Risk Of High-grade Cervical Lesions Research Articles

Human Papillomavirus Genotype Richness and the Biodiversity of Squamous and Glandular Cervical Dysplasias: A Cross-Sectional Study.

The impact of multiple infections on the risk of cervical lesions is a subject of ongoing debate. This study aims to explore whether the richness of HPV genotype infections and the biodiversity of squamous and glandular cervical dysplasias could influence the progression of precancerous lesions. We conducted a cross-sectional analysis involving 469 women who attended the Colposcopy Unit at the European Institute of Oncology in Milan, Italy, from December 2006 to December 2014. HPV type richness was measured as the number of different genotypes per patient. We calculated the associations between richness and age, as well as histologic grade, along with Simpson's biodiversity index for cervical dysplasias. We observed significant inverse relationships between the richness of high-risk (HR) genotypes and both age (p = 0.007) and histologic grade (p < 0.001). Furthermore, as the histologic grade increased, the mean biodiversity index of cervical dysplasias decreased, with exceptions noted in cases of normal histology and adenocarcinoma in situ. Different histologic grades formed five clusters with distinct mean ages and mean biodiversity indices. These findings suggest that HPV genotype richness and the biodiversity of cervical dysplasias may play a crucial role in predicting the risk of high-grade cervical lesions, enabling personalized management of precancers.

Significance of the viral load of high-risk HPV in the diagnosis and prediction of cervical lesions: a retrospective study

BackgroundThe significance of HPV viral load in the detection of cervical lesions is still controversial. This study analyzed the correlation between the high-risk HPV viral load and different cervical lesion degrees.MethodsThis retrospective study included women positive for high-risk HPV DNA and screened for cervical lesions between 01/2015 and 06/2018. The high-risk HPV DNA load was measured by the second-generation Hybrid Capture technology and classified as low, moderate, and high. Colposcopy and biopsy were performed in all patients. The patients were grouped as normal, cervical intraepithelial neoplasia (CIN) grade 1, CIN grade 2, CIN grade 3, and cervical cancer. Multivariable logistic regression was performed to explore the association between high-risk HPV DNA load and cervical lesions. The odds ratios (ORs) represent the odds for increasing from low to high viral load.ResultsFinally, 265 patients were grouped as normal (n = 125), CIN 1 (n = 51), CIN 2 (n = 23), CIN 3 (n = 46), and cervical cancer (n = 20). Among them, 139 (52.5%) had a low viral load, 90 (34.0) had a moderate viral load, and 36 (13.4%) had a high viral load. Taking the normal control group as a reference, a high viral load was an independent factor for CIN 1 (OR = 3.568, 95% CI: 1.164–10.941, P = 0.026), CIN 2 (OR = 6.939, 95% CI: 1.793–26.852, P = 0.005), CIN 3 (OR = 7.052, 95% CI: 2.304–21.586, P = 0.001), and cervical cancer (OR = 8.266, 95% CI: 2.120–32.233, P = 0.002).ConclusionsAmong women who underwent cervical biopsy, higher high-risk HPV viral load in cervical lesions was associated with a higher risk of high-grade cervical lesions.

HPV16 Load Is a Potential Biomarker to Predict Risk of High-Grade Cervical Lesions in High-Risk HPV-Infected Women: A Large Longitudinal French Hospital-Based Cohort Study.

Simple SummaryThis study aimed at assessing HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 885 women positive for hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 135 developed a high-grade lesion during the follow-up. Considering an HPV16 viral load cut-off set at 3.2 log10 GE/103 cells a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97 p ≤ 0.0001) has been identified. Moreover, a composite score based on HPV16 load, cytology and hrHPV detection allowed for CIN2+ risk stratification. To conclude, HPV16 load is a relevant biomarker to identify women at high risk for developing precancerous lesions of the cervix. High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log10GE/103 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log10GE/103 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1–100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions.

The prevalence and distribution of human papillomavirus among 10,867 Chinese Han women

ObjectiveTo assess the prevalence and distribution of HPV genotypes among Chinese Han women, and to explore the risk of high-grade cervical lesions associated with individual hr-HPV genotypes.MethodsGenotyping and histopathology data from the Chinese Multi-Center Screening Trial (CHIMUST) and its pilot screening trial, from 6 regions across mainland China, were re-analyzed. The data from physician- and self-collected samples from 10,867 Chinese Han women (ages 30–69) were used to determine the prevalence and distribution of hr-HPV and to explore the risk association between hr-HPV genotypes and precancerous lesions.Results9.2% of the study population tested hr-HPV positive in physician-collected sample. The prevalence varied regionally from the lowest in Guangdong (6.3%) to the highest in Inner Mongolia (13.0%). The most prevalent genotypes found were HPV-52 (21.7%), HPV-16 (19.2%), HPV-58 (15.0%), HPV-39 (8.9%), and HPV-51 (8.2%). The overall odds ratios for CIN2+ and CIN3+ for the presence of HPV-16 was 58.6 (95% CI 39.2–87.5) and, 91.6 (95%CI 54.3–154.6), respectively and remained the highest odds ratio for CIN3+ in all 6 regions.ConclusionGeographical variation exists in the prevalence and distribution of hr-HPV in mainland China. HPV-16/52/58 were the most prevalent genotypes, and HPV-16 had the highest risk for high-grade cervical lesions.Trial registrationCHIMUST, Registration number: ChiCTR-EOC-16008456. Registered 11 May 2016.

Reply to: Comments on cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta‐analysis

In their letter to the editor, Jayaraj et al have raised several points regarding our recent systematic review and meta-analysis on the risk of progression to precancer for human papillomavirus (HPV) positive but cytology normal women.1 We welcome the opportunity to further address these points, which may have been less clear in our original paper. We start with their most relevant point, and the last in their letter, about our adherence with PRISMA guidelines. Although we did not specifically mention the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in our publication, we assure readers that we did use PRISMA reporting guidelines when drafting the article.2 Readers will find that all PRISMA items are reported in the publication and its appendix.1 Jayaraj et al stated that the categorisation of high-risk (HR) HPV types was not detailed for readers. This reflects the fact that we used each individual study's definition of what it considered to be HR-HPV types, which differed slightly between studies due to differences in the HPV assays used. However, the vast majority of studies in our review considered the same 13 to 14 HPV types as HR (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). These are the types detected by commercial DNA assays approved for cervical cancer screening by the Food and Drug Administration,3 and HPV-DNA tests have generally been found to have comparable sensitivity and specificity in a screening population.4 Therefore, our analysis for grouped HR-HPV types is an accurate reflection of the risk associated with these 14 HPV types at the time the studies were performed. It is likely that much of the heterogeneity in cervical precancer risk between populations is due to differences in HPV-type distribution between populations, rather than differences in types detectable between assays. This is an issue that affects not just our study, but all observational and clinical trials of HPV tests, and screening in general: the underlying predictive value of a positive test result for grouped HPV types will always depend on the underlying distribution of these types in a population. This is why our type-specific HPV results are likely to be very important going forward as HPV-16 and HPV-18 prevalence is declining in many populations due to HPV vaccination.5 We disagree with Jayaraj et al that HPV type-specific progression risks are not useful for informing risk-based cervical cancer screening guidelines, given the numerous studies which found that HPV type is a strong predictor of cervical precancer risk, and which we cited in our review. Recently updated cervical cancer screening guidelines for the United States6 and Australia7 integrate HPV genotyping as a tool to stratify HPV-positive women based on their risk of high-grade cervical lesions. We expect that more countries will follow suit as they adopt HPV testing and revise their approaches to cervical cancer screening. The current perspective espoused by many scientists is that extended HPV genotyping is a promising molecular biomarker for further risk stratification of women with positive HPV test results,8 especially in the context of HPV self-sampling.9 Finally, Jayaraj et al's inappropriate argument that only 5% of all cancers are caused by HPV is not relevant here; we examined risk for women who are HPV positive in the context of cervical cancer screening, where it is established that HPV is a necessary cause of this disease; virtually all cervical cancers worldwide are caused by infection with HPV.10 ELF has served as occasional consultant to Merck and GSK on HPV vaccines, to Roche and to BD on HPV diagnostics. His institution has received unrestricted grants from Merck. ELF holds a patent related to the discovery “DNA methylation markers for early detection of cervical cancer”, registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October, 2018). A provisional utility patent application before the United States Patent & Trademark Office was also filed (November, 2018).

Risk of High-Grade Cervical Lesions in Atypical Squamous Cells of Undetermined Significance (ASC-US) Cytology: Comparison between HIV-Infected and HIV-Negative Women.

Background and objective:Women with human immunodeficiency virus (HIV) infection have an increased risk of HPV infection, cervical neoplasia. This study was undertaken to compare the risk of having high-grade cervical lesions defined as cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in HIV-infected versus HIV-uninfected women who had atypical squamous cells of undetermined significance (ASC-US) on cervical cytology. Methods:Fifty-seven HIV-positive women aged 25-65 years with ASC-US cytology undergoing colposcopic examination between January 2008 and December 2020 at Chiang Mai University Hospital were reviewed. By matching 1:5 ratio, 285 HIV-negative women with ASC-US cytology in the same period were recruited as controlled subjects for comparison. The patient characteristics, HIV status, CD4 cell count within 6 months of colposcopy, antiretroviral therapy, parity, contraception, smoking history, number of sexual partners, and histopathology on cervical biopsy were analyzed. Results: Mean age ± SD of the HIV-positive and HIV-negative groups was 44.28 ± 8.53 years and 44.28 ± 9.68 years, respectively. HIV-positive women were significantly less likely to use contraceptive methods (36.8 % versus 48.8 % in HIV-negative women; P = 0.002). HIV-infected women significantly had more sexual partners than HIV-uninfected women. Both groups had similar risk for CIN 2+ (5.3 % in HIV-positive women compared with 4.9 % in HIV-negative women; odds ratio [OR] = 1.08, 95% confidence interval [CI] = 0.30 –3.87). After adjustment for no contraception use and number of sexual partners, the risk of CIN2+ in HIV-infected women remained unchanged; adjusted OR= 1.15, 95% CI = 0.27-4.92, P= 0.846). Conclusion:The risk of underlying high-grade cervical lesions in women with ASC-US on cervical cytology was approximately 5 %, regardless of HIV status.

Effectiveness of HPV vaccination against the development of high-grade cervical lesions in young Japanese women

BackgroundAlthough more than 10 years have passed since HPV vaccination was implemented, first as an interim programme (Emergent vaccine promotion programme) in November 2010, followed by incorporating into the National Immunization Programme in April, 2013 and suspended in June 2013, limited studies have investigated the HPV vaccine effectiveness against high-grade cervical lesions in Japan.MethodsWe collected the matched data of the results of cervical biopsy and history of vaccination from the Japan Cancer Society database. The subjects were women aged 20 to 29 years screened for cervical cancer between April, 2015 and March, 2017, and with information on HPV vaccination status. We estimated the relative risk of developing high-grade cervical lesions in vaccinated subjects using Poisson regression as compared to unvaccinated subjects.ResultsAmong the 34,281 women screened, 3770 (11.0%) were vaccinated. The prevalence of CIN2+ was statistically significantly lower in the vaccinated women as compared to the unvaccinated women (Vaccine Effectiveness (VE) =76%; RR = 0.24, 95% CI:0.10–0.60). High VE against CIN3+ was also observed (91%; RR = 0.09, 95% CI:0.00–0.42).ConclusionWomen aged 20–29 years who received at least one dose of HPV vaccine had a significantly lower risk of high-grade cervical lesions than those not vaccinated. In Japan, HPV vaccination should be resumed in order to reduce the incidence of cervical cancer.

Coinfection of High-Risk Human Papillomavirus and Lower Genital Tract Pathogens in the Development of High-Grade Cervical Lesions.

Purpose This study investigated the infection status and relationship between other common lower genital tract infectious pathogens and high-risk human papillomavirus (HR-HPV) in the high-grade cervical lesions. Methods Overall, 882 patients were enrolled in this retrospective study, of which 339 patients (≥HSIL group) were confirmed with high-grade squamous intraepithelial lesions (HSIL) or cervical squamous cell carcinoma (SCC), while 543 patients (≤LSIL group) were diagnosed with low-grade squamous intraepithelial lesions (LSIL) or normal cervical pathology diagnosis. Cervical swab specimens were tested for HPV, pathogenic bacteria (PB), U. urealyticum (UU), M. hominis (MH), and C. trachomatis (CT) in both groups. Results The infection rates of HR-HPV, PB, UU (at high density), and CT were higher in the ≥HSIL group than in the ≤LSIL group (P < 0.001); however, higher infection rates with MH were not observed (P > 0.05). PB, UU, and CT were associated with HR-HPV infection (P < 0.001). The PB and UU infection rates in the ≥HSIL group were significantly different from those in the ≤LSIL group, regardless of whether there was an HR-HPV infection at the same time (P < 0.05). However, this was not the case for the CT (P > 0.05). Furthermore, 259 pathogenic bacterial strains were detected in 882 cases. The difference in the distribution of pathogenic bacterial flora in the different grades of cervical lesions had no statistical significance, which was prioritized over Escherichia coli (P > 0.05). Conclusion PB, UU, and CT infection is associated with susceptibility to HR-HPV, HR-HPV coinfection with these pathogens might increase the risk of high-grade cervical lesions, and PB and UU might be independent risk factors for cervical lesions.

Association of serum folate and vitamin B12 with pre-neoplastic cervical lesions.

Diet and lifestyle play an important role in etiology of various tumors. Serum concentration of folate and vitamin B12may be associated with carcinogenesis since they are involved in DNA methylation and nucleotide synthesis. However, the role of these micronutrients on development of cervical cancer is still controversial. Thus, the aim of this study was to analyze the association of lower status of folate and vitamin B12 with the risk of pre-neoplastic cervical lesions. Our sample group was divided in Control group (n=120) - women with normal cytology, and Case groups (n=57) - women presenting Atypical Squamous Cells of Undetermined Significance (ASC-US, n=21), Low Grade Squamous Intraepithelial Lesion (LSIL; n=16), and High-Grade lesions (n=20). We obtained cervical samples for cytology analysis and HPV detection, and blood samples for evaluation of serum concentration of folate and vitamin B12. No difference of serum folate was observed among Cases and Control groups. On the other hand, women with High-Grade lesions presented significant lower median concentration of vitamin B12 if compared to another groups. Then, we observed increased risk of High-Grade lesions among participants with low vitamin B12 levels was observed in relation to women that presented high levels of the micronutrient and from Control group [OR (95% CI): 2.09 (0.65-6.76), p=0.216], ASC-US [OR (95% CI): 3.15 (0.82-12.08), p=0.095], and LSIL [OR (95% CI): 3.10 (0.76-12.70), p=0.116]. Low concentration of vitamin B12 was associated with an increased risk of High-Grade cervical lesions. Besides, we did not observe any difference of serum folate among women with normal cytology and women with pre-neoplastic cervical lesions.

High-Risk Types of Human Papilloma Virus DNA Testing in Women with False Negative Cytology

Objective: To determine whether high-risk types of human papilloma virus (hrHPV) DNA testing is reliable for selection patients in need of further investigation with colposcopy in women with increased risk of high-grade cervical lesions as a result of false negative cytology. The secondary objective was to compare the sensitivity of hrHPV testing on self-collected versus physician-collected samples for the detection of histological high-grade cervical intraepithelial neoplasia (CIN2+). Methods: Sixty-three patients identified with a missed abnormality following the re-evaluation of benign cervical cytology were included. A patient-collected and a physician-collected sample for HPV, colposcopy and cervical specimen collection for histology and cytology were performed. Results: The sensitivity of hrHPV testing of physician-collected samples for CIN2+ was 100% (95% CI 82.7–100), and the negative predictive value (NPV) was 100% (95% CI 93.3–100). The sensitivity of the self-sampling device to identify CIN2+ was 84.6% (95% CI 59.1–96.7), and the NPV was 94.4% (95% CI 83.4–98.8). The differences in the sensitivity and NPV between the 2 methods were non-significant. The agreement between the 2 methods regarding the HPV results was good, with a kappa value of 0.74 (95% CI 0.57–0.91). Conclusion: The current findings indicate that physician-collected samples for hrHPV DNA testing may be used as triage for the colposcopy of women with false negative cytology.

Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies.

We aimed, in the present study, to measure the risk related to the high-grade cervical intraepithelial neoplasia grade 3 (CIN3) or worse (CIN3+) or worse/high-grade squamous intraepithelial lesions with respect to changes in human papillomavirus (HPV) and smoking status. A structured interview underwent for 7129 women. Then, we obtained their cervical cells and subjected to HPV testing. High-risk HPV infected and "no prevalent" cervical disease infected women were followed for cervical lesions up to 12 years (at baseline; n = 1531). Hazard ratios (HRs) for diagnosis of CIN3 (or worse) or worse/high-grade intraepithelial lesions were calculated along with the corresponding 95% confidence intervals (CIs). Among high-risk HPV-positive women, the conditions of long-term (more than 8 years) smokers and heavy (18 or more cigarettes/day) smokers are highly responsible for the increased risk for CIN3 or CIN3+. In the cases of persistent HPV-infected women, heavy smoking led to a higher risk for CIN3+ than those women who never smoked (HR, 2.31; 95% CI, 1.12-4.16). We concluded here that smoking leads to an enhanced risk of high-grade cervical lesions in persistent high-risk HPV-infected women. This makes a good understanding of smoking's role in cervical cancer.

Clinical Significance of an HPV DNA Chip Test with Emphasis on HPV-16 and/or HPV-18 Detection in Korean Gynecological Patients.

Background:Human papillomavirus (HPV) is a major risk factor for cervical cancer.Methods:We evaluated the clinical significance of the HPV DNA chip genotyping assay (MyHPV chip, Mygene Co.) compared with the Hybrid Capture 2 (HC2) chemiluminescent nucleic acid hybridization kit (Digene Corp.) in 867 patients.Results:The concordance rate between the MyHPV chip and HC2 was 79.4% (kappa coefficient, κ = 0.55). The sensitivity and specificity of both HPV tests were very similar (approximately 85% and 50%, respectively). The addition of HPV result (either MyHPV chip or HC2) to cytology improved the sensitivity (95%, each) but reduced the specificity (approximately 30%, each) compared with the HPV test or cytology alone. Based on the MyHPV chip results, the odds ratio (OR) for ≥ high-grade squamous intraepithelial lesions (HSILs) was 9.9 in the HPV-16/18 (+) group and 3.7 in the non-16/18 high-risk (HR)-HPV (+) group. Based on the HC2 results, the OR for ≥ HSILs was 5.9 in the HR-HPV (+) group. When considering only patients with cytological diagnoses of “negative for intraepithelial lesion or malignancy” and “atypical squamous cell or atypical glandular cell,” based on the MyHPV chip results, the ORs for ≥ HSILs were 6.8 and 11.7, respectively, in the HPV-16/18 (+) group.Conclusions:The sensitivity and specificity of the MyHPV chip test are similar to the HC2. Detecting HPV-16/18 with an HPV DNA chip test, which is commonly used in many Asian countries, is useful in assessing the risk of high-grade cervical lesions.

Women with cervical cancer have high levels of citrulline that are inversely correlated with percentages of circulating IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells

Event Abstract Back to Event Women with cervical cancer have high levels of citrulline that are inversely correlated with percentages of circulating IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells Astrid M. Bedoya1, 2, David J. Tate3, John R. Patterson3, Carlos M. Córdoba4, 5, Mauricio Borrero4, 6, René Pareja6, Fredy Rojas6, Beatriz Finkel-Jimenez7, Constance Porretta8, Cristiam M. Alvarez9, Armando Baena1, Rolando Herrero10, Arnold H. Zea3 and Gloria I. Sánchez1* 1 Universidad de Antioquia, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Colombia 2 Universidad de Antioquia, School of Microbiology, Colombia 3 Louisiana State University Health Sciences Center, Stanley S. Scott Cancer Center, United States 4 Universidad de Antioquia, Departament of Gynecology and Obstetrics, Colombia 5 Hospital San Vicente Fundación, Departament of Gynecology and Obstetrics, Colombia 6 Clínica Las Américas, Instituto de Cancerología Las Américas, Colombia 7 American University of the Caribbean, School of Medicine, United States 8 Louisiana State University Health Sciences Center, Alcohol Research Center, United States 9 Universidad de Antioquia, Instituto de Investigaciones Medicas, Colombia 10 International Agency for Research on Cancer, France INTRODUCTION: Cervical cancer remains a serious public health problem. Globally, 528.000 new cases and 265.000 deaths were reported in 2012. About 90% of these cases and deaths occurred in developing countries. High-Risk Human Papillomavirus (HR-HPV) infection is the necessary but not sufficient cause of cervical cancer. This common sexually transmitted virus infects the genital epithelium of almost 50% of the sexually active population in the world. The majority of women who acquire HPV, develop cervical cytological abnormalities or do not present any clinical evidence and clear the infection within one to two years. However, the small percentage of women that do not clear the infection spontaneously, develop persistent infection, which severely increases the risk of high-grade cervical lesions and cancer. The immune response plays an important role in the elimination of HPV infection and possibly in the regression of pre-neoplastic lesions. We have previously observed that sera of women with cervical cancer have high levels of arginase and low levels of L-arginine. Reduction of L-arginine by the enzyme arginase is an immune mechanism associated with T-cell dysfunction by inhibiting the expression of the CD3 zeta chain of the T-cell receptor. We also observed that in spite of low levels of L-arginine, in women with cervical cancer the majority of circulating E6 HPV 16-specific CD8+ T-cells express IFN-γ and perforin suggesting that other mechanisms could be overcoming L-arginine deficiency. The nitric oxide synthase (NOS) enzyme converts L-arginine into Nitric Oxide (NO) and citrulline. Citrulline is a naturally occurring non-essential amino acid that in turn can be converted to L-arginine by the sequential action of the enzymes argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL). In vitro observations have shown that citrulline, can substitute for L-arginine deficiency, prevent the loss of CD3 zeta chain expression in CD8+ T-cells and restore T-cell function. Since women with cervical cancer have low levels of L-arginine and the majority of their circulating E6 HPV 16-specific CD8+ T-cells express IFN-γ and perforin; our hypothesis is that women with cervical cancer have high levels of citrulline which correlate with the high percentage of circulating IFN-γ+/perforin+ E6 HPV 16-specific CD8+ T-cells. OBJECTIVES: 1. To evaluate the association between high levels of citrulline and cervical intraepithelial neoplasia 3 (CIN3) or invasive cervical cancer (ICC) 2. To describe in women with cervical cancer the relationship between citrulline and L-arginine levels with the percentage of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells. METHODS: The levels of L-arginine and citrulline were evaluated by High Performance Liquid Chromatography (HPLC) in the serum of 84, 41 and 79 women with ICC, CIN3 and normal cytology respectively. Percentages of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells were estimated in 50 ICC cases by flow cytometry using PE-labeled HLA-A*0201 E6(18-26), and HLA-A*2401 E6(49-57), (87-95) tetramers and Anti-CD3-Alexa fluor 700 (clone 17A2), anti-CD8-PerCPCy5.5 (clone HIT8a), anti-IFN-γ-APC (clone XMG1.2) and anti-perforin-FITC (clone δG9) (Beckton Dickinson). Kruskal-Wallis test was used to compare the median among groups. Logistic regression models, adjusted by age and HPV were used to evaluate the association of CIN3 and invasive cervical cancer with high levels of citrulline (upper tertile). Pearson Correlation was used to evaluate the relationship between levels of arginine, citrulline and percentages of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells. RESULTS: Circulating citrulline levels were significantly higher in women with CIN3 and invasive cervical cancer compared to controls (Kruskal-Wallis test, p <0.0001, Dunn's test p <0.001, CIN3 and invasive cervical cancer vs. controls). In the logistic regression analysis an association between higher levels (upper tertile) of citrulline and CIN3 (OR: 270.4; 95%CI: 15.6-4686) or invasive cervical cancer (OR: 156; 95%CI: 9.4-2600) was observed. In the analysis of correlation between levels of citrulline and L-arginine, we noted that in both CIN3 (Pearson test, r= 0.8749, p <0.001) and invasive cervical cancer (Pearson test, r= 0.4636, p= 0.001) there is a positive correlation between the levels of L-arginine and citrulline. However in the correlation analysis between the levels of citrulline and the percentages of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells in peripheral blood of women with invasive cervical cancer, a significant inverse correlation (Spearman r= -0.4323, p-value = 0.0011) was observed. That is, individuals with high levels of citrulline have lower percentages of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells. CONCLUSIONS: In spite of the association between high levels of citrulline and cervical cancer and the positive correlation between levels of citrulline and L-arginine in women with this cancer, we observed a negative correlation between levels of citrulline and percentages of IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells. Our results suggest that contrary to what has been observed in vitro, citrulline does not seem to abrogate the ability of arginase-induced L-arginine depletion and therefore may have not a role in restoring the dysfunction of T-cells mediated by the action of arginase. Subsequent studies testing the expression of ASS in cervical cancer, will be important to elucidate the role of citrulline as a compensation mechanism due to the effects of the depletion of L-arginine by arginase. On the other hand, our results also suggest that it may be more relevant to target the arginase producing cells, rather than supplementing patients with L-arginine or citrulline, in order to overcome the immunosuppression observed in this disease. Keywords: Citrulline, cervical cancer, HPV-16-specific CD8+ T-cells, L-arginine, Human papillomavirus 16 Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Tumor immunology Citation: Bedoya AM, Tate DJ, Patterson JR, Córdoba CM, Borrero M, Pareja R, Rojas F, Finkel-Jimenez B, Porretta C, Alvarez CM, Baena A, Herrero R, Zea AH and Sánchez GI (2015). Women with cervical cancer have high levels of citrulline that are inversely correlated with percentages of circulating IFN-γ+/perforin+ E6 HPV-16-specific CD8+ T-cells . Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00290 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 May 2015; Published Online: 15 Sep 2015. * Correspondence: Prof. Gloria I Sánchez, Universidad de Antioquia, School of Medicine and Corporación Académica para el Estudio de Patologías Tropicales, Medellin, Antioquia, Colombia, sanchezg@une.net.co Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Astrid M Bedoya David J Tate John R Patterson Carlos M Córdoba Mauricio Borrero René Pareja Fredy Rojas Beatriz Finkel-Jimenez Constance Porretta Cristiam M Alvarez Armando Baena Rolando Herrero Arnold H Zea Gloria I Sánchez Google Astrid M Bedoya David J Tate John R Patterson Carlos M Córdoba Mauricio Borrero René Pareja Fredy Rojas Beatriz Finkel-Jimenez Constance Porretta Cristiam M Alvarez Armando Baena Rolando Herrero Arnold H Zea Gloria I Sánchez Google Scholar Astrid M Bedoya David J Tate John R Patterson Carlos M Córdoba Mauricio Borrero René Pareja Fredy Rojas Beatriz Finkel-Jimenez Constance Porretta Cristiam M Alvarez Armando Baena Rolando Herrero Arnold H Zea Gloria I Sánchez PubMed Astrid M Bedoya David J Tate John R Patterson Carlos M Córdoba Mauricio Borrero René Pareja Fredy Rojas Beatriz Finkel-Jimenez Constance Porretta Cristiam M Alvarez Armando Baena Rolando Herrero Arnold H Zea Gloria I Sánchez Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Cervical Dysplasia and High-Risk Human Papillomavirus Infections among HIV-Infected and HIV-Uninfected Adolescent Females in South Africa

Background. HIV-infected adolescents may be at higher risk for high-grade cervical lesions than HIV-uninfected adolescents. The purpose of this study was to compare the prevalence of high-risk HPV (HR-HPV) infections and Pap smear abnormalities between these two groups. Methods. In this cross-sectional study, we compared the HPV DNA and Pap smear results between 35 HIV-infected and 50 HIV-uninfected adolescents in order to determine the prevalence of HR-HPV genotypes and cervical cytological abnormalities. Comparisons were made using Pearson χ 2 and independent-samples t-tests analyses, and associations between demographic and behavioral characteristics and HPV infections were examined. Results. HIV-infected participants were more likely to be infected with any HPV (88.6% versus 48.0%; P < 0.001) and with at least one HR-HPV (60.0% versus 24.0%; P = 0.001), and to have multiple concurrent HPV infections (68.6% versus 22.0%; P < 0.001). HPV 16 and 18 were relatively underrepresented among HR-HPV infections. Abnormal Pap test results were more common among HIV-infected participants (28.8% versus 12.0%; P = 0.054). A history of smoking was associated with HR-HPV infection. Conclusions. HIV-infected adolescents have an increased risk of infection with HR-HPV and of Pap test abnormalities. The majority of HR-HPV infections among our participants would not be prevented by the currently available vaccinations against HPV.

Negative Biopsy Specimens in the Setting of High A Priori Probability of Disease

More and more, newly published management guidelines are touted as evidence driven with extensive data-backed assessments of risk of disease. These risks are determined by outcomes data generated in clinical studies and formal clinical trials. As any pathologist knows, the data derived from any study are only as good as the study inputs and methodology. For instance, if the goal is to identify the risk of disease, one needs to have optimal methods and tools in place to find evidence of the disease if it is present. In addition, and looking more carefully into the process, one needs to appreciate how reproducible the targeted diagnosis actually is and how the sampling of tissue can affect detection sensitivity. It is only when these parameters are appropriately considered that reality-based assessments of risk can be input into management guidelines. But it is not just guideline development that is important in this discussion. Individual patient results are equally affected by the process noted above. If you apply an extant management guideline to a patient, that application also relies on a sound pathology diagnosis. Hence, the use of an optimized interpretive technique must also apply equally in the setting of the primary diagnosis in order for the guidelines to actually work. Therefore, both crafting and clinical use of any guideline must use optimal—and similar—pathology procedures. Risk-based management guidelines for cervical cytology have been recently published that were crafted using extensive evidence-based literature reviews and expert opinion.1 These guidelines were based on the outcomes data grounded by extensive follow-up studies aimed at identifying the risk of high-grade cervical lesions over time for the various cytologic abnormalities. Based on risk levels observed in these studies, appropriate management could be defined. …

Risk for Cervical Intraepithelial Neoplasia Grade 3 or Worse in Relation to Smoking among Women with Persistent Human Papillomavirus Infection

Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high-risk human papillomavirus (HPV) infection. In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n = 1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection (n = 312) were also conducted. HRs for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CI) were calculated in the two groups. Among high-risk HPV-positive women, an increased risk for CIN3+ was associated with long-term smoking (≥10 years) and heavy smoking (≥20 cigarettes/d). In the subgroup of women with persistent HPV infection, heavy smoking was also associated with a statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05-3.22, adjusted for length of schooling, parity, and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (P = 0.4). Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection. Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis.

DNA image cytometry and human papillomavirus (HPV) detection help to select smears at high risk of high-grade cervical lesions.

Three samples were submitted from women undergoing routine screening (n=910): two smears (one for routine cytology and one for DNA image cytometry) and a scrape for human papillomavirus (HPV) testing. DNA histograms were classified as suspect in cases of aneuploidy, polyploidy, and/or diploidy with a high proliferation rate. Follow-up was available in 239 cases. The primary end-point was the presence of a high-grade squamous intraepithelial lesion (HGSIL) at biopsy. Seventy women (7.7%) had a high-risk (HR) HPV infection and a suspect DNA profile. In 77 women with cytological abnormalities, 28 HGSILs were detected: four with a prior diagnosis of ASCUS (all HR-HPV infected including three with a suspect DNA profile), three with smears evocative of LGSIL (all with HR-HPV infection and a suspect DNA profile), and 21 with smears evocative of HGSIL (all with HR-HPV infection and 20 with a suspect DNA profile). During the follow-up period, out of 239 women with a cytologically normal smear at first entry, five developed a HGSIL; all were HR-HPV-positive and four had a suspect DNA profile at the first smear. HR-HPV detection alone gives a sensitivity of 100% for the detection of HGSIL, with a specificity of 84.3%, whereas DNA measurement associated with HPV testing significantly enhances the specificity to 95.4%. Thus, the combination of HPV testing and DNA measurement provides a highly sensitive and specific evaluation of the risk of HGSIL on cervical smears.