The diagnostic accuracy of serum and plasma microRNAs in detection of cervical intraepithelial neoplasia and cervical cancer: A systematic review and meta-analysis.

Studies suggest a need for new diagnostic approaches for cervical cancer including microRNA technology. In this review, we assessed the diagnostic accuracy of microRNAs in detecting cervical cancer and Cervical Intraepithelial Neoplasia (CIN). We performed a systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline for protocols (PRISMA-P). We searched for all articles in online databases and grey literature from 01st January 2012 to 16th August 2022. We used the quality assessment of diagnostic accuracy studies tool (QUADAS-2) to assess the risk of bias of included studies and then conducted a Random Effects Meta-analysis. We identified 297 articles and eventually extracted data from 24 studies. Serum/plasma concentration miR-205, miR-21, miR-192, and miR-9 showed highest diagnostic accuracy (AUC of 0.750, 0.689, 0.980, and 0.900, respectively) for detecting CIN from healthy controls. MicroRNA panels (miR-21, miR-125b and miR-370) and (miR-9, miR-10a, miR-20a and miR-196a and miR-16-2) had AUC values of 0.897 and 0.886 respectively for detecting CIN from healthy controls. For detection of cervical cancer from healthy controls, the most promising microRNAs were miR-21, miR-205, miR-192 and miR-9 (AUC values of 0.723, 0.960, 1.00, and 0.99 respectively). We report higher diagnostic accuracy of upregulated microRNAs, especially miR-205, miR-9, miR-192, and miR-21. This highlights their potential as stand-alone screening or diagnostic tests, either with others, in a new algorithm, or together with other biomarkers for purposes of detecting cervical lesions. Future studies could standardize quantification methods, and also study microRNAs in higher prevalence populations like in sub-Saharan Africa and South Asia. Our review protocol was registered in PROSPERO (CRD42022313275).

Prevalence of cervical intraepithelial lesions and associated factors among women attending a cervical cancer clinic in Western Uganda; results based on Pap smear cytology.

Introduction: There are high incidence and mortality rates of cervical cancer among females in East Africa. This is exacerbated by limited up-to-date data on premalignant lesions and associated factors in this setting. In this study, we determined the prevalence of cervical intraepithelial lesions and associated factors among women attending the Mbarara Regional Referral Hospital cervical cancer clinic in Southwestern Uganda. Methods: In this cross-sectional study, 364 participants were recruited from among women attending the Mbarara Regional Referral Hospital cervical cancer clinic from 1 April to 30 June 2023. On consent, the study nurse collected demographic data and Pap smears, which were microscopically examined and reported by a laboratory scientist and a pathologist following the Bethesda grading system (2014). Statistical analyses were done in STATA version 17, using proportions, Chi-square, bivariate, and multivariate logistic regression analysis to determine associated factors at ⩽0.05 significance level. Results: The mean age of participants was 41.9 years. A third of all study participants (37.6%, 132/351) were contraceptive users, mostly hormonal contraceptives (87.1%, 115/132). Almost 88% (307/351) had an unknown Human Papilloma Virus status. The prevalence of cervical intraepithelial lesions among our study participants was 6.6% (23/351), of which 73.9% (17/23) were low-grade squamous intraepithelial lesions. More than half (9/17, 52.9%) of low-grade squamous intraepithelial lesions were active hormonal contraceptive users. Use of hormonal contraceptives (OR: 3.032, p: 0.0253), use of intrauterine devices (OR: 6.284, p: 0.039), and any family history of cervical cancer (OR: 4.144, p: 0.049) were significantly associated with cervical intraepithelial lesions. Conclusion: The prevalence of cervical intraepithelial lesions was 6.6%, lower than global estimates. Use of hormonal and intrauterine device contraceptives, as well as family history of cervical cancer, were significantly associated with cervical intraepithelial lesions among our study population. Prospective studies are recommended to further understand associations between different types of intrauterine devices and hormonal contraceptives, and cervical lesions.

Development of a customized m-Health-based intervention to reduce loss to follow-up among patients undergoing treatment for cervical lesions at a rural referral Hospital, South Western Uganda.

Background: Loss to follow-up (LTFU) in individuals undergoing cervical cancer treatment is a major challenge in many low resource settings. We describe development of a customized and tailored mHealth intervention for reducing LTFU among patients undergoing cervical cancer treatment at Mbarara Regional Referral Hospital (MRRH). Methods: We interviewed all health care providers (HCPs) at the cervical cancer clinic of MRRH, between April and May 2023. Transcripts were subsequently derived, reviewed and coded to generate themes and categories using inductive content analytic approach. Four medical experts used this data to develop relevant SMS content, which was incorporated into an app. Results: HCPs had owned a phone for 13.8 ≤ years, had worked at the clinic for 5 ≤ years, and used text messages regularly. Qualitative data revealed that the main challenge to re-engagement was absence of a reminder mechanism between HCPs and patients. HCPs preferred text and or audio mode of messaging to improve health care responsiveness to LTFUs, awareness, continuity of care, and health service uptake among the majority illiterate population; though with potential constraints of costs and workload. Identified key messaging content included; the importance of attending scheduled follow-ups, follow up visit date and clinic customization and tailoring the message to the intended recipient. SMS content was uploaded onto the cc-follow-up app platform and customized according to preferred language, day, frequency and time of delivery. Conclusion: Tailoring an mHealth messaging intervention could help re-engage and reduce LTFU through improved information sharing, awareness, responsiveness, care engagement and medical compliance. A pilot study is required for our intervention in South Western Uganda.

Magnitude and trends in cervical cancer at Mbarara Regional Referral Hospital in South Western Uganda: Retrospective analysis of data from 2017-2022.

High-income countries have documented a significant decline in the incidence and mortality of cervical cancer over the past decade but such data from low and middle-income countries such as Uganda is limited to ascertain trends. There is also paucity of data on the burden of cervical cancer in comparison to other gynaecologic malignancies and there is a likelihood that the incidence might be on the rise. To describe the current trends and magnitude of cervical cancer in comparison to other gynaecological malignancies histological types, we conducted a retrospective records review of charts of patients admitted with gynaecological malignancies on the gynaecological ward of Mbarara Regional Referral Hospital (MRRH) between January 2017 and December 2022. Of 875 patients with gynaecological malignancies admitted to the MRRH in the 6-year review period, 721 (82.4%) had cervical cancer. Patients with cervical cancer were significantly older than those with other gynaecological malignancies: (50.2±11.5 versus 43.8± 15.0 respectively, p<0.001). Between 2017 and 2022, cervical cancer rates increased by 17% annually compared to other gynaecological cancers (OR:1.17; 95% CI 1.06-1.28, p = 0.0046), with the majority of patients of cervical cancer patients (92.7%, n = 668) having squamous cell carcinoma. Most patients (87.9%, n = 634) had late-stage disease (stage 2 and above) and were referred to the Uganda Cancer Institute for chemoradiation. These results imply that there is a need to scale up screening services and other preventive measures such as vaccination against human papilloma virus.

High Rate of Loss to Follow-Up Among Patients Undergoing Treatment for Premalignant Cervical Lesions at Mbarara Regional Referral Hospital, Southwestern Uganda: A Retrospective Cohort Study.

BACKGROUND: For a cervical cancer control program to be effective in reducing the incidence of the disease, there should be high compliance to treatment and follow-up of women diagnosed with precursor lesions. Screening programs in low-resource countries such as Uganda are challenged by poor adherence to follow-up following treatment for premalignant cervical lesions. This study sought to describe the burden and factors associated with loss to follow-up among women undergoing treatment for premalignant cervical lesions at a tertiary hospital in southwestern Uganda. METHODS: This was a retrospective cohort study. We reviewed the registers at the Mbarara Regional Referral Hospital (MRRH) cervical cancer clinic for a period of four years from January 2017 to December 2020. Data on age, district of residence, diagnosis, date of diagnosis, date and type of initial treatment, and date of follow-up visit were collected. We also captured data on whether patients returned on the scheduled follow-up date or within three months after the scheduled follow-up date. We defined loss to follow-up as failure to return for follow-up either on the scheduled date or within three months after the scheduled date. RESULTS: Out of the 298 patients who underwent treatment for premalignant cervical lesions in the study period, 227 (76.2%) did not return for follow-up at one year. At bivariate analysis, failure to attend the review visit at six weeks predicted the loss to follow-up at one year following treatment for premalignant lesions almost perfectly (risk ratio (RR)=2.84, 95% confidence interval (CI): 2.18-3.71, p<0.001). Negative HIV serostatus and receiving thermocoagulation slightly increased the risk of getting lost to follow-up, while being more than 45 years old reduced the odds. At multivariate analysis, treatment with thermocoagulation (adjusted risk ratio (aRR)=1.21, 95% CI: 1.07-1.36, p=0.03) was associated with loss to follow-up at one year. CONCLUSION: The proportion of women who did not return for follow-up at one year following treatment for premalignant cervical lesions at Mbarara Regional Referral Hospital is very high. There is a need to implement strategies such as telephone-aided reminders to prompt patients to return for follow-up following treatment for premalignant cervical lesions.

Vulvar leiomyosarcoma: A case report.

Vulvar leiomyosarcoma is a rare malignant smooth muscle tumor and the most common type of vulvar sarcoma. It can mimic benign tumors, and misdiagnosis may delay appropriate treatment. A 35-year-old woman presented to the outpatient gynecology clinic at the Mirebalais Teaching Hospital for a right vulvar mass. A complete excision of the mass was performed. Histopathology with immunohistochemistry demonstrated leiomyosarcoma. We describe the contextual challenges that ultimately compromised her care, highlighting the challenges to safe delivery of cancer care in our setting.

Association between obesity and cervical intraepithelial neoplasia: results from a case control study in south western Uganda.

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.

Reaching the women with the greatest needs: Two models for initiation and scale-up of gynecologic oncology fellowship trainings in low-resource settings.

Women in low- and middle-income countries (LMICs) are significantly more likely to develop and die from invasive cervical cancer, while rates of other gynecologic malignancies are comparable to those faced by women in high-income countries. Despite this increased need, there are few specialist physicians in LMICs available to treat women with gynecologic cancers. Training specialists in low-resource settings faces multiple challenges, including ensuring protected time from other clinical demands, access to best practice guidelines, training that is tailored to the specific challenges faced in the trainee's environment, and isolation from other fully trained professionals and securing support services. In addition, training specialists from LMICs in high-resource settings is costly and return of trainees to their own country is not guaranteed. Here we describe two approaches to gynecologic oncology training in LMICs. The International Gynecologic Cancer Society (IGCS) developed the Global Curriculum Mentorship and Training Program (Global Curriculum) to support gynecologic oncology fellowships in regions of the world that do not currently have formal training in gynecologic oncology. In India, on the other hand, leaders in world-class gynecologic oncology centers must find a way to meet the training needs of a vast and disparate country.

A scoping review: Facilitators and barriers of cervical cancer screening and early diagnosis of breast cancer in Sub-Saharan African health settings.

To address gaps in access to cervical cancer screening and early diagnosis of breast cancer services in Sub-Saharan African (SSA), this scoping review was conducted to explore facilitators and barriers that exist on the patient-, provider-, and system-level. An extensive literature search was conducted in accordance with scoping review methodology and the Cochrane guidelines. Our search criteria were limited to original research studies conducted in community or clinical settings in SSA within the last 10 years (2010-2020). Themes found from this review included patient knowledge and provider education, access to screening services, trust, health-related behaviors, attitudes, values, and practices, community and social values, health infrastructure, resource allocation, and political will. Identified barriers included lack of knowledge about cervical and breast cancer among patients, gaps in education and training among providers, and lack of resources and health infrastructure at the facility level and within the overall health system. Facilitators included perceived risk of cancer, support and encouragement of the provider, and utilization of novel approaches in low-resource settings by health systems. To better address individual-, provider-, and health system and facility-based facilitators and barriers to care, there is a need for political and financial investment and further research on the health service delivery in specific national health systems, especially in the context of the global campaign to eliminate cervical cancer as a public health problem.

Worthy of further consideration: An updated meta-analysis to address the feasibility, acceptability, safety and efficacy of thermal ablation in the treatment of cervical cancer precursor lesions.

Treatment of preinvasive lesions is critical to the success of secondary prevention of cervical cancer. In many settings, however, excision or ablation of preinvasive lesions can prove challenging. Thermal ablation (TA) is a form of treatment for cervical precancer that may present fewer logistical challenges in resource limited settings. In 2013, Dolman and colleagues wrote a meta-analysis of publications reporting cure rates from TA. This included only one article from a low or middle-income country (LMIC). We updated Dolman's meta-analysis to include more recent articles from LMICs. A formal review of the world literature was performed for the years 2014-2017. Article titles and abstracts were reviewed for relevance; full articles were assessed for quality. The primary endpoint was treatment outcome for cervical intraepithelial neoplasia grade 2 or higher (CIN2+). The I2 statistic was used to assess heterogeneity between studies. Studies were stratified by geographic region, decade that the study was published, World Bank economic classification of the country where the study was performed, and other factors. We reviewed 34 total reports and included 23 in our meta-analysis, including 10,995 and 6371 patients, respectively. A total of 7 studies were performed in LMICs, including 6 studies included in the meta-analysis. The overall response rate for TA treatment of biopsy proven CIN2+ was 93.8%. Consistent with the wide variety of settings and patient populations, there was significant heterogeneity between studies. TA appears to be an effective treatment for CIN2+ across a variety of settings, including in LMICs.

Cervical cancer in low and middle income countries: Addressing barriers to radiotherapy delivery.

The global cervical cancer burden falls disproportionately upon women in low and middle-income countries. Insufficient infrastructure, lack of access to preventive HPV vaccines, screening, and treatment, as well as limited trained personnel and training opportunities, continue to impede efforts to reduce incidence and mortality in these nations. These hurdles have been substantial challenges to radiation delivery in particular, preventing treatment for a disease in which radiation is a cornerstone of curative therapy. In this review, we discuss the breadth of these barriers, while illustrating the need for adaptive approaches by proposing the use of brachytherapy alone in the absence of available external beam radiotherapy. Such modifications to current guidelines are essential to maximize radiation treatment for cervical cancer in limited resource settings.

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.

Strengthening care and research for women's cancers in Sub-Saharan Africa.

•The burden of gynecologic cancers in low resource settings is overwhelming.•Areas with the highest needs have few human resources and limited infrastructure.•Cancer specialists can best help by leveraging ongoing work to assist local leaders.

Efforts towards erasing borders in gynecologic cancer?

•Cervical cancer is the second most common cancer among women in LMIC.•Major efforts to improve research in gynecologic cancer in LMIC are needed.•GOR provides a platform featuring research and review of cancer care in LMIC.

HIV Infection and Survival Among Women With Cervical Cancer.

Purpose Cervical cancer is the leading cause of cancer death among the 20 million women with HIV worldwide. We sought to determine whether HIV infection affected survival in women with invasive cervical cancer. Patients and Methods We enrolled sequential patients with cervical cancer in Botswana from 2010 to 2015. Standard treatment included external beam radiation and brachytherapy with concurrent cisplatin chemotherapy. The effect of HIV on survival was estimated by using an inverse probability weighted marginal Cox model. Results A total of 348 women with cervical cancer were enrolled, including 231 (66.4%) with HIV and 96 (27.6%) without HIV. The majority (189 [81.8%]) of women with HIV received antiretroviral therapy before cancer diagnosis. The median CD4 cell count for women with HIV was 397 (interquartile range, 264 to 555). After a median follow-up of 19.7 months, 117 (50.7%) women with HIV and 40 (41.7%) without HIV died. One death was attributed to HIV and the remaining to cancer. Three-year survival for the women with HIV was 35% (95% CI, 27% to 44%) and 48% (95% CI, 35% to 60%) for those without HIV. In an adjusted analysis, HIV infection significantly increased the risk for death among all women (hazard ratio, 1.95; 95% CI, 1.20 to 3.17) and in the subset that received guideline-concordant curative treatment (hazard ratio, 2.63; 95% CI, 1.05 to 6.55). The adverse effect of HIV on survival was greater for women with a more-limited stage cancer ( P = .035), those treated with curative intent ( P = .003), and those with a lower CD4 cell count ( P = .036). Advanced stage and poor treatment completion contributed to high mortality overall. Conclusion In the context of good access to and use of antiretroviral treatment in Botswana, HIV infection significantly decreases cervical cancer survival.

Holographic Assessment of Lymphoma Tissue (HALT) for Global Oncology Field Applications.

Low-cost, rapid and accurate detection technologies are key requisites to cope with the growing global cancer challenges. The need is particularly pronounced in resource-limited settings where treatment opportunities are often missed due to the absence of timely diagnoses. We herein describe a Holographic Assessment of Lymphoma Tissue (HALT) system that adopts a smartphone as the basis for molecular cancer diagnostics. The system detects malignant lymphoma cells labeled with marker-specific microbeads that produce unique holographic signatures. Importantly, we optimized HALT to detect lymphomas in fine-needle aspirates from superficial lymph nodes, procedures that align with the minimally invasive biopsy needs of resource-constrained regions. We equipped the platform to directly address the practical needs of employing novel technologies for "real world" use. The HALT assay generated readouts in <1.5 h and demonstrated good agreement with standard cytology and surgical pathology.

Challenges in Prevention and Care Delivery for Women with Cervical Cancer in Sub-Saharan Africa.

Virtually all cases of invasive cervical cancer are associated with infection by high-risk strains of human papilloma virus. Effective primary and secondary prevention programs, as well as effective treatment for early-stage invasive cancer have dramatically reduced the burden of cervical cancer in high-income countries; 85% of the mortality from cervical cancer now occurs in low- and middle-income countries. This article provides an overview of challenges to cervical cancer care in sub-Saharan Africa (SSA) and identifies areas for programmatic development to meet the global development goal to reduce cancer-related mortality. Advanced stage at presentation and gaps in prevention, screening, diagnostic, and treatment capacities contribute to reduced cervical cancer survival. Cost-effective cervical cancer screening strategies implemented in low resource settings can reduce cervical cancer mortality. Patient- and system-based barriers need to be addressed as part of any cervical cancer control program. Limited human capacity and infrastructure in SSA are major barriers to comprehensive cervical cancer care. Management of early-stage, locally advanced or metastatic cervical cancer involves multispecialty care, including gynecology oncology, medical oncology, radiology, pathology, radiation oncology, and palliative care. Investment in cervical cancer care programs in low- and middle-income countries will need to include effective recruitment programs to engage women in the community to access cancer screening and diagnosis services. Though cervical cancer is a preventable and treatable cancer, the challenges to cervical control in SSA are great and will require a broadly integrated and sustained effort by multiple stakeholders before meaningful progress can be achieved.

Sister Society Meeting on Global Education Development and Collaboration: Meeting Report.

OBJECTIVES: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle- income countries. METHODS: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle- income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. RESULTS: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. CONCLUSIONS: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries.

Health Care Disparities in Hereditary Ovarian Cancer: Are We Reaching the Underserved Population?

OPINION STATEMENT: Ovarian cancer is an uncommon but deadly disease. There is no effective screening for the disease, and the majority of women with ovarian cancer present in advanced stage and eventually die from their disease. The majority of families with multiple cases of breast and ovarian cancer are found to carry germline mutations in BRCA1/2. Recent, more sensitive sequencing techniques have shown that nearly 20 % of ovarian cancer is associated with germline mutations in cancer susceptibility genes, with approximately 15 % accounted for by deleterious mutations in BRCA1/2. Women found to have mutations in BRCA1/2 can be empowered to make decisions on reproduction, cancer prevention, or treatment that may either avoid cancer or prolong survival. Though initial studies suggested that African American (AA) women were significantly less likely than White women to have mutations in BRCA1/2, this has been found to be untrue. Despite this revelation, and the clear importance of BRCA1/2 mutation status to appropriate clinical management, AA women still undergo genetic counseling and testing at much lower rates than do comparable White women. This disparity is not explained by factors such as calculated risk of a mutation, insurance coverage, or previous knowledge of the availability of testing. To date, no effective strategies have been identified that can overcome this disparity. Possible approaches include use of patient navigators, online social media, or EMR-based decision support aids. Funders should support research in this area, as it represents an actionable means to decrease the burden of ovarian and breast cancer in AA women.