Kathleen M Schmeler

Phase 2 study of cetuximab (Erbitux) in patients with progressive or recurrent endometrial cancer

Overexpression of the epidermal growth factor receptor (EGFR) found in common subtypes of endometrial cancer has been associated with advanced stage disease and a poor prognosis. The purpose of this phase 2 study was to evaluate the efficacy and safety of cetuximab in patients with recurrent endometrial cancer. The study was an open-label phase 2 clinical trial conducted at two institutions. Patients with recurrent or progressive endometrial cancer of any histologic type with the exception of uterine sarcoma received cetuximab at an initial dose of 400 mg/m A total of 30 patients were enrolled with a median age of 64 years (range 42-83). Of the 20 evaluable patients, three (15%) had clinical benefit response (one complete response, two stable disease). The patient with a clinical benefit response received a total of 27 cycles and the two patients with stable disease were taken off the study due to progression after four and six cycles, respectively. Of the 10 inevaluable patients, nine received ≤1 cycle due to clinical deterioration and one had an anaphylactic reaction. One patient had a grade 3 rash which resolved after a delay in treatment. No dose reduction was reported. In this cohort, single agent therapy with cetuximab was well tolerated and had a 15% clinical benefit response. Further studies are required to better identify patients who may respond to this treatment.

Pelvic fractures and changes in bone mineral density after radiotherapy for cervical, endometrial, and vaginal cancer: A prospective study of 239 women

Background Advances in radiotherapy (RT) have led to improved oncologic outcomes for women with gynecologic cancers; however, the long‐term effects and survivorship implications need further evaluation. The purpose of this study was to determine the incidence of pelvic fractures and changes in bone mineral density (BMD) after pelvic RT. Methods Two hundred thirty‐nine women who had pelvic RT for cervical, endometrial, or vaginal cancer between 2008 and 2015 were prospectively studied. BMD scans and biomarkers of bone turnover were obtained at the baseline and 3 months, 1 year, and 2 years after RT. Imaging studies were assessed for pelvic fractures for up to 5 years. Patients with osteopenia, osteoporosis, or pelvic fractures at any point were referred to the endocrinology service for evaluation and treatment. Results The median age at diagnosis was 51 years; 132 patients (56%) were menopausal. The primary diagnoses were cervical (63.6%), endometrial (30.5%), and vaginal cancer (5.9%). Sixteen patients (7.8%; 95% confidence interval, 4.5%‐12.4%) had pelvic fractures with actuarial rates of 3.6%, 12.7%, and 15.7% at 1, 2, and 3 years, respectively. Fractures were associated with baseline osteoporosis ( P  < .001), higher baseline bone‐specific alkaline phosphatase ( P  < .001), and older age ( P  = .007). The proportion of patients with osteopenia/osteoporosis increased from 50% at the baseline to 58%, 59%, and 70% at 3 months, 1 year, and 2 years, respectively. Conclusions A high proportion of women had significant decreases in BMD after pelvic RT, with 7.8% diagnosed with a pelvic fracture. BMD screening and pharmacologic intervention should be strongly considered for these high‐risk women.

Cervical and Tumor-Associated Microbiomes in Botswana Women With and Without HIV With Carcinoma of the Cervix Before and After Definitive Chemoradiation

PURPOSE Cervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival (OS) in WLWH. PATIENTS AND METHODS Cervical samples were collected from women with cervical cancer presenting to one hospital in 2018-2019. Patients' clinical data, including HIV status, were recorded. Microbial composition was analyzed using 16S rRNA gene sequencing. Microbiome diversity and composition were evaluated using alpha and beta diversity metrics. Differential microbial abundance was analyzed using linear discriminant analysis effect size. The association between microbial taxa and OS was explored using Cox proportional hazards regression. RESULTS WLWH (n = 42) had a significantly lower Pielou evenness index than HIV-negative women (n = 11; 0.6 v 0.7, P = .02), suggesting a more imbalanced microbiome in WLWH. WLWH had higher levels of Parvimonas and members of the Corynebacteriaceae and Micrococcaceae families, suggesting a shift toward a more pathogenic microbiome. In WLWH, CRT did not significantly alter overall microbial diversity. However, Lactobacillus and Sutterella were enriched before treatment, reflecting a less pathogenic microbiome, whereas Ruminococcus and Phascolarctobacterium and the families Caulobacterales and Flavobacteriia were enriched after treatment, reflecting microbial adaptations to the altered immune and treatment environment. Notably, higher levels of Flavobacteriia after CRT were independently associated with worse OS in WLWH. CONCLUSION Microbiome profiles differ between WLWH and HIV-negative women with cervical cancer in Botswana. The microbiome might have prognostic significance. Future research is needed to better understand the significance of the microbiota in cervical cancer progression and treatment outcomes and the potential role of microbiome-targeted interventions.

Cervical Cancer Outcomes in Mozambique: Impact of an International Gynecologic Oncology Training Program

PURPOSE Cervical cancer is the most common cancer among women in Mozambique and is a major health burden. Surgery for cervical cancer is currently performed at only one hospital in the country, Maputo Central Hospital. Before 2020, there were no gynecologists in Mozambique trained to care for women with cervical cancer. In 2017, the International Gynecologic Cancer Society (IGCS) started a gynecologic oncology training program in Mozambique, and in 2020, the first three fellows graduated from this program. The main objective of this study was to report the outcomes of patients with cervical cancer who were treated surgically by the three newly trained Mozambican gynecologic oncologists. METHODS We performed a retrospective chart review of women diagnosed with cervical cancer who underwent surgical treatment by the Mozambican gynecologic oncologists between November 2020 and October 2022. The outcome of interest was survival at 2 years. RESULTS Thirty-three patients underwent radical hysterectomy with pelvic lymphadenectomy for cervical cancer treatment. The median age at diagnosis was 43 years. After surgery, 15 patients (45%) were dispositioned to surveillance and 18 (55%) were referred for adjuvant treatment with radiotherapy and/or chemotherapy. All patients had follow-up data available, with a median follow-up time of 19 months (range, 0.2 to 37.5). Only one patient died, and the overall survival is 95.7% (95% CI, 87.7% to 100%) at 12.7 months. CONCLUSION The IGCS program has provided training to physicians at Maputo Central Hospital, resulting in surgery for cervical cancer being available to patients in Mozambique. This is an important step in the global elimination of cervical cancer.

Addressing the cervical cancer burden in the Rio Grande Valley of Texas through a multi-component program to improve screening and diagnostic follow-up: A retrospective cohort study

Cervical cancer is preventable by following guidelines for vaccination, screening, diagnosis and treatment of preinvasive cervical lesions. We implemented a multicomponent intervention to increase rates of colposcopy after abnormal screening results in three clinic systems in the Rio Grande Valley, along the Texas-Mexico border. The goal of this study was to assess the outcomes of this program including participation in colposcopy within 90 days of screening for women with abnormal screening results, and the time between screening and colposcopy appointments during the first year (Year 1/baseline) and subsequent years (Years 2 through 4) of program implementation. We performed a retrospective cohort analysis of medical records of clinics participating in the program. We utilized multiple logistic regression and linear regression to assess the colposcopic outcomes of women with indication for colposcopy. A total of 1556 of the 14,846 (10.5 %) women who had undergone cervical cancer screening had abnormal results and met the criteria to be referred for colposcopy. There was a significant increase in the proportion of women who underwent colposcopy (within 90 days of screening) from Year 1/baseline (82.7 %) to Year 2 (90.6 %), OR= 1.65, p-value< 0.05. Similarly, the mean interval from screening to colposcopy decreased significantly from baseline (79 days) to Year 2 (49 days), to Years 3 and 4 (40 and 41 days, respectively), p < 0.001. Our results suggest that multicomponent interventions can improve and sustain appropriate and timely colposcopy among women in medically underserved regions, improving cervical cancer prevention efforts in resource-limited settings.

Multiscale Optical Imaging Fusion for Cervical Precancer Diagnosis: Integrating Widefield Colposcopy and High-Resolution Endomicroscopy

Early detection and treatment of cervical precancers can prevent disease progression. However, in low-resource communities with a high incidence of cervical cancer, high equipment costs and a shortage of specialists hinder preventative strategies. This manuscript presents a low-cost multiscale in vivo optical imaging system coupled with a computer-aided diagnostic system that could enable accurate, real-time diagnosis of high-grade cervical precancers. The system combines portable colposcopy and high-resolution endomicroscopy (HRME) to acquire spatially registered widefield and microscopy videos. A multiscale imaging fusion network (MSFN) was developed to identify cervical intraepithelial neoplasia grade 2 or more severe (CIN 2+). The MSFN automatically identifies and segments the ectocervix and lesions from colposcopy images, extracts nuclear morphology features from HRME videos, and integrates the colposcopy and HRME information. With a threshold value set to achieve sensitivity equal to clinical impression (0.98 [p = 1.0]), the MSFN achieved a significantly higher specificity than clinical impression (0.75 vs. 0.43, p = 0.000006). Our findings show that multiscale optical imaging of the cervix allows the highly sensitive and specific detection of high-grade precancers. The multiscale imaging system and MSFN could facilitate the accurate, real-time diagnosis of cervical precancers in low-resource settings.

Interventions to increase follow-up of abnormal cervical cancer screening results: A systematic literature review and meta-analysis

Introduction Ensuring timely follow-up of abnormal screening results is essential for eliminating cervical cancer. Objective The purpose of the study was to review single and multicomponent interventions designed to improve follow-up of women with abnormal cervical cancer screening results. We report on effectiveness across studies, and describe what aspects of these interventions might be more impactful. Methods Publications were searched between January 2000 and December 2022. The search included observational, quasi-experimental (pre-post studies) and randomized controlled studies describing at least one intervention to increase follow-up of women with abnormal cervical cancer screening results. Outcomes of studies included completion of any follow-up (i.e., attending a follow-up appointment), timely diagnosis (i.e., colposcopy results within 90 days of screening) and time to diagnostic resolution (i.e., days between screening and final diagnosis). We assessed risk of bias for observational and quasi-experimental studies using the Newcastle-Ottawa Scale (NOS) tool and the Cochrane collaboration tool for randomized studies. We conducted a meta-analysis using studies where data were provided to estimate a summary average effect of the interventions on follow-up of patients and to identify characteristics of studies associated with an increased effectiveness of interventions. We extracted the comparison and intervention proportions of women with follow-up before and after the intervention (control and intervention) and plotted the odds ratios (ORs) of completing follow-up along with the 95% confidence intervals (CIs) using forest plots for the interventions vs. controls when data were available. Findings From 7,457 identified studies, 28 met the inclusion criteria. Eleven (39%) of the included studies had used a randomized design. Most studies (63%) assessed completion of any follow-up visit as the primary outcome, whereas others measured time to definite diagnosis (15%) or diagnostic resolution (22%). Navigation was used as a type of intervention in 63% of the included studies. Most interventions utilized behavioral approaches to improve outcomes. The overall estimate of the OR for completion of follow-up for all interventions was 1.81 (1.36–2.42). The highest impact was for programs using more than one approach (multicomponent interventions) to improve outcomes with OR = 3.01 (2.03–4.46), compared with studies with single intervention approaches with OR = 1.56 (1.14–2.14). No statistical risks were noted from publication bias or small-study effects in the studies reviewed. Conclusion Our findings revealed large heterogeneity in how follow-up of abnormal cervical cancer screening results was defined. Our results suggest that multicomponent interventions were more effective than single component interventions and should be used to improve follow-up after abnormal cervical cancer screening results. Navigation appears to be an important tool for improving follow-up. We also provide recommendations for future studies and implications for policy in terms of better defining outcomes for these interventions.

The International Gynecologic Cancer Society Preinvasive Certificate Program: building a skilled workforce for the detection and treatment of cervical pre-cancer

ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer

The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer. From April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2-IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size 100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23-67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients-that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0-68.3). Three patients developed recurrent disease within 2 years of surgery-that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). Our prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

The Capulana study: a prospective evaluation of cervical cancer screening using human papillomavirus testing in Mozambique

Cervical cancer is the leading cause of cancer and related deaths among women in Mozambique. There is limited access to screening and few trained personnel to manage women with abnormal results. Our objective was to implement cervical cancer screening with human papillomavirus (HPV) testing, with navigation of women with abnormal results to appropriate diagnostic and treatment services. We prospectively enrolled women aged 30-49 years living in Maputo, Mozambique, from April 2018 to September 2019. All participants underwent a pelvic examination by a nurse, and a cervical sample was collected and tested for HPV using the careHPV test (Qiagen, Gaithersburg, Maryland, USA). HPV positive women were referred for cryotherapy or, if ineligible for cryotherapy, a loop electrosurgical excision procedure. Women with findings concerning for cancer were referred to the gynecologic oncology service. Participants (n=898) had a median age of 38 years and 20.3% were women living with the human immunodeficiency virus. HPV positivity was 23.7% (95% confidence interval 21.0% to 26.6%); women living with human immunodeficiency virus were twice as likely to test positive for HPV as human immunodeficiency virus negative women (39.2% vs 19.9%, p<0.001). Most HPV positive women (194 of 213, 91.1%) completed all steps of their diagnostic work-up and treatment. Treatment included cryotherapy (n=158, 77.5%), loop electrosurgical excision procedure (n=30, 14.7%), or referral to a gynecologist or gynecologic oncologist (n=5, 2.5%). Of eight invasive cervical cancers, 5 (2.8%) were diagnosed in women living with human immunodeficiency virus and 3 (0.4%) in human immunodeficiency virus negative women (p=0.01). Cervical cancer screening with HPV testing, including appropriate follow-up and treatment, was feasible in our study cohort in Mozambique. Women living with human immunodeficiency virus appear to be at a significantly higher risk for HPV infection and the development of invasive cervical cancer than human immunodeficiency virus negative women.

Tumor microbial diversity and compositional differences among women in Botswana with high-grade cervical dysplasia and cervical cancer

We characterized the cervical 16S rDNA microbiome of patients in Botswana with high-grade cervical dysplasia and locally advanced cervical cancer. This prospective study included 31 patients: 21 with dysplasia and 10 with cancer. The Shannon diversity index was used to evaluate alpha (intra-sample) diversity, while the UniFrac (weighted and unweighted) and Bray-Curtis distances were employed to evaluate beta (inter-sample) diversity. The relative abundance of microbial taxa was compared among samples using linear discriminant analysis effect size. Alpha diversity was significantly higher in patients with cervical cancer than in patients with cervical dysplasia (P<0.05). Beta diversity also differed significantly (weighted UniFrac Bray-Curtis, P<0.01). Neither alpha diversity (P=0.8) nor beta diversity (P=0.19) varied by HIV status. The results of linear discriminant analysis effect size demonstrated that multiple taxa differed significantly between patients with cervical dysplasia vs cancer. The results of our study suggest that differences exist in the diversity and composition of the cervical microbiota between patients with cervical dysplasia and patients with cervical cancer in Botswana. Additional studies are warranted to validate these findings and elucidate their clinical significance among women living in sub-Saharan Africa, as well as other regions of the world.

Addressing high cervical cancer rates in the Rio Grande Valley along the Texas–Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring

Aims: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas–Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. Methods: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. Results: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. Conclusions: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

Background: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. Methods: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). Results: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. Conclusions: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. Impact: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Accuracy of Smartphone Images of the Cervix After Acetic Acid Application for Diagnosing Cervical Intraepithelial Neoplasia Grade 2 or Greater in Women With Positive Cervical Screening: A Systematic Review and Meta-Analysis

PURPOSE Smartphones are used in cervical screening for visual inspection after acetic acid or Lugol's iodine (VIA/VILI) application to capture and share images to improve the sensitivity and interobserver variability of VIA/VILI. We undertook a systematic review and meta-analysis assessing the diagnostic accuracy of smartphone images of the cervix at the time of VIA/VILI (termed S-VIA) in the detection of precancerous lesions in women undergoing cervical screening. METHODS This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies from January 1, 2010, to June 30, 2020, were assessed. MEDLINE/PubMed, Embase, CINAHL, Cochrane, and LILACS were searched. Cohort and cross-sectional studies were considered. S-VIA was compared with the reference standard of histopathology. We excluded studies where additional technology was added to the smartphone including artificial intelligence, enhanced visual assessment, and other algorithms to automatically diagnose precancerous lesions. The primary outcome was the accuracy of S-VIA for the diagnosis of cervical intraepithelial neoplasia grade 2 or greater (CIN 2+). Data were extracted, and we plotted the sensitivity, specificity, negative predictive value, and positive predictive value of S-VIA using forest plots. This study was prospectively registered with The International Prospective Register of Systematic Reviews:CRD42020204024. RESULTS Six thousand three studies were screened, 71 full texts assessed, and eight studies met criteria for inclusion, with six included in the final meta-analysis. The sensitivity of S-VIA for the diagnosis of CIN 2+ was 74.56% (95% CI, 70.16 to 78.95; I2 61.30%), specificity was 61.75% (95% CI, 56.35 to 67.15; I2 95.00%), negative predictive value was 93.71% (95% CI, 92.81 to 94.61; I2 0%), and positive predictive value was 26.97% (95% CI, 24.13 to 29.81; I2 61.3%). CONCLUSION Our results suggest that S-VIA has accuracy in the detection of CIN 2+ and may provide additional support to health care providers delivering care in low-resource settings.

Human papillomavirus-independent cervical cancer: what are the implications?

Fertility-Sparing and Less Radical Surgery for Cervical Cancer

AbstractPurpose of ReviewPatients with early-stage cervical cancer who desire future fertility may be candidates for less radical surgery. We review the literature supporting this approach in early-stage disease.Recent FindingsRetrospective data have shown that in carefully selected patients, the risk of parametrial involvement is less than 1%. This has led to interest in moving away from radical surgery towards more conservative approaches. Data from the newly published ConCerv trial, a prospective study evaluating the feasibility of conservative surgery in women with early-stage, low-risk cervical carcinoma, suggest that conservative surgery is feasible and safe in this patient population. Furthermore, neoadjuvant chemotherapy is being assessed as an option to extend fertility-sparing treatment to a larger group of women.SummaryLess radical surgery may be appropriate for carefully selected women with early-stage, low-risk cervical cancer, including those desiring future fertility.

Hands-On Training Courses for Cervical Cancer Screening, Diagnosis, and Treatment Procedures in Low- and Middle-Income Countries

In 2018, there were approximately 570,000 new cases of cervical cancer worldwide. More than 85% of cases occurred in low- and middle-income countries (LMICs), primarily because of poor access to screening and a limited number of medical providers trained to diagnose and treat cervical precancerous lesions. Our objective was to provide locally arranged, hands-on training courses for medical providers in LMICs to learn to perform cervical cancer screening, diagnosis, and treatment procedures. The courses included didactic lectures and hands-on training stations using low-cost simulation models developed by bioengineers and students at Rice University in Houston, TX, United States, and the Malawi Polytechnic in Blantyre, Malawi. The hands-on training stations included visual inspection with acetic acid (VIA), colposcopy, cervical biopsy, endocervical curettage, loop electrosurgical excision procedure (LEEP), and thermal ablation. Provider pre- and postcourse confidence levels in performing the procedures were evaluated. From February 2017 to January 2020, we arranged 15 hands-on training courses in seven cities across six countries (El Salvador, Mozambique, Trinidad and Tobago, Lesotho, Malawi, and Nepal). Overall, there were 506 participants. The average number of participants per course was 38 (range 19-92). The participants included doctors, nurses, and midwives. The course duration varied from 1 to 3 days. Increased confidence in performing VIA, colposcopy and cervical biopsy, ablation, and LEEP was reported by 69%, 71%, 61%, and 76% of participants, respectively. Our findings suggest that locally arranged, hands-on cervical cancer prevention training courses in LMICs can improve provider confidence in performing cervical cancer screening, diagnosis, and treatment procedures. These courses are part of a larger strategy to build local capacity for delivering and improving cervical cancer prevention services in LMICs.

The Mulher Study: cervical cancer screening with primary HPV testing in Mozambique

To evaluate cervical cancer screening with primary human papillomavirus (HPV) testing in Mozambique, a country with one of the highest burdens of cervical cancer globally. Women aged 30-49 years were prospectively enrolled and offered primary HPV testing using either self-collected or provider-collected specimens. Patients who tested positive for HPV underwent visual assessment for treatment using visual inspection with acetic acid to determine eligibility for thermal ablation. If ineligible, they were referred for excision with a loop electrosurgical excision procedure, for cold knife conization, or for cervical biopsy if malignancy was suspected. Between January 2020 and January 2023, 9014 patients underwent cervical cancer screening. Median age was 37 years (range 30-49) and 4122 women (45.7%) were patients living with HIV. Most (n=8792, 97.5%) chose self-collection. The HPV positivity rate was 31.1% overall and 39.5% among patients living with HIV. Of the 2805 HPV-positive patients, 2588 (92.3%) returned for all steps of their diagnostic work-up and treatment, including ablation (n=2383, 92.1%), loop electrosurgical excision procedure (n=169, 6.5%), and cold knife conization (n=5, 0.2%). Thirty-one patients (1.2%) were diagnosed with cancer and referred to gynecologic oncology. It is feasible to perform cervical cancer screening with primary HPV testing and follow-up in low-resource settings. Participants preferred self-collection, and the majority of screen-positive patients completed all steps of their diagnostic work-up and treatment. Our findings provide important information for further implementation and scale-up of cervical cancer screening and treatment services as part of the WHO global strategy for the elimination of cervical cancer.

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer

PURPOSE Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings

High-risk human papillomavirus (HPV) DNA testing is widely acknowledged as the most sensitive cervical cancer screening method but has limited availability in resource-limited settings, where the burden of cervical cancer is highest. Recently, HPV DNA tests have been developed for use in resource-limited settings, but they remain too costly for widespread use and require instruments that are often limited to centralized laboratories. To help meet the global need for low-cost cervical cancer screening, we developed a prototype, sample-to-answer, point-of-care test for HPV16 and HPV18 DNA. Our test relies on isothermal DNA amplification and lateral flow detection, two technologies that reduce the need for complex instrumentation. We integrated all test components into a low-cost, manufacturable platform, and performance of the integrated test was evaluated with synthetic samples, provider-collected clinical samples in a high-resource setting in the United States, and self-collected clinical samples in a low-resource setting in Mozambique. We demonstrated a clinically relevant limit of detection of 1000 HPV16 or HPV18 DNA copies per test. The test requires six user steps, yields results in 45 min, and can be performed using a benchtop instrument and minicentrifuge by minimally trained personnel. The projected per-test cost is &lt;$5, and the projected instrumentation cost is &lt;$1000. These results show the feasibility of a sample-to-answer, point-of-care HPV DNA test. With the inclusion of other HPV types, this test has the potential to fill a critical gap for decentralized and globally accessible cervical cancer screening.

Conservative Treatment of Stage IA1 Cervical Carcinoma Without Lymphovascular Space Invasion: A 20-year Retrospective Study in Brazil

Abstract Purpose: To evaluate recurrence rates and risk factors among women with stage IA1 cervical cancer without lymph vascular space invasion managed conservatively. Methods: retrospective review of women with stage IA1 squamous cervical cancer who underwent cold knife cone or loop electrosurgical excision procedure, between 1994 and 2015, at a gynecologic oncology center in Southern Brazil. Age at diagnosis, pre-conization findings, conization method, margin status, residual disease, recurrence and survival rates were collected and analyzed. Results: 26 women diagnosed with stage IA1 squamous cervical cancer without lymphovascular space invasion underwent conservative management and had at least 12 months follow-up. The mean follow-up was 44.6 months. The mean age at diagnosis was 40.9 years. Median first intercourse occurred at age 16 years, 11.5% were nulliparous and 30.8% were current or past tobacco smokers. There was one Human immunodeficiency virus positive patient diagnosed with cervical intraepithelial neoplasia grade 2 at 30 months after surgery. However, there were no patients diagnosed with recurrent invasive cervical cancer and there were no deaths due to cervical cancer or other causes in the cohort. Conclusion: Excellent outcomes were noted in women with stage IA1 cervical cancer without lymphovascular space invasion and with negative margins who were managed conservatively, even in a developing country.

Long-term impact of cervical ablation in visual assessment of the squamocolumnar junction: implications for subsequent screening and follow-up

Cervical cancer screen-and-treat programs, which combine human papillomavirus (HPV)-based screening with immediate ablation of lesions, are a key strategy for reducing cervical cancer burden in low-resource settings. Although ablation is known to impair squamocolumnar junction (SCJ) visibility in the short-term, its long-term effects remain unclear, with potential implications for subsequent screening and follow-up. This study evaluated whether prior ablation is associated with incomplete SCJ visualization approximately 5 years post-treatment. We analyzed data from the Cervical Cancer Prevention in El Salvador program. Women aged 34 to 55 years who previously participated in Cervical Cancer Prevention in El Salvador were invited for HPV testing approximately 5 years after their initial screening. Those with positive results were further evaluated through visual inspection with acetic acid and colposcopy. We used generalized linear models to assess the association between prior ablation and incomplete SCJ visualization, adjusting for age, parity, and time since the initial HPV screen. Incomplete SCJ visualization was more frequent among women with prior ablation compared to those without previous treatment, both during colposcopy (47% vs 28%; OR 2.34, 95% CI 1.20 to 4.56) and visual inspection with acid (40% vs 25%; OR 2.06, 95% CI 1.05 to 4.01). Older age was also associated with impaired visualization, but the association between prior ablation and incomplete SCJ visibility remained significant after adjustment. Ablative treatment has a sustained impact on SCJ visualization that persists for years after the procedure, limiting the effectiveness of visualization-based surveillance. These findings underscore the need for efficient and affordable triage strategies to minimize unnecessary ablation in screen-and-treat programs and improve long-term follow-up care in low-resource settings.

Challenges and Opportunities in the Treatment of Invasive Cervical Cancer in Low-Resource Settings: A Survey of the International Gynecologic Cancer Society Fellowship Programs

PURPOSE Cervical cancer remains a leading cause of cancer mortality in low- and middle-income countries (LMICs). The International Gynecologic Cancer Society (IGCS) Global Gynecologic Oncology Fellowship aims to build human capacity to address the burden of cervical cancer in LMICs. This study assesses resource constraints experienced at fellowship sites with regard to management of cervical cancer. METHODS From September to December 2020, one fellow from each of the 12 existing IGCS fellowship programs participated in a survey that assessed capacity for cervical cancer management, including access to care, diagnostics and treatment, cancer surveillance, and palliative care. Descriptive statistics were used for analysis. RESULTS Patients at IGCS sites experienced significant delays to care, especially for chemotherapy and radiation therapy. Less than half of the sites had a gynecology-trained pathologist, and only 58% of sites had access to a magnetic resonance imaging machine, though with many delays in obtaining imaging reads. For treatment, neoadjuvant chemotherapy is not commonly used. Access to radiation therapy is poor, with 58% of sites reporting wait times of 5-8 weeks or more. The radiation machine downtime ranges from 1 to 3 months per year, creating gaps where no patients can access this treatment. Palliative care is practiced by variable members of the health care team although hospice services are rare. CONCLUSION This study demonstrates significant resource constraints experienced by gynecologic oncology providers in various LMICs when managing cervical cancer. This includes delays to diagnosis, poor access to chemoradiation services, and need for palliative care. Despite these limitations, the IGCS Global Gynecologic Oncology Fellowships have built workforce capacity to manage cervical cancer, serving as local champions to address this disease.

A randomized clinical trial to assess the effectiveness of thermal ablation versus loop electrosurgical excision procedure for cervical cancer risk reduction in women living with HIV in Mozambique.

Cervical cancer remains a leading cause of death in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) carry a 6-fold higher risk of cervical cancer than the general population. The effectiveness of thermal ablation versus loop electrosurgical excision procedure (LEEP) in women living with HIV is uncertain, prompting this study. To compare the effectiveness of thermal ablation versus LEEP for the management of abnormal cervical cancer screening results in women living with HIV. Thermal ablation is non-inferior to LEEP for treatment of cervical intra-epithelial neoplasia (CIN) 2/3 and high-risk human papillomavirus (hrHPV) infection in women living with HIV. This is a prospective randomized clinical trial. Participants undergo screening with primary hrHPV testing. Those with positive hrHPV results undergo visual inspection with acetic acid and a review of genotyping results to determine eligibility for treatment. Those who are hrHPV-positive and positive by visual assessment with acetic acid, or human papillomavirus16/18 positive regardless of visual assessment with acetic acid result, are randomized to thermal ablation or LEEP. Participants undergo follow-up at 4 to 8 weeks, 6 months, and 12 months post-procedure. Participants include 25 to 49-year-old women living with HIV in Mozambique. Exclusion criteria include pregnancy, previous total hysterectomy, history of cervical cancer or prior treatment for CIN, or any condition that would preclude adherence to the study protocol. Persistent or recurrent CIN 2/3 (or worse diagnosis) and hrHPV infection at 12 months after initial treatment. To meet our primary objectives and to achieve a power of 0.8 (α = 0.025), we will need to randomize 126 participants with CIN 2/3, 63 to thermal ablation, and 63 to LEEP. We estimate that this will require screening a total of 4844 women living with HIV. We anticipate that study accrual will be completed in 3 years (2027), with an additional 18 months to complete all follow-up visits and data analysis. We anticipate presenting results in 2029. ClinicalTrials.gov #NCT06326294.

Scaling cervical cancer screening in Mozambique: analysis of loop electrosurgical excision procedure (LEEP) specimens

As cervical cancer screening programs are implemented and expanded, an increasing number of women require loop electrosurgical excision procedure (LEEP) for treatment of pre-invasive cervical disease. Our objective was to describe the pathological results of LEEP specimens performed as part of the MULHER study and identify factors associated with positive LEEP margins. The MULHER study enrolled 9014 women who underwent HPV testing followed by visual assessment for treatment (VAT) using visual inspection with acetic acid (VIA) and thermal ablation for those with positive results. Participants with lesions ineligible for ablation underwent LEEP. Pathology reports were reviewed for specimen size/volume, number of fragments, pathological diagnosis and margin status. Multivariable regression analysis was performed to identify variables associated with positive LEEP margins. 169 participants underwent LEEP. The median age was 38 years (range 30-49). 65.1% were women living with HIV. Pathological diagnosis was available for 154 patients and included cancer (n=6, 3.9%); cervical intraepithelial neoplasia (CIN) 2/3 (n=75, 48.7%); CIN 1 (n=67, 43.5%); and normal/benign findings (n=6,3.9%). 31.8% of LEEP specimens were removed in more than one fragment. The mean specimen volume was 2.9 cm Our results showed a high number of LEEP specimens with positive margins. Additional evaluation is needed to better understand the characteristics of precancerous cervical lesions in this high-risk population. As cervical cancer screening programs are scaled in Mozambique and other lower-resource countries, there is a need to train providers to perform high-quality LEEP and for accurate and timely pathological interpretation.

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Pelvic Fractures and Radiation Therapy for Cervical Cancer

The goal of this study is to estimate how often pelvic fractures occur in women treated with radiation therapy for either newly diagnosed or recurrent cervical, endometrial, or vaginal cancer. The study will also estimate the changes in bone mineral density and the changes in the blood that relate to "bone turnover". High bone turnover can weaken bones and make you more likely to break a bone.