Imperial College London

Professor Maria Kyrgiou

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Professor of Gynaecological Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2177m.kyrgiou Website

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

225 results found

Kyrgiou M, Moscicki A-B, 2022, Vaginal microbiome and cervical cancer., Semin Cancer Biol, Vol: 86, Pages: 189-198

The female reproductive tract, similar to other mucosal sites, harbors a specific microbiome commonly dominated by Lactobacillus species (spp.), which has an essential role in maintaining health and homeostasis. Increasing evidence shows that genital tract dysbiosis and/or specific bacteria and cytokines might have an active role in the development and/or progression of HPV infection and cervical intra-epithelial neoplasia (CIN) and as a result cervical cancer. Cross-sectional and longitudinal studies reported that Lactobacillus spp. depletion increases with severity of CIN and that this may negatively affect disease regression rates. It is plausible that Lactobacillus deplete microbiome composition may lead to a pro-inflammatory environment that can increase malignant cell proliferation and HPV E6 and E7 oncogene expression. Future longitudinal cohorts and mechanistic experiments on HPV transfected cells models will further permit exploration of the impact of Lactobacillus spp. on HPV infection.

Journal article

Kechagias K, Giannos P, Paraskevaidi M, Mitra A, Kyrgiou Met al., 2022, Diverticulitis during pregnancy: a systematic review of the reported cases, Frontiers in Medicine, ISSN: 2296-858X

Journal article

Ellis L, Kyrgiou M, Bowden S, 2022, High Prevalence of HPV 51 in an Unvaccinated Population and Implications for HPV Vaccines, Vaccines, ISSN: 2076-393X

Journal article

Kiviharju M, Heinonen A, Jakobsson M, Virtanen S, Auvinen E, Kotaniemi-Talonen L, Dillner J, Kyrgiou M, Nieminen P, Aro K, Kalliala Iet al., 2022, Overtreatment rate after immediate local excision of suspected cervical intraepithelial neoplasia: A prospective cohort study., Gynecol Oncol

OBJECTIVE: The gold standard of cervical intraepithelial neoplasia (CIN) treatment is large loop excision of the transformation zone (LLETZ) after histopathological diagnosis from punch biopsies. In addition, treatment may be appropriate at initial colposcopy. Our objective was to study the applicability of immediate treatment strategy according to clinical parameters. METHODS: We conducted a prospective cohort study among patients referred to colposcopy at Helsinki University Hospital, Finland, between January 2014, and September 2018 (ISRCTN10933736). Patients treated with LLETZ, either after biopsies or immediately at initial colposcopy, were included. The main outcome measure was overtreatment (OT) rate defined as normal or low-grade histopathological findings in LLETZ specimen within both treatment groups. RESULTS: A total of 572 patients treated with LLETZ were included: 360 treated after biopsies and 212 treated immediately at initial colposcopy. When LLETZ was performed immediately after high-grade referral cytology and with colposcopic impression of high-grade disease, the overtreatment (OT) rate was 10.0% (95% CI 9.10 to 17.2), whereas when LLETZ was done after biopsy-confirmed high-grade lesions, the OT rate was 18.9% (95% CI 14.7 to 23.7), resulting in risk difference (RD) -8.91% (95% CI -16.0 to -1.82). Among HPV16/18 positive patients the OT rate was 8.22% (95% CI 3.08 to 17.0) for immediate treatment, resulting in RD of -10.7% (95% CI -18.3 to -3.04) compared to LLETZ after biopsies. CONCLUSIONS: Immediate LLETZ does not result in overtreatment when applied on selected cases, especially after high-grade referral cytology and when high-grade lesion is also colposcopically suspected.

Journal article

Kechagias K, Kalliala I, Bowden S, Athanasiou A, Paraskevaidi M, Veroniki A, Kyrgiou Met al., 2022, The role of HPV vaccination on HPV infection and recurrence of HPV-related disease after local surgical treatment: a systematic review and meta-analysis., The BMJ, Vol: 378, ISSN: 0959-8138

Objective: The efficacy of prophylactic human papillomavirus (HPV) vaccines after surgical treatment for pre-invasive genital disease remains unclear. Our aim was to explore the efficacy of HPV vaccination on HPV infection risk and risk of recurrent HPV-related disease in individuals undergoing local surgical treatment for cervical or other HPV-related disease.Methods: Design: Systematic review and meta-analysisData sources: PubMed/Medline, Scopus, Cochrane, Web of Science and ClinicalTrials.gov were screened from inception until March 2021.Inclusion criteria: Studies reporting on HPV infection risk and recurrence of HPV-related disease after local surgical treatment of pre-invasive genital disease in vaccinated individuals. Outcome measures: Primary: Recurrence risk for cervical intraepithelial neoplasia grade 2 or higher (CIN2+)(follow-up as reported by individual studies); Secondary: risk of HPV infection, other HPV-related lesions.Data extraction and risk of bias assessment: Independent and in duplicate data extraction and quality assessment using ROBINS-I and RoB-2 tools was performed for observational studies and randomised controlled trials (RCTs). Grading of Recommendations Assessment, Development and Evaluation (GRADE) was implemented for the primary outcome.Data synthesis: Observational studies and RCTs were analysed separately from post-hoc analyses of RCTs. Pooled risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using a random-effects (RE) meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals.Results: Twenty-two articles met the inclusion criteria of the review; eighteen studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational; 2 RCTs and 4 post-hoc analyses of RCTs). The risk of CIN2+ recurrence was reduced in vaccinated when compared to non-vaccinated

Journal article

Kyrgiou M, Athanasiou A, Arbyn M, Lax SF, Raspollini MR, Nieminen P, Carcopino X, Bornstein J, Gultekin M, Paraskevaidis Eet al., 2022, Terminology for cone dimensions after local conservative treatment for cervical intraepithelial neoplasia and early invasive cervical cancer: 2022 consensus recommendations from ESGO, EFC, IFCPC, and ESP, The Lancet Oncology, Vol: 23, Pages: e385-e392, ISSN: 1470-2045

Local cervical treatment for squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN) removes or ablates a cone-shaped or dome-shaped part of the cervix that contains abnormal cells. This Series paper introduces the 2022 terminology for cone dimensions after local conservative treatment for SIL, CIN, or early invasive cervical cancer. The terminology was prepared by the Nomenclature Committee of the European Society of Gynaecologic Oncology, the European Federation for Colposcopy, the International Federation of Cervical Pathology and Colposcopy, and the European Society of Pathology. Cone length should be tailored to the type of transformation zone. Treatment of SIL or CIN is associated with an increased risk of preterm birth, which escalates with increasing cone length. There is a lack of agreement regarding terms used to report excised specimen dimensions both intraoperatively and in the pathology laboratory. Consensus is needed to make studies addressing effectiveness and safety of SIL or CIN treatment comparable, and to facilitate their use to improve accuracy of antenatal surveillance and management. This Series paper summarises the current terminology through a review of existing literature, describes new terminology as agreed by a group of experts from international societies in the field of cervical cancer prevention and treatment, and recommends use of the new terminology that will facilitate communication between clinicians and foster more specific treatment guidelines that balance obstetrical harm against therapeutic effectiveness.

Journal article

Taumberger N, Joura EA, Arbyn M, Kyrgiou M, Sehouli J, Gultekin Met al., 2022, Myths and fake messages about human papillomavirus (HPV) vaccination: answers from the ESGO Prevention Committee, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 32, Pages: 1316-1320, ISSN: 1048-891X

Journal article

Valasoulis G, Michail G, Pouliakis A, Androutsopoulos G, Panayiotides IG, Kyrgiou M, Daponte A, Paraskevaidis Eet al., 2022, Effect of Condom Use after CIN Treatment on Cervical HPV Biomarkers Positivity: Prolonged Follow Up Study, CANCERS, Vol: 14

Journal article

Bergman H, Henschke N, Villanueva G, Loke YK, Golder SP, Dwan K, Crosbie EJ, Kyrgiou M, Platt J, Morrison Jet al., 2022, Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis, Cochrane Database of Systematic Reviews, Vol: 2022, ISSN: 1465-1858

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. We aim to evaluate the safety and efficacy of WHO pre-qualified human papillomavirus (HPV) vaccines given in different dose schedules, in females and males, to prevent cervical cancer and other HPV-related diseases by undertaking a network meta-analysis (NMA). We will rank the different vaccines and dose schedules according to the critical outcomes.

Journal article

Henschke N, Bergman H, Villanueva G, Loke YK, Golder SP, Crosbie EJ, Kyrgiou M, Dwan K, Morrison Jet al., 2022, Effects of human papillomavirus (HPV) vaccination programmes on community rates of HPV-related disease and harms from vaccination, Cochrane Database of Systematic Reviews, Vol: 2022, ISSN: 1465-1858

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. We aim to assess population-level effects of human papillomavirus (HPV) vaccination programmes on HPV-related disease and harms from vaccination.

Journal article

Whelan E, Kalliala I, Semertzidou A, Raglan O, Bowden S, Kechagias K, Markozannes G, Cividini S, McNeish I, Marchesi J, MacIntyre D, Bennett P, Tsilidis K, Kyrgiou Met al., 2022, Risk Factors for Ovarian Cancer: An Umbrella Review of the Literature, Cancers, Vol: 14, Pages: 2708-2708

<jats:p>Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height (RR per 10 cm 1.16, 95% confidence interval (CI) 1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk (RR 0.74, 95% CI 0.69–0.80). Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.</jats:p>

Journal article

Athanasiou A, Veroniki AA, Efthimiou O, Kalliala I, Naci H, Bowden S, Paraskevaidi M, Arbyn M, Lyons D, Martin-Hirsch P, Bennett P, Paraskevaidis E, Salanti G, Kyrgiou Met al., 2022, Comparative effectiveness and reproductive morbidity of local treatments for cervical intraepithelial neoplasia and stage 1a1 cervical cancer: a systematic review and network meta-analysis, The Lancet Oncology, Vol: 23, ISSN: 1213-9432

Background: In this network meta-analysis, we compared the effectiveness and reproductive morbidity associated with various treatment methods for cervical intraepithelial neoplasia (CIN).Methods: We searched electronic databases (MEDLINE, Embase, CENTRAL) from inception until 9 March 2022 for randomised and non-randomised studies reporting on oncological and reproductive outcomes after excisional or ablative CIN treatments. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks). The network for prematurity included also women with untreated CIN (colposcopy group). We extracted study-level data and conducted random-effects network meta-analyses to obtain odds ratios (ORs) with 95% confidence intervals. Within- and across-study risk of bias was assessed using Cochrane tools. PROSPERO registration: CRD42018115495 and CRD42018115508.Findings: Searches retrieved 11,987 citations. The networks for treatment failure and prematurity included 19,240 and 68,817 participants across 71 (25 randomised) and 29 (two randomised) studies, respectively. Compared to large loop excision of the transformation zone (LLETZ), risk of treatment failure was lower for other excisional (laser conisation: OR=0·59, 0·44–0·79; cold knife conisation [CKC]: OR=0·63, 0·50–0·81) and higher for ablative techniques (laser ablation: OR=1·69, 1·27–2·24; cryotherapy: OR=1·84, 1·33–2·55). Compared to colposcopy group, risk of prematurity was higher for all excisional techniques (CKC: OR=2·27, 1·70–3·02; laser conisation: OR=1·77, 1·29–2·43; LLETZ: OR=1·37, 1·16–1·62), whilst estimates were uncertain for ablative methods.Interpretation: More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preter

Journal article

Kyrgiou M, Athanasiou A, Arbyn M, Lax S, Raspollini MR, Nieminen P, Carcopino X, Bornstein J, Gultekin M, Paraskevaidis Eet al., 2022, 2022 ESGO/EFC/IFCPC/ESP Terminology for dimensions of cone after local conservative treatment for cervical intra-epithelial neoplasia and early invasive cervical cancer, The Lancet Oncology, ISSN: 1213-9432

This paper introduces the 2022 terminology for the cone dimensions after local conservative treatment for squamous intra-epithelial lesion/cervical intra-epithelial neoplasia (SIL/CIN) and early invasive cervical cancer. This is prepared by the Nomenclature Committee of the European Society of Gynaecologic Oncology (ESGO), the European Federation for Colposcopy (EFC), the International Federation of Cervical Pathology and Colposcopy (IFCPC) and the European Society of Pathology (ESP). It is recommended that the cone length is tailored to the type of transformation zone. Treatment of SIL/CIN is associated with preterm birth and this risk increases with increasing cone length. There is lack of agreement on the reporting definitions of the excised specimen dimensions intra-operatively and/or in the pathology laboratory. There is a need for a consensus terminology of the cone dimensions to make studies addressing effectiveness and safety of SIL/CIN treatment comparable and facilitate their use to tailor surveillance and antenatal management. This document summarises existing terminologies through a review of the literature. We further describe the new 2022 terminology as agreed by a group of experts from international societies in the field of cervical cancer prevention and treatment. We recommend the use of the 2022 terminology that will facilitate communication between clinicians and foster tailored treatment guidelines that balance obstetrical harm against therapeutic effectiveness.

Journal article

Doulgeraki T, Bowden S, Athanasiou A, Kechagias K, Lathouras K, Kalliala I, Kyrgiou Met al., 2022, Environmental and modifiable risk factors for cervical cancer: An umbrella review, Publisher: ELSEVIER, Pages: E83-E83, ISSN: 0301-2115

Conference paper

Mitra A, MacIntyre DA, Paraskevaidi M, Moscicki A-B, Mahajan V, Smith A, Lee YS, Lyons D, Paraskevaidis E, Marchesi JR, Bennett PR, Kyrgiou Met al., 2021, The vaginal microbiota and innate immunity after local excisional treatment for cervical intraepithelial neoplasia, Genome Medicine: medicine in the post-genomic era, Vol: 13, ISSN: 1756-994X

Background:Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines.Methods:We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls.Results:Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment.Conclusions:Women with CIN hav

Journal article

Giannos P, Kechagias K, Bowden S, Tabassum N, Paraskevaidi M, Kyrgiou Met al., 2021, PCNA in cervical intraepithelial neoplasia and cervical cancer: an interaction network analysis of differentially expressed genes, Frontiers in Oncology, Vol: 11, Pages: 1-8, ISSN: 2234-943X

The investigation of differentially expressed genes (DEGs) and their interactome could provide valuable insights for thedevelopment of markers to optimise cervical intraepithelial neoplasia (CIN) screening and treatment. This study investigatedpatients with cervical disease to identify gene markers whose dysregulated expression and protein interaction interface werelinked with CIN and cervical cancer (CC). Literature search of microarray datasets containing cervical epithelial samples wasconducted in Gene Expression Omnibus and Pubmed/Medline from inception untill March 2021. Retrieved DEGs were used toconstruct two protein-protein interaction (PPI) networks. Module DEGs that overlapped between CIN and CC samples, were rankedbased on 11 topological algorithms. The highest-ranked hub gene was retrieved and its correlation with prognosis, tissueexpression and tumour purity in patients with CC, was evaluated. Screening of the literature yielded 12 microarray datasets(GSE7803, GSE27678, GSE63514, GSE6791, GSE7803, GSE9750, GSE27678, GSE29570, GSE39001, GSE63514, GSE63678, GSE67522). TwoPPI networks from CIN and CC samples were constructed and consisted of 1704 and 3748 DEGs along 21393 and 79828 interactions,respectively. Two gene clusters were retreived in the CIN network and three in the CC network. Multi-algorithmic topologicalanalysis revealed PCNA as the highest ranked hub gene between the two networks, both in terms of expression and interactions.Further analysis revealed that while PCNA was overexpressed in CC tissues, it was correlated with favourable prognosis (log-rank P=0.022, HR=0.58) and tumour purity (P=9.86 × 10-4, partial rho=0.197) in CC patients. This study identified that cervical PCNAexhibited multi-algorithmic topological significance among DEGs from CIN and CC samples. Overall, PCNA may serve as a potentialgene marker of CIN progression. Experimental validation is necessary to examine its value in patients with cervical disease.

Journal article

Kechagias K, Katsikas-Triantafyllidis K, Kyriakidou M, Giannos P, Kalliala I, Veroniki A, Paraskevaidi M, Kyrgiou Met al., 2021, The relation between caffeine consumption and endometriosis: An updated systematic review and meta-analysis, Nutrients, Vol: 13, Pages: 1-12, ISSN: 2072-6643

While the contributing factors leading to endometriosis remain unclear, its clinical heterogeneity suggests a multifactorial causal background. Amongst others, caffeine has been studied extensively during the last decade as a putative contributing factor. In this systematic review and meta-analysis, we provide an overview/critical appraisal of studies that report on the association between caffeine consumption and the presence of endometriosis. In our search strategy, we screened PubMed and Scopus for human studies examining the above association. The main outcome was the relative risk of endometriosis in caffeine users versus women consuming little or no caffeine (<100 mg/day). Subgroup analyses were conducted for different levels of caffeine intake: high (>300 mg/day) or moderate (100–300 mg/day). Ten studies were included in the meta-analysis (five cohort and five case-control studies). No statistically significant association was observed between overall caffeine consumption and risk for endometriosis (RR 1.12, 95% confidence interval (CI) 0.97–1.28, I2 = 70%) when compared to little or no (<100 mg/day) caffeine intake. When stratified according to level of consumption, high intake was associated with increased risk of endometriosis (RR 1.30, 95%CI 1.04–1.63, I2 = 56%), whereas moderate intake did not reach nominal statistical significance (RR 1.18, 95%CI 0.99–1.40, I2 = 37%). In conclusion, caffeine consumption does not appear to be associated with increased risk for endometriosis. However, further research is needed to elucidate the potential dose-dependent link between caffeine and endometriosis or the probable role of caffeine intake as a measurement of other unidentified biases.

Journal article

Rockall A, Barwick T, Wilson W, Singh N, Bharwani N, Sohaib A, Nobbenhuis M, Warbey V, Miquel M, Koh D-M, De Paepe KN, Martin-Hirsch P, Ghaem-Maghami S, Fotopoulou C, Stringfellow H, Sundar S, Manchanda R, Sahdev A, Hackshaw A, Cook GJ, MAPPING Study Groupet al., 2021, Diagnostic accuracy of FEC-PET/CT, FDG-PET/CT and diffusion-weighted MRI in detection of nodal metastases in surgically treated endometrial and cervical carcinoma, Clinical Cancer Research, Vol: 27, Pages: 6457-6466, ISSN: 1078-0432

Purpose:Pre-operative nodal staging is important for planning treatment in cervical cancer (CC) and endometrial cancer (EC) but remains challenging. We compare nodal staging accuracy of 18F-ethyl-choline-(FEC)-PET/CT, 18F-Fluoro-deoxy-glucose-(FDG)-PET/CT and diffusion-weighted-MRI (DW-MRI) with conventional morphological MRI.Experimetal Design:A prospective, multicentre observational study of diagnostic accuracy for nodal metastases was undertaken in 5 gyne-oncology centres. FEC-PET/CT, FDG-PET/CT and DW-MRI were compared to nodal size and morphology on MRI. Reference standard was strictly correlated nodal histology. Eligibility included operable CC stage=>1B1 or EC (grade 3 any stage with myometrial invasion or grade 1-2 stage=>II). Results:Among 162 consenting participants, 136 underwent study DW-MRI and FDG-PET/CT, and 60 underwent FEC-PET/CT. 267 nodal regions in 118 women were strictly correlated at histology (nodal positivity rate 25%). Sensitivity per-patient (n=118) for nodal size, morphology, DW-MRI, FDG- and FEC-PET/CT were 40%*, 53%, 53%, 63%* and 67% for all cases (*p=0.016); 10%, 10%, 20%, 30% and 25% in CC (n=40); 65%, 75%, 70%, 80% and 88% in EC (n=78). FDG-PET/CT outperformed nodal size (p=0.006) and size ratio (p=0.04) for per-region sensitivity. False positive rates were all <10%. Conclusions:All imaging techniques had low sensitivity for detection of nodal metastases and cannot replace surgical nodal staging. The performance of FEC-PET/CT was not statistically different to other techniques that are more widely available. FDG-PET/CT had higher sensitivity than size in detecting nodal metastases. False positive rates were low across all methods. The low false positive rate demonstrated by FDG-PET/CT may be helpful in arbitration of challenging surgical planning decisions.

Journal article

Mitra A, MacIntyre D, Paraskevaidi M, Moscicki A-B, Mahajan V, Smith A, Lyons D, Paraskevaidis E, Marchesi J, Bennett P, Kyrgiou Met al., 2021, The vaginal microbiota and innate Immunity after local excisional treatment for cervical intraepithelial neoplasia, Publisher: BioMed Central

Background: Vaginal microbiota (VMB) are altered in women with cervical intra-epithelial neoplasia (CIN) and associate with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This interventional study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMPs levels in matched vaginal secretions. Analyses were performed to compare bacterial composition and immune analyte levels before and after CIN excision and in healthy controls.Results: Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV: 21/103, 20% vs 1/39, 3%, p=0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV: 19/103, 20% vs 1/39, 3%, p=0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1 and IL-8 remained significantly elevated pre- (p<0.0001 and p=0.0014 respectively) and post-treatment compared to untreated controls (p<0.0001 and p=0.0035 respectively). Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p<0.0001), however their levels remained lower than controls post-treatment.Conclusions: Women with CIN have increased prevalence of Lactobacillus spp. depleted, high-diversity V

Working paper

Kyrgiou M, Bowden SJ, Athanasiou A, Paraskevaidi M, Kechagias K, Zikopoulos A, Terzidou V, Martin-Hirsch P, Arbyn M, Bennett P, Paraskevaidis Eet al., 2021, Morbidity after local excision of the transformation zone for cervical intra-epithelial neoplasia and early cervical cancer, Best Practice and Research: Clinical Obstetrics and Gynaecology, Vol: 75, Pages: 10-22, ISSN: 1521-6934

The awareness that cervical intra-epithelial neoplasia (CIN) treatment increases the risk of preterm birth has led to major changes in clinical practice. Women with CIN have a higher baseline risk of prematurity but local treatment further increases this risk. The risk further increases with increasing cone length and multiplies for repeat excisions; it is unclear whether small cones confer any additional risk to CIN alone. There is no evidence to suggest that fertility is affected by local treatment, although this increases the risk of mid-trimester loss. Caution should prevail when deciding to treat women with CIN of reproductive age. If treatment is offered, this should be conducted effectively to optimise the clearance of disease and minimise the risk of recurrence. Colposcopists should alert women undergoing treatment that this may increase the risk of preterm birth and that they may be offered interventions when pregnant. The cone length should be clearly documented and used as a risk stratifier.

Journal article

Lythgoe M, Adriani M, Stebbing J, Clark J, Pickford E, Frampton A, Liu D, Kyrgiou M, Rees E, Fyvie G, Stevenson A, Krell Jet al., 2021, 543P Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours, Annals of Oncology, Vol: 32, Pages: S607-S607, ISSN: 0923-7534

BackgroundMRx0518 is an oral live biotherapeutic with potent immunostimulatory activity and anti-tumorigenic efficacy in murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer. Previous reports have demonstrated a favourable safety profile in neoadjuvant and metastatic clinical settings, with emerging evidence of immune modulation. We performed a comprehensive analysis of the gene and metagene signature in cancer patients treated with MRx0518 monotherapy.MethodsTreatment-naïve patients with a histologically confirmed diagnosis of cancer scheduled for surgical resection were recruited from April 2019 to February 2020. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011CFU) twice daily from inclusion until the day preceding surgery. Safety and tolerability (CTCAE v4.03) were the primary endpoints of this study. Comprehensive biomarker analysis was also performed in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples using the NanoString IO 360 panel to explore gene and metagene signatures.Results31 samples were collected across tumour groups including breast (n=13) prostate (n=8), uterine (n=6), melanoma (n=2) and bladder (n=2). Differential expression analysis showed significant (p<0.05) increases in genes and metagenes associated with anti-tumour activity, including antigen presentation (AXL & CXCL12), innate immune processes (CHUK, RELA, PPARG & HRAS), interferon response (IFNGR1 & IFNGR2), Th1 cells and CD8+ cells following MRx0518 therapy, echoing preclinical findings. Novel changes, not previously detected in murine models, involving endothelial, mast cells, inflammatory myeloid and inflammatory chemokines were also observed, suggesting MRx0518 may have additional in vivo anti-tumorigenic effects. These changes were more pronounced in the breast cancer cohort.ConclusionsThis analysis, mirrors previous immunostimulatory activity and anti-tumorigenic efficacy observations seen in pre-clini

Journal article

Tsilidis K, 2021, An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites, Nature Communications, Vol: 12, Pages: 1-10, ISSN: 2041-1723

There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma.

Journal article

Athanasiou A, Bowden SJ, Paraskevaidis E, Shylasree TS, Lathouras K, Kyrgiou Met al., 2021, Neoadjuvant chemotherapy and surgery versus chemoradiotherapy for locally advanced cervical cancer, Cochrane Database of Systematic Reviews, Vol: 2021, ISSN: 1465-1858

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The aim of this review is to compare neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) versus chemoradiotherapy (CRT) for locally advanced cervical cancer.

Journal article

Paraskevaidis E, Athanasiou A, Kalliala I, Batistatou A, Paraskevaidi M, Bilirakis E, Nasioutziki M, Paschopoulos M, Lyons D, Arbyn M, Cruickshank M, Martin-Hirsch P, Kyrgiou Met al., 2021, Invasive cervical cancer following treatment of pre-invasive lesions: A potential theory based on a small case series, European Journal of Obstetrics Gynecology and Reproductive Biology, Vol: 264, Pages: 56-59, ISSN: 0301-2115

PURPOSE: The aim of this study is to present a single department's experience on cervical cancer cases following previous excision of cervical intraepithelial neoplasia (CIN) and to discuss potential pathogenesis. METHODS: Nine cervical cancer cases meeting the inclusion criteria, with available pathological and follow-up data, were considered eligible for this study. RESULTS: The majority (7/9) have had clear excisional margins. The interval between initial treatment and cancer diagnosis ranged from 7 to 17 years. In all cases cancer diagnosis was "unexpected", as the prior cytological and/or colposcopic evaluation was not suggestive of significant cervical pathology. All cancers were squamous, and 5/9 at stage I. CONCLUSION: The long interval between initial CIN treatment and final diagnosis as well as the normal post-treatment follow-up may suggest a 'de novo' underlying but 'hidden' carcinogenesis process. It might be that dysplastic cells entrapped within crypts (or normal metaplastic affected by the same predisposing factors) continue undergoing their evolution, undetectable by cytology and colposcopy until they invade stroma and surfaces (endo- and/or ectocervical) approximately a decade later. Heavy cauterisation of cervical crater produced post excision might be a potential culprit of this entrapment.

Journal article

Semertzidou A, Grout-Smith H, Kalliala I, Kyrgiou Met al., 2021, Diabetes and the risk of gynaecological and obstetric outcomes: an umbrella review, Publisher: WILEY, Pages: 36-37, ISSN: 1470-0328

Conference paper

Pearson-Stuttard J, Papadimitriou N, Markozannes G, Cividini S, Kakourou A, Gill D, Rizos EC, Monori G, Ward HA, Kyrgiou M, Gunter MJ, Tsilidis KKet al., 2021, Type 2 diabetes and cancer: an umbrella review of observational and Mendelian randomisation studies, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, Pages: 1218-1228, ISSN: 1055-9965

Background Type 2 diabetes(T2DM) has been associated with an increased risk of developing several common cancers, but it is unclear whether this association is causal. We aimed to summarise the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomisation(MR) studies. Methods We performed an umbrella review of the evidence across meta-analyses of observational studies that examined associations of T2DM with risk of developing or dying from site-specific cancers, and MR studies that explored the potential causal association of T2DM and associated biomarkers with cancer risk. Results We identified eligible observational meta-analyses that assessed associations between T2DM and cancer incidence for 18 cancer sites, cancer mortality for seven sites, and cancer incidence or mortality for four sites. Positive associations between T2DM and six cancers reached strong or highly suggestive evidence. We found eight MR studies assessing the association of genetically predicted T2DM and seven and eight studies assessing the association of genetically predicted fasting insulin or fasting glucose concentrations, respectively, upon site-specific cancers. Positive associations were found between genetically predicted T2DM and fasting insulin and risk of six cancers. There was no association between genetically predicted fasting plasma glucose and cancer except for squamous cell lung carcinoma. Conclusions We found robust observational evidence for the association between T2DM and colorectal, hepatocellular, gallbladder, breast, endometrial and pancreatic cancer. Impact Potential causal associations were identified for genetically predicted T2DM and fasting insulin concentrations and risk of endometrial, pancreas, kidney, breast, lung and cervical cancer.

Journal article

Semertzidou A, MacIntyre D, Marchesi J, Bennett P, Kyrgiou Met al., 2021, The role of genital tract microbiota continuum in endometrial malignancy, Publisher: WILEY, Pages: 115-116, ISSN: 1470-0328

Conference paper

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

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

<h4>Background: </h4> 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. <h4>Methods: </h4>: 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. <h4>Results: </h4>: 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. <h4>Conclusions: </h4>: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compare

Journal article

Bowden S, Bodinier B, Kalliala I, Zuber V, Vuckovic D, Doulgeraki T, Whitaker M, Wielscher M, Cartwright R, Tsilidis K, Bennett P, Jarvelin M-R, Flanagan J, Chadeau M, Kyrgiou M, FinnGen consortiumet al., 2021, Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study, The Lancet Oncology, Vol: 22, Pages: 548-557, ISSN: 1213-9432

Background: Most uterine cervical high-risk HPV infections (hrHPV) are transient, with only a small 3fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest 4a significant inherited genetic component. Candidate gene studies and previous genome-wide 5association studies (GWAS) report associations between the human leukocyte antigen (HLA) region 6and cervical cancer. 78Methods: Adopting a genome-wide approach, we compared the genetic variation in women with 9invasive cervical cancer (ICC) and cervical intra-epithelial neoplasia (CIN) grade 3, to that in healthy 10controls using the largest reported cohort of unrelated European individuals (N=150,314)to date. We 11sought for replication in a second large independent dataset (N=128,123). We further performed a two-12sample Mendelian Randomisation approach to explore the role of risk factors in the genetic risk of 13cervical cancer.1415Findings: In our analysis (N=4,769 CIN3 and ICC cases; N=145,545 controls), of the (N=9,600,464) 16assayed and imputed SNPs, six independent variants were found associated with CIN3and ICC. These 17included novel loci rs10175462(PAX8; OR=0.87(95%CI=0.84-0.91); P=1.07x10-9) and rs27069 18(CLPTM1L;OR=0.88(95%CI=0.84-0.92); P=2.51x10-9), and previously reported signals at rs9272050 19(HLA-DQA1;OR=1.27(95%CI=1.21-1.32); P=2.51x10-28), rs6938453 (MICA;OR=0.7920(95%CI=0.75-0.83); P=1.97x10-17), rs55986091 (HLA-DQB1;OR=0.66(95%CI=0.60-0.72); 21P=6.42x10-22) and rs9266183 (HLA-B;OR=0.73(95%CI=0.64-0.83); P=1.53x10-6). Mendelian 22randomisation further supported the complementary role of smoking, age at first pregnancy, and number 23of sexual partners in the risk of developing cervical cancer.2425Interpretation: Our results provide substantial new evidence for genetic susceptibility to cervical cancer, 26including PAX8, CLPTM1LandHLA genes, suggesting disruption in apoptotic and immun

Journal article

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