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C P Crum

Publications and source records attributed to C P Crum.

At least 91 records · Page 5Linked to original sources
PubMed1992

Seroreactivity to HPV-16 proteins in women with early cervical neoplasia.

Although serological reactivity to human papillomavirus type 16 (HPV-16) proteins has been demonstrated in patients with invasive cervical carcinoma, the degree of seroreactivity to these proteins in women with preinvasive disease and its relationship to the HPV type associated with the disease are unclear. We obtained sera from 27 women undergoing cone biopsy for cervical precursor lesions and 22 controls and analyzed seroreactivity by Western blot to fusion proteins containing portions of the HPV-16 E4, L1 and L2 open-reading frames (ORFs). Positives were analyzed by scanning densitometry and intensity values for each case plotted relative to controls. Cervical biopsy specimens from patients were analyzed for HPV-16 nucleic acids by DNA.DNA in situ hybridization. Mean intensity values for seroreactivity to the pATH-E4 protein approached significance (P = 0.058) and a significantly higher proportion of cases vs controls registered values over 4.0 for pATH-E4 (26% vs 4.5%; P = 0.04) and pATH-L2 (48% vs 18%; P = 0.03) proteins. A significantly higher mean intensity value for E4 was observed for cases containing HPV-16 DNA vs HPV-16 negative cases or controls. Thus, seroreactivity to HPV-16-derived proteins may be more common in women with preinvasive cervical disease, and for some protein targets (E4) may indicate a relatively type-specific response.

Antigens, Viral↗
PubMed1992

The relationship between contraceptives, sexual practices, and cervical human papillomavirus infection among a college population.

Four hundred and sixty-five college women were evaluated to determine if specific variables of social and sexual behavior correlated with the presence of human papillomavirus (HPV) DNA in the genital tract, and if these associations differed between women who were HPV DNA positive, HPV DNA positive/clinically (cytologically) negative, or who reported previous HPV-related disease by a history of an abnormal Papanicolaou (Pap) smear or genital warts. HPV positive women had more sexual partners in the recent past, more sexual episodes per month, and used spermacides less commonly than controls. Similarly, self-reporters were more likely to have more lifetime sexual partners and earlier age of onset for sexual activity. Cytologically negative HPV positive women were distinguished only by more sexual episodes per month and sexual partners in the past year (borderline significance). Alcohol use was significantly more frequent in all groups, underscoring this variable as a risk factor for both HPV DNA positivity and related disease in young women. Potential explanations for differences between women with clinically and non-clinically related HPV positivity are discussed, with emphasis on the need for followup studies to determine if an epidemiologically distinct subset of HPV DNA positive but clinically negative women are at risk for subsequent cervical disease.

Adolescent↗
PubMed1992

The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates.

In applying the Bethesda System of classification to cervical squamous lesions, we evaluated the Papanicolaou smears, cervical biopsies, and human papillomavirus (HPV) DNA status of 76 clinic patients. The biopsy specimens and concurrent Papanicolaou smears were analyzed using criteria for low-grade and high-grade squamous intraepithelial lesions, and the biopsies were analyzed for HPV DNA by in situ hybridization. Two independent observers produced good agreement in both cytologic (kappa = 0.62) and histologic (kappa = 0.71) diagnoses. Predictive values of high-grade cytology (for high-grade histology) were high (0.95 for reviewer 1; 0.97 for reviewer 2), and both high-grade cytology and histology correlated strongly with certain "high-risk" HPV types. In contrast, the predictive value of low-grade cytology for either low-grade histology or HPV types other than "high risk" was poor. This study supports the use of certain histologic criteria for distinguishing squamous intraepithelial lesions into two grades. Limitations in cytologic-histologic correlation appear to reflect the absence of cytologic criteria for distinguishing well-differentiated precursor lesions associated with high-risk HPV types.

Biopsy↗
PubMed1992

Carcinoma of the vulva: epidemiology and pathogenesis.

Vulvar squamous carcinoma is an uncommon neoplasm that afflicts a spectrum of women and has been associated with granulomatous vulvar diseases, human papillomaviruses (HPVs), and chronic inflammatory disorders of the vulva. This review summarizes the epidemiologic, histopathologic, and viral data supporting the division of invasive vulvar carcinomas into distinct subsets. Although HPVs have received attention as etiologic agents, histopathologic and viral data indicate that a substantial proportion of vulvar carcinomas in this country may not be related to a veneareally transmitted agent. One of the principal challenges is to produce studies integrating the various disciplines in order to place HPV in proper perspective and develop strategies to identify women at risk for vulvar carcinomas that are not associated with this virus.

Female↗
PubMed1992

Papillary immature metaplasia of the cervix: a distinct subset of exophytic cervical condyloma associated with HPV-6/11 nucleic acids.

A subset of exophytic cervical precursor lesions are composed of immature metaplastic cells that differ from conventional condylomata by the virtual absence of koilocytotic atypia and the presence of slender filiform papillae. We evaluated a series of exophytic cervical lesions containing this morphology for HPV nucleic acids and compared the associated HPV types with conventional exophytic condylomata of the cervix. Six of six exophytic condylomata and five of six papillary immature metaplasias (PIM), respectively, contained HPV type 6/11 by in situ hybridization. Subtyping of three PIM by polymerase chain reaction combined with direct sequencing revealed nucleic acid sequences consistent with HPV 6/11. PIM were distinguished from high-grade squamous intraepithelial lesions by the rarity of mitoses and by the uniformity of nuclear size and staining intensity with multiple chromocenters. However, these lesions tended to involve the more cephalad region of the cervical transformation zone, and three cases extended deeply into the endocervix with two requiring conization for a definitive diagnosis. Although their bland morphology and association with HPV 6/11 nucleic acids suggest a benign process, their location within the endocervical canal implies that these variants of condyloma may differ biologically from conventional exophytic condylomas of the cervix. The differential diagnosis of PIM and potential explanations for their distinctive morphology, are discussed.

Condylomata Acuminata↗
PubMed1991

Binding by immunoglobulin to the HPV-16-derived proteins L1 and E4 in cervical secretions of women with HPV-related cervical disease.

Although DNA of the human papillomaviruses (HPV) can be identified in epithelium of a large proportion of patients with genital squamous lesions, relatively little is known about the extent of the local host immune response to this virus. We analyzed cervical secretions from patients undergoing evaluation because of abnormal Papanicolaou smears (cervical biopsy showed nonspecific atypia, flat condyloma, or intraepithelial neoplasia), as well as controls, for immunoglobulin binding to proteins produced in vitro to HPV-16 L1, E4, and E7 open reading frames. Segments of the HPV-16 genome, including portions of the L1 (nucleotides 6153-6794), E4 (nucleotides 3399-3648), and E7 (nucleotides 686-880) open reading frames, were cloned into pATH vectors and expressed as tryptophan synthetase E fusion proteins in Escherichia coli and used as a source of study antigens. Fusion proteins containing the HPV L1, E4, and E7 polypeptides were found to be distinct by molecular weight (59,000; 45,000; and 42,000) as well as by immunological determinants recognized by heterologous immune sera. Of 8 cervical intraepithelial neoplasia lesions tested by RNA-RNA in situ hybridization, 7 were found to be positive for HPV-16-related nucleic acids, in contrast to none (0 of 4) in the condyloma group (three positive for HPV DNA other than type 16). Immunoglobulin in cervical secretions showed reactivity to HPV type 16 E4 or L1 or both, with highest binding in patients with cervical intraepithelial neoplasia (P less than 0.01 for HPV-16 L1 and E4 compared with controls). Binding was not tryptophan synthetase E dependent and was, in general, coincident for the HPV-16 E4 and L1 proteins. We conclude that study of cervical secretions, using a quantitative assay for immunoglobulin binding to HPV-16 proteins produced in vitro, may be useful to document the quality and quantity of the immune response of the host to this important human pathogen.

Antigen-Antibody Complex↗
PubMed1991

Local immunity and the uterine cervix: implications for cancer-associated viruses.

Studies of cervical secretions as well as cells composing the endocervix have provided evidence for a functional and potentially important immunological system in the mucosa of that organ. The availability of the tools of cell biology as well as three agents that may be used as probes to infect cervical mucosa experimentally has made possible a detailed approach to define the structural and functional characteristics of local cervical immunity. A long-term goal of these studies is to determine how the cervical immune response may be regulated to reduce local viral replication and virus-associated diseases. With Langerhans cells for antigen presentation, cervical immune responses generally remain detectable for more than 30 days, are predominantly of the IgA isotype, can be influenced by estrogen or progesterone, and are best elicited by local rather than systemic exposure to antigen. Cervical immune responses to the human papillomaviruses (HPV) are of particular importance in this regard because this virus is associated with cervical neoplasia. While responses in serum to HPV-16 proteins L1, E4, and E7 has been found in up to 78% of persons with HPV-associated cervical neoplasms, data showing that a local response of comparable frequency consistently occurs have yet to be confirmed. The current status of local HPV-16-specific immunoglobulin as a potentially useful indicator of HPV-16-related infection or pre-cancer is controversial, and is confounded by several potentially important factors, including patient age, estrogen/progesterone level, smoking status, and sample admixture with serum immunoglobulin.

Cervix Uteri↗
PubMed1991

Vulvar squamous cell carcinoma and papillomaviruses: two separate entities?

Vulvar squamous precancers (vulvar intraepithelial neoplasia) are associated with sexual factors, cigarette smoking, and human papillomaviruses. However, epidemiologic studies of invasive carcinoma of the vulva have produced conflicting evidence for these associations, in part because of a strong association with vulvar inflammatory disease (dystrophies) in older women. We analyzed a series of 42 vulvar invasive carcinomas for papillomavirus nucleic acids by deoxyribonucleic acid-deoxyribonucleic acid in situ hybridization and correlated their presence with age, smoking history, and morphologic type. The carcinomas were divided into well-differentiated, moderately and poorly differentiated, and intraepithelial-like growth patterns, the latter composed of nests of invasive neoplastic epithelium with preserved cell polarity, similar to intraepithelial disease. Of the lesions studied, 28% were human papillomavirus deoxyribonucleic acid-positive. Intraepithelial-like neoplasms segregated in women with a younger mean age (64 versus 73 years) than that of women with conventional squamous cell carcinoma and they more frequently had a history of cigarette smoking (88% versus 28%). Moreover, intraepithelial-like lesions contained human papillomavirus nucleic acids more frequently (67% versus 13%) when analyzed by in situ hybridization. These observations confirm the diverse nature of vulvar squamous cell carcinoma and may explain in part why conflicting results are obtained from studies investigating the role of sexual and viral factors in the genesis of vulvar cancer. They suggest that many invasive vulvar cancers may not be linked to papillomaviruses.

Adult↗
PubMed1991

Pathobiology of papillomavirus-related cervical diseases: prospects for immunodiagnosis.

In recent years, the relationship between human papillomaviruses (HPV) and genital neoplasia has been explored intensively, and a molecular basis for the role of HPV in the genesis of these diseases has been convincingly demonstrated. These findings have provided justification for efforts to apply this molecular information to the early detection and possible prevention of HPV-related neoplasia. The technology of detecting viral nucleic acids in genital fluids brought with it initial hopes that it would serve to identify women at risk for having or developing precancers or cancers of the cervix. Subsequent studies, however, have demonstrated limitations of the technology for predicting future disease. Recently, molecular immunology has complemented these prior efforts, with the intent to identify serological indices of exposure to HPV and perhaps delineate individuals at risk. The molecular basis for this approach, its limitations, and future prospects for immunodiagnosis are the subject of this review.

Condylomata Acuminata↗
PubMed1991

Biologic properties and nucleotide sequence analysis of human papillomavirus type 51.

Human papillomaviruses (HPVs) may be grouped according to the site from which they are isolated and the disease with which they are associated. We recently identified and cloned HPV type 51 (HPV-51) from a low-grade precancerous lesion (G. Nuovo, E. DeVilliers, R. Levine, S. Silverstein, and C. Crum. J. Virol. 62:1452-1455, 1988). Molecular epidemiologic analysis of cervical lesions, including condylomata and low- and high-grade precancers, revealed that HPV-51 was present in about 5% of the samples we examined. We have now determined the complete nucleotide sequence of this virus and compared it with other sequenced HPVs. Our analysis reveals that the 7,808-bp genome is composed of eight open reading frames which are encoded on the same strand and that this virus is most closely related to HPV-31. Sequence comparisons place this virus in the group of high-risk viruses (those with an increased risk of progressing to malignancy) along with HPV-16, -18, -31, and -33. Morphologic transformation experiments demonstrated that HPV-51 had transformation potential and that transformed cells contained RNAs homologous to E6 and E7.

Amino Acid Sequence↗
PubMed1990

Coexpression of the human papillomavirus type 16 E4 and L1 open reading frames in early cervical neoplasia.

Although the E4 open reading frame (ORF) of human papillomaviruses (HPV) encodes an abundant protein in cutaneous warts, the location and extent of HPV E4 expression in genital precancers, specifically those associated with HPV-16, has not been described. Expression plasmids (pATH) containing segments of the HPV-16 E4 (3401-3620) and L1 (6151-6792) open reading frames (ORFs) were induced and expressed in bacteria and the resulting fusion proteins were used to elicit antisera in rabbits. Antisera reacting to the E4 and L1 components of the fusion proteins were used to screen biopsies from 150 cervical precancers (cervical intraepithelial neoplasia) and condylomata. Six biopsies exhibiting specific immunostaining with the anti-E4 sera. Staining was cytoplasmic, and occurred virtually always in foci containing immunostaining for L1 proteins. Moreover, analysis of these 6 cases and 22 others for HPV-16 RNA by RNA-RNA in situ hybridization demonstrated a similar correlation between E4 immunostaining and the presence of abundant transcripts specific to HPV-16. These data are consistent with the hypothesis that expression of the HPV-16 E4 ORF is dependent upon viral replication and epithelial differentiation, similar to L1 expression, and that the E4 epitopes identified by the rabbit antisera may be unique to HPV-16 relative to other common cervical papillomaviruses.

Condylomata Acuminata↗
PubMed1990

Clinical and molecular evaluation of acetowhite genital lesions in men.

A total of 108 male partners of women with cervical condyloma and/or dysplasia underwent evaluation for gross and subclinical condyloma via acetic acid screening with a magnified examination. Biopsies of acetowhite genital skin were obtained for histological and deoxyribonucleic acid hybridization analysis. Of the men 52 (49%) had acetowhite lesions and underwent biopsies, 44 of which were evaluable by histological and deoxyribonucleic acid analyses. Of the lesions 12 had features of condyloma or penile intra-epithelial neoplasia, among which 7 (58%) contained human papillomavirus deoxyribonucleic acid. The remaining 32 lesions revealed minimal histological changes sometimes suggesting condyloma. However, only 5 of the 32 biopsies (16%) contained human papillomavirus deoxyribonucleic acid. A tendency to overdiagnose condyloma based on histological findings is suggested. Criteria by which to identify best human papillomavirus-related morphology are presented. Acetowhite genital epithelia with minor (nonspecific) histological changes correlate poorly with human papillomavirus nucleic acids and in most cases do not represent disease involving common viral types. The application of appropriate histological criteria appears to be particularly relevant to management strategies that avoid overtreatment of minor epithelial abnormalities. It remains unclear whether acetowhite genital epithelia positive for human papillomavirus require treatment given the high tendency for recurrence and lack of demonstrated effect on the natural history of cervical carcinoma.

Acetates↗
PubMed1990

Cytologic correlates of cervical papillomavirus infection.

A fundamental question in Papanicolaou smear screening is the specificity of cytologic criteria for the recognition of genital human papillomavirus (HPV) infection. To address this problem, we conducted a two-phase study of routinely screened women to determine the efficiency with which cytologic findings identified the presence of HPV DNA, focusing on the criteria for identifying smears as "atypical." In phase 1, 25 of 290 (8.6%) smears were designated atypical, but only 3 (12%) of the samples contained HPV nucleic acids. Four of five (80%) smears designated as diagnostic of HPV/cervical HPV infection were associated with HPV nucleic acids. By applying more stringent criteria for the diagnosis of atypical in phase 2, only 3 of 166 (1.8%) were identified as atypical. Of these, two (67%) contained HPV nucleic acids. The criteria that most efficiently correlated with HPV nucleic acids included prominent nuclear enlargement with either multiple nuclei or nuclear hyperchromatism. On review of the 19 HPV-positive and 20 control HPV-negative smears originally diagnosed as cytologically negative, the above criteria identified an additional 3 cytologically atypical/positive smears versus none (0 of 20) in the control group. This study supports the concept that cytologic abnormalities suggesting "subtle" HPV infection may be extremely difficult to distinguish from non-HPV-related changes, and that criteria used to imply "suggestive but not diagnostic for HPV infection" should be continually reevaluated. The potential role of HPV DNA analysis in Papanicolaou smear interpretation is discussed.

Adult↗
PubMed1990

Molecular pathology of the lower female genital tract. The papillomavirus model.

Papillomavirus-related genital neoplasms are one area where molecular biology has had an impact at many levels. Studies of cell transformation, gene expression, and genome organization have linked papillomaviruses to neoplasia; they have also provided data suggesting potential pathways by which the papillomaviral genome exerts its effect on cells. Molecular epidemiological studies using clinical material have identified specific HPV types with neoplasia, profiled the populations at risk for these infections, and supported the emerging concept of latent infection. Studies using in situ hybridization have confirmed the close relationship of neoplastic change with certain infections (such as HPV-16), and have detailed the transcription patterns of the papillomavirus genome in warts, precancers, and carcinomas. The technology of in situ hybridization has facilitated the evaluation of archive material; using this material, the close relationship between HPV type 18 and adenocarcinomas and small-cell carcinomas has been described. Methods for expressing HPV proteins in bacteria have produced a spectrum of antisera to specific gene products, which in turn will facilitate mapping their distribution in tissues, determining their biological significance, and clarifying the host immune response to genital papillomavirus infections. Although these multidisciplinary approaches help to promote an understanding of genital HPV infections and their related neoplasms as well as clarifying the role of HPV in the evolution of genital neoplasia, the clinical utility of this information has not yet been established.

DNA, Viral↗
PubMed1990

Papillomavirus-related genital neoplasia: present and future prevention.

As our understanding of genital precancers has evolved, it has become clear that human papillomaviruses (HPV) are intimately related to the spectrum of precancerous change. Traditional approaches to removing these lesions have centered on destruction of the neoplastic epithelium and careful cytological follow up. This approach has met with success in preventing cancer, but has not addressed patients who present with invasive cancer whose precancer went undiscovered. With the realization that HPV is closely associated with precancers and invasive cancers of the female genital tract, efforts have centered on developing methodologies which would identify specific HPV types in high risk women or in the general population that might reduce the number of missed carcinomas. This approach, although attractive, has met with problems due to the high prevalence rate of HPV infections in general in the population and the knowledge that certain cofactors, either environmental or host related, play a part in selecting a subset of women who will eventually develop cancer. The impact of HPV screening on detecting and preventing the rarer forms of aggressive cancer, such as adenosquamous carcinoma and small cell carcinomas, is as yet unclear. The possibility that genital cancer may be prevented by a vaccine to HPV is supported by the identification of a host response to specific HPV products. Efforts are in progress to characterize the early and late gene products associated with HPV infection, identify the specific epitopes commonly recognized by the host, and initiate studies to determine the spectrum of the population displaying an immune response to these infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1989

Prediction of 'high-risk' cervical papillomavirus infection by biopsy morphology.

Certain human papillomavirus (HPV) types (such as type 16) have been linked to high-grade precancers and invasive carcinomas of the cervix. However, the accuracy with which morphologic characteristics will predict the presence and type of HPV infection is controversial. Three pathologists independently classified 102 consecutive cervical biopsies with the use of specific criteria and correlated their findings with the presence of HPV 11, 16, and 18 RNA sequences by in situ hybridization. Based on the presence and distribution of nuclear atypia, abnormal mitotic figures, and koilocytosis, biopsies were classified into borderline condyloma, condyloma, borderline cervical intraepithelial neoplasia (CIN) with koilocytotic atypia (CINK), and CIN. Two or more observers agreed on the diagnosis in 96% of cases. HPV 16-related sequences alone were detected in 0% of borderline condylomata, 17% of flat condylomata, 43% of borderline CINK, 67% of CINK, and 77% of CIN lesions. Other HPVs, including those producing signals with more than one probe, were present in 0, 50, 14, 9, and 0% of these lesions, respectively. The authors data suggest that consistent identification of HPV-related cervical disease requires the presence of specific cytologic changes. In the authors' series, when HPV-related disease is present, CIN is the most common lesion and most (71%) contain HPV 16-related nucleic acids. Thus, a high proportion (88%) of histologic abnormalities associated with HPV-16 could be distinguished as CIN by morphologic characteristics alone, and this distinction could be made by most observers.

Biopsy↗
PubMed1989

Topography of early HPV 16 transcription in high-grade genital precancers.

The extent to which human papillomavirus (HPV) type 16 is transcribed and the nature of the transcripts produced in genital precancers has not been clearly defined. The authors analyzed 28 cases of cervical (CIN) or vulvar (VIN) intraepithelial neoplasia by RNA-RNA in situ hybridization, using probes generated from HPV 16 open reading frames (ORFs) either upstream (E6-E7) or downstream (E2-E5-L2) to the E1 ORF, where HPV 16 genomic integration most commonly occurs. Hybridization signals corresponding to one or both probes were detected in a high proportion of cells throughout the lesional epithelium of low- and high-grade CIN, including basal layers. In serial sections analyzed with the two probes, hybridization signals were obtained from both, and in similar proportion, irrespective of CIN grade. The distribution and character of hybridization signals suggests that the morphologic progression of precancers is not associated with either cessation of HPV 16 early transcription or a change in the general character of the transcripts produced.

DNA, Neoplasm↗