Performance of Two-Stage Cervical Cancer Screening With Primary High-Risk Human Papillomavirus Testing in Women Living With Human Immunodeficiency Virus

OBJECTIVE: To evaluate the performance of cervical cancer screening algorithms for women living with human immunodeficiency virus (HIV), using primary high-risk human papillomavirus (HPV) testing followed by cytology, visual inspection with acetic acid, or colposcopy. METHODS: We conducted a prospective cohort study of women living with HIV in Botswana. All participants underwent high-risk HPV testing. Participants with positive high-risk HPV test results underwent cytology, visual inspection with acetic acid, colposcopy, and biopsy. Participants with negative high-risk HPV test results also underwent cytology. Histopathology was the reference standard for determination of preinvasive cervical disease and cervical cancer. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and likelihood ratios (LR) of high-risk HPV-based two-stage screening algorithms were calculated. RESULTS: Among 300 women screened, 88 (29%) had a positive high-risk HPV test result, and 29 of the 88 (35%) women who tested positive for high-risk HPV had CIN 2 or higher on histopathology. High-risk HPV followed by colposcopy resulted in a sensitivity of 83%, specificity of 49%, PPV of 47%, LR+ of +1.6, and LR− of −0.4. High-risk HPV followed by visual inspection with acetic acid resulted in a reduced sensitivity of 59%, specificity of 49%, PPV of 39%, LR+ of +1.2, and LR− of −0.8. High-risk HPV testing followed by cytology also resulted in a reduced sensitivity of 62%, specificity of 77%, PPV of 60%, LR+ of +2.7, and LR− of −0.5. Stratification by HPV 16/18/45 did not improve performance of the algorithms. CONCLUSION: In a high-risk population with HIV, high-risk HPV testing followed by colposcopy demonstrated the highest sensitivity and PPV in detecting high-grade cervical dysplasia. Allocating resources to colposcopy in resource-limited settings may be more effective than other screening strategies

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway

Background: Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: Two drug indications benefited from the FDA’s accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. Conclusion: The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit

Labile Heme and Heme Oxygenase-1 Maintain Tumor-Permissive Niche for Endometriosis-Associated Ovarian Cancer

Endometriosis, a painful gynecological condition accompanied by inflammation in women of reproductive age, is associated with an increased risk of ovarian cancer. We evaluated the role of peritoneal heme accumulated during menstrual cycling, as well as peritoneal and lesional macrophage phenotype, in promoting an oncogenic microenvironment. We quantified the heme-degrading enzyme, heme oxygenase-1 (HO-1, encoded by Hmox1) in normal peritoneum, endometriotic lesions and endometriosis-associated ovarian cancer (EAOC) of clear cell type (OCCC). HO-1 was expressed primarily in macrophages and increased in endometrioma and OCCC tissues relative to endometriosis and controls. Further, we compared cytokine expression profiles in peritoneal macrophages (PM) and peripheral blood mononuclear cells (PBMC) in women with endometriosis versus controls as a measure of a tumor-promoting environment in the peritoneum. We found elevated levels of HO-1 along with IL-10 and the pro-inflammatory cytokines (IL-1β, IL-16, IFNγ) in PM but not in PBMC from endometriosis patients. Using LysM-Cre:Hmox1flfl conditional knockout mice, we show that a deficiency of HO-1 in macrophages led to the suppression of growth of ID8 ovarian tumors implanted into the peritoneum. The restriction of ID8 ovarian tumor growth was associated with an increased number of Mac3+ macrophage and B cells in LysM-Cre:Hmox1flfl mice compared to controls. Functional experiments in ovarian cancer cell lines show that HO-1 is induced by heme. Low levels of exogenous heme promoted ovarian cancer colony growth in soft agar. Higher doses of heme led to slower cancer cell colony growth in soft agar and the induction of HO-1. These data suggest that perturbation of heme metabolism within the endometriotic niche and in cancer cells themselves may be an important factor that influences tumor initiation and growth

TARGETING CBX3/HP1Γ INDUCES LEF-1 AND IL-21R TO PROMOTE TUMOR-INFILTRATING CD8 T-CELL PERSISTENCE

Immune checkpoint blockade (ICB) relieves CD8+ T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting Cbx3/HP1γ in CD8+ T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at Lef1 and Il21r. LEF-1 and IL-21R are necessary for Cbx3/HP1γ-deficient CD8+ effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of Cbx3/HP1γ-deficient CD8+ T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicating Cbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumor