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More common than cervical cancer, cervical intraepithelial neoplasia (CIN) represents a precursor lesion of cervical carcinoma, being associated with HPV infection. Due to the bidirectional relationship between HPV and estrogen and progesterone in pregnancy, most of the published data claim that precancerous lesions remain stable or even regress during pregnancy, although several studies have indicated the tendency of HSILs to persist. It is considered that pregnancy-related cervical precancerous lesions undergo a postpartum regression, due to stimulatory effects of the immune microenvironment. Due to the rarity of publications on this subject, we aimed to offer a concise overview of and new insights into the current knowledge regarding the pathogenesis, diagnosis, and evolution of pregnancy-associated precancerous lesions, as well as their impact upon gestation and fertility. [ABSTRACT FROM AUTHOR]

The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003–2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (p trend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (p trend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30–39, 40–49, and 50–64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003–2006. SCC:ADC decreased from approximately 2.5:1 in 2003–2006 to 1.3:1 in 2015–2018 while the CIN3:AIS remained relatively constant, ∼10:1. Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated. • Following the introduction of 3-yearly co-testing, the detection of CIN3 and AIS increased. • Following the introduction of 3-yearly HPV and Cytology co-testing, diagnoses of cervical squamous cell carcinoma decreased. • Following the introduction of 3-yearly HPV and Cytology co-testing, diagnoses of cervical adenocarcinoma did not change. [ABSTRACT FROM AUTHOR]

Background: Trichomonas vaginalis infection is the most prevalent non‐viral sexually transmitted infection (STI) in women and has been suggested as a risk factor for developing cervical cancer. Objective: We aimed to investigate the associations between T. vaginalis infection and cervical carcinogenesis. Search Strategy: A comprehensive systematic search was conducted in five databases on 21 October 2021. Selection Criteria: Studies assessing the relationship between T. vaginalis infection, HPV co‐infections, cervical dysplasia, and cervical cancer were found eligible. Data Collection and Analysis: Summary estimates for pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with a random‐effects model. Statistical heterogeneity was measured with I2 and Cochran's Q tests. Main Results: The 29 articles included 473 740 women, of whom 8518 were T. vaginalis‐positive. Our results showed that T. vaginalis‐infected women had 1.79 times higher odds of being diagnosed with HPV co‐infection (95% CI 1.27–2.53; I2 95%). We also found that T. vaginalis infection was associated with high‐grade squamous intraepithelial lesion diagnosis (OR 2.34, 95% CI 1.10–4.95; I2 75%) and cervical cancer (OR 5.23, 95% CI 3.03–9.04; I2 3%). Conclusions: Our results showed an association between T. vaginalis and cervical carcinogenesis in sexually active women. Synopsis: We found an association between Trichomonas vaginalis and cervical carcinogenesis; in the case of Trichomonas detection, cervical dysplasia should be considered for evaluation. [ABSTRACT FROM AUTHOR]

Background: Studies on the clinical performance of p16/Ki-67 dual-staining in detecting cervical lesions by menopausal status were limited. Methods: 4364 eligible women were enrolled with valid p16/Ki-67, HR-HPV, and LBC test results, including 542 cancer and 217 CIN2/3 cases. The positivity rates of p16 and Ki-67 single staining and p16/ Ki-67 dual-staining were analyzed by different pathological grades and age groups. The sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) of each test in different subgroups were calculated and compared. Results: P16/Ki-67 dual-staining positivity increased with histopathological severity in premenopausal and postmenopausal women (P < 0.05), while no increasing trends of individual expression of p16 single staining and Ki-67 single staining were observed in postmenopausal women. P16/Ki-67 showed higher SPE (88.09% vs. 81.91%, P < 0.001) and PPV (33.8% vs. 13.18%, P < 0.001) in detecting CIN2/3, and higher SEN (89.97% vs. 82.61%, P = 0.012) and SPE (83.22% vs. 79.89%, P = 0.011) in detecting cancer in premenopausal women than postmenopausal women. For triaging the HR-HPV+ population to identify CIN2/3, p16/Ki-67 performed comparably to LBC in the premenopausal women, and showed higher PPV (51.14% vs. 23.08%, P < 0.001) in premenopausal than postmenopausal women. For triaging ASC-US/LSIL population, p16/Ki-67 demonstrated higher SPE and lower colposcopy referral rate than HR-HPV in both premenopausal and postmenopausal women. Conclusions: Expressions of p16/Ki-67 dual-staining between premenopausal and postmenopausal women are varied. P16/Ki-67 performs better in detecting cervical lesions in premenopausal women. For triaging, p16/Ki-67 is suitable for HR-HPV+ women, especially premenopausal women, to identify CIN2/3 and women with ASC-US/LSIL. [ABSTRACT FROM AUTHOR]

High-risk, cancer-causing human papillomavirus (HPV) types are associated with cervical precancer and cancer. A high proportion of high-risk HPV precancer lesions undergo immune-mediated regression. The purpose of this study was to determine if the tissue microenvironment of HPV16 and 18 (HPV16/18) cervical intraepithelial neoplasia grade 2 lesions differed from other high-risk types (HPV 'other'). Consistent with other studies, we found that progression to higher-grade disease was more frequent in HPV16/18 lesions when compared with HPV 'other' lesions. HPV16/18 lesions were significantly more likely to be indoleamine 2,3,-dioxygenase 1 (IDO1)-positive and were associated with reduced CD8 and FoxP3 T cells in the lesion. In the stroma, reduced Tbet- and CD32-positive cells and increased Blimp1-positive cells were significantly associated with HPV16/18 lesions when compared with HPV 'other' types. On analysis of the IDO1-positive tissues, lesional IDO1 was associated with significantly decreased numbers of CD4-, CD8-, and FoxP3-positive cells in the stroma compared with IDO1-negative tissues. These data suggest that IDO1 expression may impair infiltration of CD4, CD8, and FoxP3 cells into the stroma beneath the precancer lesion. Increased expression of IDO1 may contribute to immune avoidance and an increased frequency of disease progression in HPV16- and 18-positive lesions. [ABSTRACT FROM AUTHOR]

Background: Low- and middle-income countries (LMICs) account for nearly 85% of the global cervical cancer burden, yet have the least access to high-performance screening. International guidelines recommend human papillomavirus testing (HPV) as primary screening, yet implementation is inhibited by the cost of HPV testing. Atila AmpFire® HPV Assay (AmpFire) is both affordable and easy to use, and offers individual genotyping. The objective of this study was to compare the performance of the AmpFire HPV assay to the Xpert® HPV assay in detection of both HPV and clinically significant cervical disease. Methods: We utilized stored cervical specimens from a prospective cohort study of women living with human immunodeficiency virus (HIV) in Botswana conducted from May to July 2018. Positive and negative percent agreement was calculated for the AmpFire and Xpert assays, as was detection of high-grade cervical dysplasia. Results: 63 stored cervical specimens had detectable DNA after thawing and were included in the analysis. The positive percent agreement was 91.2% (95%CI 76.3–98.1) and negative percent agreement was 79.3% (95% CI 60.3–92.0). Six cases positive by AmpFire but negative by Xpert were HPV genotypes 35, 52 (n = 2), 58, 68, and co-infection with HPV 45 and 68. Both Xpert and AmpFire assays detected HPV in all 10 samples of women who had high-grade cervical dysplasia. Conclusions: The AmpFire HPV assay demonstrated excellent analytic performance in both detection of HPV and clinically significant cervical disease. AmpFire HPV is a promising option to increase access to affordable, type-specific HPV screening for cervical cancer in LMICs. [ABSTRACT FROM AUTHOR]

Background: Though obesity has been said to be associated with a number of malignancies including cervical cancer, its association with cervical intraepithelial neoplasia (CIN) is still a contentious issue. This study was designed to determining the prevalence and association between obesity and CIN. Methods: This was an unmatched case control study, involving women with cervical intraepithelial neoplasia (cases) and those negative for intraepithelial lesions or malignancy (controls) at the cervical cancer clinic of Mbarara Regional Referral Hospital, in south-western Uganda, between April and November 2022. Cases and controls provided written informed consent and were recruited in a ratio of 1:1. Cases were identified by visual inspection with acetic acid (VIA) and subsequent confirmation with cytology and/or histology. Demographic information was collected using an enrolment form and height, weight and waist circumference were recorded. We calculated body mass index (BMI) and identified obese women as those with body mass index of ≥ 30 kg/m2 from both case and control groups. Central obesity was defined as waist: height ration of ≥ 0.5. Data was analysed using STATA version 17. Categorical variables were analysed using proportions, chi-square and logistic regression analysis to determine association between obesity and CIN. Our level of statistical significance was set at ≤ 0.05. Results: The prevalence of general and central obesity among cases was 25.5% (24/94) and 0% (0/94) respectively while the prevalence of general and central obesity among controls was 33.3% (37/111) and 0% (0/111) respectively. There was an increased prevalence of general obesity among women with low grade squamous intraepithelial lesions (LSIL). However, there was no statistically significant association between general obesity and CIN. Factors associated with general obesity included residing in Mbarara city (AOR 2.156, 95%CI 1.085–4.282, P-value 0.028), age group of 31–45 years (AOR 2.421, 95%CI 1.577–9.705, P-value 0.003) and ≥ 46 years (AOR 1.971, 95%CI 1.022–11.157, P-value 0.046). Conclusion: We observed an increased prevalence of general obesity among women with LSIL. However, there was no association between obesity and CIN. Factors associated with general obesity included residing in Mbarara city, and being in the age groups of 31–40 and ≥ 46 years. This highlights the need to rethink management of CIN to control other non-communicable diseases that could arise due to general obesity. [ABSTRACT FROM AUTHOR]

Background: Colposcopic examination with biopsy is the standard procedure for referrals with abnormal cervical cancer screening results; however, the decision to biopsy is controvertible. Having a predictive model may help to improve high-grade squamous intraepithelial lesion or worse (HSIL+) predictions which could reduce unnecessary testing and protecting women from unnecessary harm. Methods: This retrospective multicenter study involved 5,854 patients identified through colposcopy databases. Cases were randomly assigned to a training set for development or to an internal validation set for performance assessment and comparability testing. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to reduce the number of candidate predictors and select statistically significant factors. Multivariable logistic regression was then used to establish a predictive model which generates risk scores for developing HSIL+. The predictive model is presented as a nomogram and was assessed for discriminability, and with calibration and decision curves. The model was externally validated with 472 consecutive patients and compared to 422 other patients from two additional hospitals. Results: The final predictive model included age, cytology results, human papillomavirus status, transformation zone types, colposcopic impressions, and size of lesion area. The model had good overall discrimination when predicting HSIL + risk, which was internally validated (Area Under the Curve [AUC] of 0.92 (95%CI 0.90–0.94)). External validation found an AUC of 0.91 (95%CI 0.88–0.94) across the consecutive sample, and 0.88 (95%CI 0.84–0.93) across the comparative sample. Calibration suggested good coherence between predicted and observed probabilities. Decision curve analysis also suggested this model would be clinically useful. Conclusion: We developed and validated a nomogram which incorporates multiple clinically relevant variables to better identify HSIL + cases during colposcopic examination. This model may help clinicians determining next steps and in particular, around the need to refer patients for colposcopy-guided biopsies. [ABSTRACT FROM AUTHOR]

Introduction: Accessible planning tools tailored for low-and middle-income countries can assist decision makers in comparing implementation of different cervical cancer screening approaches and treatment delivery scenarios in settings with high cervical cancer burden.Methods: The Cervical Precancer Planning Tool (CPPT) was developed by PATH for users to explore and compare the accuracy of screening approaches, what treatment equipment to procure, and how best to deploy treatment equipment in a given country. The CPPT compares four screening approaches: 1) visual inspection with acetic acid (VIA), 2) HPV testing, 3) HPV testing followed by a VIA triage, and 4) HPV testing followed by an enhanced triage test. Accuracy of screening outcomes (e.g., true positives, false positives) is based on published sensitivity and specificity of tests to detect cervical precancerous lesions. The CPPT compares five scenarios for deploying ablative treatment equipment: 1) cervical precancer equipment at every location a woman is screened (single visit approach), 2) equipment only at a hospital level, 3) a single unit of equipment in each district, 4) allowing two districts to share a single unit of equipment, and 5) equipment placed at select district hospitals paired with mobile outreach. Users can customize the CPPT by adjusting pre-populated baseline values and assumptions, including population estimates, screening age range, screening frequency, HPV and HIV prevalence, supply costs, and health facility details.Results: The CPPT generates data tables and graphs that compare the results of implementing each of the four screening and five treatment scenarios disaggregated by HIV status. Outputs include the number and outcomes of women screened, cost of each screening approach, provider time and cost saved by implementing self-sampling for HPV testing, number of women treated, treatment equipment needed by type, and the financial and economic costs for each equipment deployment scenario.Conclusion: The CPPT provides practical information and data to compare tradeoffs of patient access and screening accuracy as well as efficient utilization of equipment, skilled personnel, and financial resources. Country decision makers can use outputs from the CPPT to guide the scale-up of cervical cancer screening and treatment while optimizing limited resources. [ABSTRACT FROM AUTHOR]

Simple Summary: There is an unmet clinical need for new methods to aid clinicians in the early detection of cervical cancer and precancer. Spectroscopic methods such as Raman spectroscopy can provide a rapid, label-free and nondestructive measurement of the biochemical fingerprint of cells, tissues and biofluids. This study aims to demonstrate the clinical utility of Raman spectroscopy for the identification of cervical precancer. Raman spectra were recorded from cervical smear samples (n = 662) and a classifier was developed based on histology. A classification accuracy of 91.3% was achieved in an independent blinded test set (n = 69), demonstrating the potential clinical utility of Raman spectroscopy. The mortality associated with cervical cancer can be reduced if detected at the precancer stage, but current methods are limited in terms of subjectivity, cost and time. Optical spectroscopic methods such as Raman spectroscopy can provide a rapid, label-free and nondestructive measurement of the biochemical fingerprint of a cell, tissue or biofluid. Previous studies have shown the potential of Raman spectroscopy for cervical cancer diagnosis, but most were pilot studies with small sample sizes. The aim of this study is to show the clinical utility of Raman spectroscopy for identifying cervical precancer in a large sample set with validation in an independent test set. Liquid-based cervical cytology samples (n = 662) (326 negative, 200 cervical intraepithelial neoplasia (CIN)1 and 136 CIN2+) were obtained as a training set. Raman spectra were recorded from single-cell nuclei and subjected to a partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 69). A classification accuracy of 91.3% was achieved with only six of the blinded samples misclassified. This study showed the potential clinical utility of Raman spectroscopy with a good classification of negative, CIN1 and CIN2+ achieved in an independent test set. [ABSTRACT FROM AUTHOR]

Introduction: cervical precancer screening with same day treatment facilitates maximization of benefits of secondary prevention of cervical cancer. This is particularly important for women living with human immunodeficiency virus (WLHIV) infection because of their exceptional risk for cervical cancer. The availability of HIV programmes in low- and middle-income countries (LMICs) provide unique opportunity for possible introduction "human papillomavirus (HPV) screening followed by visual inspection after application of acetic acid (VIA) with same day treatment of eligible patients". This study piloted this concept. Methods: in this prospective, cohort study, 98 WLHIV had HPV and VIA screening for cervical precancer lesions in a HIV clinic in Nigeria. Participants positive to HPV and/or VIA had biopsies from the visible lesions or quadrant of transformation zone. Participants positive to VIA and/or HPV16 or HPV18/45 had same-day thermal ablation treatment and the number of cases documented. The HPV, VIA and scenario of HPV followed by VIA results were compared with histologically confirmed cervical lesion grade 2 or worse statistically. Results: same day treatment was achieved in 95.0% of eligible cases. Statistically, sensitivity and specificity of VIA was 25.0% and 50.0% and HPV had 95.5% and 75.0%, respectively. In the HPV screening with VIA triage, sensitivity dropped to 45.5% but specificity improved to 100.0%. Conclusion: triaging HPV positive test with VIA for same-day treatment in cervical precancer screening among PLWHIV looks feasible. The improved specificity will reduce the overtreatment rate, loss to follow-up associated with repeat clinic visits and improve completion of continuum of care. [ABSTRACT FROM AUTHOR]

Background: Colposcopy was referred in cases with severe abnormalities in co-testing. Although p16/Ki67 dual staining reduced the referral rate, its sensitivity and specificity need to be enhanced. Methods: The expressions of p16, Ki-67, SMAD3, YAP1, RELA were evaluated in the colposcopy referral population. The inclusion criteria included 30– 60 years and diagnosed with HPV16/18-positive, other HR-HPV-positive with ASCUS, LSIL, AGC (atypical glandular cell) in co-testing. Colposcopies, endocervical curettages of cervical biopsies were also collected. Cases were excluded if there were no biopsies, if the interval between a cervical screening test and biopsies was more than 6 months, or if insufficient tissue was available as a formalin-fixed paraffin-embedded block. The pathology was independently reviewed by two pathologists. Discrepant interpretations were adjudicated by a third pathologist. Results: In total, 1194 of 1273 cases who were referred to colposcopy were evaluated in the present study. The sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 62.1% and 89.5%, respectively. p16+ combined with YAP1+ and/or RELA+ provided a sensitivity and specificity of 70.9% and 89.5%, respectively, while 72.8% and 86.4% were achieved by p16+ combined with YAP1+ and/or SMAD3+ and/or RELA+. In HPV16/18+ and LSIL subgroups, the sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 67.7% and 87.6%, respectively, for the former group and 58.6%, 88.8%, respectively, for the latter group. p16+, YAP1+/RELA+ showed a better performance for predicting CIN2+ with a better sensitivity and considerable specificity in the other HPV+ combined with ASCUS group than were achieved by p16+ combined with Ki-67+. RELA+ and the combination of p16 and RELA/YAP1 also provided the Max AUC area. Conclusion: Our study shows that RELA and the combination of p16 and RELA/YAP1 achieved better sensitivity and specificity for detecting morphologically CIN2+ lesions. [ABSTRACT FROM AUTHOR]

Purpose: Treatment of cervical precancer is the primary aim in secondary prevention of cervical cancer. The purpose of this study was to examine factors associated with treatment uptake among women with acetic acid/Lugol's iodine positive lesions identified by digital cervicography (DC) in a cervical cancer prevention program in Cameroon. Patients and Methods: We conducted a cross-sectional survey of medical records from 2013 to 2018 of 755 women in Cameroon who screened positive with acetic acid/Lugol's iodine in 2013. Results: Of the 755 women, 422 (55.9%) had treatment/biopsy on the same day or followed up later, but only 344 (45.6%) received treatment/biopsy and 333 (44.1%) were lost to follow-up. Overall, 180 (52.3%) of the 344 women were treated/biopsied the same day they were screened, and 164 (47.7%) were treated/biopsied after the initial visit. Women aged 30– 49 and HIV-positive women were significantly more likely to have received treatment or returned for treatment than women less than 30 and HIV-negative women. Of the 266 women who followed up at a later date, the lesions of 78 (29.3%) women regressed spontaneously without treatment. Women with low-grade lesions, HIV-negative women and women who had follow-up more than a year after the initial exam were significantly more likely to have spontaneous regression with regression rates of 30.6%, 32.1% and 62.2%, respectively (p< 0.001). Age was not a significant determinant of spontaneous regression (p=0.149). Conclusion: Efforts to increase treatment uptake are needed in this population, including adherence to same day "See and treat" policies. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the outcomes of cryotherapy and thermo‐coagulation in the treatment of cervical precancers. Method: Prospective analytical study. Women who screened positive to visual inspection with acetic acid and confirmed by colposcopy using the Swede's score were randomized to receive either cryotherapy or thermo‐coagulation. Participants were re‐evaluated 6 months later. Results: A total of 11 124 women were screened. Only 1023 of the 1294 colposcopically confirmed positive cases were eligible for ablative therapy. Five hundred and twelve women received cryotherapy while 511 women received thermo‐coagulation. Cryotherapy had similar cure rate with thermo‐coagulation (85.5 vs 89.2%, P = 0.09). The mean patient satisfaction score for thermo‐coagulation was higher than that for cryotherapy (3.9 ± 1.3 vs 2.8 ± 1.7; P < 0.0001). The mean duration of treatment per patient was higher for cryotherapy than thermo‐coagulation (660.0 ± 0.0 vs 50.9 ± 15.3 s, P < 0.0001). The mean cost of treatment per patient was significantly higher for cryotherapy than for thermo‐coagulation (2613.1 ± 254.9 vs 533.2 ± 45.2 Nigerian Naira, P < 0.0001). Higher proportion of women who had thermo‐coagulation reported no side effect (55.2 vs 12.5%, P < 0.0001). Conclusion: Cryotherapy and thermo‐coagulation have similar efficacy in the treatment of cervical precancers. Thermo‐coagulation offers lower cost and lower duration of treatment, less side effects and higher patient satisfaction than cryotherapy. Thermo‐coagulation should be the recommended ablative treatment method for low‐resource settings of the world. [ABSTRACT FROM AUTHOR]

Purpose: This pilot study explores the barriers to adherence to follow-up among women with cervical precancer in urban Cameroon. While follow-up of women with a positive screening of cervical precancer is the most important aspect of cervical cancer secondary prevention, women with cervical precancer do not adhere frequently to recommended follow-up schedule in Cameroon. The aim of the study was to explore and describe the barriers and facilitators to follow-up for cervical precancer among women infected and uninfected with HIV in Cameroon. Participants and methods: A qualitative research design was used to answer the research questions. Participants included eight HIV-infected and -uninfected women diagnosed with cervical precancer and 19 nurses. Data were collected by in-depth individual patient interviews and focus groups with nurses. An interview guide with open-ended questions, using the social ecological model as a framework, included questions that addressed the complexities of the lives of individuals and professionals within a relational context. The interviews were audio-taped and transcribed verbatim in English language. Thematic analysis of data was completed with no epistemological or theoretical perspective underpinning the analyses. Results: Four major themes emerged from the study. They were clinic, personal, and social barriers, and strategies to improve follow-up. Conclusion: The use of reminder phone calls and fee reduction, coupled with peer counseling and navigation of women who have been diagnosed with cervical precancer, could be effective ways of improving adherence to follow-up. Further research is needed to explore the same phenomenon among women in rural areas, especially those who were initially attended to in mobile clinics. [ABSTRACT FROM AUTHOR]

We report the ex vivo results of an in-house fabricated portable device based on polarized fluorescence measurements in the clinical environment. This device measures the polarized fluorescence and elastic scattering spectra with 405-nm laser and white light sources, respectively. The dominating fluorophore with 405-nm excitation is flavin adenine dinucleotide (FAD) with a fluorescence peak around 510 nm. The measured spectra are highly modulated by the interplay of scattering and absorption effects. Due to this, valuable information gets masked. To reduce these effects, intrinsic fluorescence was extracted by normalizing polarized fluorescence spectra with polarized elastic scattering spectra obtained. A number of fluorophores contribute to the fluorescence spectra and need to be decoupled to understand their roles in the progression of cancer. Nelder-Mead method has been utilized to fit the spectral profile with Gaussian to decouple the different bands of contributing fluorophores (FAD and porphyrin). The change in concentration of FAD during disease progression manifests in the change in ratio of total area to FWHM of its Gaussian profile. Receiver operating characteristic (ROC) curve analysis has been used to discriminate different grades of cervical precancer by using the ratio as input parameter. The sensitivity and specificity for discrimination of normal samples from CIN I (cervical intraepithelial neoplasia) are 75% and 54%, respectively. Further, the normal samples can be discriminated from CIN II samples with 100% and 82% sensitivity and specificity, respectively, and the CIN I from CIN II samples can also be discriminated with 100% sensitivity and 90% specificity, respectively. The results show that the change in the concentration of (FAD) can be used as a marker to discriminate the different grades of the cancer and biochemical changes at an early stage of the cancer can also be monitored with this technique. [ABSTRACT FROM AUTHOR]

Women previously vaccinated against human papillomavirus (HPV) type 16 and 18 are now reaching the age (21 years) at which cervical-cancer screening is recommended in the U.S. The impact of HPV vaccination on risks of cervical precancer following a positive and negative screen among women aged 21-24 years who just started routine cervical screening are not well described. Therefore, three-year absolute and relative (RR) cumulative risks of cervical intraepithelial neoplasia grade 2 or more severe diagnoses (≥CIN2) and grade 3 or more severe diagnoses (≥CIN3) were estimated for women undergoing cervical screening at Kaiser Permanente Northern California. Risks were estimated in women aged 21-24 years (n = 75,008) undergoing cervical screening since late 2006, 6 months after HPV vaccination became available; women were categorized vaccinated at ages <18, 18-20, and 21-24 years and compared to those who were unvaccinated. Three-year risks were estimated for normal, low-grade, and high-grade cytology results. Three-year risks of ≥CIN2 and ≥CIN3 for unvaccinated women following low-grade cytology were 10.89% for and 3.70%, respectively. By comparison, Three-year risks of ≥CIN2 and ≥CIN3 were 5.26% (RR = 0.48, 95%CI = 0.24-0.99) and 0.99% (RR = 0.27, 95%CI = 0.06-1.13), respectively, for women vaccinated under the age of 18 years. Three-year ≥CIN2 and ≥CIN3 risks were lower for those HPV vaccinated at younger age for any screening result (ptrend ≤ 0.01 for all comparisons). These data support initiating cervical screening at an older age or changing the management of a low-grade cytology result in women aged 21-24 years who were vaccinated against HPV younger than age of 18 years. [ABSTRACT FROM AUTHOR]

Objective: There are no currently approved options for medical management of cervical intraepithelial neoplasia (CIN) 2/3. This article describes the use of intravaginal 5% 5-fluorouracil (5-FU) for treatment of CIN 2/3. Materials and Methods: This retrospective case-series describes 25 women who used low-dose intravaginal 5-FU (2 g once every 2 weeks for 8 doses) between January 1, 2014, and July 30, 2018, for the following indications: primary therapy (CIN 2/3 present on colposcopic biopsy); adjuvant therapy (positive margins after excisional procedure); or neoadjuvant therapy (excision delayed due to severe immunodeficiency). Descriptive analyses were performed. Results: Within the 12-month follow-up period, 16 women (64%) of women had regression to CIN 1 or normal histology after use of low dose 5-FU. Seven of the 8 who did not regress reported completing < 4 of the 8 recommended doses of 5-FU. Six women discontinued 5-FU treatment: 2 due to allergy, 3 due to self-resolving local side-effects, and 1 due to desire to stop contraception. Conclusions: Based on this study, there is patient interest and potential efficacy in alternatives to conventional management of CIN. The use of intravaginal therapies for treatment of CIN 2/3 merits further study. [ABSTRACT FROM AUTHOR]

There is an unmet need for methods to help in the early detection of cervical precancer. Optical spec-troscopy-based techniques, such as Raman spectroscopy, have shown great potential for diagnosis of different cancers, including cervical cancer. However, relatively few studies have been carried out on liquid-based cytology (LBC) pap test specimens and confounding factors, such as blood contamination, have been identified. Previous work reported a method to remove blood contamination before Raman spectroscopy by pretreatment of the slides with hydrogen peroxide. The aim of the present study was to extend this work to excessively bloody samples to see if these could be rendered suitable for Raman spectroscopy. LBC ThinPrep specimens were treated by adding hydrogen peroxide directly to the vial before slide preparation. Good quality Raman spectra were recorded from negative and high grade (HG) cytology samples with no blood contamination and with heavy blood contamination. Good classification between negative and HG cytology could be achieved for samples with no blood contamination (sensitivity 92%, specificity 93%) and heavy blood contamination (sensitivity 89%, specificity 88%) with poorer classification when samples were combined (sensitivity 82%, specificity 87%). This study demonstrates for the first time the improved potential of Raman spectroscopy for analysis of ThinPrep specimens regardless of blood contamination. [ABSTRACT FROM AUTHOR]

Precancerous cervical lesions precede the development of invasive cervical cancer by 10-20 years, making cervical cancer preventable if these lesions are detected and effectively treated. Treatment has evolved in the last few decades and now includes ablative options that can be performed in lower-resource settings where surgical excision is not feasible or routinely available. Gas-based cryotherapy, which freezes cervical tissue to induce localized necrosis, is the most commonly used ablative treatment. However, its implementation in low-resource settings is difficult because the refrigerant gas can be difficult to procure and transport, and is expensive. New cryotherapy devices that do not require an external supply of gas appear promising. Thermal coagulation, which burns cervical tissue to induce necrosis, has become more widely available in the last few years owing to its portability and the feasibility of using battery-powered devices. These two ablative treatments successfully eradicate 75%-85% of high-grade cervical lesions and have minor adverse effects. [ABSTRACT FROM AUTHOR]

This invited commentary discusses the article by Richards et al. describing differences in rates of on-time HPV vaccination and cervical cancer screening in 2018 among enrollees in different insurance plans. The commentary focuses on the larger problem of low vaccination HPV rates and decreasing cervical cancer screening rates seen across all sectors. We outline challenges posed by the COVID-19 pandemic on HPV vaccination and cervical cancer screening, and discuss opportunities to improve cervical cancer prevention. [ABSTRACT FROM AUTHOR]

Cervical cancer is a public health emergency in low- and middle-income countries where resource limitations hamper standard-of-care prevention strategies. The high-resolution endomicroscope (HRME) is a low-cost, point-of-care device with which care providers can image the nuclear morphology of cervical lesions. Here, we propose a deep learning framework to diagnose cervical intraepithelial neoplasia grade 2 or more severe from HRME images. The proposed multi-task convolutional neural network uses nuclear segmentation to learn a diagnostically relevant representation. Nuclear segmentation was trained via proxy labels to circumvent the need for expensive, manually annotated nuclear masks. A dataset of images from over 1600 patients was used to train, validate, and test our algorithm; data from 20% of patients were reserved for testing. An external evaluation set with images from 508 patients was used to further validate our findings. The proposed method consistently outperformed other state-of-the art architectures achieving a test per patient area under the receiver operating characteristic curve (AUC-ROC) of 0.87. Performance was comparable to expert colposcopy with a test sensitivity and specificity of 0.94 (p = 0.3) and 0.58 (p = 1.0), respectively. Patients with recurrent human papillomavirus (HPV) infections are at a higher risk of developing cervical cancer. Thus, we sought to incorporate HPV DNA test results as a feature to inform prediction. We found that incorporating patient HPV status improved test specificity to 0.71 at a sensitivity of 0.94. • Deep learning to detect cervical precancer from high-resolution in vivo optical images. • Multi-task nuclear segmentation drives the network's attention to nuclear features. • Method outperformed state-of-the-art benchmarks even as training data was reduced. • Performance for independent validation set matched expert clinical impression. • Combining optical image data with HPV test results improved ability to detect cervical precancer. [ABSTRACT FROM AUTHOR]

Cervical cancer is a disease which still affects too many women, even if we live in the XXIst century. Pap smear represented for few decades an important tool in the diagnosis of this pathology and is consider the most important screening method with a good acceptance from the patients. We know the importance of human papilloma virus (HPV) infection in cervical malignant pathology and its evolution. The diagnosis of presence of HPV-high risk type can give a prognosis for precancerous lesions. These lesions appear with months or years before malignant affections of the cervix and if we put the diagnosis of an increased cell proliferation, or we demonstrate the infection with HPV-HR, we can use this time to monitories or give the appropriate treatment for the precancerous lesions. There are immunomarkers for these kind of investigations and from them, we used Ki-67 and p53, trying to demonstrate the usefulness of immunochemical markers in the diagnosis and prognosis of cervical precancerous lesions. [ABSTRACT FROM AUTHOR]

Abstract: Human papillomavirus (HPV) genotyping could be clinically useful, depending on the results of large, prospective studies like the HPV persistence and progression (PaP) cohort. The cohort is based on genotyping and follow-up of Hybrid Capture-positive women at Kaiser Permanente, Northern California. HPV DNA testing by Hybrid Capture 2 requires denaturation with alkali, possibly damaging the DNA for optimal PCR-based genotyping. A feasibility study was conducted on paired aliquots of anonymized specimens from 100 women with low-grade intraepithelial lesion cytology. Test aliquots were left in denaturant for 10 or 18h at 4°C and then neutralized; comparison aliquots were not denatured but diluted to match the timing, temperature, concentration and salt conditions of the treated specimens. The masked aliquots were tested using a commercialized PCR-based assay that detects of 37 HPV genotypes. There was no overall effect of treatment on test positivity or number of types. HPV16 was marginally more likely to be detected in untreated versus treated aliquots (P =0.09) but HPV45 was marginally more likely to be detected in treated than untreated aliquots (P =0.07), suggesting that these differences represented chance (intra-test variability). It can be concluded that residual Hybrid Capture-positive specimens can be genotyped by PCR after Hybrid Capture 2 processing. [Copyright &y& Elsevier]

Background: Investigation of the potential association of single nucleotide polymorphisms (SNPs) at –308 G/A and –238 G/A of Tumor necrosis factor α (TNFα) with susceptibility to HPV-16 associated cervical cancer in Indian women. Methods: The study included 165 histologically confirmed cases with 45 precancer and 120 cancer patients and an equal number (165) of healthy controls with normal cervical cytology. PCR-RFLP was employed to analyze TNFα promoter polymorphisms, which were confirmed by direct sequencing. Both patients and controls were screened for Human Papillomavirus (HPV) infection. Results: The frequency of –308 A allele in TNFα was significantly higher in cases compared with control subjects (21% in cases vs. 9% in controls; p<0.01), with an odds ratio of 2.7 (95% CI = 1.41–5.15). Also, women carrying A allele for this locus presented 3 times increased susceptibility to HPV 16 infection as evident from carrier genotype distribution between HPV positive cases and control subjects (24% in HPV positive cases vs. 9% in controls; p<0.01; OR = 3.1; 95% CI = 1.60–6.03). No such association was found for TNFα–238 (G/A) polymorphism with the risk of development of cervical cancer. Conclusion: It suggests that SNP at –308 (G/A) of TNFα promoter may represent an increased risk for HPV infection and development of cervical cancer in Indian women. [ABSTRACT FROM AUTHOR]

Objectives Sexually transmitted diseases (STDs) and anogenital cancers are the major health problems in Indian women but no reliable estimate of the prevalence of either genital chlamydial infection or human papillomavirus (HPV) infection in STD patients is available. The aim of this study was to detect the frequency of Chlamydia trachomatis and the most prevalent high-risk HPV type 16 (HPV 16) infection in Indian women, with STDs and precancerous and cancerous lesions of the uterine cervix by polymerase chain reaction (PCR), and their comparison with those of conventional serology and antigen tests used for C. trachomatis detection. Methods Endocervical swabs or scrapes were collected from 50 women with STDs and 30 normal healthy women attending the STD clinics of Smt. Sucheta Kripalani Hospital, New Delhi. Scraped cervical cell specimens were also collected from 50 women with precancerous and cancerous lesions of the uterine cervix. Detection of C. trachomatis and HPV was carried out by PCR using chlamydia and HPV genome-specific oligonucleotide primers. The detection of chlamydial antigen and IgG-specific antibodies was carried out by enzyme immunoassay (EIA) and serological enzyme-linked immunosorbent assay (ELISA), respectively. Results A chlamydia plasmid-based PCR assay detected 50% (25 of 50) positivity of C. trachomatis in STD patients and HPV 16 DNA was found in 30% (15 of 50) of these cases which are significantly higher than those found in healthy controls. The PCR estimate of chlamydia was found to be higher than its reported frequency by tissue culture. The EIA could detect chlamydial antigen in only 13 cases (26%) while serological ELISA revealed evidence of chlamydia IgG-specific antibodies in 26 (52%) cases. Interestingly, in women with precancerous and cancerous lesions, the rate of HPV 16 infection was very high (52% and 72%, respectively), whereas the frequency of chlamydia infection was found to be 12–22% only. Occurrence of other sexually transmitted agents was also evaluated in the women. Conclusions This is the first PCR estimate of genital chlamydial (50%) and HPV 16 (30%) infection in STD patients and women with precancerous and cancerous lesions of the uterine cervix in India. The PCR method seems to be a good alternative to tissue culture. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has a major impact on a wide range of health outcomes. Disruptions of elective health services related to cervical screening, management of abnormal screening test results, and treatment of precancers, may lead to increases in cervical cancer incidence and exacerbate existing health disparities. Modeling studies suggest that a short delay of cervical screening in subjects with previously negative HPV results has minor effects on cancer outcomes, while delay of management and treatment can lead to larger increases in cervical cancer. Several approaches can mitigate the effects of disruption of cervical screening and management. HPV-based screening has higher accuracy compared to cytology, and a negative HPV result provides longer reassurance against cervical cancer; further, HPV testing can be conducted from self-collected specimens. Self-collection expands the reach of screening to underserved populations who currently do not participate in screening. Self-collection and can also provide alternative screening approaches during the pandemic because testing can be supported by telehealth and specimens collected in the home, substantially reducing patient-provider contact and risk of COVID-19 exposure, and also expanding the reach of catch-up services to address backlogs of screening tests that accumulated during the pandemic. Risk-based management allows prioritizing management of patients at highest risk of cervical cancer while extending screening intervals for those at lowest risk. The pandemic provides important lessons for how to make cervical screening more resilient to disruptions and how to reduce cervical cancer disparities that may be exacerbated due to disruptions of health services. [ABSTRACT FROM AUTHOR]

Simple Summary: Persistent high-risk human papillomavirus (HPV) infection can lead to cervical precancer and cancer. Recently, HPV testing has been introduced for primary cervical screening, but the HPV DNA test cannot distinguish between transient and persistent HPV infection. Thus, there is an unmet clinical need to develop a new test to identify women with a high-risk persistent HPV infection. Raman spectra were recorded from cervical smear samples (n = 60) and, on the basis of HPV DNA and HPV mRNA test results, a classifier was developed to identify persistent HPV infection. A further blinded independent test set (n = 14) was used to validate the model, and sensitivity of 90% and specificity of 100% were achieved. Improved triage would allow women with a high-risk persistent HPV infection to be referred for immediate treatment, while women with a low-risk transient infection could avoid overtreatment. The role of persistent high-risk human papillomavirus (HPV) infection in the development of cervical precancer and cancer is now well accepted, and HPV testing has recently been introduced for primary cervical screening. However, the low specificity of HPV DNA testing can result in large numbers of women with an HPV-positive result, and additional triage approaches are needed to avoid over-referral to colposcopy and overtreatment. The aim of this study was to assess Raman spectroscopy as a potential triage test to discriminate between transient and persistent HPV infection. HPV DNA status and mRNA status were confirmed in ThinPrep® cervical samples (n = 60) using the Cobas 4800 and APTIMA HPV test, respectively. Raman spectra were recorded from single-cell nuclei and subjected to partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 14). Sensitivity of 85% and specificity of 92% were achieved for the classification of transient and persistent HPV infection, and this increased to 90% sensitivity and 100% specificity when mean sample spectra were used instead of individual cellular spectra. This study showed that Raman spectroscopy has potential as a triage test for HPV-positive women to identify persistent HPV infection. [ABSTRACT FROM AUTHOR]

The primary goal of cervical screening is to identify women with cervical precancers who need treatment to prevent invasive cervical cancer. Cervical cancer screening programs in high-resource settings rely on a multi-step process to reassure the majority of women of low cancer risk and treat the small number of women at high risk of precancer and cancer. The requirement of major resource investment for training and capacity building of multi-step cervical cancer screening programs prevents their introduction in low- and middle-income countries (LMICs). Screen-and-treat programs have been evaluated and introduced in some countries that use mainly ablative treatment as primary treatment options. Ablative treatment with cryotherapy and thermal ablation has a favorable tradeoff of benefits and harms and can be introduced more widely than excisional treatment in LMICs. While most women below 40 are eligible for ablative procedures, fewer than 50% are eligible by age 50 and ablative treatment is not appropriate over age 50. Excisional treatment is required for women ineligible for ablative treatment. Since screening programs in LMICs necessarily detect invasive cancers, cancer treatment and palliative care needs to be considered as well. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the depth of necrosis achieved using CO2- and N2O-cryotherapy. Method: We treated 20 women with CO2-cryotherapy and 20 with N2O-cryotherapy 24 h prior to undergoing total hysterectomy for reasons unrelated to cervical cancer. Depth of necrosis in the ectocervix was measured on surgically removed tissue. Results: The mean depth of necrosis for the anterior lip achieved by N2O-cryotherapy was 5.3 mm compared with 3.4 mm by CO2-cryotherapy (P <0.001). We found similar results for the posterior lip (5.0 vs 3.1 mm; P <0.001). N2O-cryotherapy was more likely than CO2-cryotherapy to achieve a depth of necrosis of ≥4.8 mm for the anterior lip (75% vs 15%; P <0.001) and posterior lip (60% vs 5%; P <0.001). Conclusions: Our study showed that CO2-cryotherapy may not achieve the depth of necrosis necessary to completely destroy cervical precancer and therefore may be less robust than N2O-cryotherapy. [Copyright &y& Elsevier]

Abstract: Objectives. : We explore the clinical potential of reflectance and fluorescence confocal microscopy to image the morphologic and biochemical changes associated with precancer, in order to aid in the detection and diagnosis of cervical dysplasia. Methods. : Cervical epithelial tissue samples imaged ex vivo or in vivo were obtained from M. D. Anderson Cancer Center and Lyndon B. Johnson Hospital in Houston, Texas. Confocal reflectance microscopy was used to image ex vivo cervical biopsies and in vivo cervical tissue. Confocal fluorescence microscopy was used to image ex vivo cervical tissue slices. Results. : We present reflectance and fluorescence confocal images of cervical tissue demonstrating the ability to differentiate between normal and abnormal cervical tissue. Conclusions. : We believe that there is significant clinical potential for confocal microscopy to provide a sensitive and specific method for cervical precancer detection. [Copyright &y& Elsevier]