Multi-task network for automated analysis of high-resolution endomicroscopy images to detect cervical precancer and cancer.

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.

Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.

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.

Depth of Cervical Intraepithelial Neoplasia Grade 3 in Peruvian Women: Implications for Therapeutic Depth of Necrosis.

OBJECTIVE: To determine the involvement of cervical intraepithelial neoplasia grade 3 (CIN3) in a population of women in a lower-resource setting. METHODS: One hundred twelve consecutive cone excision specimens with histological diagnosis of CIN3 were retrieved from the National Institute of Neoplastic Diseases in Lima Peru. Two pathologists independently evaluated each specimen microscopically and confirmed 107 cases that could be measured by optical micrometry. Depth and breadth of the lesions were measured microscopically. RESULTS: The mean maximal depth of cervical involvement by CIN3 was 2 ± 0.13 mm; depth was less than 3.5 mm in 89.7% of cases and less than 5 mm in 93.5%. Mean breadth of CIN3 was 7.3 ± 4.4 mm; breadth was less than 15.9 mm in 95% of cases and less than 20.5 mm in 99.7%. The correlation coefficient between breadth and depth of CIN3 was 0.61. No significant correlation was found between age and depth. CONCLUSIONS: Depth of CIN3 involvement in a developing country is significantly deeper than that reported in the United States. Treatment selection for women with CIN3 and risk of treatment failure may vary between developing and developed countries because of the difference in the depth of lesions. Countries with underscreened populations need to consider the increased disease severity in devising treatment strategies.

Cervical Precancer Treatment in Low- and Middle-Income Countries: A Technology Overview.

Cervical cancer is the fourth leading cause of cancer-related death in women worldwide, with 90% of cases occurring in low- and middle-income countries (LMICs). There has been a global effort to increase access to affordable screening in these settings; however, a corresponding increase in availability of effective and inexpensive treatment modalities for ablating or excising precancerous lesions is also needed to decrease mortality. This article reviews the current landscape of available and developing technologies for treatment of cervical precancer in LMICs. At present, the standard treatment of most precancerous lesions in LMICs is gas-based cryotherapy. This low-cost, effective technology is an expedient treatment in many areas; however, obtaining and transporting gas is often difficult, and unwieldy gas tanks are not conducive to mobile health campaigns. There are several promising ablative technologies in development that are gasless or require less gas than conventional cryotherapy. Although further evaluation of the efficacy and cost-effectiveness is needed, several of these technologies are safe and can now be implemented in LMICs. Nonsurgical therapies, such as therapeutic vaccines, antivirals, and topical applications, are also promising, but most remain in early-stage trials. The establishment of evidence-based standardized protocols for available treatments and the development and introduction of novel technologies are necessary steps in overcoming barriers to treatment in LMICs and decreasing the global burden of cervical cancer. Guidance from WHO on emerging treatment technologies is also needed.

Synthetic osmotic dilators with adjunctive misoprostol for same-day dilation and evacuation: a randomized controlled trial.

OBJECTIVE: This study aims to evaluate buccal misoprostol as an adjunct to synthetic osmotic dilators for same-day dilation and evacuation (D&E). STUDY DESIGN: A randomized, double-blinded, placebo-controlled trial of women 16 0/7 to 20 6/7 weeks gestation desiring D&E was used. Participants received synthetic osmotic cervical dilators (Dilapan-S®) at least 4 h prior to D&E and were randomized to 400mcg buccal misoprostol or placebo 3 h preoperatively, stratified by gestational age. The primary outcome was operative time with 36 participants needed to detect a 4-min difference (two-sided α=0.05, 80% power). Secondary outcomes included total procedure time, patient and provider acceptability, baseline cervical dilation and complications. RESULTS: Twenty-nine women were enrolled (misoprostol n=14, placebo n=15) and mean operative time was similar between the groups (11.1 vs. 13.5 min, respectively, p=.17). Complications were nonsignificantly more common for participants ≥19 weeks compared to <19 weeks (22% vs. 9%, p=.62) and those who received placebo compared to misoprostol (27% vs. 7%, p=.33). Two serious adverse events in the placebo group prompted early study closure for safety and futility. Placebo participants had longer overall procedure times (24 vs. 18 min, p=.03) and less cramping preoperatively (p<.01) but similar results for other secondary outcomes compared to those receiving misoprostol. Women strongly preferred same-day cervical preparation (98%). CONCLUSIONS: Adjunctive buccal misoprostol may not decrease operative times but may decrease complications when combined with synthetic osmotic dilators for cervical preparation for same-day D&E procedures. IMPLICATIONS: Although the trial was halted early and underpowered to make conclusions about the primary outcome, complication frequency and type warrant caution for use of synthetic osmotic dilators alone for cervical preparation for same-day D&E at ≥19 weeks gestation.

Introducing a High-Risk HPV DNA Test Into a Public Sector Screening Program in El Salvador.

OBJECTIVE: In a primary human papillomavirus (HPV) screening program, we compared the 6-month follow-up among colposcopy and noncolposcopy-based management strategies for screen-positive women. MATERIALS AND METHODS: Women aged 30 to 49 years were screened with HPV DNA tests using both self-collection and provider collection of samples. Women testing positive received either (1) colposcopy management (CM) consisting of colposcopy and management per local guidelines or (2) screen-and-treat (ST) management using visual inspection with acetic acid to determine cryotherapy eligibility, with eligible women undergoing immediate cryotherapy. One thousand women were recruited in each cohort. Of these, 368 (18.4%) of 2000 women were recruited using a more intensive outreach strategy. Demographics, HPV positivity, and treatment compliance were compared across recruitment and management strategies. RESULTS: More women in the ST cohort received treatment within 6 months compared with those in the CM cohort (117/119 [98.3%] vs 64/93 [68.8%]; p < .001). Women recruited through more intensive outreach were more likely to be HPV positive, lived in urban areas, were more educated, and had higher numbers of lifetime sexual partners and fewer children. CONCLUSIONS: Women in the CM arm were less likely to complete care than women in the ST arm. Targeted outreach to underscreened women successfully identified women with higher prevalence of HPV and possibly higher disease burden.

Factors affecting attendance to cervical cancer screening among women in the Paracentral Region of El Salvador: a nested study within the CAPE HPV screening program.

BACKGROUND: Cervical cancer is the third most commonly occurring cancer among women and the fourth leading cause of cancer-related deaths in women worldwide, with more than 85 % of these cases occurring in developing countries. These global disparities reflect the differences in cervical cancer screening rates between high-income and medium- and low-income countries. At 19 %, El Salvador has the lowest reported screening coverage of all Latin American countries. The purpose of this study is to identify factors affecting public sector HPV DNA-based cervical cancer screening participation in El Salvador. METHODS: This study was nested within a public sector screening program where health promoters used door-to-door outreach to recruit women aged 30-49 years to attend educational sessions about HPV screening. A subgroup of these participants was chosen randomly and questioned about demographic factors, healthcare utilization, previous cervical cancer screening, and HPV knowledge. Women then scheduled screening appointments at their public health clinics. Screening participants were adherent if they attended their scheduled appointment or rescheduled and were screened within 6 months. The association between non-adherence and demographic variables, medical history, history of cancer, sexual history, birth control methods, and screening barriers was assessed using Chi-square tests of significance and logistic regression. RESULTS: All women (n = 409) enrolled in the study scheduled HPV screening appointments, and 88 % attended. Non-adherence was associated with a higher number of lifetime partners and being under-screened-defined as not having participated in cervical cancer screening within the previous 3 years (p = 0.03 and p = 0.04, respectively); 22.8 % of participants in this study were under-screened. CONCLUSIONS: Adherence to cervical cancer screening after educational sessions was higher than expected, in part due to interactions with the community-based health promoters as well as the educational session itself. More effective recruitment methods targeted toward under-screened women are required.

The comparative and cost-effectiveness of HPV-based cervical cancer screening algorithms in El Salvador.

Cervical cancer is the leading cause of cancer death among women in El Salvador. Utilizing data from the Cervical Cancer Prevention in El Salvador (CAPE) demonstration project, we assessed the health and economic impact of HPV-based screening and two different algorithms for the management of women who test HPV-positive, relative to existing Pap-based screening. We calibrated a mathematical model of cervical cancer to epidemiologic data from El Salvador and compared three screening algorithms for women aged 30-65 years: (i) HPV screening every 5 years followed by referral to colposcopy for HPV-positive women (Colposcopy Management [CM]); (ii) HPV screening every 5 years followed by treatment with cryotherapy for eligible HPV-positive women (Screen and Treat [ST]); and (iii) Pap screening every 2 years followed by referral to colposcopy for Pap-positive women (Pap). Potential harms and complications associated with overtreatment were not assessed. Under base case assumptions of 65% screening coverage, HPV-based screening was more effective than Pap, reducing cancer risk by ∼ 60% (Pap: 50%). ST was the least costly strategy, and cost $2,040 per year of life saved. ST remained the most attractive strategy as visit compliance, costs, coverage, and test performance were varied. We conclude that a screen-and-treat algorithm within an HPV-based screening program is very cost-effective in El Salvador, with a cost-effectiveness ratio below per capita GDP.

Acceptability of self-collected versus provider-collected sampling for HPV DNA testing among women in rural El Salvador.

OBJECTIVE: To determine the acceptability of self-collected versus provider-collected sampling among women participating in public sector HPV-based cervical cancer screening in El Salvador. METHODS: Two thousand women aged 30-49 years underwent self-collected and provider-collected sampling with careHPV between October 2012 and March 2013 (Qiagen, Gaithersburg, MD, USA). After sample collection, a random sample of women (n=518) were asked about their experience. Participants were questioned regarding sampling method preference, previous cervical cancer screening, HPV and cervical cancer knowledge, HPV risk factors, and demographic information. RESULTS: All 518 women approached to participate in this questionnaire study agreed and were enrolled, 27.8% (142 of 511 responding) of whom had not received cervical cancer screening within the past 3 years and were considered under-screened. Overall, 38.8% (n=201) preferred self-collection and 31.9% (n=165) preferred provider collection. Self-collection preference was associated with prior tubal ligation, HPV knowledge, future self-sampling preference, and future home-screening preference (P<0.05). Reasons for self-collection preference included privacy/embarrassment, ease, and less pain; reasons cited for provider-collection preference were result accuracy and provider knowledge/experience. CONCLUSION: Self-sampling was found to be acceptable, therefore screening programs could consider offering this option either in the clinic or at home. Self-sampling at home may increase coverage in low-resource countries and reduce the burden that screening places upon clinical infrastructure.

Cervical cancer screening and treatment training course in El Salvador: experience and lessons learned.

BACKGROUND: Visual inspection with acetic acid (VIA) is a simple, low-cost alternative to traditional Pap smears that could greatly benefit the amount of screening and treatment available in low-resource areas, such as rural El Salvador. The objective of this study was to train Salvadoran health providers in VIA and cryotherapy using a week-long competency course. METHODS: Health providers participated in the VIA training course, which consisted of 1 half-day of didactics, followed by 4 and 1 half days of clinical training. Pretests and posttests were administered. A 1-day didactic refresher course was administered to assess the quality of services being provided. RESULTS: Sixty-eight nurses and physicians completed the training course. Each trainee screened approximately 120 women and performed, on average, seven cryotherapy treatments. The average trainee improved his or her score by 15% on the theoretical test and 16.7% on the image test. At the completion of the 1-day refresher, average test scores were the highest among all the courses. The final assessment was based on 41 providers. CONCLUSIONS: The course proved a successful tool for training healthcare providers in methods of cervical cancer screening and treatment. The course is replicable in other low-resource settings in different countries. It also provided trainees with the opportunity to adapt their clinical skills in their realistic work setting.

Knowledge and attitudes about intrauterine devices among women's health care providers in El Salvador.

In order to gain an understanding of Salvadoran health care providers' clinical knowledge, attitudes, and practice toward the intrauterine device (IUD), Ministry of Health providers completed a self-administered, anonymous survey. Surveys were completed by 135 participants. The majority (94.7% and 97.0%) agreed the IUD is a safe and effective form of contraception. Only 46.6% of participants had ever received training in IUD placement, and 32.0% of them had ever inserted more than 10 IUDs. The majority of providers (54.2%) believed that the IUD was associated with a higher rate of infection than is described in the literature. Lack of formal training and knowledge about persistent infection rates associated with IUDs may contribute to low IUD placement by Salvadoran providers. Health care providers surveyed are open to learning more about the IUD and sharing the information with their patients.

Knowledge and attitudes about intrauterine devices among women's health care providers in El Salvador / Conocimientos y actitudes de los prestadores de atención de salud de la mujer en El Salvador acerca de los dispositivos intrauterinos

In order to gain an understanding of Salvadoran health care providers' clinical knowledge, attitudes, and practice toward the intrauterine device (IUD), Ministry of Health providers completed a self-administered, anonymous survey. Surveys were completed by 135 participants. The majority (94.7 percent and 97.0 percent) agreed the IUD is a safe and effective form of contraception. Only 46.6 percent of participants had ever received training in IUD placement, and 32.0 percent of them had ever inserted more than 10 IUDs. The majority of providers (54.2 percent) believed that the IUD was associated with a higher rate of infection than is described in the literature. Lack of formal training and knowledge about persistent infection rates associated with IUDs may contribute to low IUD placement by Salvadoran providers. Health care providers surveyed are open to learning more about the IUD and sharing the information with their patients.

A fin de evaluar el conocimiento, las actitudes y las prácticas clínicas de los prestadores de atención de salud salvadoreños en torno al dispositivo intrauterino (DIU), se solicitó a un grupo de prestadores del Ministerio de Salud que respondiera un cuestionario anónimo autoadministrado. Se recibieron 135 respuestas. La mayoría manifestó que el DIU es un método anticonceptivo seguro (94,7 por ciento) y eficaz (97,0 por ciento). Solo 46,6 por ciento de los participantes habían recibido algún tipo de capacitación acerca de la colocación del DIU y 32,0 por ciento habían colocado más de 10 dispositivos. La mayoría de los prestadores (54,2 por ciento) consideraron que el DIU está asociado a una incidencia de infecciones más alta que la descrita en la bibliografía. La escasa frecuencia con que los prestadores salvadoreños colocan el DIU probablemente sea atribuible, en cierta medida, a la falta de capacitación formal y de conocimiento acerca de los índices de infección persistente asociados a los DIU. Los prestadores de servicios de salud encuestados refirieron estar dispuestos a instruirse más acerca del DIU y a transmitir la información a sus pacientes.

Diagnostic reproducibility of cervical intraepithelial neoplasia 3 and atrophy in menopausal women on hematoxylin and eosin, Ki-67, and p16 stained slides.

OBJECTIVE: To establish diagnostic accuracy and reproducibility of a diagnosis of cervical intraepithelial neoplasia 3 (CIN 3) in menopausal women on routinely stained hematoxylin and eosin (H&E) slides and compare it to slides processed for p16 and Ki-67. MATERIALS AND METHODS: Confirmed cases of CIN 3 and benign atrophic changes were reviewed independently by 4 pathologists. The samples were studied on separate occasions using H&E staining, p16, and Ki-67. Differences in sensitivity and specificity between reviewers or methods were tested for significance using the McNemar test, whereas differences in positive and negative predictive values were tested for significance using a marginal probability generalized linear model for agreement. RESULTS: Sensitivity was high for H&E (93.3%-100%) and Ki-67 (93.3%-100%) and lower for p16 (70.0%-90.0%). Intraobserver variability was also lower for p16 (76.7% vs 90.0%, although this difference was not statistically significant, p = .219). p16 agreement, however, for CIN 3 is significantly lower than that for atrophy (76.7% vs 97.4%, p = .018). CONCLUSIONS: Routine histopathologic diagnosis of CIN 3 in menopausal women is highly accurate and reproducible. Both H&E and Ki-67 are useful immunohistochemical stains in helping differentiate atrophy from high-grade cervical intraepithelial lesions in postmenopausal cervical biopsies. There may be more disagreement among readers using p16.

Digital assessment of the reproductive tract versus colposcopy for directing biopsies in women with abnormal Pap smears.

OBJECTIVE: This study aimed to compare digital camera assessment of the reproductive tract (DART) to colposcopy for the evaluation of abnormal Pap smears. MATERIALS AND METHODS: Participants included 207 women with abnormal Pap smears. Colposcopy and DART were performed on each patient by separate examiners with the goal of lesion detection. Analysis was performed per patient and per biopsy. RESULTS: Patients had an average of 2.9 biopsies. Forty-two patients and 81 biopsies were positive for cervical intraepithelial neoplasia 2+. Both DART and colposcopy detected 41 (97.6%) of 42 patients (95% CI = 85.9%-99.9%). Digital camera assessment of the reproductive tract detected 66/81 (81.4%; CI = 70.7%-88.9%) and colposcopy detected 69/81 (85.2%; CI = 73.2%-92.4%) of biopsies that were cervical intraepithelial neoplasia 2+. CONCLUSIONS: Digital camera assessment of the reproductive tract detects high-grade lesions of the cervix with similar sensitivity to colposcopy. It holds great promise to expand cervical cancer precursor lesion detection in areas with limited resources.

Pregnancy outcomes after laminaria placement and second-trimester removal.

BACKGROUND: Even after comprehensive counseling, patients change their mind about the decision to terminate a pregnancy. There are few data about the effect of laminaria placement and removal on subsequent pregnancy outcome. CASE: We describe four cases of laminaria removal at 12-17 weeks of gestation with varying outcomes. Two of the four cases developed cervical dilation and delivered early with documented acute chorioamnionitis. CONCLUSION: Patients should be counseled that pregnancy termination begins with laminaria placement and that their removal could result in premature delivery.

Exploring factors in the decision to choose sterilization vs alternatives in rural El Salvador.

CONTEXT: To explore the factors that influence rural Salvadoran women to undergo tubal sterilization versus opting for alternative methods of family planning. EVIDENCE ACQUISITION: A moderator fluent in English and Spanish conducted eleven 90-minute focus groups consisting of 5-10 women each. Eligible women in the municipality of San Pedro Perulapan, El Salvador, were identified and recruited by local health workers. Participant demographics and information about family planning decisions were collected through detailed notes and tape-recorded sessions. The tapes were transcribed verbatim, and all data were analyzed using grounded theory procedures to identify common themes. EVIDENCE SYNTHESIS: Eighty women aged 24-45 years who had previously been sterilized participated in the study. Three major themes influenced a woman's decision to undergo sterilization instead of opting for alternative forms of family planning: (1) availability: tubal sterilization is readily available, (2) fears about side effects of other methods: these women associated negative side effects with other forms of family planning, (3) effectiveness: the women in these focus groups thought sterilization was more effective than other forms of family planning. CONCLUSIONS: This study shows that there is a lack of information, and misinformation, about other effective methods of contraception, especially the intrauterine device and oral contraceptives. Reproductive health education projects, especially those providing services in locations similar to rural El Salvador, should focus on providing accurate information about all forms of contraception, including tubal sterilization.