[Show abstract][Hide abstract] ABSTRACT: We found a large number of false-positive readings by visual inspection with acetic acid (VIA) in a study of cervical cancer
screening strategies (VIA, human papillomavirus HPV DNA testing, and Pap cytology) in a periurban community in Andhra Pradesh,
India. We evaluated whether these false-positive readings might be occurring as a result of infections with Epstein-Barr virus
(EBV) or cytomegalovirus (CMV), prevalent latent herpesviruses known to be shed from the female genital tract. While we found
that there was no association between VIA results and the presence of EBV or CMV in the cervix, we did find a high prevalence
of both viruses: 20% for EBV and 26% for CMV. In multivariate analyses, CMV prevalence was associated with younger age, lack
of running water in the home, and visually apparent cervical inflammation. EBV prevalence was associated with older age and
a diagnosis of cervical intraepithelial neoplasia grade 1 or greater. The biological and clinical implications of these viruses
at the cervix remain to be determined. The strong association between the presence of EBV and cervical disease warrants future
exploration to determine whether EBV plays a causal role in disease development or if it is merely a bystander in the process.
[Show abstract][Hide abstract] ABSTRACT: Studies conducted in the USA have demonstrated that micronutrients such as folate and vitamin B12 play a significant role in modifying the natural history of high-risk human papillomaviruses (HR-HPVs), the causative agent for developing invasive cervical cancer (CC) and its precursor lesions.
The purpose of the current study was to investigate whether these micronutrients have similar effects on HR-HPV infections in Indian women.
The associations between serum concentrations of folate and vitamin B12 and HR-HPV infections were evaluated in 724 women who participated in a CC screening study in the southern state of Andhra Pradesh, India. Serum folate and vitamin B12 concentrations were measured by using a competitive radio-binding assay. Digene hybrid capture 2 (HC2) assay results were used to categorize women into two groups, positive or negative for HR-HPVs. Unconditional logistic regression models specified a binary indicator of HC2 (positive/negative) as the dependent variable and serum folate concentrations combined with serum vitamin B12 concentrations as the independent predictor of primary interest. Models were fitted, adjusting for age, education, marital status, parity, type of fuel used for cooking and smoking status.
Women with higher concentrations of serum folate (>6 ng/mL) and vitamin B12 (>356 pg/mL) were at lower risk of being positive for HR-HPVs compared to those with serum folate ≤6 ng/mL and serum vitamin B12 ≤ 356 pg/mL (odds ratio = 0.26; 95% confidence interval: 0.08-0.89; P = 0.03).
These results demonstrated that improving folate and vitamin B12 status in Indian women may have a beneficial impact on the prevention of CC. Micronutrient based interventions for control of HR-HPV infections may represent feasible alternatives to vaccine based approaches to HPV disease prevention, which are currently unaffordable for use in resource limited areas in rural India.
Full-text · Article · Aug 2010 · International Journal of Women's Health
[Show abstract][Hide abstract] ABSTRACT: Visual inspection of the cervix after acetic acid application (VIA) is widely recommended as the method of choice in cervical cancer screening programs in resource-limited settings because of its simplicity and ability to link with immediate treatment. In testing the effectiveness of VIA, human papillomavirus DNA testing, and Pap cytology in a population-based study in a peri-urban area in Andhra Pradesh, India, we found the sensitivity of VIA for detection of cervical intraepithelial neoplasia grade 2 and worse (CIN2+) to be 26.3%, much lower than the 60% to 90% reported in the literature. We therefore investigated the determinants of VIA positivity in our study population.
We evaluated VIA positivity by demographics and reproductive history, results of clinical examination, and results from the other screening methods.
Of the 19 women diagnosed with CIN2+, only 5 were positive by VIA (positive predictive value, 3.1%). In multivariate analysis, VIA positivity (12.74%) was associated with older age, positive Pap smear, visually apparent cervical inflammation, and interobserver variation. Cervical inflammation of unknown cause was present in 21.62% of women. In disease-negative women, cervical inflammation was associated with an increase in VIA positivity from 6.1% to 15.5% (P<0.001). Among the six gynecologists who performed VIA, the positivity rate varied from 4% to 31%.
The interpretation of VIA is subjective and its performance cannot be readily evaluated against objective standards.
VIA is not a robust screening test and we caution against its use as the primary screening test in resource-limited regions.
Full-text · Article · May 2010 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: The vast majority of invasive cervical carcinomas harbor additional copies of the chromosome arm 3q, resulting in genomic amplification of the human telomerase gene TERC. Here, we evaluated TERC amplification in routinely collected liquid based cytology (LBC) samples with histologically confirmed diagnoses. A set of 78 LBC samples from a Swedish patient cohort were analyzed with a four-color fluorescence in situ hybridization probe panel that included TERC. Clinical follow-up included additional histological evaluation and Pap smears. Human papillomavirus status was available for all cases. The correlation of cytology, TERC amplification, human papillomavirus typing, and histological diagnosis showed that infection with high-risk human papillomavirus was detected in 64% of the LBC samples with normal histopathology, in 65% of the cervical intraepithelial neoplasia (CIN)1, 95% of the CIN2, 96% of the CIN3 lesions, and all carcinomas. Seven percent of the lesions with normal histopathology were positive for TERC amplification, 24% of the CIN1, 64% of the CIN2, 91% of the CIN3 lesions, and 100% of invasive carcinomas. This demonstrates that detection of genomic amplification of TERC in LBC samples can identify patients with histopathologically confirmed CIN3 or cancer. Indeed, the proportion of TERC-positive cases increases with the severity of dysplasia. Among the markers tested, detection of TERC amplification in cytological samples has the highest combined sensitivity and specificity for discernment of low-grade from high-grade dysplasia and cancer.
Full-text · Article · Nov 2009 · American Journal Of Pathology
[Show abstract][Hide abstract] ABSTRACT: Worldwide esophageal cancer ranks among the ten most common cancers. Although, there is a rising entity of adenocarcinoma, the majority of carcinoma of the esophagus are squamous-cell carcinoma. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir valley, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study polymorphisms in oncogenes viz., KRAS, NRAS, BRAF and beta-catenin in 47 ESCC patients from Kashmir valley. The hot spot mutation regions of KRAS, NRAS, BRAF and beta-catenin were analyzed in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. None of the tumors showed the presence of commonly reported mutations in either BRAF or beta-catenin but our analysis indicated the presence of mutations in RAS (NRAS- exon 2; 4/47 and KRAS- exon 1; 1/47). In view of the fact that HPV has been linked to pathogenesis of esophageal cancer, we screened for presence of HPV in all the tumors. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for HPV. Interestingly we did not detect HPV in any of the specimens. In conclusion our results suggest that squamous cell carcinoma of esophagus in Kashmir may arise independent of oncogenic BRAF and beta-catenin mutations but RAS mutations most likely play a role in the pathogenesis of ESCC. Moreover, in our present study HPV is unlikely to be an etiologic factor for ESCC in this region.