Publications
58 results found
Mitra A, MacIntyre D, Lai J, et 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
Kottaridi C, Kyrgiou M, Pouliakis A, et 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.
Kyrgiou M, Kalliala I, Mitra A, et 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
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.
Mitra A, Paraskevaidis M, Lai J, et 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
Kyrgiou M, Athanasiou A, Paraskevaidi M, et 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.
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.
Mitra A, Macintyre DA, marchesi, et 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.
Kyrgiou M, Mitra A, Athanasiou A, et al., 2016, The risk of preterm birth after treatment for cervical pre-invasive and early invasive disease increases with increasing cone depth: a systematic review and meta-analysis, Blair Bell Research Society Annual Academic Meeting, Publisher: Wiley, Pages: E8-E8, ISSN: 1470-0328
Mitra A, MacIntyre D, Lee Y, et 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
Kyrgiou M, Kalliala I, Mitra A, et al., 2016, Immediate referral to colposcopy vs. cytological surveillance for low-grade cervical cytological abnormalities in the absence of HPV test: A systematic review and a meta-analysis of the literature, International Journal of Cancer, Vol: 140, Pages: 216-223, ISSN: 1097-0215
We performed a systematic review and meta-analysis to explore the optimum management strategy for women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis) cytological abnormalities at primary screening in the absence of HPV DNA test. We searched MEDLINE, EMBASE and CENTRAL and included randomised controlled trials comparing immediate colposcopy to cytological surveillance in women with ASCUS/LSIL. The outcomes of interest were occurrence of different histological grades of cervical intra-epithelial neoplasia (CIN) and default rates during follow-up. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect model and with inverse variance weighting. Interstudy heterogeneity was assessed using I2 statistics. Six RCTs were included. Immediate colposcopy significantly increased detection of unimportant abnormalities as opposed to repeat cytology (koilocytosis:32% vs.21%, RR:1.49, 95%CI=1.17-1.90); CIN1:21% vs.8%, RR:2.58, 95%CI=1.69-3.94). Although immediate colposcopy detected CIN2, CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN3+:10.3 vs.11.9%, RR:1.02, 95%CI=0.53-1.97), with significant inters-study heterogeneity (p<0.001,I2=93%). Default risk was significantly higher for repeat cytology (6months: 6.3 vs.13.3%, RR:3.85, 95%CI=1.27-11.63; 12months: 6.3 vs.14.8%, RR:6.39, 95%CI=1.24-32.95; 24 months: 0.9 vs.16.1%, RR:19.1,95%CI=9.02-40.4). Detection of CIN2+ for cytological surveillance over two years is similar to that of immediate colposcopy, although patients may default. Colposcopy may be first choice when good compliance is not assured, but may increase detection of insignificant lesions. This emphasizes the need for a reflex triage test to distinguish women who need diagnostic work-up from those who can return to routine recall.
Mitra A, Tzafetas M, Lyons D, et al., 2016, Cervical intraepithelial neoplasia: screening and management., British Journal of Hospital Medicine, Vol: 77, Pages: C118-C123, ISSN: 1750-8460
Globally, cervical cancer remains the fourth most common female malignancy, with over 528 000 new cases and 266 000 deaths in 2012; 84% of these occurred in low-resource settings (Ferlay et al, 2015). Cervical cancer is largely preventable through organized screening programmes, which can detect pre-malignant disease and treat it before invasive disease develops. Cervical intraepithelial neoplasia is the pre-malignant, dysplastic condition of the uterine cervix, which in a small proportion of cases will eventually progress to invasive cervical cancer if left untreated.
Mitra A, Kindinger L, Kalliala I, et al., 2016, Obstetric complications after treatment of cervical intraepithelial neoplasia, British Journal of Hospital Medicine, Vol: 77, Pages: C124-C127, ISSN: 1750-8460
Kyrgiou M, Athanasiou A, Paraskevaidi M, et al., 2016, Adverse obstetrical outcomes after local treatment for cervical pre-invasive and early invasive disease according to the cone depth: a systematic review and meta-analysis, BMJ, Vol: 354, Pages: 1-15, ISSN: 0959-8138
Objective: To assess the effect of treatment for CIN on obstetric outcomes and to correlate this to the cone depth and comparison group used.MethodsDesign: Systematic review and meta-analysisData Sources: CENTRAL, MEDLINE, EMBASE from 1948 to April 2016.Eligibility Criteria: Studies assessing obstetric outcomes in women with or without a previous local cervical treatment.Data Extraction & Synthesis: Independent reviewers extracted the data and performed quality assessment using the Newcastle-Ottawa criteria. Studies were classified according to method and obstetric endpoint. Pooled risk ratios (RR) were calculated using a random-effect model and inverse variance. Inter-study heterogeneity was assessed with I2 statistics.Main outcomes and measures: Obstetric outcomes; preterm birth (PTB) (spontaneous and threatened), premature rupture of the membranes (pPROM), chorioamnionitis, mode of delivery, length of labour, induction of delivery, oxytocin use, haemorrhage, analgesia, cervical cerclage & cervical stenosis. Neonatal outcomes; low birth weight (LBW), neonatal intensive care unit (NICU) admission, stillbirth, APGAR scores and perinatal mortality.Results: Seventy-one studies were included (6338982 participants: 65082 treated-6292563 untreated). Treatment significantly increased the risk of overall (<37weeks)(10.7 v 5.4%, RR=1.78[1.60 to 1.98]), severe (<34/32weeks)(3.5 v 1.4%, RR=2.40[1.92 to 2.99]) and extreme (<30/28weeks)(1.0 v 0.3%, RR=2.54[1.77 to 3.63]) PTB. The magnitude of the effect was higher for techniques removing or ablating more tissue (<37weeks: CKC (RR=2.70[2.14 to 3.40]), LC (RR=2.11[1.26 to 3.54)], excision not otherwise specified (NOS) (RR=2.02[1.60 to 2.55]), LLETZ (RR=1.56[1.36 to 1.79]), ablation NOS (RR=1.46[1.27 to 1.66]). The risk of PTB increased with repeat treatment (13.2 v 4.1%, RR=3.78[2.65 to 5.39]) and with increasing cone depth (≤12/10mm: 7.1 v 3.4%, RR=1.54[1.09 to 2.18]; ≥10/12mm: 9.8 v 3.4%, RR=1.93[1.62
kyrgiou M, Mitra A, Moscicki AB, 2016, Does the vaginal microbiota plays a role in the development of cervical cancer?, Translational Research, Vol: 179, Pages: 168-182, ISSN: 1931-5244
Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next-generation sequencing techniques identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host’s innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks.
Halliwell DE, Morais CLM, Lima KMG, et al., 2016, Imaging cervical cytology with scanning near-field optical microscopy (SNOM) coupled with an IR-FEL, Scientific Reports, Vol: 6, ISSN: 2045-2322
Cervical cancer remains a major cause of morbidity and mortality among women, especially in the developing world. Increased synthesis of proteins, lipids and nucleic acids is a pre-condition for the rapid proliferation of cancer cells. We show that scanning near-field optical microscopy, in combination with an infrared free electron laser (SNOM-IR-FEL), is able to distinguish between normal and squamous low-grade and high-grade dyskaryosis, and between normal and mixed squamous/glandular pre-invasive and adenocarcinoma cervical lesions, at designated wavelengths associated with DNA, Amide I/II and lipids. These findings evidence the promise of the SNOM-IR-FEL technique in obtaining chemical information relevant to the detection of cervical cell abnormalities and cancer diagnosis at spatial resolutions below the diffraction limit (≥0.2 μm). We compare these results with analyses following attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy; although this latter approach has been demonstrated to detect underlying cervical atypia missed by conventional cytology, it is limited by a spatial resolution of ~3 μm to 30 μm due to the optical diffraction limit.
Kyrgiou M, Mitra A, Paraskevaidis E, 2016, The Impact of Conservative Treatment for Cervical Intraepithelial Neoplasia and Early Cervical Cancer on Fertility and Early Pregnancy Outcomes, JAMA Oncology, 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 (less than 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.
Mitra A, Paraskevaidi M, Lai J, et al., 2016, Cervical Antimicrobial Peptides Are Decreased Following Excisional Treatment for Cervical Intraepithelial Neoplasia., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 96A-97A, ISSN: 1933-7191
Kyrgiou M, Athanasiou A, Paraskevadi M, et al., 2016, Risk of Preterm Birth After Treatment for Cervical Precancer Increases with Increasing Cone Depth: Systematic Review and Meta-Analysis., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 189A-190A, ISSN: 1933-7191
Mitra A, MacIntyre D, Lee Y, et al., 2016, Cervical Intraepithelial Neoplasia Disease Progression Is Associated with Increased Vaginal Microbiome Diversity., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 66A-66A, ISSN: 1933-7191
Mitra A, Maclntyre D, Lee Y, et al., 2016, Characterisation of the vaginal microbiome in cervical intraepithelial neoplasia, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 75-75, ISSN: 0140-6736
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Mitra A, MacIntyre D, lee YS, et al., 2015, Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity, Scientific Reports, Vol: 5, ISSN: 2045-2322
Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.
Mitra A, MacIntyre DA, Lee YS, et al., 2015, THE VAGINAL MICROBIOME OF WOMEN WITH CERVICAL INTRAEPITHELIAL NEOPLASIA, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 25, Pages: 976-977, ISSN: 1048-891X
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Kyrgiou M, Mitra A, Arbyn M, et al., 2015, FERTILITY AND EARLY PREGNANCY OUTCOMES AFTER TREATMENT FOR CERVICAL INTRAEPITHELIAL NEOPLASIA: SYSTEMATIC REVIEW AND META-ANALYSIS, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 25, Pages: 321-321, ISSN: 1048-891X
Kyrgiou M, Mitra A, Arbyn M, et al., 2015, Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia, Cochrane Database of Systematic Reviews, Vol: 9, ISSN: 1469-493X
BACKGROUND: Cervical intra-epithelial neoplasia (CIN) typically occurs in young women of reproductive age. Although several studies have reported the impact that cervical conservative treatment may have on obstetric outcomes, there is much less evidence for fertility and early pregnancy outcomes. OBJECTIVES: To assess the effect of cervical treatment for CIN (excisional or ablative) on fertility and early pregnancy outcomes. SEARCH METHODS: We searched in January 2015 the following databases: the Cochrane Gynaecological Cancer Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 12, 2014), MEDLINE (up to November week 3, 2014) and EMBASE (up to week 52, 2014). SELECTION CRITERIA: We included all studies reporting on fertility and early pregnancy outcomes (less than 24 weeks of gestation) in women with a history of CIN treatment (excisional or ablative) as compared to women that had not received treatment. DATA COLLECTION AND ANALYSIS: Studies were classified according to the treatment method used and the fertility or early pregnancy endpoint. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model and inter-study heterogeneity was assessed with I(2). Two review authors (MK, AM) independently assessed the eligibility of retrieved papers and risk of bias. The two review authors then compared their results and any disagreements were resolved by discussion. If still unresolved, a third review author (MA) was involved until consensus was reached. MAIN RESULTS: Fifteen studies (2,223,592 participants - 25,008 treated and 2,198,584 untreated) that fulfilled the inclusion criteria for this review were identified from the literature search. The meta-analysis demonstrated that treatment for CIN did not adversely affect the chances of conception. The overall pregnancy rate was higher for treated (43%) versus untreated women (38%; RR 1.29, 95% CI 1.02 to 1.64; 4 studies, 38,050
O'Brien AL, Chandiramani M, Lees CC, et al., 2014, MIDWIFE LED DELIVERY NICE guidance on place of birth falls short of neutrality, BMJ-BRITISH MEDICAL JOURNAL, Vol: 349, ISSN: 1756-1833
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Kyrgiou M, Mitra A, Arbyn M, et al., 2014, Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis, British Medical Journal, Vol: 349, Pages: 1-17, ISSN: 1468-5833
Objective To determine the impact of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes.Design Systematic review and meta-analysis of cohort studies.Data sources Medline and Embase.Eligibility criteria Studies assessing fertility and early pregnancy outcomes in women with a history of treatment for cervical intraepithelial neoplasia versus untreated women. We classified the included studies according to treatment type and fertility or early pregnancy endpoint.Analysis Pooled relative risks and 95% confidence intervals using a random effect model, and interstudy heterogeneity with I2 statistics.Results 15 studies fulfilled the inclusion criteria and were included. The meta-analysis did not provide any evidence that treatment for cervical intraepithelial neoplasia adversely affected the chances of conception. The overall pregnancy rate was higher for treated women than for untreated women (four studies; 43% v 38%, pooled relative risk 1.29, 95% confidence interval 1.02 to 1.64), although the heterogeneity between studies was high (P<0.0001). Pregnancy rates did not differ between women with an intention to conceive (two studies; 88% v 95%, 0.93, 0.80 to 1.08) and the number requiring more than 12 months to conceive (three studies, 15% v 9%, 1.45, 0.89 to 2.37). Although the rates for total miscarriages (10 studies; 4.6% v 2.8%, 1.04, 0.90 to 1.21) and miscarriage in the first trimester (four studies; 9.8% v 8.4%, 1.16, 0.80 to 1.69) was similar for treated and untreated women, cervical treatment was associated with a significantly increased risk of miscarriage in the second trimester. The rate was higher for treated women than for untreated women (eight studies; 1.6% v 0.4%, 16 558 women; 2.60, 1.45 to 4.67). The number of ectopic pregnancies (1.6% v 0.8%; 1.89, 1.50 to 2.39) and terminations (12.2% v 7.4%; 1.71, 1.31 to 2.22) was also higher for treated women.Conclusion There is no evidence suggesting that tre
Howells LM, Mitra A, Manson MM, 2007, Comparison of oxaliplatin‐ and curcumin‐mediated antiproliferative effects in colorectal cell lines, International Journal of Cancer, Vol: 121, Pages: 175-183, ISSN: 0020-7136
<jats:title>Abstract</jats:title><jats:p>Colorectal cancer remains a leading cause of cancer death worldwide, despite markedly improved response rates to current systemic therapies. Oxaliplatin either alone or incorporated into 5‐fluorouracil/leucovorin regimes has resulted in increased survival rates, particularly with regards to metastatic colorectal carcinoma. The chemopreventive polyphenol curcumin, which is currently in clinical trial, has been advocated for use in colorectal cancer either singly or in combination with chemotherapeutic drugs. In this study, the antiproliferative capacity of both compounds was compared in HCEC (normal‐derived), HT29 (p53 mutant adenocarcinoma) and HCT116 (p53wt adenocarcinoma) colorectal cell lines to determine whether effects were cell‐type specific at pharmacologically achievable doses, and whether the combination resulted in enhanced efficacy. Both oxaliplatin and curcumin displayed marked antiproliferative capacity at therapeutic concentrations in the two tumor cell lines. Order of sensitivity to oxaliplatin was HCT116>HT29>HCEC, whereas order of sensitivity to curcumin was HT29>HCT116>HCEC. HCT116 cells underwent induction of G2/M arrest in response to both oxaliplatin (irreversible) and curcumin (reversible). Apoptosis was induced by both agents, and up to 16‐fold induction of p53 protein was observed in response to the combination. Antiproliferative effects in HT29 cells were largely cell cycle independent, and were mediated by induction of apoptosis. Effects were greatly enhanced in both cell lines when agents were combined. This study provides further evidence that curcumin may be of use in therapeutic regimes directed against colorectal cancer, and suggests that in combination with oxaliplatin it may enhance efficacy of the latter in both p53wt and p53 mutant colorectal tumors. © 2007 Wiley‐Liss, Inc.</jats:p>
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