Frederick Haynes Van der Merwe

Targeting treatment resistance in cervical cancer: A new avenue for senolytic therapies

Cervical cancer poses a significant global health challenge, particularly impacting women in economically developing nations. This disparity stems from a combination of factors, including inadequate screening infrastructure and resource limitations. However, the foremost contributor is the widespread lack of awareness and limited accessibility to Human Papillomavirus (HPV) vaccination, which is a key preventative measure against cervical cancer development. Despite advancements in cervical cancer prevention, treatment resistance remains a major hurdle in achieving improved patient outcomes. Cellular senescence, specifically the senescence-associated secretory phenotype (SASP) and its bidirectional relationship with the immune system, has been implicated in resistance to conventional cervical cancer chemotherapy treatments. The exact mechanisms by which this state of growth arrest and the associated changes in immune regulation contribute to cervical cancer progression and the associated drug resistance are not entirely understood. This underscores the necessity for innovative strategies to address the prevalence of treatment-resistant cervical cancer, with one promising avenue being the utilisation of senolytics. Senolytics are agents that have promising efficacy in clearing senescent cells from tumour tissues, however neither the utilisation of senolytics for addressing senescence-induced treatment resistance nor the potential integration of immunotherapy as senolytic agents in cervical cancer treatment has been explored to date. This review provides a concise overview of the mechanisms underlying senescence induction and the pivotal role of the immune system in this process. Additionally, it explores various senolytic approaches that hold significant potential for advancing cervical cancer research.

Aptima HPV E6/E7 mRNA and cytology cross-sectional performance as primary screening tests for detection of high-grade cervical lesions in HIV positive and negative women in South Africa

Objective To assess the performance of APTIMA ® HPV E6/E7 mRNA assay (AHPV) with HPV 16 and 18/45 genotyping (AHPV-GT) and cytology in detecting cervical cancer and precancer in HIV positive and negative women in South Africa. Methods A multicentre cross-sectional study was performed in women aged 25–64 (n = 992) with cytology and AHPV with AHPV-GT reflex testing. All screen-positive and a random subset of screen-negative women were referred for colposcopy and biopsy. Results On cytology, low-grade squamous intraepithelial lesion (LSIL) or higher was found in 9.7% of HIV negative and 35.8% of HIV positive women. HPV mRNA positivity was 19.5% (4.4% HPV 16, 2.8% HPV 18/45, and 6.9% other high-risk HPV) in HIV negative women, compared to 45.8% (9.4% HPV 16, 9.7% HPV 18/45, and 27.6% other high-risk HPV) in HIV positive women . The prevalence of histological abnormalities in HIV negative vs HIV positive women was 24.3 vs 46.0% for cervical intraepithelial neoplasia (CIN) 2+, 10.2 vs 24.1% for CIN3+, and 1.4 vs 2.4% for invasive squamous cell carcinoma. AHPV sensitivity for detection of CIN3 + performed the best: 69.0% (95% confidence interval (CI) 56.8–81.1) in HIV negative vs 81.4% (95% CI 73.7–89.0) in HIV positive women, followed by ASCUS + (atypical squamous cells of undetermined significance) cytology: 58.6% (95% CI 45.7–71.6) vs 76.5% (95% CI 68.1–84.8). The best positive predictive value for CIN2 + was for AHPV-GT16, followed by AHPV-GT16,18/45 and cytology LSIL+: HIV-negative women 84.0% (95% CI 68.9–99.1); 76.9% (95% CI 63.3–90.6); 75.0% (95 CI% 61.2–88.9) and HIV-positive women 92.5% (95% CI 84.1–100); 86.8% (95% CI 79.1–94.6); 84.0% (95% CI 77.6–90.3). Conclusion Significantly more HPV infection and cytological/histological abnormalities and advanced disease were seen in HIV positive women. The lower than expected clinical sensitivities of all screening tests are comparable to HPV DNA sensitivities reported in similar populations. AHPV with AHPV-GT performed better than cytology as a screening and triage test.