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Philip E Castle

Publications and source records attributed to Philip E Castle.

At least 19 recordsLinked to original sources
PubMed2007

Viral determinants of human papillomavirus persistence following loop electrical excision procedure treatment for cervical intraepithelial neoplasia grade 2 or 3.

BACKGROUND: Persistent infection with carcinogenic human papillomavirus (HPV) causes cervical precancer (cervical intraepithelial neoplasia grade 2+) which, in the United States, is commonly treated using the loop electrical excision procedure (LEEP). Data from Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion Triage Study were used to evaluate HPV persistence and reappearance after LEEP. METHODS: Cervical specimens, collected before LEEP and at 6-month study visits, were tested by L1-PCR for detection of >or=27 HPV types. HPV persistence, defined as the same HPV type being present before and 6 months after LEEP, was evaluated by: (a) genotype, (b) carcinogenicity, and (c) phylogenetic species. HPV infections that cleared post-LEEP (the complement of persistence) were followed for reappearance of the same type. RESULTS: HPV infections (n = 1,130) were detected among 481 women who underwent LEEP. Overall, 20.4% [95% confidence interval (95% CI), 18.2-22.9%] of infections persisted. Assessment of heterogeneity within the three categorizations of HPV showed that phylogenetic species best fit the data. Persistence was significantly greater by HPV types in the alpha3 species [all are noncarcinogenic; 40.9% (95% CI, 31.8-50.4%)] compared with HPV types in the alpha9 (HPV16 and related types) and alpha7 species (HPV18 and related types; 17.6% and 17.9%, respectively; P < 0.001 for both). HPV reappeared in 7.8% (95% CI, 6.1-9.9%) of infections that cleared after LEEP. Infections in the alpha3 species (22.6%) were the most likely to reappear compared with HPV types in the alpha9 (7.5%) and alpha7 (6.8%) species. CONCLUSIONS: Patterns of HPV persistence and reappearance following LEEP were better explained by phylogenetic rather than standard classifications. HPV types likely to persist after LEEP as well as those likely to repopulate the cervical/vaginal epithelium were those in the alpha3 species, which are in effect not treated, but are not associated with cervical cancer and are unlikely to cause disease.

Electrosurgery↗
PubMed2006

Human papillomavirus prevalence in women who have and have not undergone hysterectomies.

We compared human papillomavirus (HPV) prevalence in an age-stratified random sample of women who have undergone a hysterectomy (WH) (n=573) with the HPV prevalence in age-matched women with intact cervices (women who have not undergone a hysterectomy [WNH]) (n=581) participating in a study at Kaiser Permanente in Portland, Oregon. Testing cervicovaginal lavage fluids for >40 HPV genotypes using an MY09/11 L1 consensus primer polymerase chain reaction method, we found no statistical differences in the prevalence of HPV (16% for WNH vs. 13.9% for WH) or carcinogenic HPV (6.5% for WNH vs. 4.5% for WH) between the 2 groups of women. Although WH have a similar prevalence of carcinogenic HPV infection, compared with WNH without a cervix, they have minimal risk of HPV-induced cancer and are unlikely to benefit from HPV testing.

Adult↗
PubMed2006

Cervical cytology of atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes.

BACKGROUND: The 2001 Bethesda System category of atypical squamous cells (ASC) denotes changes suggestive, but inconclusive for, a squamous intraepithelial lesion (SIL). ASC is subcategorized as: 1) "undetermined significance (ASC-US)," when changes suggest low-grade or indeterminate-grade SIL and 2) "cannot exclude high-grade squamous intraepithelial lesion (ASC-H)," when a cancer precursor is suspected. METHODS: To better define the characteristics of ASC-H, the authors analyzed and compared human papillomavirus (HPV) testing data and outcomes after 2 years for participants in the Atypical Squamous Cells of Undetermined Significance Low-Grade SIL Triage Study (ALTS), a randomized trial of 5060 women. RESULTS: Among women with thin-layer cytology findings of ASC-H, 84% tested positive for HPV, 50% (95% confidence interval [95% CI], 41%-60%) were diagnosed with cervical intraepithelial neoplasia (CIN) type 2+, and 30% (95% CI, 22-39%) were diagnosed with CIN3+. Positive HPV tests and diagnoses of CIN2+ and CIN3+ were found to be more common among women with ASCH compared with those with ASC-US, but the highest frequencies were found to be associated with high-grade SIL. For women age < 35 years with ASC-H, HPV detection exceeded 85%, whereas only 4 of 10 women (40%) age >/=35 years tested positive for HPV (P = 0.009). CONCLUSIONS: A finding of ASC-H seems to confer a substantially higher risk for CIN2+ and CIN3+ than ASC-US. Immediate colposcopy may be the appropriate management for young women with ASC-H, but the utility of HPV testing for managing older women with ASC-H requires additional study.

Colposcopy↗
PubMed2006

Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality.

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 approximately 40 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 alpha3/alpha15 types, although highly prevalent, uncommonly caused cytologic abnormalities (13.1%; 95% CI, 9.8-17.0). In contrast, one quarter to nearly one half of infections with a single major carcinogenic species type (alpha9/alpha11/alpha7/alpha5/alpha6) 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 alpha9 types were high grade or worse, consistent with strong carcinogenicity, compared with 10.7% in women infected with alpha7 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 alpha7-related lesions.

Adult↗
PubMed2006

Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer.

BACKGROUND: Prospective data on the risks of cervical precancer associated with specific human papillomavirus (HPV) genotypes are limited. METHODS: In 5060 women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS), we determined the cumulative 2-year risks of cervical intraepithelial neoplasia (CIN) grade 2 or more severe (> or =CIN2) and of grade 3 or more severe (> or =CIN3) for 38 individual HPV genotypes, as detected by polymerase chain reaction. RESULTS: The most common HPV genotypes detected at baseline, in descending order of prevalence, were 16, 52, 51, 31, 18, 53, 39, 56, 62, 59, and 58. When detected as a single-type HPV infection, HPV-16 had a 2-year cumulative risk of 50.6% (95% confidence interval [CI], 44.1%-57.2%) for > or =CIN2 and 39.1% (95% CI, 32.9%-45.7%) for > or =CIN3. For other singly detected carcinogenic HPV types, the risk of > or =CIN2 ranged from 4.7% (for HPV-59) to 29.5% (for HPV-31), and the risk of > or =CIN3 ranged from 0.0% (for HPV-59) to 14.8% (for HPV-31). Multiple infections with HPV genotypes of different risk classes resulted in a risk that was similar to, and not significantly different from, the risk observed for the HPV genotype of the highest risk class. CONCLUSIONS: Genotype-specific HPV testing may be useful for identifying women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions who are at higher and lower risk of prevalent and incipient cervical precancer.

Colposcopy↗
PubMed2006

Pilot study of a commercialized human papillomavirus (HPV) genotyping assay: comparison of HPV risk group to cytology and histology.

We evaluated a commercialized PCR assay, Linear Array, that detects 37 human papillomavirus (HPV) genotypes, using a sample of liquid cytology specimens (n = 534). We found a strong association of an increasing level of HPV risk (HPV type 16 [HPV16] > HPV18 > other carcinogenic types > noncarcinogenic types > negative specimens) with increasing severities of cytologic interpretations (P(Trend) < 0.0005) and histologic diagnoses (P(Trend) < 0.0005).

Cytodiagnosis↗
PubMed2006

Chapter 7: Achievements and limitations of cervical cytology screening.

This chapter reviews the contribution of cervical cytology, what makes it successful, the management of screen positives and how technological advances may affect its use in the future. Cervical screening has saved hundreds of thousands of lives but has not been available to women in the poorest countries. In countries where wide coverage has been achieved and quality assurance is in place, incidence and death rates have fallen by over 50% even though cervical cytology is logistically complex. The management of high-grade cervical intraepithelial neoplasia (CIN) is very effective, but low-grade cytological abnormalities require care to avoid over-treatment. The increasing rate of human papillomavirus (HPV) testing and the prospect of prophylactic vaccination will change the way cervical cytology is used, possibly giving way to HPV testing as the primary test in secondary prevention.

Female↗
PubMed2006

Age-related changes of the cervix influence human papillomavirus type distribution.

Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the alpha9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the alpha3/alpha15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of alpha9 or alpha3/alpha15 types. Prevalence of alpha9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of alpha3/alpha15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of alpha9 infections increased (P(trend) < 0.0005) but alpha3/alpha15 infections decreased (P(trend) < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an alpha3/alpha15 infection compared with having an alpha9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential.

Adult↗
PubMed2006

Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease.

BACKGROUND: Loop electrosurgical excision procedure (LEEP) is the predominant treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+) in the United States, yet following treatment approximately 10% of women are diagnosed again with CIN2+, necessitating close follow-up of such patients. METHODS: Surveillance strategies using cytology and/or human papillomavirus (HPV) testing were compared among women who underwent LEEP (n = 610) in the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. Cervical specimens, collected at 6-month visits for 2 years, were used for cytology, Hybrid Capture 2 (HC2) detection of carcinogenic HPVs, and PCR for genotyping of carcinogenic and noncarcinogenic HPV types. At exit, women had colposcopy for safety and disease ascertainment. RESULTS: At the visit post-LEEP (median time: 4.5 months after LEEP), 36.9% [95% confidence interval (95% CI), 32.7-41.1%] of women were positive for carcinogenic HPV by PCR and 33.7% (95% CI, 29.7-37.9) had ASCUS or more severe (ASCUS+) cytology. The overall 2-year cumulative incidence of histologically confirmed posttreatment CIN2+ was 7.0%; this could be further stratified by the HPV risk category detected at the 6-month visit after LEEP. The 2-year risk associated with HPV16 positivity was 37.0%, significantly higher than for other carcinogenic HPV types (10.8%, P < 0.001), noncarcinogenic types (1.5%, P < 0.001), or testing HPV negative (0%). Post-LEEP cytology (using a positive threshold of ASCUS+) was 78.1% (95% CI, 60.0-90.7%) sensitive for detection of posttreatment CIN2+. By comparison, PCR for carcinogenic HPV and combination testing (using a positive result from carcinogenic HPV testing or cytology as the test threshold with HPV-negative ASCUS not referred) were significantly more sensitive (96.9% for each, P = 0.03); HC2 alone was nonsignificantly more sensitive (90.6%, P = 0.3). Specificity was similar for ASCUS+ cytology (69.1%, 95% CI, 64.6-73.3%) and PCR for carcinogenic HPV (67.1%, P = 0.5), yet was lower for HC2 (63.8%, P = 0.048) and combination testing (62.9%, P = 0.02). CONCLUSION: Women who tested positive after LEEP for carcinogenic HPV types, especially HPV16, had high risk of subsequent CIN2+. HPV-based detection methods, alone or in combination with cytology, may be useful to incorporate in post-LEEP management strategies.

Adult↗
PubMed2005

Hormonal contraceptive use, pregnancy and parity, and the risk of cervical intraepithelial neoplasia 3 among oncogenic HPV DNA-positive women with equivocal or mildly abnormal cytology.

Oral contraceptive (OC) use, hormonal contraceptive use and multiparity are potential risk factors for cervical precancer, cervical intraepithelial neoplasia 3 (CIN3), but a limited number of studies have adequately accounted for possible confounding effect of oncogenic human papillomavirus (HPV) infection. To examine the relationships of these factors with CIN3, we conducted an analysis of women (n = 5,060) with minimally abnormal Pap smears who were enrolled in the ASCUS and LSIL Triage Study (ALTS), a clinical trial to evaluate management strategies. Cervical specimens collected at enrollment were tested for HPV DNA using 2 methods. Multivariate logistics regression models were used to assess associations (odds ratio [OR] with 95% confidence intervals [CI]) of the potential risk factors (e.g., OC use and parity) with testing oncogenic HPV positive among controls (<CIN2) (n = 4,114) and with rigorously reviewed cases of CIN3 identified throughout the study (n = 499) among women with oncogenic HPV (n = 3,126). Only former oral contraceptive use (OR = 1.3, 95% CI = 1.0-1.7) was associated marginally with having an oncogenic HPV infection among controls. Restricted to women with oncogenic HPV, current injectable hormonal contraceptive users were at an elevated risk of CIN3 (OR = 1.6, 95% CI = 1.2-2.1) compared to women who never used them. Similarly, restricted to women with HPV16 infection, current users of injectable contraceptives were at a marginally elevated risk of CIN3 (OR = 1.5, 95% CI = 1.0-2.3) compared to women who never used them. Oral contraceptive use, Norplant (implantable hormonal contraceptive) use, a history of pregnancy, age at first pregnancy, lifetime numbers of pregnancies and lifetime numbers of live births were not associated with CIN3. We conclude that only current injectable hormonal contraceptive use slightly elevated the risk (approximately 50%) of CIN3 in this young and low parity population of women with oncogenic HPV and minimally abnormal Pap smears but further confirmation of this relationship is needed.

Contraceptive Agents, Female↗
PubMed2005

Increasing incidence of testicular germ cell tumors among black men in the United States.

PURPOSE: There has been marked disparity in the incidence of testicular germ cell tumors (TGCT) among white and black men for a number of decades in the United States. Since at least the beginning of the Surveillance, Epidemiology, and End Results (SEER) Program in 1973, incidence rates among white men have been five times higher than rates among black men. In addition, rates among white men have been increasing, whereas rates among black men have remained stable. However, a recent examination of ethnic-specific rates suggested that the incidence among black men may have begun to change in the 1990s. PATIENTS AND METHODS: TGCT incidence data from nine registries of the SEER Program were analyzed for the years 1973 to 2001. Trends were examined separately for seminoma and nonseminoma. RESULTS: Analyses found that the incidence of TGCT began to increase among black men between the 1988 to 1992 and 1993 to 1997 periods. Before that time, incidence among black men had decreased by 14.8%. Between 1988 to 1992 and 1998 to 2001, however, the incidence increased by 100%, with the incidence of seminoma increasing twice as much (124.4%) as the incidence of nonseminoma (64.3%). Over the 29-year time period, there was no evidence of a change in the proportion of tumors diagnosed at earlier stages among black men. In contrast, the proportion of tumors diagnosed at localized stages significantly increased among white men. CONCLUSION: The incidence of TGCT among black men has increased since 1988 to 1992. Although the reasons for this increase are unclear, screening and earlier diagnosis of TGCT do not seem to be factors.

Adult↗
PubMed2005

Immunohistochemical evaluation of heat shock proteins in normal and preinvasive lesions of the cervix.

Heat Shock Proteins (HSPs) are molecular chaperons with multiple functions relating to cellular homeostasis. Primary, HSPs are expressed in response to cellular stresses that may also include carcinogenesis. Patterns of expression have not been extensively evaluated in the multi-step carcinogenesis of cervical cancer (Normal --> HPV infection --> Cervical Precancer --> Cancer). We evaluated the expression of HSP40, HSP60, HSP70, and HSP90 in normal tissues (N=30), in cervical intraepithelial neoplasia grade 1 (CIN1)(synonymous with productive HPV infections) (N=32), and in CIN3 (cervical precancer)(N=25) by immunohistochemistry staining (graded 0-3) and compared the results to p16INK4a, a biomarker of oncogenic HPV infections and CIN3. We found strong patterns of increased HSP40, HSP60, and HSP70 immunostaining with increasing severity of the lesion in a manner similar to p16INK4a (P(Trend)<0.0005). No difference in staining intensity by grade of lesion was observed for HSP90 (P(Trend)=0.8). Tissue patterns in CIN3 of diffuse immunostaining for HSP40 and HSP70 were analogous to those observed for p16INK4a; HSP60 immunostaining appeared more punctate within cells than for other antigens although similar tissue patterns were observed. We conclude that HSP40, HSP60, and HSP70 expressions are up-regulated in response to the development of CIN3 akin to p16INK4a expression.

Biomarkers, Tumor↗
PubMed2005

Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities.

BACKGROUND: The 2-year absolute risk for cervical precancer attributable to infection by human papillomavirus type 16 (HPV16), the most common and oncogenic HPV type, in the millions of women diagnosed annually with equivocal or mildly abnormal cytology has not been definitively evaluated. METHODS: Baseline cervical specimens of 5060 women with equivocal (atypical squamous cells of undetermined significance [ASCUS]) or mildly abnormal (low-grade squamous intraepithelial lesion [LSIL]) cytology were tested for HPV DNA using Hybrid Capture 2 (HC2) and type-specific L1 consensus primer polymerase chain reaction. We calculated absolute risks with 95% confidence intervals (CIs) for cumulative diagnosis, during the 2-year study period, of cervical intraepithelial neoplasia grade 3 (CIN3) (n = 535) or cancer (n = 7) (collectively referred to as > or = CIN3) and compared risk by HPV16 status and by other oncogenic HPV types using logistic regression. All statistical tests were two-sided. RESULTS: The baseline prevalences of HPV16 in women with ASCUS or LSIL cytology were 14.9% and 21.1%, respectively. Women with ASCUS or LSIL cytology who were HPV16 DNA positive at baseline had 2-year cumulative absolute risks for > or = CIN3 of 32.5% (95% CI = 28.4% to 36.8%) and 39.1% (95% CI = 33.8% to 44.7%), respectively. By comparison, women with ASCUS who were positive by HC2 for other oncogenic HPV types combined had an 8.4% (95% CI = 6.9% to 10.4%) risk for > or = CIN3, which was similar to the risk posed by having ASCUS (risk = 8.8%, 95% CI = 7.9% to 9.8%) without knowledge of the oncogenic HPV DNA status. Women with LSILs who were positive by HC2 for other oncogenic HPV types combined had a 9.9% (95% CI = 8.0% to 12.0%) 2-year risk for > or = CIN3, which was less than the risk posed by having LSILs (risk = 15.0%, 95% CI = 13.3% to 16.9%) without knowledge of the oncogenic HPV DNA status. Together, women with ASCUS or LSILs who were HPV16-positive had the highest 2-year risk for > or = CIN3 compared with women who were HPV-negative (odds ratio [OR] = 38, 95% CI = 22 to 68; P < .001 ), fivefold greater than the increased risk in women who were positive for other oncogenic HPV types (OR = 7.2, 95%CI = 4.2 to 13, P < .001). CONCLUSIONS: Distinguishing the high absolute risk for cervical precancer in HPV16-positive women from the lower risk posed by other oncogenic HPV types might have clinical implications.

Adult↗
PubMed2005

The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice.

BACKGROUND: Human papillomavirus (HPV) types 16 and 18 cause 60%-70% of cervical cancer worldwide, and other HPV types cause virtually all remaining cases. Pooled HPV testing for 13 oncogenic types, including HPV16 and 18, is currently used in clinical practice for triage of equivocal cytology and, in conjunction with Pap tests, is an option for general screening among women 30 years of age and older. It is not clear to what extent individual identification of HPV16 or HPV18 as an adjunct to pooled oncogenic HPV testing might effectively identify women at particularly high risk of cervical cancer or its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3). METHODS: From April 1, 1989, to November 2, 1990, a total of 20 810 women in the Kaiser Permanente health plan in Portland, OR, enrolled in a cohort study of HPV and cervical neoplasia. Women were tested for 13 oncogenic HPV types by Hybrid Capture 2 (HC2), and those women with a positive HC2 test were tested for HPV16 and 18. Enrollment Pap smear interpretation and HPV test results were linked to histologically confirmed CIN3 and cervical cancer (> or = CIN3) occurring during 10 years of cytologic follow-up. We calculated cumulative incidence rates with 95% confidence intervals for each interval up to 122 months using Kaplan-Meier methods. RESULTS: The 10-year cumulative incidence rates of > or = CIN3 were 17.2% (95% confidence interval [CI] = 11.5% to 22.9%) among HPV16+ women and 13.6% (95% CI = 3.6% to 23.7%) among HPV18+ (HPV16-) women, but only 3.0% (95% CI = 1.9% to 4.2%) among HC2+ women negative for HPV16 or HPV18. The 10-year cumulative incidence among HC2- women was 0.8% (95% CI = 0.6% to 1.1%). A subanalysis among women 30 years of age and older with normal cytology at enrollment strengthened the observed risk differences. CONCLUSIONS: HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of > or = CIN3 and may permit less aggressive management of other women with oncogenic HPV infections.

Adult↗