Prognostic factors for spontaneous regression of high-risk human papillomavirus-positive cervical intra-epithelial neoplasia grade 2.

INTRODUCTION: Since the implementation of human papillomavirus (HPV)-based screening for cervical cancer, the majority of cervical intra-epithelial neoplasia grade 2 (CIN2) lesions are high-risk (hr)HPV positive. Evidence on prognostic factors in hrHPV-positive CIN2 is lacking, hampering the individual counseling of women undergoing observation as routine management. The aim of this study is to identify prognostic factors for the spontaneous regression of hrHPV-positive CIN2. METHODS: A retrospective cohort study was conducted at the Maastricht University Medical Center, the Netherlands. Women with hrHPV-positive CIN2 who underwent observation between January 1, 2000 and April 30, 2013 were included. Regression was defined as Pap 1/2 cytology (normal or atypical squamous cells of undetermined significance (ASCUS) cytology) or ≤CIN1 histology at the 24 month follow-up and no diagnosis of ≥CIN2 before the 24 month follow-up visit. Potential prognostic factors (HPV-16/18, p16 staining, KI67 staining, age, smoking status, last Pap smear result, multiple CIN2 lesions, oral contraception use, and parity) were assessed using logistic regression analysis. RESULTS: A total of 56 women were included in the study, of which 34 (61%) showed spontaneous regression of their lesion. Of all studied potential prognostic factors, only not smoking and nulliparity were significantly associated with disease regression (OR 3.84, 95% CI 1.04 to 14.21, and OR 5.00, 95% CI 1.32 to 19.00, respectively, in the univariate analysis). Both effects remained significant after correction for age and HPV-16/18 in a multivariable regression analysis. In women who smoked, disease regression occurred in 10 of 22 women (46%), compared with 16 of 21 women (76%) who did not smoke. In parous women, regression occurred in 12 of 27 women (44%), compared with 16 of 20 nulliparous women (80%). DISCUSSION: Smoking status and parity may influence the likelihood of disease regression in hrHPV-positive CIN2. These factors could be considered in individual patient counseling regarding the choice between immediate treatment or conservative management.

Gain of Chromosomal Region 3q26 as a Prognostic Biomarker for High-Grade Cervical Intraepithelial Neoplasia: Literature Overview and Pilot Study.

Approximately 20-40% of high-grade Cervical Intraepithelial Neoplasia (CIN) regresses spontaneously, but the natural prognosis of an individual lesion is unpredictable. Gain of the chromosomal 3q region, which contains the human telomerase RNA gene on 3q26, is found in CIN lesions and cervical carcinoma and shows correlation with disease grade. The aim of this study is to assess whether 3q26 gain as a single genetic marker can predict the natural prognosis of high-grade CIN, by performing a review of the literature and pilot study. A literature review was conducted. Additionally, we performed a pilot study in 19 patients with histologically confirmed high-grade CIN lesions who were followed for a mean of 115 days, after which loop excision was performed. Fluorescent in situ hybridization analysis was performed on the initial diagnostic biopsies to determine gain of 3q26. Eight studies were included in the literature overview, with a total of 407 patients. Of these, only 22 patients had high-grade lesions. All studies found an association between 3q26 gain and disease prognosis. Positive predictive values (PPV) ranged from 50 to 93%, negative predictive values (NPV) ranged from 75 to 100%. Only five out of 155 patients (3.2%) without 3q26 gain showed disease persistence or progression. In our pilot study on 3q26 gain in high-grade CIN, the PPV of 3q26 gain for disease persistence was 67%, the NPV 100%. All four patients without 3q26 gain showed disease regression. In conclusion, the absence of 3q26 gain in diagnostic biopsies may be applied to identify high-grade CIN lesions with a high probability of disease regression.

Treatment of Cervical Intraepithelial Neoplasia: Patients Preferences for Surgery or Immunotherapy with Imiquimod.

Imiquimod has been studied as a noninvasive pharmacological treatment alternative to large loop excision of the transformation zone (LLETZ) for high-grade cervical intraepithelial neoplasia (CIN), to prevent long-term obstetric complications from surgical treatment. This study aims to investigate womens' preferences for treatment of high-grade CIN with imiquimod or LLETZ. A labeled discrete choice experiment was conducted among 100 women with abnormal cervical cytology in 5 hospitals in the Netherlands between March 2014 and December 2015. Participants were asked to choose between imiquimod treatment or standard surgical treatment in 9 separate scenarios, based on the following treatment characteristics: treatment success rate, rate of side effects, risk of premature birth in subsequent pregnancies, and risk of subfertility after treatment. The levels of these characteristics differed for the imiquimod alternatives. Women assigned a positive utility to LLETZ compared with imiquimod. When making a choice for imiquimod, women preferred a higher treatment success rate and a lower risk of premature birth, infertility and side effects. The choice for imiquimod treatment was also influenced by the intention of a future pregnancy. Subgroup analyses revealed that a lower efficacy regarding imiquimod might be more acceptable for women who desired a future pregnancy compared with women who did not desire a future pregnancy. Women with a future pregnancy wish may prefer treatment of high-grade CIN with imiquimod cream over LLETZ, if the risk of subfertility and premature birth is low.

A prediction model for spontaneous regression of cervical intraepithelial neoplasia grade 2, based on simple clinical parameters.

This study aims to develop a prediction model for spontaneous regression of cervical intraepithelial neoplasia grade 2 (CIN 2) lesions based on simple clinicopathological parameters. The study was conducted at Maastricht University Medical Center, the Netherlands. The prediction model was developed in a retrospective cohort of 129 women with a histologic diagnosis of CIN 2 who were managed by watchful waiting for 6 to 24months. Five potential predictors for spontaneous regression were selected based on the literature and expert opinion and were analyzed in a multivariable logistic regression model, followed by backward stepwise deletion based on the Wald test. The prediction model was internally validated by the bootstrapping method. Discriminative capacity and accuracy were tested by assessing the area under the receiver operating characteristic curve (AUC) and a calibration plot. Disease regression within 24months was seen in 91 (71%) of 129 patients. A prediction model was developed including the following variables: smoking, Papanicolaou test outcome before the CIN 2 diagnosis, concomitant CIN 1 diagnosis in the same biopsy, and more than 1 biopsy containing CIN 2. Not smoking, Papanicolaou class <3, concomitant CIN 1, and no more than 1 biopsy containing CIN 2 were predictive of disease regression. The AUC was 69.2% (95% confidence interval, 58.5%-79.9%), indicating a moderate discriminative ability of the model. The calibration plot indicated good calibration of the predicted probabilities. This prediction model for spontaneous regression of CIN 2 may aid physicians in the personalized management of these lesions.

The detection of sentinel nodes in ovarian cancer: a feasibility study.

UNLABELLED: Few sentinel node (SN) studies in ovarian cancer have been reported, mainly because of the risk of tumor dissemination associated with the injection of tracers into the ovarian cortex. To our knowledge, the injection of tracers into the ovarian ligaments has not been explored. The aim of this study was to determine the feasibility of the SN procedure in ovarian cancer with tracer injection into the ovarian ligaments and to establish whether the procedure is safe for the healthcare workers. METHODS: The study included patients who were at high risk of ovarian malignancy. Blue dye and radioactive colloid were injected into the proper ovarian ligament and suspensory ligament of the ovary. To measure professional radiation exposure, ring dose meters were worn by the surgeon, theater nurse, and pathologist during 3 procedures. RESULTS: An SN procedure was performed in 21 patients, and at least 1 SN location was identified in all patients using the γ probe before retroperitoneal exploration. SNs were located in the paraaortic and paracaval regions only in 67% of the patients, in the pelvic region only in 9%, and in both the paraaortic/paracaval and the pelvic regions in 24%. All but 2 SNs were found on the ipsilateral side. In 6 patients who underwent retroperitoneal exploration, 1-4 SNs were identified using the γ probe and resected. Blue-stained SNs were detected in 2 patients. Positive SNs were detected in 1 patient with lymph node metastases. The amount of radiation exposure to the surgeon, theater nurse, and pathologist did not exceed the safe limit. CONCLUSION: The identification of SNs in all cases suggests that the SN procedure performed by injection of tracers in the ovarian ligaments is feasible and promising. The procedure is safe for the involved personnel. Further investigation is necessary to determine the clinical application of this new technique.

Sentinel node in ovarian cancer: study protocol for a phase 1 study.

BACKGROUND: The concept of sentinel lymph node surgery is to determine whether the cancer has spread to the very first lymph node or sentinel node. If the sentinel node does not contain cancer, then there is a high likelihood that the cancer has not spread to other lymph nodes. The sentinel node technique has been proven to be effective in different types of cancer. In this study we want to determine whether a sentinel node procedure in patients with ovarian cancer is feasible when the tracers are injected into the ovarian ligaments. METHODS/DESIGN: Patients with a high likelihood of having an ovarian malignancy in whom a median laparotomy and a frozen section analysis is planned and patients with endometrial cancer in whom a staging laparotomy is planned will be included.Before starting the surgical staging procedure, blue dye and radioactive colloid will be injected into the ligamentum ovarii proprium and the ligamentum infundibulo-pelvicum. In the analysis we calculate the percentage of patients in whom it is feasible to identify sentinel nodes. Other study parameters are the anatomical localization of the sentinel node(s) and the incidence of false negative lymph nodes. TRIAL REGISTRATION: Approval number: NL40323.068.12Name: Medical Ethical Committee Maastricht University Hospital, University of MaastrichtAffiliation: Maastricht University HospitalBoard Chair Name: Medisch Ethische Commissie azM/UM.