宫颈癌癌前病变及宫颈癌患者阴道微生态失调相关因素

目的 探讨宫颈癌癌前病变及宫颈癌患者阴道微生态失调相关因素。 方法 选择2016年7月至2018年12月我院收治的200例宫颈癌和癌前病变患者为研究对象,其中宫颈癌患者100例(宫颈癌组),癌前病变患者100例(癌前组),另选50例健康女性为对照组。观察各组对象阴道微生态指标(菌群密集度、菌群多样性、pH和H2O2)水平、HPV感染情况及乳杆菌分布情况。分析患者阴道微生态变化与HPV感染的关系。 结果 癌前组和宫颈癌组阴道菌群密集度Ⅰ-Ⅳ级的患者分别占33.00%和42.00%,显著高于对照组的10.00%(χ2=15.762 9,P=0.000 1);菌群多样性Ⅰ-Ⅳ级的患者分别占35.00%和41.00%,同样高于对照组的6.00%(χ2=19.783 1,P4.5的患者分别占53.00%和56.00%,高于对照组的12.00%(χ2=29.267 3,P2O2阴性患者占比分别为63.00%和70.00%,显著高于对照组的18.00%(χ2=39.343 7,P2=63.624 2,P2=8.742 1,P结论 宫颈癌前病变和宫颈癌的发生与患者阴道微生态失调、HPV感染、乳杆菌减少密切相关;同时癌前病变的发展与阴道微生态失调具有相关性。     

PCR-RFLP and FTIR-based detection of high-risk human papilloma virus for cervical cancer screening and prevention

BackgroundApproximately 70% of cervical carcinoma cases show the presence of high-risk Human Papilloma Virus (HPV), especially HPV-16 and HPV-18, and can be used to stratify high risk patients from low risk and healthy. Currently, molecular biology techniques such as polymerase chain reaction (PCR) are used to identify the presence of virus in patient samples. While the methodology is highly sensitive, it is labor intensive and time-consuming. Alternative techniques, such as vibrational spectroscopy, has been suggested as a possible rapid alternative. Therefore, in this study, we evaluate the efficiency of cervical fluid Fourier Transform Infrared spectroscopy (FTIR) in patient risk stratification informed by PCR.MethodsCervical fluid samples (n = 91) were obtained from patients who have undergone routine Papanicolaou (Pap) test. Viral genome was identified and classified as high/low-risk by PCR-Restriction Fragment Length Polymorphism (PCR-RFLP). FTIR spectra were acquired from samples identified by PCR-RFLP as No-HPV (n = 10), high-risk HPV (n = 7), and low-risk HPV (n = 7).ResultsOf the 91 samples, was detected the viral genome by PCR in 36 samples. Of these 36 samples, nine samples were identified to contain high-risk HPV (HR-HPV) and nine samples were found to have low-risk HPV (LR-HPV). The FTIR spectra acquired from No-HPV, LR-HPV, and HR-HPV showed differences in 1069, 1437, 1555, 1647, 2840, 2919, and 3287 cm^-1 bands. Principal Component Analysis (PCA) showed distinct clusters for No-HPV and HR-HPV and No-HPV and LR-HPV, but there was significant overlap in the clusters of HR-HPV and LR-HPV. PCA-Linear Discriminant Analysis (PC-LDA) after Leave One Out Cross Validation (LOOCV) classified No-HPV from HR-HPV and No-HPV from LR-HPV with 100% efficiency in the 1400-1800 cm^-1 spectral range. LOOCV classifications for LR-HPV and HR-HPV from each other were 71 and 75%, respectively, in the 2800-3400 cm^-1 spectral range.ConclusionsThe results highlight the high sensitivity of PCR-RFLP in HPV identification and show that FTIR can classify samples identified as healthy, low, and high-risk samples by PCR-RFLP.General significanceWe show the possibility of using FTIR for initial cervical cancer risk stratification followed by detailed PCR-RFLP investigations for suspect cases.     

Human papillomavirus genotyping by multiplex pyrosequencing in cervical cancer patients from India

Cervical cancer is a leading cause of cancer-related deaths among women in India.Human papillomavirus (HPV) infection is the causative agent of cervical cancer; and infection with the high-risk genotypes, predominantly HPV16 and 18,is the biggest risk factor.Vaccines targeting HPV16 and 18 have been found to confer protection in large- scale clinical trials.HPV genotyping has traditionally been carried out to screen the population "at risk" using indirect methods based on polymerase chain reaction (PCR) using consensus primers combined with various DNA hybridization techniques,and often followed by the sequencing of candidate products.Recently,a high-throughput and direct method based on DNA sequencing has been described for HPV genotyping using multiplex pyrosequencing. We present a pilot study on HPV genotyping of cervical cancer and non-malignant cervical samples using multiplex pyrosequencing.Using genomic DNA from cell lines,cervical biopsies,surgical tissues or formalin-fixed,paraffin- embedded tissue samples,we could successfully resolve 6 different HPV types out of the 7 tested,with their prevalence found to be in agreement with earlier reports. We also resolved coinfections with two different HPV types in several samples. An HPV16 genotype with a specific and recurrent sequence variation was observed in 8 cancer samples and one non-malignant sample. We find this technique eminently suited for high-throughput applications,which can be easily extended to large sample cohorts to determine a robust benchmark for HPV genotypes prevalent in India.     

The burden of cervical cancer in Vietnam: Synthesis of the evidence

There is currently no national cervical screening or HPV immunization program in Vietnam. This study aims to synthesize available data on the burden of disease and to project the burden of cervical cancer to 2049 if no major interventions are implemented. We reviewed published data sources on risk factors for HPV prevalence, high-grade lesions, cervical cancer incidence and mortality in Vietnam from 1990 to 2017. We then used the available data to project the number of new cervical cancer cases for the period 2013–2049. Data on cervical cancer incidence and mortality in Vietnam are limited; two Vietnamese cancer registries have been reported on by the International Agency for Research on Cancer, which cover urban populations representing ∼20% of the national population. The reported age-standardized cervical cancer incidence in Hanoi was 6.7 (1993–1997), compared to 28.8 and 14.1 per 100,000 women in Ho Chi Minh City (1995–1998 and 2009–2012, respectively). Cancer mortality data are not uniformly available from cancer registries or mortality surveys in Vietnam because cause of death has not been routinely ascertained. Based on available urban population registry data, estimated rates in the rural population, and forward projection of existing trends, we estimate that without any further intervention, the number of new cases will increase from 6930 (range 5671–8493) in 2012 to 8562 (range 5775–12,762) in 2049, giving a total of 379,617 (range 276,879–542,941) new cases over the period 2013–2049. These findings help underpin the case for the delivery of HPV vaccination and cervical screening in Vietnam, and support similar initiatives in other low- and middle-income countries.     

宫颈癌高危因素及筛查研究进展

宫颈癌发病率在女性恶性肿瘤占第二位。宫颈癌的高危因素很多,如病毒感染、性行为、宫颈病变等因素。大量的研究已经证实人乳头瘤病毒(Human Papillomavirus HPV)感染是宫颈癌发生的必要条件。近年来,宫颈癌的筛查方法也取得了较大的进展,新发展的薄层液基细胞学(Liquid-based cytology test,LCT)、检测高危型HPVDNA的技术及宫颈癌筛查系统(TruScreen),显著提高了宫颈癌和癌前病变的灵敏性和特异性,从而降低了宫颈癌的发生率。     

兰州地区宫颈癌组织标本中HPV16感染情况的初步分析

人乳头瘤病毒的感染与宫颈癌有密切关系。通过兰州地区宫颈癌患者的HPV感染情况的分析对HPV16与宫颈癌之间的关系进行了研究。采用套式PCR方法,以HPV DNA的早期基因E6,E7和结构基因L1为扩增目的基因,对13份兰州地区宫颈癌组织进行扩增,将扩增阳性片段测序,并与HPV16标准序列进行比较,13份组织中有12份扩增到了HPV的目的基因。证实了HPV与宫颈癌有密切关系。     

Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer

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阴道炎症与宫颈癌发生的相关性研究进展

阴道炎症是妇科疾病中发病率最高的疾病,不同年龄和种族的妇女均可患病。近年来,阴道炎症与妇科肿瘤的相关性日益受到关注。而在妇科恶性肿瘤中,宫颈癌的发病率高居第一。虽然高危型HPV感染很常见,但是宫颈癌的发病率却并不高,这是因为若缺乏协同因素作用就不会有宫颈癌的发生。目前认为阴道炎症除了与阴道黏膜被破坏、免疫功能受到抑制有关外,还与HPV感染、宫颈癌前病变和宫颈癌的发生发展密切相关。因此,阴道炎症与宫颈癌的相关性研究已成为人们关注的热点,本文就阴道炎症及其与宫颈癌的关系的研究进展作一综述。     

Improving inhaler adherence in patients with Chronic Obstructive Pulmonary Disease: a cost-effectiveness analysis

Background

The PHARMACOP-intervention significantly improved medication adherence and inhalation technique for patients with COPD compared with usual care. This study aimed to evaluate its cost-effectiveness.

Methods

An economic analysis was performed from the Belgian healthcare payer’s perspective. A Markov model was constructed in which a representative group of patients with COPD (mean age of 70 years, 66% male, 43% current smokers and mean Forced Expiratory Volume in 1 second of % predicted of 50), was followed for either receiving the 3-month PHARMACOP-intervention or usual care. Three types of costs were calculated: intervention costs, medication costs and exacerbation costs. Outcome measures included the number of hospital-treated exacerbations, cost per prevented hospital-treated exacerbation and cost per Quality Adjusted Life-Year. Follow-up was 1 year in the basecase analysis. Sensitivity and scenario analyses (including long-term follow-up) were performed to assess uncertainty.

Results

In the basecase analysis, the average overall costs per patient for the PHARMACOP-intervention and usual care were €2,221 and €2,448, respectively within the 1-year time horizon. This reflects cost savings of €227 for the PHARMACOP-intervention. The PHARMACOP-intervention resulted in the prevention of 0.07 hospital-treated exacerbations per patient (0.177 for PHARMACOP versus 0.244 for usual care). Results showed robust cost-savings in various sensitivity analyses.

Conclusions

Optimization of current pharmacotherapy (e.g. close monitoring of inhalation technique and medication adherence) has been shown to be cost-saving and should be considered before adding new therapies.     

Human papillomavirus genotype distribution in invasive cervical cancer in Bosnia and Herzegovina

PurposeCountries of the former Yugoslavia bear some of the highest cervical cancer burden in Europe. In Bosnia and Herzegovina (B&H), data on human papillomavirus (HPV) genotype distribution among cervical cancer cases is scarce. This baseline information is critical in order to evaluate the impact of prophylactic HPV vaccines. This study aims to provide specific information for B&H.MethodsThe final analysis comprised 283 cases of invasive cervical cancer identified at the Polyclinic for Laboratory Diagnostic, University Clinical Center Tuzla in B&H between 1984 and 2004. HPV was detected through amplification of HPV DNA using SPF-10 broad spectrum primers followed by deoxyribonucleic acid enzyme inmunoassay and genotyping by reverse line probe assay (LiPA₂₅, version 1).ResultsMost cases (92.2%) were histologically classified as squamous cell carcinoma (SCC). A total of 268 cases (94.7%) were positive for HPV. Infections were mainly present as single (95.5%) and HPV16 and 18 accounted for 77.8% of the positive cases. The next most common HPV types were HPV45 (4.4%), HPV33 (3.1%), HPV51 (2.3%) and HPV31 (2.2%). The mean age of cases infected with the seven most common types worldwide (HPV16/18/45/31/33/52/58) was 51.1 (SD = 11.6), six years younger than the one for cases infected with other types (56.3, SD = 12.9).ConclusionsAvailable HPV vaccines could potentially prevent 77.8% of Bosnian cervical cancer cases (i.e. those associated with HPV16/18). If the reported magnitude of the cross-protection of licensed vaccines for non-vaccine HPV types is long lasting, an additional 6 to 10% of cases could be prevented.     

Haemochromatosis gene (HFE) mutations in viral-associated neoplasia: Linkage to cervical cancer

The present study examines the frequency of the two main HFE mutations (C282Y and H63D) in a randomly selected population of 346 individuals including 201 DNA samples from women with cervical neoplasia (including high-grade squamous intraepithelial lesions and invasive squamous cell carcinoma) and a control population of 146 women from the same geographical area. We found a significantly lower risk of development of cervical neoplasia in H63D carriers (OR = 0.56; 95% CI 0.35-0.92; p = 0.01). Multivariate logistic regression analysis confirms this observation (OR = 0.55; 95% CI 0.35-0.88, p = 0.01). Regarding the C282Y mutation no association was found (OR = 1.32; 95% CI 0.53-3.33; p = 0.52). In addition, a significant difference between H63D carrier and non-carrier women on the time-to-onset of cervical lesions was observed (log-rank test: p = 0.0012). These results indicate that HFE could be considered a candidate modifier gene of viral-related neoplasia such as cervical carcinoma possibly by a dual role on iron metabolism and immunological system.     

Modulation of apoptosis by early human papillomavirus proteins in cervical cancer

Cervical cancer (CC) constitutes a major women health problem. Clinical, molecular, and epidemiological investigations have identified persistent infection with high risk human papillomavirus (HR-HPV) as the major cause of CC. HR-HPVs lead to development of cervical carcinoma, predominantly through the action of E5, E6 and E7 viral oncoproteins. After HR-HPV infection, viral proteins employ strategies to modulate apoptosis. The E2 viral protein induces apoptosis in both normal and HPV-transformed cells through activation of caspase-8. The E5 protein can impair CD95L- and TRAIL-mediated apoptosis, which suggests that it may prevent apoptosis at early stages of viral infection. E6 inhibits apoptosis through the proteolytic inactivation of pro-apoptotic proteins such as p53, FADD, or procaspase-8, employing the ubiquitin proteasome pathway, or through interactions with proteins that form the death-inducing signaling complex (DISC) such as TNF-R1. On the other hand, E7 oncoprotein expressing cells are usually predisposed to undergo apoptosis. Useful targets for therapeutic strategies would interfere with expression or function of HR-HPV proteins to eliminate cells that express viral oncoproteins. In this review, we summarize the available data on the interaction of early HPV proteins with cellular factors that promote cell death, and the functional consequences of these interactions on apoptosis.     

Present status of sentinel lymph node biopsy in cervical cancer

Cervical cancer is the fourth most common cancer in women, and seventh overall. This disease represents a medical, economic and social burden. In early FIGO stage patients (IA, IB1 and IIA1), nodal involvement is the most important prognostic factor. Imaging evaluation of nodal metastasis is of limited value. In order to determine lymph node involvement, allow loco-regional control of the disease, define the need for adjuvant radiotherapy and improve survival, standard surgery for early disease is radical hysterectomy with systematic pelvic lymphadenectomy. However, this surgical treatment has risks and complications: longer operative time, larger blood loss, neurovascular or ureteral injury, lower-limb lymphedema, symptomatic lymphocysts, hydronephrosis. A method that allows to define the presence of regional metastasis with less morbidity and equal or greater precision is particularly relevant. The use of the sentinel lymph node biopsy is intended to reach that purpose. The present study reviews recent literature on the role of sentinel lymph node biopsy in cervical cancer, analyzing its indications and contraindications, injection and detection techniques, tracers used, surgical and pathological approaches and its applicability in up-to-date clinical practice.     

Advancing cervical cancer prevention initiatives in resource-constrained settings: insights from the Cervical Cancer Prevention Program in Zambia

Groesbeck Parham and colleagues describe their Cervical Cancer Prevention Program in Zambia, which has provided services to over 58,000 women over the past five years, and share lessons learned from the program's implementation and integration with existing HIV/AIDS programs.     

Diagnosing idiopathic learning disability: a cost-effectiveness analysis of microarray technology in the National Health Service of the United Kingdom

Array based comparative genomic hybridisation (aCGH) is a powerful technique for detecting clinically relevant genome imbalance and can offer 40 to > 1000 times the resolution of karyotyping. Indeed, idiopathic learning disability (ILD) studies suggest that a genome-wide aCGH approach makes 10–15% more diagnoses involving genome imbalance than karyotyping. Despite this, aCGH has yet to be implemented as a routine NHS service. One significant obstacle is the perception that the technology is prohibitively expensive for most standard NHS clinical cytogenetics laboratories. To address this, we investigated the cost-effectiveness of aCGH versus standard cytogenetic analysis for diagnosing idiopathic learning disability (ILD) in the NHS. Cost data from four participating genetics centres were collected and analysed. In a single test comparison, the average cost of aCGH was ￡442 and the average cost of karyotyping was ￡117 with array costs contributing most to the cost difference. This difference was not a key barrier when the context of follow up diagnostic tests was considered. Indeed, in a hypothetical cohort of 100 ILD children, aCGH was found to cost less per diagnosis (￡3,118) than a karyotyping and multi-telomere FISH approach (￡4,957). We conclude that testing for genomic imbalances in ILD using microarray technology is likely to be cost-effective because long-term savings can be made regardless of a positive (diagnosis) or negative result. Earlier diagnoses save costs of additional diagnostic tests. Negative results are cost-effective in minimising follow-up test choice. The use of aCGH in routine clinical practice warrants serious consideration by healthcare providers. Copyright statement The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd, and its Licensees to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and to exploit all subsidiary rights, as set out in our licence (bmj.com/advice/copyright.shtml). Authorship The authors included on this paper fulfil the criteria of authorship and no one who fulfils the criteria has been excluded from authorship. The authors made a substantial contribution to the conception, design, analysis and interpretation of data. They were involved in drafting the article or revising it critically for important intellectual content and approving the version to be published. Contributorship Sarah Wordsworth (Guarantor): Planning, conducting and reporting work, interpretation of data, drafting and revising article. James Buchanan: Conducting and reporting work, interpretation of data, revising article. Regina Regan: Completing costing questionnaire, providing protocol details, other costing information, interpretation of data, information about learning disability and genome imbalance and revising article. Val Davison: Completing costing questionnaire, providing protocol details, sharing overall laboratory experience and drafting article. Kim Smith: Completing costing questionnaire, providing protocol details, drafting article. Sara Dyer: Completing costing questionnaire and providing protocol details. Carolyn Campbell: Completing costing questionnaire and providing protocol details. Edward Blair: Critical appraisal of article for clinical content and revising article. Eddy Maher: Completing costing questionnaire, providing protocol details, sharing overall laboratory experience and drafting article. Jenny Taylor: Planning and facilitating work between centres. Drafting and revising article. Samantha JL Knight: Completing costing questionnaire, providing protocol details, other costing information, interpretation of data, providing information about learning disability and genome imbalance, drafting and revising article. Jenny Taylor and Samantha JL Knight contributed equally to the work presented.     

UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells

UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is an important epigenetic regulator that plays a part in DNA methylation, protein methylation and ubiquitination. It is also frequently overexpressed in many types of cancers, including cervical cancer, which is caused by human papillomavirus (HPV). In this study, we showed that UHRF1 was up-regulated in HPV oncogene E7 expressing cells and HPV-positive cervical cancer cells. We demonstrated that UHRF1 down-regulated the expression of UBE2L6 gene that encodes the ISG15-conjugating enzyme UbcH8. Overexpression of UHRF1 reduced UBE2L6 while knockdown UHRF1 elevated the expression of UBE2L6. We showed that UHRF1 regulated UBE2L6 gene by promoter hypermethylation in cervical cancer cells. Consistent with the functions of UHRF1, restored expression of UbcH8 induced apoptosis. These findings establish UBE2L6 as a novel target of UHRF1 that regulates the apoptosis function of UHRF1. Our studies suggest that UHRF1/ UbcH8 can be manipulated for therapy in cervical cancer.     

Proteomics strategies to analyze HPV-transformed cells: relevance to cervical cancer

Cervical cancer is the second most common malignant tumor among women worldwide. The initiating event of cervical cancer is the infection with certain types of human papillomavirus (HPV). Interestingly, viral oncogene expression is necessary but not per se sufficient to promote cervical cancer and other factors are involved in neoplastic progression. Thus, major research efforts should be focused to identify novel co-carcinogenic factors and to understand the mechanisms played into tumor development. To reach this goal, proteomics strategies are powerful tools and a number of studies performed by following this approach have contributed to unravel the interplay between viral infection and protein dysfunction that ultimately results in cancer. The present review summarizes the most relevant findings obtained by applying proteomics technologies to both cell culture models and human tissue specimens. The results suggest that viral oncogenes selectively interact with a subset of intracellular proteins mainly involved in apoptosis resistance, cell growth and differentiation and cell transformation.     

阴道微生态与宫颈疾病发生发展的相关性研究

微生态学是近年新兴的学科,女性生殖道是一个重要的微生态区域。生殖道微生态体系是由正常的解剖结构、生殖道各种菌群、周期性内分泌变化、局部免疫系统四个部分组成。随着阴道微生态平衡理论的提出和发展,阴道微生态和HPV感染、宫颈上皮内瘤变、宫颈癌的内在关联引起了极大的重视。阴道微生态与宫颈疾病的发生发展相关,宫颈病变影响了阴道微生态环境,长期的阴道菌群失调也会反作用于宫颈,导致宫颈的病变加重甚至恶化,如此形成恶性循环。因此阴道微生态对宫颈疾病的诊断、治疗和预防将具有重要的临床意义。     

Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines

K. Sigurdsson
Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines This paper reviews the Icelandic experience regarding the age‐specific effectiveness, optimal targeted age range and intervals in cervical cancer screening and the screening implications of the HPV16/18 vaccines. The background material is based on data from a screening programme with centralized records dating back to 1964, as well as from population‐based studies on the distribution of oncogenic HPV types in cancer and histologically verified CIN2‐3 lesions and from the Icelandic arm of the Future II trial with Gardasil^®. The findings confirm significant increased rates in the screened population of CIN2‐3, stage IA (microinvasive) cancer since 1979, mainly in the age group 20–34 years. These lesions start to accumulate within 3 years of a normal smear. Studies on the distribution of HPV types indicate that the marketed vaccines could lower the incidence of cancer and CIN2‐3 by about 67% and 53%, respectively, after taking into account reported cross‐protection. About 65% of women below 25 years of age had lesions related to the non‐vaccine types and after the last normal smear these cases accumulated at the same frequency as cases with vaccine‐included types. Cases with combined vaccine and non‐vaccine types accumulated at a slower rate. We conclude that screening should continue to start at age 20 years, with invitations at 2‐year intervals up to age 39 years and thereafter at 4‐year intervals up to age 65–69 years. Current data support the conclusion that the optimal age for catch‐up HPV vaccination should be considered in the context of sexual practices and the data do not support changes in the lower age limit or screening intervals for the vaccinated women.