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Mark Schiffman

Publications and source records attributed to Mark Schiffman.

At least 55 records · Page 3Linked to original sources
PubMed2005

Towards improved biomarker studies of cervical neoplasia: effects of precolposcopic procedures on gene expression patterns.

Among tumor sites, cervical cancer offers an ideal model for investigating differences in gene expression associated with transitions from normal to precancer and invasion to cancer. To evaluate the validity of assessing gene expression in cervical tissues acquired in a clinical setting, we investigated whether standard procedures, namely the application of acetic acid and/or Lugol's iodine, employed for the visualization of colposcopically directed biopsies, altered patterns in oligonucleotide (oligo) arrays. We compared microarray profiles from six women, each with three adjacent tissue samples removed from benign hysterectomy specimens and treated as follows: immediately frozen, acetic acid application only, acetic acid, and Lugol's iodine. Of the 22,464 original spots on the microarray, 4,850 spots were expressed at detectable levels for further evaluation upon data normalization and filtration. For each spot, the difference between topical applications was computed, and P values were calculated using a bivariate T2 test. Upon adjustment for multiple comparisons using both the Holm's and Hochberg's procedures as well as the False Discovery Rate (Benjamini-Hochberg and Benjamini-Yeuketili [BY]), we failed to identify genes differentially expressed and conclude that standard precolposcopic procedures do not substantially affect the overall gene expression patterns in the normal cervix.

Artifacts↗
PubMed2005

Semiquantitative human papillomavirus type 16 viral load and the prospective risk of cervical precancer and cancer.

We examined whether higher human papillomavirus type 16 (HPV16) viral load predicted risk of cervical intraepithelial neoplasia 3 (CIN3) or cancer (together termed > or =CIN3) within a cohort of 20,810 women followed for 10 years with cytologic screening. Semiquantitative viral load for HPV16 was measured on baseline cervicovaginal specimens using a type-specific hybridization probe test with signal amplification. An increased risk of > or =CIN3 associated with higher HPV16 viral load was found only among cytologically negative women in early follow-up, suggesting that these cases were related to the detection of prevalent lesions missed at baseline. Women with higher HPV16 viral load were more likely to undergo ablative treatment during follow-up than those with lower viral load (P(trend) = 0.008), possibly diminishing any additional risk for > or =CIN3 attributable to higher HPV16 viral loads.

Adolescent↗
PubMed2005

Smoking is a risk factor for cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology.

BACKGROUND: Smoking is a potential risk factor for cervical cancer and its immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3), but few studies have adequately taken into account the possible confounding effect of oncogenic human papillomavirus (HPV) infection. METHODS: Women (n = 5,060) with minimally abnormal Papanicolaou smears were enrolled in the ASCUS and LSIL Triage Study, a clinical trial to evaluate management strategies, and were seen every 6 months for the 2-year duration of the study. Cervical specimens were tested for HPV DNA using both Hybrid Capture 2 and PGMY09/11 L1 consensus primer PCR with reverse line blot hybridization for genotyping. Multivariate logistics regression models were used to assess associations [odds ratio (OR) with 95% confidence intervals (95% CI)] between smoking behaviors and rigorously reviewed cases of cervical intraepithelial neoplasia grade 3 or cancer (> or =CIN3) identified throughout the study (n = 506) in women with oncogenic HPV (n = 3,133). RESULTS: Current smoking was only weakly associated with increased HPV infection. Among infected women, current smokers (OR, 1.7; 95% CI, 1.4-2.1) and past smokers (OR, 1.7; 95% CI, 1.2-2.4) were more likely to be diagnosed with > or =CIN3 than nonsmokers. Greater smoking intensity (P(Trend) < 0.0005) and duration (P(Trend) < 0.0005) increased the strength of the association, with smoking > or =2 packs/d (OR, 3.3; 95% CI, 1.5-7.5) and smoking for > or =11 years (OR, 2.1; 95% CI, 1.5-2.9) most strongly associated with > or =CIN3 as compared to non-smokers. The effects of intensity and duration seemed additive. CONCLUSIONS: Women with oncogenic HPV and minimally abnormal Papanicolaou smears who smoke were up to three times more likely to be diagnosed with > or =CIN3 than nonsmokers. Smoking cessation trials targeting this population might be warranted.

Adolescent↗
PubMed2005

Evaluating the risk of cervical precancer with a combination of cytologic, virologic, and visual methods.

Several test modalities (cytologic, molecular, and visual) may be used for cervical cancer screening, triage, and follow-up. Although no currently available single test for cervical neoplasia can detect disease with both high sensitivity and specificity, combinations of available tests allow for improved risk prediction. We therefore evaluated the combination of liquid-based cytology (LBC), human papillomavirus (HPV) DNA testing, and visual inspection (cervicography), taken at a single point in time, to predict risk of subsequent cervical intraepithelial neoplasia 3 (CIN3) or cancer developing within 2 years in a triage population of 5,060 women referred for equivocal or mildly abnormal cytology. The concurrent administration of all three test modalities showed that combinations of these test modalities permitted clear and distinct risk stratification. Among HPV-positive women with high-grade LBC and high-grade cervicography results, 79.1 % [95% confidence interval (95% CI), 64.0- 90.0] were diagnosed with histologic CIN3 or cancer within 2 years, supporting a "see-and-treat" clinical application. Conversely, only 1.4% (95% CI, 0.7-2.5) of women with a negative HPV, normal cervigram, and second normal cytology result developed CIN3 or cancer. Because this low absolute risk was largely attributable to the negative HPV test, our results suggest a lack of benefit for a secondary or tertiary test result given an HPV-negative test result. Within HPV-positive women, however, we observed a steadily increasing absolute risk for cervical precancer/cancer with increasing numbers and severity of abnormal test results. We conclude that the clear discrimination of cervical cancer risk provided by multiple test modalities is consistent with our understanding of cervical etiology related to HPV natural history.

Adult↗
PubMed2005

A comparison of a prototype PCR assay and hybrid capture 2 for detection of carcinogenic human papillomavirus DNA in women with equivocal or mildly abnormal papanicolaou smears.

We evaluated Hybrid Capture 2 (HC2) and polymerase chain reaction (PCR) results for paired specimens collected at 19,187 visits from 5,026 of 5,060 women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). We examined the test agreement between HC2 and PCR detection for any of 13 carcinogenic human papillomavirus types targeted by HC2 and compared clinical performance of the 2 tests for detecting concurrent and follow-up cervical intraepithelial neoplasia (CIN) 3 or cancer. The k value for the 2 assays was 0.65 (95% confidence interval, 0.64-0.66), with 82.7% crude agreement. HC2 was more sensitive (93.6% vs 89.3%; P < .0005) but less specific (41.2% vs 48.5%; P < .0005) than PCR for detecting 2-year cumulative CIN 3 or cancer (n = 503). The presence of multiple types as detected by PCR and/or cytologic abnormality increased the likelihood of an HC2+ result. Increased sensitivity of HC2 compared with PCR was surprising, given the theoretical advantages of PCR-based methods for analytic sensitivity. Smaller amounts of material used in PCR could have limited its sensitivity, but our results demonstrate the importance of optimization and standardization of PCR-based assays for clinical applications.

Adolescent↗
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

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

Hybrid capture 2 viral load and the 2-year cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer.

OBJECTIVE: The purpose of this study was to determine the clinical value of a semiquantitative measure of human papillomavirus viral load by the hybrid capture 2 assay for stratification of the risk of histologic cervical intraepithelial neoplasia grade 3 or carcinoma. STUDY DESIGN: The Atypical Cells of Unknown Significance and Low-Grade Squamous Intraepithelial Lesions Triage Study was a randomized clinical trial of 5060 women with 2 years of follow-up to evaluate treatment strategies for women with equivocal or mildly abnormal cervical cytologic condition. The usefulness of the continuous hybrid capture 2 output relative light units/positive controls that were above the positive threshold (1.0 relative light units/positive controls), which was a surrogate for human papillomavirus viral load, for distinguishing between hybrid capture 2 positive women who were diagnosed with cervical intraepithelial neoplasia grade 3 or carcinoma during the study from those who were not diagnosed with cervical intraepithelial neoplasia grade 3 or carcinoma was examined with the use of receiver-operator characteristic analyses. RESULTS: Relative light units/positive controls values did not further discriminate between hybrid capture 2 positive women with cervical intraepithelial neoplasia grade 3 or carcinoma from those with less than cervical intraepithelial neoplasia grade 3 or carcinoma. The use of a cervical intraepithelial neoplasia grade 2 or more severe or carcinoma case definition did not alter our findings. CONCLUSION: Among women with atypical cells of unknown significance or low-grade squamous intraepithelial lesion cervical cytologic findings, the hybrid capture 2 viral load measurement did not improve the detection of 2-year cumulative cases of cervical intraepithelial neoplasia grade 3 or carcinoma significantly.

DNA, Viral↗
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

Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening.

Human papillomavirus (HPV) DNA testing was recently approved by the Food and Drug Administration for use as an adjunct to cytology for cervical cancer screening. To help provide guidance to clinicians and patients when using HPV DNA testing as an adjunct to cervical cytology for screening, a workshop was cosponsored by the National Institutes of Health-National Cancer Institute, American Society of Colposcopy and Cervical Pathology (ASCCP), and American Cancer Society. Consensus was reached based on a literature review, expert opinion, and unpublished results from large ongoing screening studies. The conclusions of the workshop were that HPV DNA testing may be added to cervical cytology for screening in women aged 30 years or more. Women whose results are negative by both HPV DNA testing and cytology should not be rescreened before 3 years. Women whose results are negative by cytology, but are high-risk HPV DNA positive, are at a relatively low risk of having high-grade cervical neoplasia, and colposcopy should not be performed routinely in this setting. Instead, HPV DNA testing along with cervical cytology should be repeated in these women at 6 to 12 months. If test results of either are abnormal, colposcopy should then be performed. This guidance should assist clinicians in utilizing HPV DNA testing in an effective manner, while minimizing unnecessary evaluations and treatments.

Adult↗
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

Interlaboratory reliability of Hybrid Capture 2.

We evaluated the interlaboratory reproducibility of the Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD), a test for oncogenic human papillomavirus (HPV) DNA, using data from 4 clinical center (CC) laboratories and the quality control (QC) laboratory participating in the ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesion) Triage Study (ALTS). Residual liquid cytology specimens were tested routinely throughout the duration of ALTS at CC laboratories, and a stratified (by time in the study) random sample of specimens was retested by the HPV QC laboratory using equivalent protocols. Of the specimens selected (N = 1,175, 5.50% of all specimens obtained), 1,072 (91.23%) had sufficient specimen volume for retesting. The kappa value between all CC laboratories and the HPV QC laboratory was 0.84 (95% confidence interval, 0.78-0.89), with kappa values for individual CCs and the HPV QC laboratory ranging from 0.79 to 0.89. Agreement between test results was lowest among results for women with negative cytologic findings (0.73); among those with equivocal or abnormal cytologic findings, kappa values were 0.80 or more. These data show that HC2 is a reliable test for detecting clinically relevant oncogenic HPV DNA.

Cytodiagnosis↗
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↗
PubMed2004

Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica.

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.

Adolescent↗