Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3):A Nonrandomized Multicenter Study

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN

Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer:Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study)

Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO

Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer: a nationwide Dutch cohort study

Objectives: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. Methods: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. Results: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. Conclusions: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. Critical relevance statement: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. Key points: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach. Graphical Abstract: (Figure presented.

Outcome of ovarian cancer after breast cancer in BRCA1 and BRCA2 mutation carriers

Background: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. Methods: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. Results: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). Conclusions: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy

Natural history of high-grade cervical intraepithelial neoplasia: a review of prognostic biomarkers

The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary

Comparison of Intraoperative gamma-Probe Imaging and Postoperative SPECT/CT in Detection of Sentinel Nodes Related to the Ovary

Tracer injection into ovarian ligaments has been shown to detect sentinel nodes (SNs) in patients with ovarian cancer. To determine the possibility that SNs are missed, this feasibility study compared their detection during surgery with their detection on postoperative SPECT/CT. Methods: In 8 patients (with either ovarian or endometrial cancer), after a staging lymphadenectomy including resection of SNs related to the ovary, SPECT/CT was performed within 24 h. Results: SPECT/CT identified hotspots in 4 patients at sites where SNs were resected. In 6 patients, additional sites were found, mainly in the pelvic region. Conclusion: Discrepancies between the gamma-probe and SPECT/CT may be due to missed SNs during surgery, but with respect to pelvic hotspots, in most cases they are more probably related to remnants of tracer at injection sites. With respect to sites where SNs were resected, remaining hotspots may have been caused by residual lymphatic flow after resection

Angiosarcomas of primary gynecologic origin : a clinicopathologic review and quantitative analysis of survival

Objective: Angiosarcomas are aggressive, malignant soft tissue neoplasms of endothelial origin and occur rarely in the female genital tract. There is lack of consensus on risk factors for poor outcome and optimal treatment. To this end, we performed a clinicopathologic review and survival analysis. Methods: We report a case of a woman with an angiosarcoma of the vagina. Published English literature was reviewed for angiosarcomas of the vulva, vagina, uterus, and ovary. Survival was evaluated by using Kaplan-Meier analysis and the effect of clinical and demographic variables on survival by using Cox regression analysis. Results: A total of 51 patients were identified with a median age of 47 years (range, 17-87 years). Two of the patients had an angiosarcoma of the vulva; 2 had an angiosarcoma of the vagina; 18 had an angiosarcoma of the uterus, and 29 had an angiosarcoma of the ovary. Five-year overall survival was 27% (SE, 8%). Most patients presented with locoregional disease, having surgery as their primary intervention. Overall, adjuvant therapy significantly improved survival (hazards ratio, 0.17; 95% confidence interval, 0.05-0.59; adjusted for age and tumor size). Adjuvant treatment consisted of radiotherapy for angiosarcomas of the vulva, vagina, and uterus and chemotherapy for ovarian angiosarcomas. Subgroup analysis of the female genital tract site was hampered by the small number of cases. Conclusions: This review supports the use of surgical and adjuvant radiotherapy for angiosarcomas of the vulva, vagina, and uterus. Cytoreductive surgery and adjuvant chemotherapy remain the primary treatment of angiosarcomas of the ovary

Quality improvement strategies for organizational change: a multiphase observational study to increase insight into nonparticipating organizations

Abstract Background The scope of implementation research is often restricted to the analysis of organizations that participate voluntarily in implementation interventions. The recruitment of participants for a quality improvement collaborative increases awareness of the specific innovation. The objective of this multiphase observational study was to identify differences between organizations that participated in a large-scale implementation project aiming to improve perioperative care, functional recovery, and length of hospital stay after gynecologic surgery and organizations that did not participate. A secondary objective was to explore how perioperative practice changed among nonparticipants. Methods Of the seven gynecology departments of nonparticipating Dutch hospitals, five agreed to participate in a retrospective analysis. Baseline data of participating hospitals’ (N = 19) characteristics, time to functional recovery, and length of hospital stay were compared. Outcome measures for the subsequent pre-post awareness study in the five nonparticipating hospitals were: (1) overall adherence to predefined evidence-based perioperative elements; and (2) change in functional recovery and length of hospital stay. Multivariable regression models, adjusted for baseline characteristics, were used for analysis. Results In retrospect, nonparticipating and participating hospitals did not differ in baseline characteristics, functional recovery, and length of hospital stay. In three of the five nonparticipating hospitals, adherence to the selected evidence-based perioperative elements increased significantly after awareness of the trial (overall mean difference 9.7%, 95% CI 6.9 to 12.5%, p <  0.001). Linear regression models revealed no statistically significant or clinically relevant differences in time to functional recovery (mean difference − 0.2 days, 95% CI -0.7 to 0.2, p = 0.319) or length of hospital stay (mean difference − 0.4 days, 95% CI -1.3 to 0.5, p = 0.419) in the nonparticipating hospitals. None of these hospitals managed to reduce time to functional recovery or length of hospital stay significantly. Conclusions No differences in perioperative outcomes between the nonparticipating and participating hospitals were identified at baseline. Despite the statistically significant improvement in overall evidence-based perioperative care, the awareness raised by recruitment activities alone was not enough to reduce time to functional recovery and length of hospital stay in nonparticipating hospitals. Insight into the trends of nonparticipants is valuable to existing implementation effectiveness research

Interdepartmental Spread of Innovations:: A Multicentre Study of the Enhanced Recovery After Surgery Programme

Spread of evidence-based innovations beyond pioneering settings is essential to improve quality of care. This study aimed to evaluate the influence of a national project to implement 'Enhanced Recovery After Surgery' (ERAS) among colorectal teams on the spread of this innovation to gynaecological procedures.A retrospective observational multicentre study was performed of a consecutive sample of patients who underwent major elective gynaecological surgery in 2012-2013. Ten Dutch hospitals (294 patients) had participated in a colorectal breakthrough project implementing ERAS on a nationwide basis and were assigned to the intervention group. Thirteen hospitals (390 patients) that had not participated in this project acted as controls. Outcome measures were time to functional recovery and total length of postoperative hospital stay. Multilevel models adjusted for clustering and baseline demographics were used for analysis. The uptake of ten selected perioperative care elements was evaluated for each hospital.The estimated mean difference (95% confidence interval) between the intervention and control hospitals was -0.3 (-0.9 to 0.3) days in the time to recovery and 0.2 (-0.8 to 1.3) days in the total length of hospital stay. The mean (+/- standard deviation) absolute rate of implemented perioperative care elements per hospital was 28.9 +/- 14.9% in the control, versus 29.3 +/- 11.1% in the intervention group (p = 0.934).Initial implementation effects seem to be restricted to the participating teams and do not automatically spread to other surgical teams in the same hospital.</p