Accuracy of detection of high-grade cervical intraepithelial neoplasia using electrical impedance spectroscopy with colposcopy.

OBJECTIVE: To determine if electrical impedance spectroscopy (EIS) improves the diagnostic accuracy of colposcopy when used as an adjunct. DESIGN: Prospective, comparative, multi-centre clinical study. SETTING: Three colposcopy clinics: two in England and one in Ireland. POPULATION: Women referred with abnormal cytology. METHODS: In phase 1, EIS was assessed against colposcopic impression and histopathology of the biopsies taken. In phase 2, a probability index and cut-off value for the detection of high-grade cervical intraepithelial neoplasia (HG-CIN, i.e. grade CIN2+) was derived to indicate sites for biopsy. EIS data collection and analyses were performed in real time and blinded to the clinician. The phase-2 data were analysed using different cut-off values to assess performance of EIS as an adjunct. MAIN OUTCOME MEASURE: Histologically confirmed HG-CIN (CIN2+). RESULTS: A total of 474 women were recruited: 214 were eligible for analysis in phase 1, and 215 were eligible in phase 2. The average age was 33.2 years (median age 30.3 years, range 20-64 years) and 48.5% (208/429) had high-grade cytology. Using the cut-off from phase 1 the accuracy of colposcopic impression to detect HG-CIN when using EIS as an adjunct at the time of examination improved the positive predictive value (PPV) from 78.1% (95% CI 67.5-86.4) to 91.5%. Specificity was also increased from 83.5% (95% CI 75.2-89.9) to 95.4%, but sensitivity was significantly reduced from 73.6% (95% CI 63.0-82.5) to 62.1%, and the negative predictive value (NPV) was unchanged. The positive likelihood ratio for colposcopic impression alone was 4.46. This increased to 13.5 when EIS was used as an adjunct. The overall accuracy of colposcopy when used with EIS as an adjunct was assessed by varying the cut-off applied to a combined test index. Using a cut-off set to give the same sensitivity as colposcopy in phase 2, EIS increased the PPV to detect HG-CIN from 53.5% (95% CI 45.0-61.8) to 67%, and specificity increased from 38.5% (95% CI 29.4-48.3) to 65.1%. NPV was not significantly increased. Alternatively, applying a cut-off to give the same specificity as colposcopy alone increased EIS sensitivity from 88.5% (95% CI 79.9-94.4) to 96.6%, and NPV from 80.8% (95% CI 67.5-90.4) to 93.3%. PPV was not significantly increased. The receiver operator characteristic (ROC) to detect HG-CIN had an area under the curve (AUC) of 0.887 (95% CI 0.840-0.934). CONCLUSIONS: EIS used as an adjunct to colposcopy improves colposcopic performance. The addition of EIS could lead to more appropriate patient management with lower intervention rates.

Clinical and immunological response to photodynamic therapy in the treatment of vulval intraepithelial neoplasia.

Vulval intraepithelial neoplasia (VIN) is a premalignant condition of the vulva and its incidence is increasing. The common type of VIN is associated with oncogenic types of human papilloma virus (HPV) infection. The standard modalities of treatment for VIN, surgical excision and laser ablation, are both sub-optimal, associated with high rates of disease recurrence. There is a need for non-surgical treatment options for VIN and photodynamic therapy (PDT), by altering the local immunological parameters, has the potential to clear both VIN and HPV. This article reviews the studies of PDT treatment for VIN and discusses the clinical and immunological responses to PDT treatment in the various studies.

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia.

BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure. METHODS: We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed. RESULTS: Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, non-responders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens. CONCLUSION: The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.

Hormone replacement therapy and the endometrium.

The life-expectancy for women has increased significantly in the 20th century, although the time of onset of menopause has not. Almost a third of a woman's life is now postmenopausal and therefore many postmenopausal women consider using hormone replacement therapy (HRT) to improve their quality of life. Most cases of endometrial carcinoma arise in postmenopausal women and this raises concern among patients and clinicians with regard to the safety of HRT in this age group. Whenever the use of HRT is considered, a careful consideration of the actual benefit in terms of symptom relief and quality of life must be balanced against the risks for each individual woman. This review discusses the effects of HRT on the endometrium and the evidence regarding HRT use and risk of endometrial cancer.