Imperial College London

DrAnitaMitra

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Research Fellow
 
 
 
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a.mitra

 
 
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Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
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49 results found

Mitra A, 2021, Blood clots, covid vaccines & the contraceptive pill: are we heading for a repeat of the 1995 pill scare?, BMJ Sexual & Reproductive Health, ISSN: 2515-1991

Journal article

Raglan O, MacIntyre D, Mitra A, Lee YS, Smith A, Assi N, Nautiyal J, Purkayastha S, Gunter MJ, Gabra H, Marchesi JR, Bennett P, Kyrgiou Met al., 2021, The association between obesity and weight loss after bariatric surgery on the vaginal microbiota, Microbiome, Vol: 9, Pages: 1-17, ISSN: 2049-2618

Background: Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery.Methods: Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. Results: The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus-dominant VMB and higher prevalence of a high diversity (Lactobacillus spp., and Gardnerella- spp. depleted) VMB, compared with non-obese subjects (p<0.001). Obese women had higher relative abundance of Dialister species (p<0.001), Anaerococcus vaginalis (p=0.021) and Prevotella timonensis (p=0.020) and decreased relative abundance of Lactobacillus crispatus (p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α, and TNFα levels were all higher among obese women, however only IL-1β and IL-8 correlated with VMB species diversity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery, however 75% of these women remained obese at six months. Prior to surgery there was no relationship between body mass index (BMI) and VMB structure, however post-surgery women with a Lactobacillus-dominant VMB had a significantly lower BMI than those with a high diversity VMB.Conclusions: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB, however, those with the greatest

Journal article

Paraskevaidi M, Cameron SJS, Whelan E, Bowden S, Tzafetas M, Mitra A, Semertzidou A, Athanasiou A, Bennett P, MacIntyre D, Takats Z, Kyrgiou Met al., 2020, Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening, EBioMedicine, Vol: 60, ISSN: 2352-3964

BackgroundThe introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.MethodsIn this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.FindingsIn a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.InterpretationThis automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.

Journal article

Tahmasebi F, Stewart S, Mitra A, Morje M, Sayasneh Aet al., 2020, Transvaginal saline contrast sonohystography to investigate postmenopausal bleeding: a systematic review, Cureus, Vol: 12, Pages: 1-14, ISSN: 2168-8184

Transvaginal ultrasound (TVUS) is the initial investigation of choice for postmenopausal bleeding (PMB), followed by diagnostic hysteroscopy and endometrial sampling if abnormalities are detected. Saline contrast sonohysterography (SCSH) - injection of saline through the cervix into the uterine cavity prior to TVUS - allowed increased diagnostic accuracy in women with PMB in several small, heterogeneous studies.The objectives of the current study were to evaluate the diagnostic accuracy of SCSH in women with PMB, comparing findings with surgical and pathological reports, highlight the necessity of SCSH in guiding clinical decision-making, and establish if there is an increase/decrease in the number of hysteroscopies performed for PMB and, hence, the adherence of clinicians to imaging referral guidelines.The search strategy included formulating search terms identifying all synonyms of SCSH and postmenopause. The databases searched were MEDLINE, Embase, and the Cochrane Library.Only studies comparing SCSH to an alternative method were selected. The studies were screened and data analysis performed using content analysis. Data reduction was performed through systematic coding and the generation of themesWe identified 18 studies, comprising 974 women, using SCSH to evaluate the endometrial cavity in women with PMB; most support SCSH improving diagnostic accuracy through delineating intracavitary structures.In effect, SCSH could be a first-line investigative modality to assess the uterine cavity once a larger, well-designed study has been conducted to clarify its specificity, sensitivity, and positive predictive value (PPV). Owing to its relatively non-invasive nature and potentially high diagnostic accuracy, SCSH could allow for more accurate decisions regarding the need for further investigation and subsequent management.

Journal article

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Manoli E, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424

Journal article

Mitra A, MacIntyre D, Ntritsos G, Smith A, Tsilidis K, Marchesi J, Bennett P, moscicki A-B, Kyrgiou Met al., 2020, The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions, Nature Communications, Vol: 11, Pages: 1-13, ISSN: 2041-1723

Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.

Journal article

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 7338-7346, ISSN: 0027-8424

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.

Journal article

Bowden SJ, Kalliala I, Veroniki AA, Arbyn M, Mitra A, Lathouras K, Mirabello L, Chadeau-Hyam M, Paraskevaidis E, Flanagan JM, Kyrgiou Met al., 2019, The use of Human Papillomavirus DNA Methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis, EBioMedicine, Vol: 50, Pages: 246-259, ISSN: 2352-3964

BackgroundMethylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus(HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detectinghigh-grade cervical intra-epithelial neoplasia (CIN).MethodsWe performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted induplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effectsbinary regression model were applied to determine pooled effect estimates.Findings44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamousintra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN(≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled differencein mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3%(95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse(pooled sensitivity 77% (95%CI:63–87), specificity 64% (95%CI:55–71), area under the curve (0·73(95%CI:0·69–0·77)).InterpretationHigher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use islimited by the need for a multi-genotype and standardised ass

Journal article

Tzafetas M, Mitra A, Kalliala I, Lever S, Bodai Z, Rosini F, Savage A, McKenzie J, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2019, THE IKNIFE AND ITS APPLICATION FOR THE TREATMENT OF CERVICAL ABNORMALITIES, Publisher: BMJ PUBLISHING GROUP, Pages: A589-A589, ISSN: 1048-891X

Conference paper

Bowden S, Kalliala I, Veroniki A, Arbyn M, Mitra A, Lathouras K, Mirabello L, Chadeau-Hyam M, Paraskevaidis E, Flanagan J, Kyrgiou Met al., 2019, THE USE OF HUMAN PAPILLOMAVIRUS DNA METHYLATION IN CERVICAL INTRAEPITHELIAL NEOPLASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A86, ISSN: 1048-891X

Conference paper

Mitra A, Macintyre D, Ntritsos G, Smith A, Tsilidis K, Marchesi J, Bennett P, Moscicki A-B, Kyrgiou Met al., 2019, THE ROLE OF THE VAGINAL MICROBIOTA IN THE REGRESSION OF UNTREATED CIN2 LESIONS, Publisher: BMJ PUBLISHING GROUP, Pages: A37-A37, ISSN: 1048-891X

Conference paper

Mitra A, Macintyre D, Lee Y, Smith A, Marchesi J, Lyons D, Stock S, Bennett P, Kyrgiou Met al., 2019, CERVICAL INTRAEPITHELIAL NEOPLASIA IS ASSOCIATED WITH AN ALTERED VAGINAL MICROBIOME AND INNATE IMMUNE DISRUPTION, Publisher: BMJ PUBLISHING GROUP, Pages: A71-A71, ISSN: 1048-891X

Conference paper

Tzafetas M, Mitra A, Lever S, Kalliala I, MacIntyre D, Ghaem-Maghami S, Kyrgiou Met al., 2019, ONCOLOGICAL AND REPRODUCTIVE OUTCOMES AFTER FERTILITY-SPARING SURGERY IN WOMEN WITH CERVICAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 1048-891X

Conference paper

Wiik J, Sengpiel V, Kyrgiou M, Nilsson S, Mitra A, Tanbo T, Jonassen CM, Tannæs TM, Sjøborg Ket al., 2019, Cervical microbiota in women with cervical intra-epithelial neoplasia, prior to and after local excisional treatment, a Norwegian cohort study, BMC Women's Health, Vol: 19, ISSN: 1472-6874

BackgroundLocal treatment for cervical intraepithelial neoplasia (CIN) by Loop Electrosurgical Excision Procedure (LEEP) has been correlated with reproductive morbidity, while the cervicovaginal microbiota is also known to affect the risk of preterm delivery. CIN and treatment by LEEP might change the cervical microbiota. The main aim of this study was to describe the cervical microbiota before and after LEEP and assess its associaton with cone depth and HPV persistence. Further, we aimed to compare the microbiota to references with normal cervical cytology.MethodsBetween 2005 and 2007, we prospectively identified 89 women planned for LEEP in a Norwegian hospital and recruited 100 references with a normal cervical cytology. Endocervical swabs were collected prior to treatment and at six (n = 77) and 12 months (n = 72) post LEEP for bacterial culture and PCR, and post LEEP for DNA testing for human papillomavirus (HPV). We compared the cervical microbiota composition before and after treatment and between women planned for LEEP vs references.ResultsThere was a reduction in the number of non-Lactobacillus bacterial species six and 12 months after LEEP compared to before treatment and a tendency towards a concomitant increase in Lactobacillus. No association between the detection of cervical bacteria, HPV persistence or cone depth was found.Women planned for LEEP carried significantly more Bacteroides spp., Gardnerella vaginalis, Mycoplasma hominis and Ureaplasma parvum as well as a greater number of bacterial species than the references.ConclusionsLocal excisional treatment appears to alter the cervical microbiota towards a less diverse microbiota. Women with CIN have a more diverse cervical microbiota compared to women with normal cervical cytology.

Journal article

Tzafetas M, Mitra A, Kalliala I, Lever S, Fotopoulou C, Farthing A, Smith JR, Martin-Hirsch P, Paraskevaidis E, Kyrgiou Met al., 2018, Fertility-sparing surgery for presumed early-stage invasive cervical cancer: a survey of practice in the United Kingdom., Anticancer Research, Vol: 38, Pages: 3641-3646, ISSN: 0250-7005

AIM: To explore current practice in fertility-sparing surgery for cervical cancer in the UK. MATERIALS AND METHODS: A web-based structured questionnaire was designed and circulated to all members of the British Gynaecological Cancer Society. RESULTS: From 111 recipients, a total of 49 responses were collected. The majority of centres treated between 20-29 cases of invasive cervical cancer surgically (21/49, 42.9%) and performed between 0-5 cases of radical trachelectomy annually (29/49, 59.2%). The vaginal approach was the one most commonly used and was offered by almost half of the centres (21/49, 42.9%); laparoscopic techniques were offered in 13 (13/49, 26.6%). The responses were divided as to whether these cases should have been referred to supra-regional centres (25/49, 51.0%). CONCLUSION: With the use of Human Papillomavirus vaccination leading to a projected decrease in the number of cervical cancer incidence, patients may need to be referred to supraregional centres in the future.

Journal article

Tzafetas M, Mitra A, Kalliala I, Bodai Z, Rosini F, Phelps D, Savage A, Lyons D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2018, iKnife - improving surgical outcomes in pre-invasive and invasive cervical disease, RCOG World Congress 2018, Publisher: Wiley, Pages: 17-17, ISSN: 1470-0328

Conference paper

Kyrgiou M, Athanasiou A, Kalliala IEJ, Paraskevaidi M, Mitra A, Martin-Hirsch PP, Arbyn M, Bennett P, Paraskevaidis Eet al., 2017, Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease., Cochrane Database of Systematic Reviews, Vol: 11, ISSN: 1469-493X

BACKGROUND: The mean age of women undergoing local treatment for pre-invasive cervical disease (cervical intra-epithelial neoplasia; CIN) or early cervical cancer (stage IA1) is around their 30s and similar to the age of women having their first child. Local cervical treatment has been correlated to adverse reproductive morbidity in a subsequent pregnancy, however, published studies and meta-analyses have reached contradictory conclusions. OBJECTIVES: To assess the effect of local cervical treatment for CIN and early cervical cancer on obstetric outcomes (after 24 weeks of gestation) and to correlate these to the cone depth and comparison group used. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 5), MEDLINE (up to June week 4, 2017) and Embase (up to week 26, 2017). In an attempt to identify articles missed by the search or unpublished data, we contacted experts in the field and we handsearched the references of the retrieved articles and conference proceedings. SELECTION CRITERIA: We included all studies reporting on obstetric outcomes (more than 24 weeks of gestation) in women with or without a previous local cervical treatment for any grade of CIN or early cervical cancer (stage IA1). Treatment included both excisional and ablative methods. We excluded studies that had no untreated reference population, reported outcomes in women who had undergone treatment during pregnancy or had a high-risk treated or comparison group, or both DATA COLLECTION AND ANALYSIS: We classified studies according to the type of treatment and the obstetric endpoint. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model and inverse variance. Inter-study heterogeneity was assessed with I2 statistics. We assessed maternal outcomes that included preterm birth (PTB) (spontaneous a

Journal article

Mitra A, MacIntyre D, Lee Y, Smith A, Marchesi J, Lyons D, Bennett P, Kyrgiou Met al., 2017, THE VAGINAL MICROBIOTA AFTER EXCISIONAL TREATMENT FOR CERVICAL INTRAEPITHELIAL NEOPLASIA, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 979-979, ISSN: 1048-891X

Conference paper

kalliala I, Markozannes G, Gunter M, Paraskevaidis E, Gabra H, Mitra A, terzidou V, Martin-Hirsch P, Tsilidis K, Kyrgiou Met al., 2017, Obesity and gynaecological and obstetrical conditions: an umbrella review of the literature, British Medical Journal, Vol: 7, ISSN: 0959-8138

Objective To study the strength and validity of associations between adiposity and risk of any type of obstetric or gynaecological conditions.Design An umbrella review of meta-analyses.Data sources PubMed, Cochrane database of systematic reviews, manual screening of references for systematic reviews or meta-analyses of observational and interventional studies evaluating the association between adiposity and risk of any obstetrical or gynaecological outcome.Main outcomes Meta-analyses of cohort studies on associations between indices of adiposity and obstetric and gynaecological outcomes.Data synthesis Evidence from observational studies was graded into strong, highly suggestive, suggestive, or weak based on the significance of the random effects summary estimate and the largest study in the included meta-analysis, the number of cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. Interventional meta-analyses were assessed separately.Results 156 meta-analyses of observational studies were included, investigating associations between adiposity and risk of 84 obstetric or gynaecological outcomes. Of the 144 meta-analyses that included cohort studies, only 11 (8%) had strong evidence for eight outcomes: adiposity was associated with a higher risk of endometrial cancer, ovarian cancer, antenatal depression, total and emergency caesarean section, pre-eclampsia, fetal macrosomia, and low Apgar score. The summary effect estimates ranged from 1.21 (95% confidence interval 1.13 to 1.29) for an association between a 0.1 unit increase in waist to hip ratio and risk endometrial cancer up to 4.14 (3.61 to 4.75) for risk of pre-eclampsia for BMI >35 compared with <25. Only three out of these eight outcomes were also assessed in meta-analyses of trials evaluating weight loss interventions. These interventions significantly reduced the risk of caesarean section and pre

Journal article

Mitra A, Mahajan V, Macintyre D, Lee Y, Smith A, Marchesi J, Lyons D, Bennett P, Kyrgiou Met al., 2017, Comparison of vaginal microbiota sampling techniques: cytobrush versus swab, Scientific Reports, Vol: 7, ISSN: 2045-2322

Evidence suggests the vaginal microbiota (VM) may influence risk of persistent Human Papillomavirus (HPV) infection and cervical carcinogenesis. Established cytology biobanks, typically collected with a cytobrush, constitute a unique resource to study such associations longitudinally. It is plausible that compared to rayon swabs; the most commonly used sampling devices, cytobrushes may disrupt biofilms leading to variation in VM composition. Cervico-vaginal samples were collected with cytobrush and rayon swabs from 30 women with high-grade cervical precancer. Quantitative PCR was used to compare bacterial load and Illumina MiSeq sequencing of the V1-V3 regions of the 16S rRNA gene used to compare VM composition. Cytobrushes collected a higher total bacterial load. Relative abundance of bacterial species was highly comparable between sampling devices (R2 = 0.993). However, in women with a Lactobacillus-depleted, high-diversity VM, significantly less correlation in relative species abundance was observed between devices when compared to those with a Lactobacillus species-dominant VM (p = 0.0049). Cytobrush and swab sampling provide a comparable VM composition. In a small proportion of cases the cytobrush was able to detect underlying high-diversity community structure, not realized with swab sampling. This study highlights the need to consider sampling devices as potential confounders when comparing multiple studies and datasets.

Journal article

Halliwell DE, Morais CLM, Lima KMG, Trevisan J, Siggel-King MRF, Craig T, Ingham J, Martin DS, Heys K, Kyrgiou M, Mitra A, Paraskevaidis E, Theophilou G, Martin-Hirsch PL, Cricenti A, Luce M, Weightman P, Martin FLet al., 2017, An imaging dataset of cervical cells using scanning near-field optical microscopy coupled to an infrared free electron laser, SCIENTIFIC DATA, Vol: 4, ISSN: 2052-4463

Using a scanning near-field optical microscope coupled to an infrared free electron laser (SNOM-IR-FEL) in low-resolution transmission mode, we collected chemical data from whole cervical cells obtained from 5 pre-menopausal, non-pregnant women of reproductive age, and cytologically classified as normal or with different grades of cervical cell dyskaryosis. Imaging data are complemented by demography. All samples were collected before any treatment. Spectra were also collected using attenuated total reflection, Fourier-transform (ATR-FTIR) spectroscopy, to investigate the differences between the two techniques. Results of this pilot study suggests SNOM-IR-FEL may be able to distinguish cervical abnormalities based upon changes in the chemical profiles for each grade of dyskaryosis at designated wavelengths associated with DNA, Amide I/II, and lipids. The novel data sets are the first collected using SNOM-IR-FEL in transmission mode at the ALICE facility (UK), and obtained using whole cells as opposed to tissue sections, thus providing an ‘intact’ chemical profile. These data sets are suited to complementing future work on image analysis, and/or applying the newly developed algorithm to other datasets collected using the SNOM-IR-FEL approach.

Journal article

Mitra A, MacIntyre D, Lai J, Lee Y, Smith A, Marchesi J, Lyons D, Bennett P, Kyrgiou Met al., 2017, The impact of excisional treatment for cervical intraepithelial neoplasia on the vaginal microbiota, 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage Publications, Pages: 89A-89A, ISSN: 1071-5576

Conference paper

Kottaridi C, Kyrgiou M, Pouliakis A, Magkana M, Aga E, Spathis A, Mitra A, Makris G, Chrelias C, Mpakou V, Paraskevaidis E, Panayiotides J, Karakitsos Pet al., 2017, Quantitative measurement of L1 HPV16 methylation for the prediction of pre-invasive and invasive cervical disease, Journal of Infectious Diseases, Vol: 215, Pages: 764-771, ISSN: 1537-6613

Background: Methylation of the HPV DNA has been proposed as a novel biomarker. Here, we correlated the mean methylation level of 12 CpG sites within L1 gene, to the histological grade of cervical precancer and cancer. We assessed whether HPV L1 gene methylation can predict the presence of high-grade disease at histology in women testing positive for HPV 16 genotype. Methods: Pyrosequencing was used for DNA methylation quantification and 145 women were recruited. Results: We found that the L1 HPV16 mean methylation (+/-SD) significantly increased with disease severity [CIN3=17.9%(±7.2) vs CIN2=11.6%(±6.5), p<0.001 or vs CIN1 =9.0%(±3.5), p<0.001). Mean methylation was a good predictor of CIN3+ cases; the Area Under the Curve (AUC) was higher for sites 5611 in the prediction of CIN2+ and higher for position 7145 for CIN3+. The evaluation of different methylation thresholds for the prediction of CIN3+, showed that the optimal balance of sensitivity and specificity (75.7% and 77.5%, respectively), PPV and NPV (74.7% and 78.5%, respectively) was achieved for a methylation of 14.0% with overall accuracy of 76.7%. Conclusion: Elevated methylation level is associated with increased disease severity and has good ability to discriminate HPV16 positive women that have high-grade disease or worse.

Journal article

Kyrgiou M, Kalliala I, Mitra A, fotopoulou C, Ghaem-maghami S, Martin-Hirsch P, Cruickshank M, Arbyn M, Paraskevaidis Eet al., 2017, Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test, Cochrane Database of Systematic Reviews, Vol: 1, ISSN: 1469-493X

BackgroundA significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommendsurveillance as spontaneous regression might occur. However,attendance for cytological follow-up decreases with time and might putsome women at risk of developing invasive disease.ObjectivesTo assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells ofundetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV(human papillomavirus) DNA test.Search methodsWe searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4 2016), MEDLINE,and Embase from inception to 21 April 2016.Selection criteriaWe included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atyp-ical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/milddyskaryosis).Data collection and analysisThe primary outcome measure studied was the occurrence of cervicalintra-epithelial neoplasia (CIN). The secondary outcome measuresstudied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possibleexit-examination. We calculated pooled risk ratios (RR) and 95%confidence intervals (CI) using a random-effects model with inversevariance weighting. Inter-study heterogeneity was assessedwith I2statistics.Main resultsWe identified five RCTs with 11,466 participants that fulfilledthe inclusion criteria. There were 18 cases of invasive cervical cancer,seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detectsCIN2+ and CIN3+ earlier

Journal article

Kyrgiou M, 2016, Tracking the impact of excisional cervical treatment on the cervix using biospectroscopy, Scientific Reports, Vol: 6, ISSN: 2045-2322

Local excisional treatment for cervical intra-epithelial neoplasia (CIN) is linked to significant adverse sequelae including preterm birth, with cone depthand radicality of treatment correlatingto the frequency and severity of adverse events. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy can detect underlying cervical disease more accurately than conventional cytology. The chemical profile of cells pre-and post-treatment may differas a result of altered biochemical processes due to excision,or treatment of the disease.Since pre-treatment cervicallength variesamongst women, the percentage of cervix excised may correlate more accurately to riskthan absolute dimensions. We show that treatment for CIN significantly altersthe biochemistry ofthe cervix, compared with women who have not had treatment; this is due to the excision of cervical tissue rather thana disease-controlling effect. However, the spectra do seem to correlate to the cone depth or proportion of cervical length excised.Future research should aim to explore the impact of treatment in a larger cohort.

Journal article

Mitra A, Paraskevaidis M, Lai J, Lyons D, Bennett P, Stock S, Kyrgiou Met al., 2016, Reduction in antimicrobial peptides after excisional treatment for cervical intraepithelial neoplasia: a possible mechanism of subsequent preterm birth?, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 123, Pages: E11-E11, ISSN: 1470-0328

Journal article

Kyrgiou M, Mitra A, Paraskevaidis E, 2016, Fertility and early pregnancy outcomes following conservative treatment for cervical intraepithelial neoplasia and early cervical cancer, JAMA Oncology, Vol: 2, Pages: 1496-1498, ISSN: 2374-2445

Clinical Question: Does local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer adversely affect successful conception and early pregnancy outcomes in the first and second trimester (<24 weeks of gestation)? Clinical Application: Local cervical treatment does not adversely affect fertility or first trimester miscarriage, although it is associated with a significant increase in the risk of second trimester miscarriages.

Journal article

Mitra A, Macintyre DA, marchesi, lee YS, bennett PR, kyrgiou Met al., 2016, The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?, Microbiome, Vol: 4, ISSN: 2049-2618

The vaginal microbiota plays a significant role in health and disease of the female reproductive tract. Next-generation sequencing techniques based upon analysis of bacterial 16S rRNA genes permits in-depth study of vaginal microbial community structure to a level of detail not possible with standard culture based microbiological techniques. The Human Papillomavirus (HPV) causes both cervical intraepithelial neoplasia (CIN) and cervical cancer. Although the virus is highly prevalent, only a small number of women have a persistent HPV infection and subsequently develop clinically significant disease. There is emerging evidence which leads us to conclude that increased diversity of vaginal microbiota combined with reduced relative abundance of Lactobacillus spp. is involved in HPV acquisition and persistence, and the development of cervical precancer and cancer. In this review we summarise the current literature, and discuss potential mechanisms for the involvement of vaginal microbiota in the evolution of CIN and cervical cancer. The concept of manipulation of vaginal bacterial communities using pre- and probiotics is also discussed as an exciting prospect for the field of cervical pathology.

Journal article

Kyrgiou M, Athanasiou A, Paraskevaidi M, Mitra A, Kalliala I, Martin-Hirsch P, Arbyn M, Bennett P, Paraskevaidis Eet al., 2016, Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. Editorial Comment, Obstetrical & Gynecological Survey, Vol: 71, Pages: 646-648, ISSN: 1533-9866

Local cervical treatment for preinvasive cervical disease such as cervical intraepithelial neoplasia (CIN) has been associated with an increased risk of preterm birth, perinatal morbidity, and mortality in a later pregnancy. This meta-analysis aimed to investigate the impact of treatment for cervical preinvasive and early invasive disease on obstetric outcomes and to see how this risk could be modified by the cone depth and comparison group.

Journal article

Mitra A, MacIntyre D, Lee Y, Smith A, Marchesi J, Lehne B, Bhatia R, Lyons D, Paraskevaidis E, Holmes E, Nicholson J, Bennett P, Kyrgiou Met al., 2016, Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity, Blair Bell Research Society Annual Academic Meeting, Publisher: Wiley, Pages: E11-E12, ISSN: 1470-0328

Conference paper

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