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancer. Cytologic abnormalities are the manifestations of HPV infections used to identify women at risk. To compare the potential of the full range of anogenital HPV genotypes to induce cytopathic effects, we examined the influences of HPV type, viral load, and age on cytopathology among 1,222 women having a single HPV type at enrollment into a 10,000-woman population-based study in Costa Rica. Cervical specimens were tested for f40 HPV types by MY09/MY11 L1 primer PCR and type-specific dot blot hybridization. Types were organized by phylogenetic species and cancer risk. PCR signal strength served as a qualitative surrogate for viral load. Overall, 24.8% [95% confidence interval (95% CI), 22.4-27.3] of single prevalent HPV infections had concurrent abnormalities (atypical squamous cells or worse) ranging from 0.0% to 80.0% based on HPV type. Noncarcinogenic A3/A15 types, although highly prevalent, uncommonly caused cytologic abnormalities (13.1%; 95% CI,. In contrast, one quarter to nearly one half of infections with a single major carcinogenic species type (A9/A11/A7/A5/A6) produced abnormalities. Greater abnormalities were observed with increasing qualitative viral load of carcinogenic types; fewer abnormalities were observed among older women (>54 years). A high percentage (46.2%) of detected abnormalities in women infected with HPV16 or related A9 types were high grade or worse, consistent with strong carcinogenicity, compared with 10.7% in women infected with A7 types, including HPV18, a major cause of adenocarcinoma. The lack of evident severe abnormalities associated with HPV18 and related HPV types might have implications for screening for poorly detected glandular and A7-related lesions.
Background: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few popul... more Background: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types. Methods: We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system. Results: Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500). Conclusions: We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancerassociated HPV types may be able to prevent most cases of cervical disease in this region. [J Natl Cancer Inst 2000;92:
See the editorial commentary by Winer and Koutsky, the article by Castle et al., and the brief re... more See the editorial commentary by Winer and Koutsky, the article by Castle et al., and the brief report by Dunne et al., on pages 1787-9, 1808-16, and 1817-9, respectively.)
Background: Associations between human leukocyte antigens (HLA) alleles and cervical cancer are l... more Background: Associations between human leukocyte antigens (HLA) alleles and cervical cancer are largely representative of squamous cell carcinoma (SCC), the major histologic subtype. We evaluated the association between HLA class I (A, B, and C) and class II (DRB1 and DQB1) loci and risk of cervical adenocarcinoma (ADC), a less common but aggressive histologic subtype.
Automated cytology devices have utility in quality assurance applications, but the effectiveness ... more Automated cytology devices have utility in quality assurance applications, but the effectiveness of these devices in primary screening is unknown. Enrollment smears obtained from 7323 women participating in a population-based study sponsored by the National Cancer Institute were screened manually in Costa Rica and then evaluated independently in the U.S. with the PAPNET system (Neuromedical Systems, Inc., Suffern, NY), a semiautomated, neural network-based device. Smears with abnormal PAPNET images were microscopically rescreened and then diagnosed by a U.S. cytopathologist. ThinPrep slides (Cytyc Corporation, Boxborough, MA), prepared from rinses of the cytologic sampler, and cervigrams (National Testing Laboratories, Fenton, MO) were also evaluated. Women with any abnormal cytologic diagnosis or a positive cervigram were referred for colposcopy with biopsy and definitive therapy if indicated. Based on the U.S. cytotechnologist's review of the PAPNET images, 1017 (13.9%) of 7323 smears were selected for manual screening, resulting in the selection of 492 (6.7%) possibly abnormal slides for referral to the U.S. pathologist. Ultimately, 312 smears (4.3% of the total) were diagnosed as containing squamous cells of undetermined significance or a more severe abnormality (> or =ASCUS), resulting, hypothetically, in the referral of 66.5% of women with a final diagnosis of a squamous intraepithelial lesion or a more severe abnormality (> or =SIL) and 86.0% of patients with > or =high grade SIL. Conventional microscopic screening performed in Costa Rica resulted in the hypothetical referral of 6.5% of patients with > or =ASCUS for colposcopy, including 69.5% of patients with > or =SIL and 79.8% of those with > or =high grade SIL. In this study, PAPNET-assisted cytologic screening accurately identified smears obtained from women with high grade SIL or carcinoma. Determination of the clinical cost-effectiveness of PAPNET-assisted screening in routine practice awaits future study.
Revista Panamericana De Salud Publica-pan American Journal of Public Health, 1997
En este documento se informa sobre la fase de inscripción de un estudio de la historia natural de... more En este documento se informa sobre la fase de inscripción de un estudio de la historia natural de la neoplasia de cuello uterino basado en la población de Guanacaste, una provincia rural de Costa Rica con tasas constantemente elevadas de cáncer cervicouterino invasor. Las ...
Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical... more Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1 -2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis. Published by Elsevier Inc.
The vast majority of cervical cancer cases are attributable to human papillomavirus (HPV) infecti... more The vast majority of cervical cancer cases are attributable to human papillomavirus (HPV) infection . Our current challenge is to identify factors involved in the rare progression of HPV infection, which is common and usually benign, to cervical cancer and its immediate precursor, high-grade squamous intraepithelial lesions (HSIL).
We describe a sample of skulls, mandibles and isolated dentitions of Machairodus aphanistus from ... more We describe a sample of skulls, mandibles and isolated dentitions of Machairodus aphanistus from the Spanish late Vallesian (late Miocene) site of Batallones-1, near Madrid. This is the first time that the cranial morphology of this species has been seen in detail, and shows that late Vallesian M. aphanistus combined a relatively primitive cranial and mandibular morphology with very specialized upper canines, as flattened as in the later, cranially derived species M. giganteus. Cranio-mandibular adaptations for the canine shear-bite are incipient or non-existent, suggesting that the specialized canines of M. aphanistus were used within the context of a biting mechanism more similar to the canine bite of modern felids. Evolution of more extreme machairodont craniodental features in later members of the homotherin lineage converged with smilodontins but occurred independently of the initial development of derived saber-like canines. The high number of specimens, at least 14 individuals represented, reveals considerable variation in size within the population, with indications of sexual dimorphism in the size of the upper canines. Differences in cranial morphology suggest separation at the generic level between M. aphanistus and M. giganteus.
International Journal of Gynecological Pathology, 2007
We wished to compare the relative reproducibility and validity of cervical intraepithelial neopla... more We wished to compare the relative reproducibility and validity of cervical intraepithelial neoplasia (CIN) 2 and CIN3 diagnoses. In a population-based cohort study (1993-2001) of human papillomavirus (HPV) and cervical neoplasia in Costa Rica, we compared community pathologists' diagnoses with those of the 2 independent reviewers from the United States (total, n = 357). As measures of validity, we correlated primary and review diagnoses with HPV positivity and cytological interpretations. Two review pathologists agreed with 84% and 81%, respectively, of initial diagnoses of CIN3 compared with 13% and 31% of CIN2. The CIN3 diagnoses made by review pathologists were 94% oncogenic HPV positive, compared with 72% of CIN2 diagnoses. Eighty-one percent of CIN3 diagnoses versus 61% of CIN2 were correlated with high-grade cytological interpretations. The CIN3 is a substantially more reproducible diagnosis that can be validated more frequently with HPV tests and cytological interpretations than CIN2.
Revista Panamericana De Salud Publica-pan American Journal of Public Health, 2004
Objective. The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the ro... more 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 ≥ 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 ≥ CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop ≥ 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 ABSTRACT Rev Panam Salud Publica/Pan Am J Public Health 15(2), 2004 75 Bratti MC, Rodríguez AC, Schiffman M, Hildesheim A, Morales J, Alfaro M, et al. Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10 000 women in Guanacaste, Costa Rica. Rev Panam Salud Publica. 2004;15(2):75-89.
American Journal of Obstetrics and Gynecology, 1999
Cervicography was evaluated as a primary screening method for cervical cancer. Cervigrams of 8460... more Cervicography was evaluated as a primary screening method for cervical cancer. Cervigrams of 8460 women were taken on enrollment into a population-based study of cervical neoplasia. Cervicography results were compared with a referent diagnosis determined by histologic analysis and 3 cytologic tests, and with the performance of conventional cytologic evaluation. Cervicography identified all 11 cancers, whereas cytologic testing missed 1. Cervicography yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 49.3% overall (specificity, 95.0%), 54.6% in women younger than 50 years of age, and 26.9% in women 50 years of age and older. Cytologic testing yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 77.2% overall (specificity, 94. 2%), 75.5% in women younger than 50 years of age, and 84.6% in women 50 years of age and older. Cytologic testing performed better than cervicography for the detection of high-grade squamous intraepithelial lesions. Cervicography performed marginally better than cytologic testing for the detection of invasive cervical cancer. Cervicography is not recommended for postmenopausal women.
In a study using a split-sample design, liquid-based cytology (ThinPrep Processor, Cytyc Corporat... more In a study using a split-sample design, liquid-based cytology (ThinPrep Processor, Cytyc Corporation, Boxborough, MA) was compared with the conventional Papanicolaou (Pap) smear in Guanacaste, Costa Rica. The study provides the first population-based comparison of the ThinPrep screening technology and includes "gold standard" measures of diagnostic accuracy. The population-based study was performed among over 8000 women residing in a Costa Rican province with a high incidence of cervical carcinoma. Conventional smears were prepared and diagnosed in Costa Rica, while the residual material on the sampling device was collected into a liquid preservative and shipped to the U.S., where ThinPrep cytologic slides were prepared and diagnosed. Cytologic diagnoses based on the two techniques, categorized according to the Bethesda System, were compared with a "gold standard" final case diagnosis for each patient, also based on Bethesda terminology, that reflected an integrated interpretation of all available data, including cytology, histology, and cervicography. Results were also compared with the results of HPV DNA detection (Hybrid Capture, Digene Corporation, Silver Spring, MD). ASCUS was the threshold for colposcopy referral. There were significantly more women referred according to this threshold with the ThinPrep slide (12.7%) than with the conventional smear (6.7%, P<0.001). Compared with the final case diagnosis, referral by ThinPrep slides detected 92.9% of cases with high grade squamous intraepithelial lesions (HSIL) and 100% of carcinoma cases. Smears detected 77.8% of HSIL and 90.9% of carcinomas. Thus, ThinPrep cytology was significantly more sensitive in the detection of HSIL and cancer (McNemar test, P<0.001). Adjudication of cases in which the ThinPrep and smear diagnoses disagreed, using the final case diagnoses and the HPV DNA test results as reference standards, suggested that the ThinPrep method was detecting additional true SIL as opposed to false-positives. In a population-based study of high risk women, ThinPrep cytology demonstrated significantly increased sensitivity for detecting HSIL and carcinoma, with a concurrent significant increase in colposcopy referrals.
Mark E. Sherman, MD 1,2 BACKGROUND. Several new techniques have been developed to improve the sen... more Mark E. Sherman, MD 1,2 BACKGROUND. Several new techniques have been developed to improve the sensi-Mark H. Schiffman, MD, MPH 2 tivity of cervical carcinoma screening and reduce equivocal cytologic diagnoses Attila T. Lorincz, Ph.D. 3 referred to as atypical ...
Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 1... more Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10 049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n ¼ 9949), HPV-18 (n ¼ 9928), HPV-31 (n ¼ 9932), and HPV-45 (n ¼ 3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n ¼ 573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA-and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.
Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all... more Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancer. Cytologic abnormalities are the manifestations of HPV infections used to identify women at risk. To compare the potential of the full range of anogenital HPV genotypes to induce cytopathic effects, we examined the influences of HPV type, viral load, and age on cytopathology among 1,222 women having a single HPV type at enrollment into a 10,000-woman population-based study in Costa Rica. Cervical specimens were tested for f40 HPV types by MY09/MY11 L1 primer PCR and type-specific dot blot hybridization. Types were organized by phylogenetic species and cancer risk. PCR signal strength served as a qualitative surrogate for viral load. Overall, 24.8% [95% confidence interval (95% CI), 22.4-27.3] of single prevalent HPV infections had concurrent abnormalities (atypical squamous cells or worse) ranging from 0.0% to 80.0% based on HPV type. Noncarcinogenic A3/A15 types, although highly prevalent, uncommonly caused cytologic abnormalities (13.1%; 95% CI,. In contrast, one quarter to nearly one half of infections with a single major carcinogenic species type (A9/A11/A7/A5/A6) produced abnormalities. Greater abnormalities were observed with increasing qualitative viral load of carcinogenic types; fewer abnormalities were observed among older women (>54 years). A high percentage (46.2%) of detected abnormalities in women infected with HPV16 or related A9 types were high grade or worse, consistent with strong carcinogenicity, compared with 10.7% in women infected with A7 types, including HPV18, a major cause of adenocarcinoma. The lack of evident severe abnormalities associated with HPV18 and related HPV types might have implications for screening for poorly detected glandular and A7-related lesions.
Background: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few popul... more Background: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types. Methods: We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system. Results: Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500). Conclusions: We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancerassociated HPV types may be able to prevent most cases of cervical disease in this region. [J Natl Cancer Inst 2000;92:
See the editorial commentary by Winer and Koutsky, the article by Castle et al., and the brief re... more See the editorial commentary by Winer and Koutsky, the article by Castle et al., and the brief report by Dunne et al., on pages 1787-9, 1808-16, and 1817-9, respectively.)
Background: Associations between human leukocyte antigens (HLA) alleles and cervical cancer are l... more Background: Associations between human leukocyte antigens (HLA) alleles and cervical cancer are largely representative of squamous cell carcinoma (SCC), the major histologic subtype. We evaluated the association between HLA class I (A, B, and C) and class II (DRB1 and DQB1) loci and risk of cervical adenocarcinoma (ADC), a less common but aggressive histologic subtype.
Automated cytology devices have utility in quality assurance applications, but the effectiveness ... more Automated cytology devices have utility in quality assurance applications, but the effectiveness of these devices in primary screening is unknown. Enrollment smears obtained from 7323 women participating in a population-based study sponsored by the National Cancer Institute were screened manually in Costa Rica and then evaluated independently in the U.S. with the PAPNET system (Neuromedical Systems, Inc., Suffern, NY), a semiautomated, neural network-based device. Smears with abnormal PAPNET images were microscopically rescreened and then diagnosed by a U.S. cytopathologist. ThinPrep slides (Cytyc Corporation, Boxborough, MA), prepared from rinses of the cytologic sampler, and cervigrams (National Testing Laboratories, Fenton, MO) were also evaluated. Women with any abnormal cytologic diagnosis or a positive cervigram were referred for colposcopy with biopsy and definitive therapy if indicated. Based on the U.S. cytotechnologist's review of the PAPNET images, 1017 (13.9%) of 7323 smears were selected for manual screening, resulting in the selection of 492 (6.7%) possibly abnormal slides for referral to the U.S. pathologist. Ultimately, 312 smears (4.3% of the total) were diagnosed as containing squamous cells of undetermined significance or a more severe abnormality (> or =ASCUS), resulting, hypothetically, in the referral of 66.5% of women with a final diagnosis of a squamous intraepithelial lesion or a more severe abnormality (> or =SIL) and 86.0% of patients with > or =high grade SIL. Conventional microscopic screening performed in Costa Rica resulted in the hypothetical referral of 6.5% of patients with > or =ASCUS for colposcopy, including 69.5% of patients with > or =SIL and 79.8% of those with > or =high grade SIL. In this study, PAPNET-assisted cytologic screening accurately identified smears obtained from women with high grade SIL or carcinoma. Determination of the clinical cost-effectiveness of PAPNET-assisted screening in routine practice awaits future study.
Revista Panamericana De Salud Publica-pan American Journal of Public Health, 1997
En este documento se informa sobre la fase de inscripción de un estudio de la historia natural de... more En este documento se informa sobre la fase de inscripción de un estudio de la historia natural de la neoplasia de cuello uterino basado en la población de Guanacaste, una provincia rural de Costa Rica con tasas constantemente elevadas de cáncer cervicouterino invasor. Las ...
Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical... more Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1 -2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis. Published by Elsevier Inc.
The vast majority of cervical cancer cases are attributable to human papillomavirus (HPV) infecti... more The vast majority of cervical cancer cases are attributable to human papillomavirus (HPV) infection . Our current challenge is to identify factors involved in the rare progression of HPV infection, which is common and usually benign, to cervical cancer and its immediate precursor, high-grade squamous intraepithelial lesions (HSIL).
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Papers by Jorge Morales