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Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

ABSTRACT: Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer.

SUBMITTER: Strasak AM

PROVIDER: S-EPMC5911687 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

Strasak Alexander M AM Goebel Georg G Concin Hans H Pfeiffer Ruth M RM Brant Larry J LJ Nagel Gabriele G Oberaigner Willi W Concin Nicole N Diem Günter G Ruttmann Elfriede E Gruber-Moesenbacher Ulrike U Offner Felix F Pompella Alfonso A Pfeiffer Karl P KP Ulmer Hanno H

Cancer research 20100413 9

Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood ...[more]

PMID: 20388786

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Project description:BackgroundTreatments for cervical intraepithelial neoplasia remove precancerous cells from the cervix by excising or ablating the transformation zone. Most studies show no association between cervical intraepithelial neoplasia treatments and fertility outcomes. However, only 2 studies have examined time to pregnancy, both using retrospective study designs, with 1 study showing no association and the other showing a 2-fold increased risk of infertility (time to pregnancy >12 months) following excisional or ablative treatment.ObjectiveWe examined the association between cervical intraepithelial neoplasia treatments and fecundability.Materials and methodsWe analyzed data from Pregnancy Study Online (PRESTO), a prospective cohort study of North American pregnancy planners enrolled during 2013-2019. At baseline, women reported whether they ever had an abnormal Papanicolaou test result, the number of abnormal Papanicolaou test results, and their age at first abnormal Papanicolaou test result. They also reported whether they underwent diagnostic (colposcopy) or treatment (excisional or ablative) procedures, and their age at each procedure. We restricted analyses to 8017 women with 6 or fewer cycles of attempt time at enrollment who reported receiving a Papanicolaou test in the previous 3 years. We estimated fecundability ratios and 95% confidence intervals using proportional probabilities models adjusted for sociodemographics, healthcare use, smoking, number of sexual partners, history of sexually transmitted infections, and human papillomavirus vaccination.ResultsA history of abnormal Papanicolaou test results showed little association with fecundability (fecundability ratio, 1.00; 95% confidence interval, 0.95-1.06). Likewise, receipt of colposcopy or treatment procedures, and time since treatment were not materially associated with fecundability. Results were similar when stratified by age and smoking status.ConclusionWe observed no appreciable association of self-reported history of abnormal Papanicolaou test results, colposcopy, treatments for cervical intraepithelial neoplasia, or recency of treatment with fecundability. These results agree with the majority of previous studies in indicating little effect of cervical intraepithelial neoplasia treatments on future fertility.

Project description:SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III.HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 microg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of >50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR.Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p=0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0.95-6.19, p=0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p=0.04 using Wilcoxon rank sum test).HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.

Project description:ObjectiveBacterial vaginosis (BV), the most common vaginal disorder among women of reproductive age, has been suggested as co-factor in the development of cervical cancer. Previous studies examining the relationship between BV and cervical intra-epithelial neoplasia (CIN) provided inconsistent and conflicting results. The aim of this study is to clarify the association between these two conditions.MethodsA systematic review and meta-analysis were conducted to summarize published literature on the association between BV and cervical pre-cancerous lesions. An extensive search of electronic databases Medline (Pubmed) and Web of Science was performed. The key words 'bacterial vaginosis' and 'bacterial infections and vaginitis' were used in combination with 'cervical intraepithelial neoplasia', 'squamous intraepithelial lesions', 'cervical lesions', 'cervical dysplasia', and 'cervical screening'. Eligible studies required a clear description of diagnostic methods used for detecting both BV and cervical pre-cancerous lesions. Publications were included if they either reported odds ratios (OR) and corresponding 95% confidence intervals (CI) representing the magnitude of association between these two conditions, or presented data that allowed calculation of the OR.ResultsOut of 329 articles, 17 cross-sectional and 2 incidence studies were selected. In addition, two studies conducted in The Netherlands, using the national KOPAC system, were retained. After testing for heterogeneity and publication bias, meta-analysis and meta-regression were performed, using a random effects model. Although heterogeneity among studies was high (χ(2) = 164.7, p<0.01, I(2) = 88.5), a positive association between BV and cervical pre-cancerous lesions was found, with an overall estimated odds ratio of 1.51 (95% CI, 1.24-1.83). Meta-regression analysis could not detect a significant difference between studies based on BV diagnosis, CIN diagnosis or study population.ConclusionsAlthough most studies were cross-sectional and heterogeneity was high, this meta-analysis confirms a connection between BV and CIN.

Dataset Information

Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

Publications

Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

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