Non-speculum clinician-taken samples for human papillomavirus testing: a cross-sectional study in older women.

BACKGROUND: Cervical cancer incidence and mortality are high in women aged ≥65 years, despite the disease being preventable by screening. Speculum-based screening can become more uncomfortable after the menopause. AIM: To examine test performance and acceptability of human papillomavirus (HPV) testing on clinician-collected vaginal samples without a speculum (non-speculum). DESIGN AND SETTING: Cross-sectional study in 11 GP practices and four colposcopy clinics in London, UK, between August 2017 and January 2019. METHOD: Non-speculum and conventional (speculum) samples were collected from women aged ≥50 years attending for a colposcopy (following a speculum HPV-positive screening result) or women aged ≥35 years (with confirmed cervical intraepithelial neoplasia (CIN) 2+), and women aged 50-64 years attending routine screening. Sensitivity to CIN2+ was assessed among women with confirmed CIN2+ (colposcopy). Specificity to HPV relative to speculum sampling and overall concordance was assessed among women with negative cytology (routine screening). RESULTS: The sensitivity of non-speculum sampling for detecting CIN2+ was 83.3% (95% confidence interval [CI] = 60.8 to 94.2) (n = 15/18). There was complete concordance among women with positive CIN2+ who had a speculum sample ≤91 days prior to the non-speculum sample (n = 12). Among 204 women with negative cytology, the specificity to HPV was 96.4% (95% CI = 92.7 to 98.5), with 96.6% concordant results (κ 72.4%). Seventy-one percent (n = 120/170) of women preferred a non-speculum sample for their next screen. CONCLUSION: HPV testing on non-speculum clinician-taken samples is a viable approach that warrants further exploration in larger studies. Overall test performance was broadly comparable with that of self-sampling.

Non-speculum sampling approaches for cervical screening in older women: randomised controlled trial.

BACKGROUND: Cervical cancer disproportionately affects women ≥65 years, especially those not screened regularly. Speculum use is a key barrier. AIM: To assess if offering non-speculum clinician-taken sampling and self-sampling increases uptake for lapsed attenders aged 50-64 years. DESIGN AND SETTING: Pragmatic randomised control trial conducted at 10 general practices in East London, UK. METHOD: Participants were 784 women aged 50-64 years, last screened 6-15 years before randomisation. Intervention participants received a letter offering the choice of non-speculum clinician- or self-sampling. Control participants received usual care. The main outcome measure was uptake within 4 months. RESULTS: Screening uptake 4 months after randomisation was significantly higher in the intervention arm: 20.4% (n = 80/393) versus 4.9% in the control arm (n = 19/391, absolute difference 15.5%, 95% confidence interval [CI] = 11.0% to 20.0%, P<0.001). This was maintained at 12 months: intervention 30.5% (n = 120/393) versus control 13.6% (n = 53/391) (absolute difference 17.0%, 95% CI = 11.3% to 22.7%, P<0.001). Conventional screening attendance within 12 months was very similar for both intervention 12.7% (n = 50/393) and control 13.6% (n = 53/391) arms. Ethnic differences were seen in screening modality preference. More White women opted for self-sampling (50.7%, n = 38/75), whereas most Asian and Black women and those from other ethnic backgrounds opted for conventional screening. CONCLUSION: Offering non-speculum clinician-taken sampling and self-sampling substantially increases uptake in older lapsed attendee women. Non-speculum clinician sampling appeals to women who dislike the speculum but still prefer a clinician to take their sample. Providing a choice of screening modality may be important for optimising cervical screening uptake.

A Randomized Comparison of Different Vaginal Self-sampling Devices and Urine for Human Papillomavirus Testing-Predictors 5.1.

BACKGROUND: Human papillomavirus (HPV)-based screening is rapidly replacing cytology as the cervical screening modality of choice. In addition to being more sensitive than cytology, it can be done on self-collected vaginal or urine samples. This study will compare the high-risk HPV positivity rates and sensitivity of self-collected vaginal samples using four different collection devices and a urine sample. METHODS: A total of 620 women referred for colposcopy were invited to provide an initial stream urine sample collected with the Colli-Pee device and take two vaginal self-samples, using either a dry flocked swab (DF) and a wet dacron swab (WD), or a HerSwab (HS) and Qvintip (QT) device. HPV testing was performed by the BD Onclarity HPV Assay. RESULTS: A total of 600 vaginal sample pairs were suitable for analysis, and 505 were accompanied by a urine sample. Similar positivity rates and sensitivities for CIN2+ and CIN3+ were seen for DF, WD, and urine, but lower values were seen for QT and HS. No clear user preferences were seen between devices, but women found urine easiest to collect, and were more confident they had taken the sample correctly. The lowest confidence in collection was reported for HS. CONCLUSIONS: Urine, a DF swab, and WD swab all performed well and were well received by the women, whereas the Qvintip and HerSwab devices were less satisfactory. IMPACT: This is the first study to compare five self-sampling methods in the same women taken at the same time. It supports wider use of urine or vaginal self-sampling for cervical screening.

Lectins in Cervical Screening.

Cervical screening in low-resource settings remains an unmet need. Lectins are naturally occurring sugar-binding glycoproteins whose binding patterns change as cancer develops. Lectins discriminate between dysplasia and normal tissue in several precancerous conditions. We explored whether lectins could be developed for cervical screening via visual inspection. Discovery work comprised lectin histochemistry using a panel of candidate lectins on fixed-human cervix tissue (high-grade cervical intraepithelial neoplasia (CIN3, n = 20) or normal (n = 20)), followed by validation in a separate cohort (30 normal, 25 CIN1, 25 CIN3). Lectin binding was assessed visually according to staining intensity. To validate findings macroscopically, near-infra red fluorescence imaging was conducted on freshly-resected cervix (1 normal, 7 CIN3), incubated with topically applied fluorescently-labelled lectin. Fluorescence signal was compared for biopsies and whole specimens according to regions of interest, identified by the overlay of histopathology grids. Lectin histochemistry identified two lectins-wheat germ agglutinin (WGA) and Helix pomatia agglutinin (HPA)-with significantly decreased binding to CIN3 versus normal in both discovery and validation cohorts. Findings at the macroscopic level confirmed weaker WGA binding (lower signal intensity) in CIN3 vs. normal for biopsies (p = 0.0308) and within whole specimens (p = 0.0312). Our findings confirm proof-of-principle and indicate that WGA could potentially be developed further as a probe for high-grade cervical disease.

The Role of KRAS in Endometrial Cancer: A Mini-Review.

Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as up-regulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options.

Women with high BMI: should they be managed differently due to antagonising action of leptin in labour?

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. There is evidence that leptin may be responsible for various complications in obese and morbidly obese women in labour by its effect on the myometrium causing uterine smooth muscle relaxation (causes less Ca(2+) flux in myometrium). By doing this, we believe it opposes oxytocin effect on the myometrium which in fact promotes uterine smooth muscle contractions (causes more Ca(2+) flux in myometrium). The opposing action of these two hormone may contribute to the dysfunctional labour process, prolonged first stage of labour, increase in operative vaginal delivery in second stage of labour and increase in caesarean section rate both in first and second stage of labour in obese women. Also, there is increased incidence of postdated pregnancy, induction of labour and atonic postpartum haemorrhage in obese and morbidly obese women. Does this mean labour should be managed differently in women with high BMI?

Leptin - a novel pharmacological agent for treatment of women with overactive bladder symptoms?

Overactive bladder is a common condition and is significantly known to affect quality of life in both men and women. It is usually associated with urinary urgency, frequency, nocturia with or without urinary incontinence. The exact aetiology of overactive bladder is unknown. The two main theories put forward include (a) disruption of central control of the bladder by excessive suprapontine excitation or reduced suprapontine inhibition (b) Peripheral abnormality due to excessive cholinergic excitation (increases release of acetylcholine which is calcium dependent) or reduced neuropeptidergic inhibition. The other factors which contribute to its cause include increase in caffeine intake and behavioural problems. Therefore the initial treatments are based on excluding pathology and implementing behavioural changes, bladder training and caffeine reduction. Anticholinergic drugs are the main pharmacological agents used in the treatment of overactive bladder and they are usually used in conjunction with the above treatment methods. Recently, an increase in serum leptin levels has been associated with overactive bladder symptoms. This possibly is not true because leptin actually reduces Ca2+ influx in the smooth muscle. The addition of increasing doses of leptin on uterine smooth muscle (in vitro) has shown to inhibit spontaneous as well as induced uterine contractions (myometrial biopsies taken from obese women) by reducing Ca2+ influx in obese women compared to normal weight women. We believe it may have similar action on the bladder and therefore expect inhibition of the bladder detrusor smooth muscle contraction rather than stimulation which may lead to overactive bladder symptoms. This action can be considered anticholinergic rather than cholinergic and therefore should improve overactive bladder symptoms. So could this hormone (leptin) be used as a new novel agent for treating women suffering with overactive bladder symptoms?

Leptin--a tocolytic agent for the future?

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. When biopsies of human myometrium from obese women were exposed to leptin, it showed a cumulative inhibitory effect on spontaneous as well as induced contractions. This lead to the proposed theory that leptin may be the cause of dysfunctional labour in obese women leading to increased caesarean section rates. There is an increased rate of post-dated pregnancies in obese women when compared to normal weight women with a consequent increased induction rate in women with a raised body mass index (BMI). Likewise there a decrease in the rate of spontaneous preterm delivery in obese women. These findings suggest that leptin inhibits uterine contractions in these women and this effect could be considered a tocolytic effect on uterine muscle. So could this hormone (leptin) be used as a tocolytic agent for threatened preterm labour in the future?