Safety and Acceptability of Three Ablation Treatments for High-Grade Cervical Precancer: Early Data From a Randomized Noninferiority Clinical Trial.

PURPOSE: This ongoing trial is comparing the efficacy and safety of three ablation treatments for cervical intraepithelial neoplasia grade 2 or higher. Here, we present early data regarding pain, side effects, and acceptability of CO2 gas-based cryotherapy (CO2), nongas cryotherapy, and thermal ablation (TA). Efficacy results are expected to become available in late 2023. MATERIALS AND METHODS: This noninferiority randomized trial is taking place in El Salvador, China, and Colombia. Patients are 1,152 eligible women with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or higher who will receive one of three ablation treatments. Pain is measured before, during, and after treatment with a visual analog scale (1-10). Side effects and acceptability are assessed at 6 weeks. RESULTS: To date, 1,024 of 1,152 (89%) women were randomly assigned to treatment. The median pain level was higher during TA (4, IQR = 4) than CO2 (2, IQR = 4) or nongas cryotherapy (2, IQR = 4) (P < .01, range: 0-10). The most common post-treatment symptom was watery discharge, reported by 97.9% of women, and it lasted longer in the CO2 group than the other two treatments (in days, median [IQR]: CO2 = 20[20], nongas cryotherapy = 15[10], TA = 18[15], P < .01). Bleeding was reported more frequently in women treated with TA (27.6%) than CO2 (17.5) or nongas cryotherapy (18.7%) (P < .01). The majority of patients reported being very satisfied with the treatment they received at 6 weeks (91%) and again at 12 months post-treatment (97%). CONCLUSION: Despite differences in pain and side effects across ablation treatments, all were safe and highly acceptable to patients. In addition to efficacy, considerations such as cost and portability may be more significant in choosing a treatment method.

Performance Evaluation of Parametric and Nonparametric Methods When Assessing Effect Measure Modification.

Effect measure modification is often evaluated using parametric models. These models, although efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often require larger samples to achieve a given accuracy. We conducted a simulation study to evaluate performance tradeoffs between correctly specified parametric and nonparametric models to detect effect modification of a binary exposure by both binary and continuous modifiers. We evaluated generalized linear models and doubly robust (DR) estimators, with and without sample splitting. Continuous modifiers were modeled with cubic splines, fractional polynomials, and nonparametric DR-learner. For binary modifiers, generalized linear models showed the greatest power to detect effect modification, ranging from 0.42 to 1.00 in the worst and best scenario, respectively. Augmented inverse probability weighting had the lowest power, with an increase of 23% when using sample splitting. For continuous modifiers, the DR-learner was comparable to flexible parametric models in capturing quadratic and nonlinear monotonic functions. However, for nonlinear, nonmonotonic functions, the DR-learner had lower integrated bias than splines and fractional polynomials, with values of 141.3, 251.7, and 209.0, respectively. Our findings suggest comparable performance between nonparametric and correctly specified parametric models in evaluating effect modification.

Effect of Human Development Index and other socioeconomic factors on mortality-to-incidence ratio of lips and oral cavity cancer in Mexican states: an ecological study.

OBJECTIVES: To assess the association between the Human Development Index (HDI) and covariates on the mortality-to-incidence ratio (MIR) of lips and oral cavity cancer (LOCC) in Mexico. DESIGN: Ecological study. SETTING: Data from 32 Mexican states for year 2019. PARTICIPANTS: Data set of male and female populations from Mexico. EXPOSURES: Socioeconomic conditions based on HDI and covariates related to healthcare system capacity (total health spending per capita, school dropout and ratio of medical personnel in direct contact with patients). PRIMARY AND SECONDARY OUTCOME MEASURES: MIR of LOCC by state and sex was calculated from the Global Burden of Disease Study website for year 2019. Data for calculating HDI 2019 by state and covariates were obtained from the National Institute of Statistics and Geography. A multiple regression model was constructed to measure the effects of HDI and covariates on LOCC-MIR. RESULTS: Among the states with the highest HDI (>0.780), Colima had the highest aged-standardised rates per 100.000 in men for incidence (5.026) and mortality (3.118). The greatest burden of the disease was found on men, with the highest Men:Women MIR in Colima (3.10) and Baja California Sur (2.73). The highest MIR (>0.65) was found among the states with the lowest HDI (Oaxaca and Chiapas). For each unit of increase of the HDI there was a decrease in the LOCC- MIR of -0.778, controlling for the covariates. The most suitable regression model explained the 57% (F (p): 0.000) of the variance. CONCLUSIONS: Men were most affected by LOCC in Mexican states. The highest MIRs of LOCC were found in the states with the highest HDI. But a worse prognosis of the disease, expressed as a higher MIR, is expected in contexts with lower HDI in the country, even with lower MIRs.

Outcomes for Step-Wise Implementation of a Human Papillomavirus Testing-Based Cervical Screen-and-Treat Program in El Salvador.

PURPOSE: The Cervical Cancer Prevention in El Salvador (CAPE) project is a public-sector intervention introducing lower-cost human papillomavirus (HPV) testing in all four departments of the Paracentral region that screened a total of 28,015 women. After demonstrating success of an HPV screen-and-treat (S&T) algorithm over colposcopy management in the first two phases, the third phase scaled up the S&T strategy. We present results from phase III and evaluate S&T components across the entire project. METHODS: During phase III, 17,965 women age 30-59 years underwent HPV testing. HPV-positive women were asked to return and, if eligible, received gas-based cryotherapy. We compare loss to follow-up and time intervals between S&T steps across the three phases. RESULTS: There were no differences in HPV positivity across phases (phase I, 11.9%; phase II, 11.4%; phase III, 12.3%; P = .173). Although most HPV-positive women completed indicated follow-up procedures within 6 months in phases I (93.3%, 111 of 119) and II (92.3%, 429 of 465), this proportion declined to 74.9% (1,659 of 2,214; P < .001) in phase III. Mean days between testing and delivery of results to patients increased over program phases (phase I, 23.2 days; phase II, 46.7 days; phase III, 99.8 days; P < .001). CONCLUSION: A public-sector implementation of an HPV-based S&T algorithm was successfully scaled up in El Salvador, albeit with losses in efficiency. After CAPE, the Ministry of Health changed its screening guidelines and procured additional tests to expand the program.

Cervical Cancer Screening with Human Papillomavirus Self-Sampling Among Transgender Men in El Salvador.

Purpose: Sexual and gender minority persons in low-income countries have very limited access to routine health services. This study evaluated the feasibility of using a self-sampled human papillomavirus (HPV) test to increase access to screening for cervical cancer among transgender men in El Salvador. Methods: We partnered with a local advocacy organization for recruitment. A total of 24 transgender men (men assigned female at birth) ages 19-55 were enrolled and provided consent. Questionnaires assessed sociodemographics, health and sexual histories, and knowledge about HPV and cervical cancer. Screening was performed with a self-sampled HPV test. Participants with a positive test were offered colposcopy and cryotherapy treatment, if appropriate. Those with a negative test were advised to return in 5 years for rescreening. Results: Out of 24 consenting participants, 23 (95.83%) agreed to conduct HPV self-sampling, and 22/23 (95.65%) expressed willingness to self-sample in the future. Among self-sampled individuals, 3/23 (13%) tested positive and accepted colposcopy and biopsy. Analyses of biopsied tissue revealed one case of cervical intraepithelial neoplasia grade 1. Conclusion: HPV self-sampling and subsequent procedures were accepted by the majority of participants. This screening method may be a viable alternative to cytology among transgender men in El Salvador.

The cost-effectiveness of human papillomavirus self-collection among cervical cancer screening non-attenders in El Salvador.

Cervical cancer screening with human papillomavirus (HPV) DNA testing has been incorporated into El Salvador's national guidelines. The feasibility of home-based HPV self-collection among women who do not attend screening at the clinic (i.e., non-attenders) has been demonstrated, but cost-effectiveness has not been evaluated. Using cost and compliance data from El Salvador, we informed a mathematical microsimulation model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis from the societal perspective. We estimated the reduction in cervical cancer risk, lifetime cost per woman (2017 US$), life expectancy, and incremental cost-effectiveness ratio (ICER, 2017 US$ per year of life saved [YLS]) of a program with home-based self-collection of HPV (facilitated by health promoters) for the 18% of women reluctant to screen at the clinic. The model was calibrated to epidemiologic data from El Salvador. We evaluated health and economic outcomes of the self-collection intervention for women aged 30 to 59 years, alone and in concert with clinic-based HPV provider-collection. Home-based self-collection of HPV was projected to reduce population cervical cancer risk by 14% and cost $1210 per YLS compared to no screening. An integrated program reaching 99% coverage with both provider- and home-based self-collection of HPV reduced cancer risk by 74% (compared to no screening), and cost $1210 per YLS compared to provider-collection alone. Self-collection facilitated by health promoters is a cost-effective strategy for increasing screening uptake in El Salvador.

Evaluation of two alternative ablation treatments for cervical pre-cancer against standard gas-based cryotherapy: a randomized non-inferiority study.

INTRODUCTION: Gas-based cryotherapy is the conventional ablative treatment for cervical pre-cancer in low-income settings, but the use of gas poses significant challenges. We compared the depth of necrosis induced by gas-based cryotherapy with two gas-free alternatives: cryotherapy using CryoPen,and thermoablation. METHODS: We conducted a five-arm randomized non-inferiority trial: double-freeze carbon dioxide (CO2) cryotherapy (referent), single-freeze CO2 cryotherapy, double-freeze CryoPen, single-freeze CryoPen, and thermoablation. Subjects were 130 women scheduled for hysterectomy for indications other than cervical pathology, and thus with healthy cervical tissue available for histological evaluation of depth of necrosis post-surgery. The null hypothesis was rejected (ie, conclude non-inferiority) if the upper bound of the 90% confidence interval (90% CI) for the difference in mean depth of necrosis (referent minus each experimental method) was <1.14 mm. Patient pain during treatment was reported on a scale of 0 (no pain) to 10 (worst pain). RESULTS: A total of 133 patients were enrolled in the study. The slides from three women were deemed unreadable. One patient was excluded because her hysterectomy was postponed for reasons unrelated to the study, and two patients were excluded because treatment application did not follow the established protocol. For the remaining 127 women, mean depth of necrosis for double-freeze CO2 (referent) was 6.0±1.6 mm. Differences between this and other methods were: single-freeze CO2 = 0.4 mm (90% CI -0.4 to 1.2 mm), double-freeze CryoPen= 0.7 mm (90% CI 0.04 to 1.4 mm), single-freeze CryoPen= 0.5 mm (90% CI -0.2 to 1.2 mm), and thermoablation = 2.6 mm (90% CI 2.0 to 3.1 mm). Mean pain levels were 2.2±1.0 (double-freeze CO2 cryotherapy), 1.8±0.8 (single-freeze CO2 cryotherapy), 2.5±1.4 (double-freeze CryoPen), 2.6±1.4 (single-freeze CryoPen), and 4.1±2.3 (thermoablation). DISCUSSION: Compared with the referent, non-inferiority could not be concluded for other methods. Mean pain scores were low for all treatments. Depth of necrosis is a surrogate for treatment efficacy, but a randomized clinical trial is necessary to establish true cure rates.

Ablative Therapies for Cervical Intraepithelial Neoplasia in Low-Resource Settings: Findings and Key Questions.

Barriers to access for cervical precancer care in low-resource settings go beyond cost. Gas-based cryotherapy has emerged as the standard treatment in these areas, but there are barriers to this technology that have necessitated the development and implementation of affordable and portable alternatives. This review identifies knowledge gaps with regard to technologies primarily used in low-resource settings, including standard cryotherapy, nongas-based cryotherapy, and thermoablation. These gaps are addressed using evidence-based guidelines, patient and provider acceptability, long-term obstetric outcomes, and treatment of women with HIV infection. This review highlights the need for prospective studies that compare ablative methods, especially given the increasing use of thermoablation.

The Impact of Computing Interpregnancy Intervals Without Accounting for Intervening Pregnancy Events.

BACKGROUND: Short interpregnancy intervals (IPI) are associated with poor birth outcomes. Often, only livebirths are considered to estimate IPI. The objective of our work is to explore whether the associations between demographic, behavioural, and pregnancy variables and IPI change when events other than livebirth are included. METHODS: We used data from the 2006-10 and 2011-13 period of the National Survey of Family Growth (NSFG). We defined IPI using the conception date of the index pregnancy and the event date of the previous one ending in (i) livebirth; (ii) stillbirth; (iii) miscarriage; (iv) abortion; or (v) any of these events. Risk ratios (RR) were estimated for short IPI (<18 months), and demographic, pregnancy, and behavioural variables using log-linear models. RESULTS: When intervening events are included, the association between short IPI and its predictors vary by definition, especially for unintended versus intended pregnancies (only livebirth risk ratio [RR] 1.34, 95% confidence interval [CI] 1.2, 1.5) versus livebirth and miscarriage RR 1.14, 95% CI 1.0, 1.3) and women older than 30 vs. younger than 20 at resolution of the previous pregnancy (only livebirth RR 1.22, 95% CI 1.0, 1.5 versus livebirth and miscarriage RR 1.36, 95% CI 1.2, 1.6). CONCLUSIONS: Including miscarriage as an intervening event in the calculation of IPI changes the association between several risk factors and short IPI. However, the association between short IPI and preterm birth does not vary when different IPI calculations are used.

Familial autoimmune thyroid disease and PTPN-22.

AIM: Autoimmune thyroid disease (AITD) is a multifactorial disease with a genetic predisposition. The protein tyrosine phosphatase-22 (PTPN-22) gene is a powerful inhibitor of T-cell activation. The aim of this study was to compare messenger RNA (mRNA) PTPN22 expression between healthy persons and patients with hypothyroidism and with their affected relatives. METHODS: This was a cross-sectional, prospective and descriptive study. DNA was extracted from leukocytes (4,000-10,000 cells) using the Magna Pure LC 2.0 Instrument and MagNA Pure LC RNA Isolation Kit I (Roche, Germany). A real-time polymerase reaction (qPCR) was performed utilizing the primer sets specific for the PTPN-22 gene, and the succinate dehydrogenase complex, the subunit A, Flavoprotein (Fp) (SDHA) constitutive gene. All reactions were performed with the 7500 Fast Real Time PCR System (Applied Biosystems, Applera International, Inc. Cheshire, UK) employing the SYBR Advantage qPCR Premix Kit (Clontech, USA). RESULTS: Twenty five patients with AITD (hypothyroidism), all females (mean age 39.6 ± 11.8 years) and 23 control subjects (mean age 24.4 ± 4.2 years) were included in the study. There was no statistical difference between both groups in PTPN-22 mRNA expression (p = 0.125). CONCLUSION: There is no clear difference in mRNA PTPN-22 expression. The ideal genes for a systematic screening for familial AITD are yet to be found.