IntroductionHuman papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC.Methods and analysisWomen aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre.Ethics and disseminationThe study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT01881659
HPV testing is a better alternative for cervical cancer screening, but additional procedures are required for triage of HPV positive women. HPV encoded oncoproteins E6 and E7, as the main effectors of HPV carcinogenicity represent promising triage alternatives. To evaluate performance of the test, we included 155 women from a screening study and 59 from the same referral population attending colposcopy and with precancerous lesions. All were HPV‐tested with HC2 and genotyped with LiPA, and cervical swabs were tested for HPV16/18 E6 oncoproteins. Histologic specimens were reviewed and adjudicated using p16 immunohistochemistry and 55 women had confirmed histologic HSIL, 31 (56.3%) associated with HPV 16/18, 23 with other HPV types and one HPV negative. Sensitivity and specificity were estimated with histologic HSIL/cancer as gold standard. E6 oncoprotein was detectable in all but one HSIL and in all cancers where HPV16/18 DNA was detected, but in none of the cases associated with other HPV types or HPV negatives. Among the few HPV16/18 DNA positive subjects initially without HSIL (n = 4) who were E6 oncoprotein positive, precancer was detected during follow‐up in 2 out of 3 with available information. Estimated sensitivity for HPV16/18‐related HSIL+ was 96.8% (95%CI = 83.8–99.8) and for all HSIL+ regardless of HPV type it was 56.4% (95%CI = 43.3–68.6). Specificity was 97.5% (95%CI = 93.7–99.0). E6 oncoprotein proved as a highly sensitive and specific marker for detection of HPV16/18‐related HSIL lesions in this Honduran population with limited previous screening and may be useful as a triage method in screening programs, particularly in low income countries.
BackgroundReplacement of cytology screening with HPV testing is recommended and essential for cervical cancer elimination. HPV testing for primary screening was implemented in 12 laboratories within 9 Latin American countries, as part of the ESTAMPA cervical cancer screening study. Our observations provide information on critical operational aspects for HPV testing implementation in diverse resource settings.MethodsWe describe the implementation process of HPV testing in ESTAMPA, focusing on laboratory aspects. We assess the readiness of 12 laboratories to start HPV testing and their continuity capacity to maintain good quality HPV testing until end of recruitment or up to December 2021. Readiness was based on a checklist. Information from the study database; regular meetings and monitoring visits; and a questionnaire on laboratory operational aspects sent in May 2020 were used to assess continuity capacity. Compliance with seven basic requirements (readiness) and eight continuity requirements (continuity capacity) was scored (1 = compliant, 0 = not compliant) and totaled to classify readiness and continuity capacity as very limited, limited, moderate or high. Experiences, challenges, and enablers of the implementation process are also described.ResultsSeven of 12 laboratories had high readiness, three moderate readiness, and of two laboratories new to HPV testing, one had limited readiness and the other very limited readiness. Two of seven laboratories with high readiness also showed high continuity capacity, one moderate continuity capacity, and the other four showed limited continuity capacity since they could not maintain good quality HPV testing over time. Among three laboratories with moderate readiness, one kept moderate continuity capacity and two reached high continuity capacity. The two laboratories new to HPV testing achieved high continuity capacity. Based on gained expertise, five laboratories have become part of national screening programs.ConclusionHigh readiness of laboratories is an essential part of effective implementation of HPV testing. However, high readiness is insufficient to guarantee HPV testing high continuity capacity, for which a “culture of quality” should be established with regular training, robust monitoring and quality assurance systems tailored to local context. All efforts to strengthen HPV laboratories are valuable and crucial to guarantee effective implementation of HPV-based cervical screening.
Cervical cancer is one of the most common cancers in women. Despite progress in prevention through Human Papilloma Virus (HPV) vaccination and success in early detection of cervical cancer through cytologic screening and HPV detection, there remains an unequal cervical cancer burden in low-resource settings, both in developed and developing countries. We have previously shown that the CervicalMethDx test can provide a Cervical Intraepithelial Neoplasia (CIN) grade 2-3 risk score, by assessing DNA methylation in a panel of three human genes (ZNF516, FKBP6 and INTS1) in samples from the United States (US), Puerto Rico, and Chile. We now tested the performance of the CervicalMethDx test on HPV-positive CIN2 and CIN3 cases (n=113) from Honduras collected from participants in the ESTAMPA clinical trial (NCT01881659). ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) is a multicentric study of cervical cancer screening with HPV testing and assessment of triage methods in Latin America, which has accrued close to 50,000 participants from twelve recruitment centers in nine Latin American countries since 2013. We hypothesized that the CervicalMethDx test can identify HPV positive women most likely to be diagnosed with CIN grades 2 and 3 by anatomic pathologists, before they are referred to colposcopy-driven biopsies. We assessed DNA methylation by quantitative Real Time Methylation Specific PCR (qMSP) analysis of sodium bisulfite-modified genomic DNA. Primers and probes were previously designed to specifically amplify the promoters of the 3 genes of interest and the promoter of a reference gene, β-actin, to assess DNA input. We performed blinded retrospective studies on well-characterized clinical samples in PreservCyt sample transport media (ThinPrep, Hologic), comparing DNA methylation levels in samples from Honduras and 88 HPV-positive previously tested US samples with No Intraepithelial Lesions or Malignancy (NILM), as controls. Our results showed that the CervicalMethDx test can correctly classify 96% of CIN2 (n=62) samples with 92% Sensitivity, 98% Specificity, and an AUC of 0.96 as well as 97% of CIN3 (n=51) samples with 96% Sensitivity, 98% Specificity, and an AUC of 0.97. Moreover, the assay correctly classified 96% of CIN2-CIN3 samples combined (n=113) with 95% Sensitivity, 98% Specificity, and AUC of 0.97, when compared to samples with NILM (n=88). Our results suggest that the CervicalMethDx test is a new and valuable tool to stratify HPV positive women prior to colposcopy-driven biopsies in developed countries and ablative treatment in developing countries, most of which are unnecessary. These results warrant further evaluation of the CervicalMethDX test in prospective, population-based studies, assessing the use of precision DNA methylation algorithms to triage HPV positive women before referral to colposcopy-driven biopsies or ablative treatments in cervical cancer screening clinics world-wide. Citation Format: Laura Palmieri, Fernando Zamuner, Yessy Cabrera, Jafet Ortiz-Quintero, Dieila Giomo De Lima, Ana Purcell-Wiltz, Amanda García-Negrón, Ashley Ramos-López, Mariana Brait, David Sidransky, Annabelle Ferrera, Rafael E. Guerrero-Preston. A precision DNA methylation test to triage HPV positive women before referral to colposcopy-driven biopsies or ablative treatment in cervical cancer screening clinics worldwide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB107.
Background: Cord blood serum levels of IgM are normally below 200 g/mL (20 mg%) while no IgE is usually present in healthy newborns. Since these immunoglobulins are not transferred from the mother, abnormally high levels at birth may reflect fetal exposition to infectious agents or response to antigens traversing the placenta. A test which allows detection of altered levels of IgM or IgE in filter paper embedded blood (FPEB) could be used to screen congenital infections or allergies. The aim of this study was to correlate the levels of IgM and IgE eluted from FPEB in Guthrie cards to their corresponding serum concentration. Methods: Forty eight cord blood samples were obtained at the General Hospital "Manuel Gea González" of Mexico City. Guthrie cards and serum samples were prepared by standard procedures. Both samples were tested using antigen-capture ELISAs to determine IgM and IgE concentrations. Those cases with abnormal values were localized and clinically attended to diagnose specific congenital infections, as well as maternal history of allergy, vaccination or clinical problems. Results: Mean IgM concentration in cord blood serum was 104.5 ± 19.6 g/mL; four out of the 48 cases (8.3%) presented abnormally high levels. The mother of the newborn with the highest IgM level (>400) had prolonged cystitis along pregnancy, and other mothers had been vaccinated agaisnt tetanus. A high correlation (r = 0.89) between serum and FPEB was obtained, with 39% elution efficiency (figure). Correlation between first and second samples (taken 7-10 days later) was r = 0.99, with an increase of around 25% of the original concentration due to aging. Only two (4.2%) serum samples were positive for IgE (above 2 g/mL) but no relation to maternal or newborn clinical or exposition factor was found. FPEB samples gave more erratic IgE results than sera. e198 15th ICID Abstracts / International Journal of Infectious Diseases 16S (2012) e158-e316 sanitation and health education can be expected to have substantial impact on childhood morbidity.
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