Treatment methods for cervical intraepithelial neoplasia in England: A cost-effectiveness analysis.

OBJECTIVE: To compare the cost-effectiveness of different treatments for cervical intraepithelial neoplasia (CIN). DESIGN: A cost-effectiveness analysis based on data available in the literature and expert opinion. SETTING: England. POPULATION: Women treated for CIN. METHODS: We developed a decision-analytic model to simulate the clinical course of 1000 women who received local treatment for CIN and were followed up for 10 years after treatment. In the model we considered surgical complications as well as oncological and reproductive outcomes over the 10-year period. The costs calculated were those incurred by the National Health Service (NHS) of England. MAIN OUTCOME MEASURES: Cost per one CIN2+ recurrence averted (oncological outcome); cost per one preterm birth averted (reproductive outcome); overall cost per one adverse oncological or reproductive outcome averted. RESULTS: For young women of reproductive age, large loop excision of the transformation zone (LLETZ) was the most cost-effective treatment overall at all willingness-to-pay thresholds. For postmenopausal women, LLETZ remained the most cost-effective treatment up to a threshold of £31,500, but laser conisation became the most cost-effective treatment above that threshold. CONCLUSIONS: LLETZ is the most cost-effective treatment for both younger and older women. However, for older women, more radical excision with laser conisation could also be considered if the NHS is willing to spend more than £31,500 to avert one CIN2+ recurrence.

Preventing cervical cancer: what are the risks and benefits of different treatments?

The studyKyrgiou M, Athanasiou A, Cieslak-Jones D. Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis. Lancet Oncol 2022;23:1097-108.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/prevention-of-cervical-cancer-what-are-the-risks-and-benefits-of-different-treatments/.

Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies.

BACKGROUND: Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear. METHODS: In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995). RESULTS: We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89-2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27-1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40-1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation. CONCLUSIONS: Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis.

OBJECTIVE: To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. DESIGN: Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. REVIEW METHODS: Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects 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: 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. CONCLUSION: HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021237350.

Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis.

BACKGROUND: The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508. FINDINGS: 7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low. INTERPRETATION: More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning. FUNDING: National Institute for Health and Care Research: Research for Patient Benefit.

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.

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.

Minimally invasive oesophagectomy in the prone versus lateral decubitus position: a systematic review and meta-analysis.

The thoracic phase of minimally invasive esophagectomy was initially performed in the lateral decubitus position (LDP); however, many experts have gradually transitioned to a prone position (PP) approach. The aim of the present systematic review and meta-analysis is to quantitatively compare the two approaches. A systematic literature search of the MEDLINE, Embase, Google Scholar, Web of Knowledge, China National Knowledge Infrastructure and ClinicalTrials.gov databases was undertaken for studies comparing outcomes between patients undergoing minimally invasive esophageal surgery in the PP versus the LDP. In total, 15 studies with 1454 patients (PP; n = 710 vs. LDP; n = 744) were included. Minimally invasive esophagectomy in the PP provides statistically significant reduction in postoperative respiratory complications (Risk ratios 0.5, 95% confidence intervals [CI] 0.34-0.76, P < 0.001), blood loss (weighted mean differences [WMD] -108.97, 95% CI -166.35 to -51.59 mL, P < 0.001), ICU stay (WMD -0.96, 95% CI -1.7 to -0.21 days, P = 0.01) and total hospital stay (WMD -2.96, 95% CI -5.14 to -0.78 days, P = 0.008). In addition, prone positioning increases the overall yield of chest lymph node dissection (WMD 2.94, 95% CI 1.54-4.34 lymph nodes, P < 0.001). No statistically significant difference in regards to anastomotic leak rate, mortality and 5-year overall survival was encountered. Subgroup analysis revealed that the protective effect of prone positioning against pulmonary complications was more pronounced for patients undergoing single-lumen tracheal intubation. A head to head comparison of minimally invasive esophagectomy in the prone versus the LDP reveals superiority of the former method, with emphasis on the reduction of postoperative respiratory complications and reduced length of hospitalization. Long-term oncologic outcomes appear equivalent, although validation through prospective studies and randomized controlled trials is still necessary.

Invasive cervical cancer following treatment of pre-invasive lesions: A potential theory based on a small case series.

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.

Captopril versus atenolol to prevent expansion rate of thoracic aortic aneurysms: rationale and design.

Thoracic aortic aneurysms are correlated with significant mortality and morbidity. No therapy, however, is effective at limiting aneurysm expansion and preventing rupture. Angiotensin-converting enzyme inhibitors can reduce the wall shear stress and inflammation, both of which play vital roles in the expansion of the aneurysm. A total of 636 patients will be randomized into one of three parallel arms, receiving captopril, atenolol or placebo. The primary end point will be the rate of change in the absolute diameter of the aortic root and ascending aorta on MRI of the aorta after 36 months. The trial will investigate the efficacy of angiotensin-converting enzyme inhibitors versus beta-blocker therapy in reducing the growth rate of thoracic aortic aneurysms and rupture. Trial registration number: NCT04224675.

Bisphenol-A and polycystic ovary syndrome: a review of the literature.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age with reproductive, metabolic and endocrine implications. While the exact pathophysiological mechanisms of the syndrome are unknown, its heterogeneity suggests a multifactorial causal background. In the last two decades, numerous environmental chemicals, including Bisphenol-A (BPA) that is used in the synthesis of polycarbonate plastics, have been proposed as potential contributors to the aetiology of PCOS. This review provides a holistic overview of the available data regarding the possible relation of PCOS with BPA exposure. We have included a total number of 24 studies. Eleven human case-control and 13 animal studies provided data regarding this potential relation. Accumulating evidence suggests that a correlation between high levels of BPA and the presence of PCOS may exist. Contradicting results from human and animal studies, however, render it difficult to conclude on the exact role of BPA in the pathogenesis of PCOS. BPA may constitute a consequence of the syndrome rather than a cause, but further research is still needed to clarify this. Continued efforts to study the early origins of PCOS, using prospective-designed studies, are required to identify the exact effect of BPA on women with PCOS.

Prasugrel in the treatment of acute coronary syndrome.

Dual antiplatelet therapy is the mainstay therapy in patients with acute coronary syndrome. The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. The newer P2Y12 inhibitors (prasugrel and ticagrelor) have better efficacy than clopidogrel. Prasugrel provides greater inhibition of platelet aggregation and has a rapid onset of action. Current acute coronary syndrome guidelines recommend the use of both newer P2Y12 inhibitors. However, emerging data have shown that prasugrel is more efficient than ticagrelor in reducing the incidence of nonfatal myocardial infarction, stroke or cardiovascular death, without increased risk of major bleeding.

Cervical Pathology Following HPV Vaccination in Greece: A 10-year HeCPA Observational Cohort Study.

BACKGROUND: In Greece the population-level impact of HPV vaccination is unknown due to lack of official registries. This study presents in a pragmatic frame the comparison of cervical pathology data between HPV-vaccinated and unvaccinated women referred for colposcopy. PATIENTS AND METHODS: This is an observational prospective cohort study performed in 7 academic Obstetrics and Gynaecology Departments across Greece between 2009-2019. Cases were women that had completed HPV vaccination before coitarche and were referred for colposcopy due to abnormal cytology. For each vaccinated woman an unvaccinated matched control was selected. RESULTS: A total of 849 women who had been vaccinated before coitarche and 849 unvaccinated controls were recruited. The combination of cytological, colposcopic and molecular findings necessitated treatment in only a single case among vaccinated (0.1%) and in 8.4% among unvaccinated. CONCLUSION: HPV vaccination at a proper age can markedly reduce development of severe cervical precancers and consequently the need for treatment, as well as their long-term related obstetrical morbidity.