Use of the Aptima mRNA high-risk human papillomavirus (HR-HPV) assay compared to a DNA HR-HPV assay in the English cervical screening programme: a decision tree model based economic evaluation.

OBJECTIVE: To estimate the impact of using the Aptima messenger RNA (mRNA) high-risk human papilloma virus (HR-HPV) assay versus a DNA HR-HPV assay in a primary HPV cervical screening programme. DESIGN: One hypothetical cohort followed for 3 years through HPV primary cervical screening. SETTING: England. PARTICIPANTS: A hypothetical cohort of women aged 25-65 years tested in the National Health Service (NHS) Cervical Screening Programme (CSP) for first call or routine recall testing. METHODS: A decision tree parameterised with data from the CSP (2017/18) and the HORIZON study. Uncertainty analyses were conducted using data from the FOCAL and GAST studies, other DNA HPV tests in addition to one-way and probabilistic sensitivity and scenarios analyses, to test the robustness of results. INTERVENTIONS: Aptima mRNA HR-HPV assay and a DNA HR-HPV assay (cobas 4800 HPV assay). MAIN OUTCOME MEASURES: Primary: total colposcopies and total costs for the cohort. Secondary: total HPV and cytology tests, number lost to follow-up. RESULTS: At baseline for a population of 2.25 million women, an estimated £15.4 million (95% credibility intervals (CI) £6.5 to 24.1 million) could be saved and 28 009 (95% CI 27 499 to 28 527) unnecessary colposcopies averted if Aptima mRNA assays are used instead of a DNA assay, with 90 605 fewer unnecessary HR-HPV and 253 477 cytology tests performed. These savings are due to a lower number of HPV positive samples in the mRNA arm. When data from other primary HPV screening trials were compared, results indicated that using the Aptima mRNA assay generated cost savings and reduced testing in every scenario. CONCLUSION: Using the Aptima mRNA assay versus a DNA assay would almost certainly yield cost savings and reduce unnecessary testing and procedures, benefiting the NHS and women in the CSP.

Use of electrochemotherapy in women with vulvar cancer to improve quality-of-life in the palliative setting: a meta-analysis.

INTRODUCTION: Electrochemotherapy involves the use of transient tumor permeabilization via electric pulses in combination with low-dose chemotherapeutic agents. It has recently emerged as an alternative treatment modality in vulvar cancer. The aim of this meta-analysis was to ascertain the effectiveness of electrochemotherapy in the context of palliative care. METHODS: The following databases were searched: MEDLINE, Scopus, and Cochrane Database, to identify all registered articles pertaining to palliative vulvar cancer treatment with electrochemotherapy from inception until August 2019, in line with PRISMA guidelines. A single-proportion meta-analysis was performed for the outcomes of overall response, complete response, partial response, stable disease, and progressive disease raterespectively, using the random-effect model. Sensitivity analysis was performed to address heterogeneity. RESULTS: Four studies were included totaling 104 women. The studies were of moderate quality. Pooled results from four studies rendered a summary proportion of 78.8% (95% CI 70.4% to 86.1%) for the outcome of overall response. The median age ranged between 68 and 85 years. The sample size per study ranged between eight and 61 women. The tumors' histological types included: squamous-cell carcinoma (96.2%), Paget's disease (2.9%), and malignant melanoma (0.9%). A total of 65 patients (62.5%) presented with a single nodule, whilst 39 patients (37.5%) presented with multiple nodules. Eighty-nine women (85.6%) were previously submitted to other treatment modalities. The overall response rate ranged from 73.2% to 80.9%. The pooled proportion for the outcomes of complete and partial response rate was 48.7% (95% CI 30.74% to 61.5%) and 30.2% (95% CI 21.7% to 39.4%), respectively. The follow-up ranged from 1 to 51 months. No severe adverse effects were reported. The safety profile of electrochemotherapy was favorable. CONCLUSIONS: Electrochemotherapy is an effective and minimally invasive treatment modality in the palliative care management of patients with vulvar cancer. The effective control of vulvar tumors by electrochemotherapy may contribute to improvement of quality-of-life. In light of the moderate quality of evidence, a multi-center cooperation is warranted to confirm its palliative benefit.

Diagnostic accuracy of colposcopy with dynamic spectral imaging for cytology-negative/high-risk HPV positive (failed test of cure) after large loop excision of the transformation zone (LLETZ) of the cervix: Results of the DySIS colposcopy 1 study.

After treatment for cervical intraepithelial neoplasia (CIN), in the UK women who are cytology-negative, high-risk (HR) human papilloma virus (HPV) positive are referred to colposcopy. This pilot study assessed the incidence of residual/recurrent CIN and the diagnostic accuracy of colposcopy with dynamic spectral imaging (DSI) mapping in their detection.This was a prospective service evaluation carried out in a UK National Health Service (NHS) colposcopy clinic. All women, referred with negative cytology/HR-HPV positive result following treatment for CIN from March 2013 until November 2014, who were examined with the DSI digital colposcope were included. We excluded 3 cases because of poor-quality imaging from user errors. Everyday clinical practice was followed. Initial colposcopic impression, DSI map indication, and biopsy site selections were recorded. CIN2+ was considered the primary outcome and CIN of any grade a secondary outcome.A total of 105 women were included of which 5 (4.8%) had CIN2+ histology and 24 (22.9%) had CIN1. Pre-DSI map colposcopy suggested normal/low grade in all 5 of the CIN2+ cases and DSI suggested high-grade (HG) CIN in 4 of the 5 cases. Sensitivity of standard colposcopy for CIN2+ was 0%, improving to 80% with the incorporation of the DSI map.The CIN burden in this population is higher than previously expected. Colposcopic identification of HG CIN appears to improve significantly with DSI in this cohort leading to refinement in patient management. A larger, multicentric prospective study (DySIS colposcopy 2) is planned to confirm these initial findings.

Standardized Digital Colposcopy with Dynamic Spectral Imaging for Conservative Patient Management.

BACKGROUND: Colposcopy is subjective and management of young patients with high-grade disease is challenging, as treatments may impair subsequent pregnancies and adversely affect obstetric outcomes. Conservative management of selected patients is becoming more popular amongst clinicians; however it requires accurate assessment and documentation. Novel adjunctive technologies for colposcopy could improve patient care and help individualize management decisions by introducing standardization, increasing sensitivity, and improving documentation. CASE: A nulliparous 27-year-old woman planning pregnancy underwent colposcopy following high-grade cytology. The colposcopic impression was of low-grade changes, whilst the Dynamic Spectral Imaging (DSI) map of the cervix suggested potential high-grade. A DSI-directed biopsy confirmed CIN2. At follow-up, both colposcopy and DSI were suggestive of low-grade disease only, and image comparison confirmed the absence of previously present acetowhite epithelium areas. Histology of the transformation zone following excisional treatment, as per patient's choice, showed no high-grade changes. CONCLUSION: Digital colposcopy with DSI mapping helps standardize colposcopic examinations, increase diagnostic accuracy, and monitor cervical changes over time, improving patient care. When used for longitudinal tracking of disease and when it confirms a negative colposcopy, it can help towards avoiding overtreatment and hence decrease morbidity related to cervical excision.

Intraoperative frozen section analysis for the diagnosis of early stage ovarian cancer in suspicious pelvic masses.

BACKGROUND: Women with suspected early-stage ovarian cancer need surgical staging which involves taking samples from areas within the abdominal cavity and retroperitoneal lymph nodes in order to inform further treatment. One potential strategy is to surgically stage all women with suspicious ovarian masses, without any histological information during surgery. This avoids incomplete staging, but puts more women at risk of potential surgical over-treatment.A second strategy is to perform a two-stage procedure to remove the pelvic mass and subject it to paraffin sectioning, which involves formal tissue fixing with formalin and paraffin embedding, prior to ultrathin sectioning and multiple site sampling of the tumour. Surgeons may then base further surgical staging on this histology, reducing the rate of over-treatment, but conferring additional surgical and anaesthetic morbidity.A third strategy is to perform a rapid histological analysis on the ovarian mass during surgery, known as 'frozen section'. Tissues are snap frozen to allow fine tissue sections to be cut and basic histochemical staining to be performed. Surgeons can perform or avoid the full surgical staging procedure depending on the results. However, this is a relatively crude test compared to paraffin sections, which take many hours to perform. With frozen section there is therefore a risk of misdiagnosing malignancy and understaging women subsequently found to have a presumed early-stage malignancy (false negative), or overstaging women without a malignancy (false positive). Therefore it is important to evaluate the accuracy and usefulness of adding frozen section to the clinical decision-making process. OBJECTIVES: To assess the diagnostic test accuracy of frozen section (index test) to diagnose histopathological ovarian cancer in women with suspicious pelvic masses as verified by paraffin section (reference standard). SEARCH METHODS: We searched MEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015) and relevant Cochrane registers. SELECTION CRITERIA: Studies that used frozen section for intraoperative diagnosis of ovarian masses suspicious of malignancy, provided there was sufficient data to construct 2 x 2 tables. We excluded articles without an available English translation. DATA COLLECTION AND ANALYSIS: Authors independently assessed the methodological quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) domains: patient selection, index test, reference standard, flow and timing. Data extraction converted 3 x 3 tables of per patient results presented in articles into 2 x 2 tables, for two index test thresholds. MAIN RESULTS: All studies were retrospective, and the majority reported consecutive sampling of cases. Sensitivity and specificity results were available from 38 studies involving 11,181 participants (3200 with invasive cancer, 1055 with borderline tumours and 6926 with benign tumours, determined by paraffin section as the reference standard). The median prevalence of malignancy was 29% (interquartile range (IQR) 23% to 36%, range 11% to 63%). We assessed test performance using two thresholds for the frozen section test. Firstly, we used a test threshold for frozen sections, defining positive test results as invasive cancer and negative test results as borderline and benign tumours. The average sensitivity was 90.0% (95% confidence interval (CI) 87.6% to 92.0%; with most studies typically reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to 99.7%; range 96% to 100%).Similarly, we analysed sensitivity and specificity using a second threshold for frozen section, where both invasive cancer and borderline tumours were considered test positive and benign cases were classified as negative. Average sensitivity was 96.5% (95% CI 95.5% to 97.3%; typical range 83% to 100%), and average specificity was 89.5% (95% CI 86.6% to 91.9%; typical range 58% to 99%).Results were available from the same 38 studies, including the subset of 3953 participants with a frozen section result of either borderline or invasive cancer, based on final diagnosis of malignancy. Studies with small numbers of disease-negative cases (borderline cases) had more variation in estimates of specificity. Average sensitivity was 94.0% (95% CI 92.0% to 95.5%; range 73% to 100%), and average specificity was 95.8% (95% CI 92.4% to 97.8%; typical range 81% to 100%).Our additional analyses showed that, if the frozen section showed a benign or invasive cancer, the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively.In cases where the frozen section diagnosis was a borderline tumour, on average 21% of the final diagnoses would turn out to be invasive cancer.In three studies, the same pathologist interpreted the index and reference standard tests, potentially causing bias. No studies reported blinding pathologists to index test results when reporting paraffin sections.In heterogeneity analyses, there were no statistically significant differences between studies with pathologists of different levels of expertise. AUTHORS' CONCLUSIONS: In a hypothetical population of 1000 patients (290 with cancer and 80 with a borderline tumour), if a frozen section positive test result for invasive cancer alone was used to diagnose cancer, on average 261 women would have a correct diagnosis of a cancer, and 706 women would be correctly diagnosed without a cancer. However, 4 women would be incorrectly diagnosed with a cancer (false positive), and 29 with a cancer would be missed (false negative).If a frozen section result of either an invasive cancer or a borderline tumour was used as a positive test to diagnose cancer, on average 280 women would be correctly diagnosed with a cancer and 635 would be correctly diagnosed without. However, 75 women would be incorrectly diagnosed with a cancer and 10 women with a cancer would be missed.The largest discordance is within the reporting of frozen section borderline tumours. Investigation into factors leading to discordance within centres and standardisation of criteria for reporting borderline tumours may help improve accuracy. Some centres may choose to perform surgical staging in women with frozen section diagnosis of a borderline ovarian tumour to reduce the number of false positives. In their interpretation of this review, readers should evaluate results from studies most typical of their population of patients.

Patient Support Groups Identifying Clinical Equipoise in UK Gynaecological Oncology Surgeons as the Basis for Trials in Ultraradical Surgery for Advanced Ovarian Cancer.

"Clinical equipoise" is defined as the genuine uncertainty by the expert medical community of the most beneficial treatment. A survey performed in 2013 by a patient support group, Ovacome, of gynaecological oncologists in the UK on ultra-radical surgery in advanced ovarian cancer has shown that there is a wide variation in surgical practice across the country. In addition, there were mixed views on the quality of published evidence justifying it's performance, signifying a state of clinical equipoise. The survey also identified widespread insufficient infra-structural resources and lack of surgical training and skills. The majority of respondents would be prepared to undertake additional training to acquire the surgical skills and/or refer to other centres/surgeons already performing the surgery and/or recruit to surgical trials investigating ultra-radical surgery in advanced ovarian cancer.

Pathological Risk Factors and Outcomes in Women With Stage IB2 Cervical Cancer Treated With Primary Radical Surgery Versus Chemoradiotherapy.

OBJECTIVE: Both radical hysterectomy with pelvic lymphadenectomy and primary chemoradiotherapy have been shown to be effective in the management of women with stage IB2 cervical cancer. This study aims to review the outcomes related to each treatment modality and the effects of pathological risk factors on overall survival (OS) and disease-free survival. METHODS: We performed a retrospective study of 92 women with stage IB2 cervical cancer who were treated at the Northern Gynecological Oncology Center (Gateshead, United Kingdom) across a 22-year period between January 1991 and July 2013. Women were divided into those undergoing primary surgery and those undergoing primary radiotherapy/chemoradiotherapy. The main outcome measures were OS and progression-free survival (PFS). Pathological risk factors of survival were assessed using multivariate analysis. RESULTS: Sixty-seven women (72.8%) underwent primary surgery, and 25 women (27.2%) had primary radiotherapy/chemoradiotherapy. Thirty-one of 67 women (46.3%) required adjuvant radiotherapy/chemoradiotherapy after surgery because of positive lymph nodes in 77.4% of cases. The median follow-up was 57.5 months (range, 3-137 months). Thirty-two women (34.8%) had disease recurrence: 6 women (16.7%) in the group undergoing surgery alone, 15 women (48.4%) in the group requiring adjuvant treatment after surgery, and 11 women (44%) in the group having primary radiotherapy/chemoradiotherapy. Overall survival and PFS were higher for women undergoing surgery alone (91.7% and 83.3%) compared with women requiring adjuvant treatment after surgery (54.8% and 51.4%) and those having primary radiotherapy/chemoradiotherapy (60% and 56%) (P = 0.0004 and P = 0.005, respectively). Lymph node metastasis was a significant pathological risk factor of OS and PFS in multivariate analysis. CONCLUSIONS: Most women require adjuvant treatment after surgery because of positive lymph nodes. Because survival outcomes for women requiring dual treatment are similar to those for women undergoing primary chemoradiotherapy, nodal assessment before definitive treatment should guide the management of these women and identify a low-risk group that can be treated with surgery alone.

Proportion of cervical excision for cervical intraepithelial neoplasia as a predictor of pregnancy outcomes.

OBJECTIVE: To assess how the proportion of the cervical volume/length removed during treatment for cervical intraepithelial neoplasia (CIN) varies and whether this correlates to the pregnancy duration at delivery. METHODS: The present prospective observational study included 142 women undergoing CIN treatment at a university hospital during 2009-2013. The pretreatment and post-treatment cervical dimensions and cone size were measured with magnetic resonance imaging, three-dimensional transvaginal ultrasonography, or two-dimensional transvaginal ultrasonography, and the correlation between pregnancy outcomes and the relative proportion of the cervix excised was assessed. RESULTS: Pretreatment cervical volumes and cone volumes varied substantially (range 11-40 cm(3) and 0.6-8 cm(3), respectively). The proportion of the volume excised ranged from 2.2% to 39.4%. Sixteen (11%) women conceived following treatment; 12 had a live birth (seven at term, three preterm). The pregnancy duration at delivery was significantly correlated with the proportion of the cervical volume (r=-0.9; P<0.001) and length (r=-0.7; P=0.01) excised and the cone volume (r=-0.6; P=0.04). CONCLUSION: The pretreatment cervical dimensions and the proportions of the volume/length excised vary substantially, and the latter correlates with the pregnancy duration. Assessment of the proportion excised might help to stratify women at risk who need intensive surveillance when pregnant.

Histology verification demonstrates that biospectroscopy analysis of cervical cytology identifies underlying disease more accurately than conventional screening: removing the confounder of discordance.

BACKGROUND: Subjective visual assessment of cervical cytology is flawed, and this can manifest itself by inter- and intra-observer variability resulting ultimately in the degree of discordance in the grading categorisation of samples in screening vs. representative histology. Biospectroscopy methods have been suggested as sensor-based tools that can deliver objective assessments of cytology. However, studies to date have been apparently flawed by a corresponding lack of diagnostic efficiency when samples have previously been classed using cytology screening. This raises the question as to whether categorisation of cervical cytology based on imperfect conventional screening reduces the diagnostic accuracy of biospectroscopy approaches; are these latter methods more accurate and diagnose underlying disease? The purpose of this study was to compare the objective accuracy of infrared (IR) spectroscopy of cervical cytology samples using conventional cytology vs. histology-based categorisation. METHODS: Within a typical clinical setting, a total of n = 322 liquid-based cytology samples were collected immediately before biopsy. Of these, it was possible to acquire subsequent histology for n = 154. Cytology samples were categorised according to conventional screening methods and subsequently interrogated employing attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. IR spectra were pre-processed and analysed using linear discriminant analysis. Dunn's test was applied to identify the differences in spectra. Within the diagnostic categories, histology allowed us to determine the comparative efficiency of conventional screening vs. biospectroscopy to correctly identify either true atypia or underlying disease. RESULTS: Conventional cytology-based screening results in poor sensitivity and specificity. IR spectra derived from cervical cytology do not appear to discriminate in a diagnostic fashion when categories were based on conventional screening. Scores plots of IR spectra exhibit marked crossover of spectral points between different cytological categories. Although, significant differences between spectral bands in different categories are noted, crossover samples point to the potential for poor specificity and hampers the development of biospectroscopy as a diagnostic tool. However, when histology-based categories are used to conduct analyses, the scores plot of IR spectra exhibit markedly better segregation. CONCLUSIONS: Histology demonstrates that ATR-FTIR spectroscopy of liquid-based cytology identifies the presence of underlying atypia or disease missed in conventional cytology screening. This study points to an urgent need for a future biospectroscopy study where categories are based on such histology. It will allow for the validation of this approach as a screening tool.

Large loop excision of the transformation zone and cervical intraepithelial neoplasia: a 22-year experience.

AIM: To review the 22-year experience of the use of large loop excision of the transformation zone (LLETZ) for the treatment of cervical intraepithelial neoplasia (CIN). DESIGN: Retrospective observational study. SETTING: University Hospital of Ioannina, Greece. PERIOD: January 1989 until December 2011. POPULATION: Women undergoing excisional treatment with LLETZ for CIN. Women with invasive disease were excluded. INTERVENTION: Excisional treatment with LLETZ. Women had post-operative surveillance with cytology and colposcopy at 6, 12, 18 and 24 months, and yearly thereafter. OUTCOMES: We assessed the histological outcomes and margin involvement, as well as the rate of treatment failures requiring a repeat conization. RESULTS: A total of 3861 LLETZ biopsies were recorded during the study period. The histological evaluation of the cone specimens showed CIN1 in 897 (23.2%), CIN2 in 1129 (29.3%), CIN3 in 1322 (34.2%), microinvasive disease in 158 (4.1%), HPV lesions in 206 (5.3%) and normal histological findings in 149 (3.9%) women. The margins were reported as clear in 3166 (82%) cases, involved in 437 (11.3%) cases and uncertain in 258 (6.7%) cases. A total of 239 (6.2%) women underwent a second conization due to treatment failure. CONCLUSION: LLETZ remains the most popular conservative technique of treatment for women with precancerous cervical lesions. Post-treatment surveillance of these women is essential in order to detect residual or recurrent disease. New HPV biomarkers, introduced over the last two years, appear to be useful in the follow-up after treatment. A scoring system may allow for accurate prediction of women at risk of treatment failure and for tailored post-treatment surveillance.

Human papillomavirus DNA and mRNA positivity of the anal canal in women with lower genital tract HPV lesions: predictors and clinical implications.

OBJECTIVE: Women with HPV related pathology of the lower genital tract are at higher risk for AIN and anal cancer than the general population. A strategy to identify anal disease in these women has not been formulated. The aim of this study is to examine the feasibility of HPV related biomarker testing on anal smears, to identify the risk factors for anal HPV positivity and to provide information of the clinical implications of anal HPV infection in this population. METHODS: In women referred for colposcopy because of HPV related pathology of the lower genital tract (cervical cancer, CIN, VIN, warts) a detailed questionnaire, an anal smear and a cervical smear were taken. On each sample morphological cytology, flow cytometric evaluation of E6&7 mRNA, and HPV DNA detection and typing were performed. Women with a positive anal result were referred for high resolution anoscopy. RESULTS: So far 235 women have been included (mean age 34.3). HPV DNA, high-risk HPV DNA, high-risk mRNA was detected in 45%, 31% and 8% of the anal smears and in 56%, 39% and 25% of the cervical smears respectively. Absolute or partial concordance of the types between the cervix and the anus was seen in 74%. Positivity for mRNA was significantly lower in the anus than the cervix (8% vs 25%). Logistic regression analysis revealed risk factors for the presence of anal HPV DNA (>3 lifetime sexual partners and presence of cervical HPV DNA), hr HPV DNA (presence of cervical hr HPV DNA), and hr mRNA (presence of cervical hr mRNA). Twelve months after LLETZ 53% of women were cervical HPV negative, but 25% of those were still HPV positive in the anus. CONCLUSIONS: HPV infection of the anus is common in this group and is interlinked with the cervical infection. Anal HPV E6&7 mRNA expression is less common than in the cervix. Possible clinical implications of anal infection could be the development of AIN and recurrence of CIN after treatment due to cervical reinfection from the anal reservoir. The use of HPV biomarkers is feasible in anal smears, although especially DNA testing as triage method for referral to anoscopy is probably inappropriate due to high positivity rate.