Edith M. G. van Esch

Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC‐2): A randomised controlled trial

AbstractObjectiveTo investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ).DesignRandomised controlled non‐inferiority trial.SettingOne academic and one regional hospital in the Netherlands.PopulationThirty‐five women with rrCIN were included in the study between May 2016 and May 2021.MethodsWomen were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment).Main outcome measuresThe primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high‐risk human papilloma virus (hr‐HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored.ResultsTreatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow‐up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow‐up.ConclusionsThis is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr‐HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

Immunologic factors involved in the malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma

Endometriosis is a risk factor for low-grade serous, clear cell, and endometroid ovarian carcinoma. In both endometriosis and ovarian carcinoma, immunological factors are associated with clinical outcome. Chronic inflammation in endometriosis may be linked to tumorigenesis, but exact processes contributing to endometriosis-associated ovarian carcinoma remain unknown. This review aims to describe potential immunological factors involved in the malignant transformation of endometriosis into ovarian carcinoma. PubMed and Embase were searched from inception up to October 2020 for studies comparing immunological processes in endometriosis and endometriosis-associated ovarian carcinoma. Detailed analysis of immune components in the malignant transformation of endometriosis into endometriosis-associated ovarian carcinoma is lacking. Altered levels of chemokines and cytokines as IL-6, IL-8, IL-10, and TNF-α are reported and the function, number and polarization of NK cells, dendritic cells, and monocytes differ between endometriosis and associated ovarian carcinoma compared to healthy tissue. In addition, altered inflammasome and complement systems, indicate a role for the immune system in the carcinogenesis of endometriosis. Chronic inflammation in endometriosis may potentially drive inflammation-induced carcinogenesis in endometriosis-associated ovarian carcinoma. Exact immunological pathways and cellular processes remain unknown and require more thorough investigation.

Vaginal Microbiota and Local Immunity in HPV-Induced High-Grade Cervical Dysplasia: A Narrative Review

Persistent high-risk Human Papillomavirus infection is the primary factor in cervical carcinogenesis. However, other host-related features are believed to play a role as well. Recent research suggests that the vaginal microbiome and the immune microenvironment play a significant role in the acquisition and persistence of Human Papillomavirus infection, as well as in the regression or progression of cervical intraepithelial lesions. Studies in this emerging field describe factors associated with this interaction, though the precise nature remains incompletely understood. In this narrative review, we aim to summarize the current literature on the topic and propose hypotheses and recommendations for future research and treatment strategies.

Risk factors for recurrence of vulvar high-grade squamous intra-epithelial lesions: long-term follow-up of the PITVIN Study (primary imiquimod vs surgery for vulvar intra-epithelial neoplasia).

To assess risk factors for long-term recurrence of vulvar high-grade squamous intra-epithelial lesions (vulvar HSIL) and other high-risk human papillomavirus-related genital dysplasia after primary treatment with imiquimod or surgery. This was a long-term follow-up of the PITVIN trial (Clinicaltrials.gov identifier: NCT01861535), a multi-center, randomized, phase 3 non-inferiority clinical study of topical imiquimod versus surgery for vulvar HSIL. Number of recurrent vulvar HSIL or other HSIL and related treatment types were assessed. The relationship between initial study treatment, patient characteristics, primary response (quick versus slow) to imiquimod, and pre-treatment immune infiltrates in recurrent and non-recurrent HSIL were analyzed. Long-term clinical data was available for 87 patients (42 imiquimod, 45 surgery) of the 107 patients included in the original intention-to-treat analysis. Mean follow-up time was 70 months (standard deviation ±24). Among the 80 patients with per-protocol treatment in the initial study, recurrent vulvar HSIL was diagnosed in 33% (12/36) after imiquimod and in 20% (9/44) after surgery (p =.20). Baseline recurrence status, age, and smoking were not associated with vulvar HSIL recurrence. Within the imiquimod study group, patients with an initial slow or partial response to imiquimod experienced recurrent HSIL lesions in 54% (7/13), and patients with an initial quick response in 22% (5/23) of cases (p =.05). Recurrent vulvar HSILs showed significantly higher initial intra-epithelial infiltration of cluster of differentiation 33+ immature monocytes compared with non-recurrent lesions (p =.04), suggesting tumor-mediated immunosuppression. In the intention-to-treat population, 21% (18/87) developed cervical HSIL (n = 9), vaginal HSIL (n = 3), anal HSIL (n = 3), cervical cancer (n = 1), anal cancer (n = 1) and vulvar cancer (n = 1) during long-term follow-up. Topical imiquimod and surgical treatment of vulvar HSIL are effective in long-term follow-up, with recurrences occurring in 20% to 33% of patients within 5 years. Initial slow or partial treatment response to imiquimod and the composition of pre-treatment immune infiltrates may be predictors of an increased long-term recurrence risk.