Mark F. Munsell

Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome

Abstract Purpose: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. Patients and Methods: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. Results: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. Conclusions: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.

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.

Cervical cancer stage distribution and survival outcomes in Africa: a systematic review and meta-analysis

Cervical cancer is a leading cause of cancer-related deaths among women, with a disproportionate burden in sub-Saharan Africa. Understanding the cervical cancer stage and outcomes is crucial for developing effective interventions and reducing its burden. We aimed to undertake a systematic review and meta-analysis of cervical cancer stage distribution and survival outcomes in Africa. We searched MEDLINE, Embase, PubMed, Cochrane Library, Clarivate Analytics Web of Science, and the World Health Organization African Index Medicus database for publications in all languages from the inception of databases to July 2021. A total of 144 studies published between 1978 and 2021 from 33 African countries were included, encompassing 55,747 patients. We revealed that 53.3% (95% CI 50.9 to 55.6) of cervical cancer cases in Africa were diagnosed at late stages (stage III-IV). This proportion varied significantly across countries and regions, ranging from 7.7% to 86.3%. The study also highlighted disparities by Human Development Index (HDI) grouping, with low HDI countries exhibiting higher proportions of late-stage diagnoses (56.0%, 95% CI 51.6 to 60.4) compared with medium (51.2%, 95% CI 47.5 to 54.9) and high (50.7%, 95% CI 47.0 to 54.5) HDI countries. Notably, there was no stage migration observed over time (p = .53). The median overall survival was 24.0 months (interquartile range, 19.2-39.4). These stage and outcomes data highlight the need for expanding cervical cancer screening and treatment and are crucial for policymakers to develop evidence-based strategies aimed at accelerating the elimination of cervical cancer in Africa. Additionally, standardized data collection and reporting are needed to facilitate better monitoring of cervical cancer outcomes across 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.

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.

Demographic and social determinants of human immunodeficiency virus status among women with cervical cancer in a low-resource setting.

Zambia faces one of the world's highest cervical cancer and human immunodeficiency virus (HIV) burdens, yet how demographics and social determinants of health relate to HIV status among women with cervical cancer remains unclear. We conducted a prospective, Institutional Review Board-approved cross-sectional study of women aged ≥18 years with newly diagnosed cervical cancer at the Cancer Diseases Hospital in Lusaka, Zambia, from June 2022 to April 2025. Participants completed a culturally adapted Accountable Health Communities Health-Related Social Needs questionnaire. Demographic and social need variables were compared by HIV status, with associated factors evaluated via univariable and multi-variable logistic regression. Among 290 women, 160 (55.2%) were living with HIV. They were younger (median age 48 vs 53 years, p = .002), more often unmarried (49% vs 31%, p = .002), and more likely to live in urban areas (62% vs 43%, p = .003) than women living without HIV. They reported greater prior cervical cancer screening (48% vs 28%, p < .001) and knowledge (40% vs 25%, p = .008). Social needs were high across both groups: food insecurity (77%), transport barriers (82%), financial hardship (88%), loneliness (65%), and perceived stress (75%), with no HIV-related differences. In multi-variable analysis, younger age (adjusted odds ratio [aOR] 0.76 per 5 years, 95% confidence interval [CI] 0.66 to 0.87), unmarried status (aOR 3.06, 95% CI 1.79 to 5.35), urban residence (aOR 2.00, 95% CI 1.21 to 3.32), and prior knowledge of cervical cancer (aOR 1.86, 95% CI 1.08 to 3.23) were associated with HIV. No social need domain showed an independent association. In Zambian women with cervical cancer, HIV status is linked to demographic factors and cancer awareness, but not social needs, which were uniformly high across patients. This highlights the need to expand education and screening, especially for younger and unmarried women, and integrate socioeconomic support to improve outcomes in Zambia and similar high-burden settings.