Is Anterior Cervical Discectomy and Fusion Superior to Corpectomy and Fusion for Treatment of Multilevel Cervical Spondylotic Myelopathy? A Systemic Review and Meta-Analysis

Objective

Both anterior cervical discectomy with fusion (ACDF) and anterior cervical corpectomy with fusion (ACCF) are used to treat cervical spondylotic myelopathy (CSM), however, there is considerable controversy as to whether ACDF or ACCF is the optimal treatment for this condition. To compare the clinical outcomes, complications, and surgical trauma between ACDF and ACCF for the treatment of CSM, we conducted a meta-analysis.

Methods

We conducted a comprehensive search in MEDLINE, EMBASE, PubMed, Google Scholar and Cochrane databases, searching for relevant controlled trials up to July 2013 that compared ACDF and ACCF for the treatment of CSM. We performed title and abstract screening and full-text screening independently and in duplicate. A random effects model was used for heterogeneous data; otherwise, a fixed effect model was used to pool data, using mean difference (MD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes.

Results

Of 2157 citations examined, 15 articles representing 1372 participants were eligible. Overall, there were significant differences between the two treatment groups for hospital stay (M = −5.60, 95% CI = −7.09 to −4.11), blood loss (MD = −151.35, 95% CI = −253.22 to −49.48), complications (OR = 0.50, 95% CI = 0.35 to 0.73) and increased lordosis of C2–C7 (MD = 3.70, 95% CI = 0.96 to 6.45) and fusion segments angles (MD = 3.38, 95% CI = 2.54 to 4.22). However, there were no significant differences in the operation time (MD = −9.34, 95% CI = −42.99 to 24.31), JOA (MD = 0.24, 95% CI = −0.10 to 0.57), VAS (MD = −0.06, 95% CI = −0.81 to 0.70), NDI (MD = −1.37, 95% CI  = −3.17 to 0.43), Odom criteria (OR = 0.88, 95% CI = 0.60 to 1.30) or fusion rate (OR = 1.17, 95% CI = 0.34 to 4.11).

Conclusions

Based on this meta-analysis, although complications and increased lordosis are significantly better in the ACDF group, there is no strong evidence to support the routine use of ACDF over ACCF in CSM.     

Cervical Screening at Age 50–64 Years and the Risk of Cervical Cancer at Age 65 Years and Older: Population-Based Case Control Study

Background

There is little consensus, and minimal evidence, regarding the age at which to stop cervical screening. We studied the association between screening at age 50–64 y and cervical cancer at age 65–83 y.

Methods and Findings

Cases were women (n = 1,341) diagnosed with cervical cancer at age 65–83 y between 1 April 2007 and 31 March 2012 in England and Wales; age-matched controls (n = 2,646) were randomly selected from population registers. Screening details from 1988 onwards were extracted from national databases. We calculated the odds ratios (OR) for different screening histories and subsequent cervical cancer. Women with adequate negative screening at age 65 y (288 cases, 1,395 controls) were at lowest risk of cervical cancer (20-y risk: 8 cancers per 10,000 women) compared with those (532 cases, 429 controls) not screened at age 50–64 y (20-y risk: 49 cancers per 10,000 women, with OR = 0.16, 95% CI 0.13–0.19). ORs depended on the age mix of women because of the weakening association with time since last screen: OR = 0.11, 95% CI 0.08–0.14 at 2.5 to 7.5 y since last screen; OR = 0.27, 95% CI 0.20–0.36 at 12.5 to 17.5 y since last screen. Screening at least every 5.5 y between the ages 50 and 64 y was associated with a 75% lower risk of cervical cancer between the ages 65 and 79 y (OR = 0.25, 95% CI 0.21–0.30), and the attributable risk was such that in the absence of screening, cervical cancer rates in women aged 65+ would have been 2.4 (95% CI 2.1–2.7) times higher. In women aged 80–83 y the association was weaker (OR = 0.49, 95% CI 0.28–0.83) than in those aged 65–69 y (OR = 0.12, 95% CI 0.09–0.17). This study was limited by an absence of data on confounding factors; additionally, findings based on cytology may not generalise to human papillomavirus testing.

Conclusions

Women with adequate negative screening at age 50–64 y had one-sixth of the risk of cervical cancer at age 65–83 y compared with women who were not screened. Stopping screening between ages 60 and 69 y in women with adequate negative screening seems sensible, but further screening may be justifiable as life expectancy increases. Please see later in the article for the Editors'' Summary     

Curcumin and Emodin Down-Regulate TGF-β Signaling Pathway in Human Cervical Cancer Cells

Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling) and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug) upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.     

Cervical flexion–relaxation response to neck muscle fatigue in males and females

In this study the effect of muscle fatigue on the cervical spine flexion–relaxation response was studied. Twenty healthy participants (10 males and 10 females) were recruited for data collection. The Sorenson protocol was utilized to induce neck muscle fatigue. Surface electromyography and optical motion capture systems were used to measure neck muscle activation and head–neck posture, respectively. A post-fatigue reduction in the Flexion–Relaxation Ratio (FRR) and higher FRR for females compared to males were observed. A post-fatigue decrease was also observed in the onset and offset angles resulting in an expansion of the myoelectric silence period. Gender had no effect on the onset and offset angles of the silence period. Post-fatigue shift in the onset and offset angles and the expansion of the silence period indicate an increased contribution by the passive viscoelastic tissues in stabilizing the cervical spine under fatigued condition.     

HSV-2 Increases TLR4-Dependent Phosphorylated IRFs and IFN-β Induction in Cervical Epithelial Cells

Our previous studies demonstrated that HSV-2 infection up-regulates TLR4 expression and induces NF-kB activity, thereby facilitating innate immune response in human cervical epithelial cells. This process requires involvement of TLR4 adaptors, Mal and MyD88. In the current study, we found that HSV-2 infection increases levels of phosphoryalted IRF3 and IRF7, then regulating expression of type I IFN. As expected, these changes induced by HSV-2 infection depended upon TLR4. Knockdown of TRIF and/or TRAM by siRNAs indicated that TRIF/TRAM might be involved in expression of IFN-β. Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN-β expression in response to HSV-2 in its primary infected genital epithelial cells. Thus, TLR4-Mal/MyD88 and TLR4-TRIF/TRAM signaling may synergize and/or cooperate in innate immune response of cervical epithelial cells to HSV-2 infection.     

Modeling the Relationship Between Cervical Cancer Mortality and Trace Elements Based on Genetic Algorithm–Partial Least Squares and Support Vector Machines

The relationship between the mortality of cervical cancer and soil trace elements of 23 regions of China was investigated. A total of 25 elements (i.e., Na, K, Mg, Ca, Sr, Hg, Pb, B, Tm, Th, U, Sn, Hf, Bi, Ta, Te, Mo, Br, I, As, Cr, Cu, Fe, Zn, and Se) were considered. First, 23 samples were split into the training set with 12 samples and the test set with 11 samples. Then, a combination strategy called genetic algorithm–partial least squares (GA–PLS) was used to pick out five important elements. i.e., Br, Ta, Pb, Cr, and As. Afterwards, the classic partial least squares (PLS) model and least square support vector machine (LSSVM) model were developed and compared. The results revealed that the SVM model significantly outperforms the PLS model, indicating that the combination of GA–PLS and LSSVM can serve as a potential tool for predicting the mortality of cancer based on trace elements.     

Seasonality in the Incidence of Cervical Carcinoma in Teenagers and Young Adults in Northern England, 1968–2005

Infection with human papillomavirus is an established risk factor for cervical carcinoma. However, the role of other environmental factors is less well established. To further investigate whether other agents may be involved, the authors have analyzed seasonal variation in cervical cancer with respect to month of birth and separately month of diagnosis. All 85 cases diagnosed in 15–24-yr-olds during the period 1968–2005 were extracted from the specialist population-based Northern Region Young Persons' Malignant Disease Registry. The chi-square heterogeneity test was used to assess overall nonuniform variation in month of birth and separately month of diagnosis. Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data using month of birth and month of diagnosis in separate models. Based on month of birth, there was statistically significant heterogeneity (p?=?.03) and a significant sinusoidal pattern, with an incidence peak involving births in the autumn months (p?=?.03). Based on month of diagnosis, there was marginally significant heterogeneity (p?=?.06). The evidence of seasonal variation around time of birth for cervical carcinoma is highly novel and suggests possible early etiological involvement of environmental factors. (Author correspondence: Richard.McNally@ncl.ac.uk)     

Cervical cancer risk: is there a genetic component?

Human papilloma virus (HPV) is a major risk factor for the development of cervical cancer. As only some infected women develop cancer, other factors must be important for disease development. Genetic epidemiological studies show that genetic factors contribute significantly to disease risk. Genetic susceptibility to HPV exposure and/or infection appears to be important in determining the individual risk to develop this virally induced cancer.     

The Zinc Finger Protein ZNF268 Is Overexpressed in Human Cervical Cancer and Contributes to Tumorigenesis via Enhancing NF-κB Signaling

Cervical cancer is one of the most common tumors affecting women''s health worldwide. Although human papillomavirus can be detected in nearly all cases, the mechanism of cervical carcinogenesis remains to be further addressed. Here, we demonstrated that ZNF268, a Krüppel-associated box-containing zinc finger protein, might contribute to the development of cervical cancer. We found that ZNF268b2, an isoform of ZNF268, was overexpressed in human squamous cervical cancer specimens. Knockdown of ZNF268 in cervical cancer cells caused cell cycle arrest at the G₀/G₁ phase, reduced colony formation, and increased sensitivity to TNFα-induced apoptosis. In addition, HeLa cell growth in xenograft nude mice was suppressed by ZNF268 knockdown, with increased apoptosis. Furthermore, ZNF268b2 was shown to increase NF-κB signaling in vitro and in vivo. Reconstitution of NF-κB activity restored proliferation in ZNF268 knockdown HeLa cells. Of note, we observed a high frequency of NF-κB activation in ZNF268-overexpressing cervical cancer tissues, suggesting a pathological coincidence of ZNF268b2 overexpression and NF-κB activation. Taken together, our results reveal a novel role of ZNF268b2 that contributes to cervical carcinogenesis in part through enhancing NF-κB signaling.     

Cervical Cancer Screening in Partly HPV Vaccinated Cohorts – A Cost-Effectiveness Analysis

Background

Vaccination against the oncogenic human papillomavirus (HPV) types 16 and 18 will reduce the prevalence of these types, thereby also reducing cervical cancer risk in unvaccinated women. This (measurable) herd effect will be limited at first, but is expected to increase over time. At a certain herd immunity level, tailoring screening to vaccination status may no longer be worth the additional effort. Moreover, uniform screening may be the only viable option. We therefore investigated at what level of herd immunity it is cost-effective to also reduce screening intensity in unvaccinated women.

Methods

We used the MISCAN-Cervix model to determine the optimal screening strategy for a pre-vaccination population and for vaccinated women (~80% decreased risk), assuming a willingness-to-pay of €50,000 per quality-adjusted life year gained. We considered HPV testing, cytology testing and co-testing and varied the start age of screening, the screening interval and the number of lifetime screens. We then calculated the incremental cost-effectiveness ratio (ICER) of screening unvaccinated women with the strategy optimized to the pre-vaccination population as compared to with the strategy optimized to vaccinated women, assuming different herd immunity levels.

Results

Primary HPV screening with cytology triage was the optimal strategy, with 8 lifetime screens for the pre-vaccination population and 3 for vaccinated women. The ICER of screening unvaccinated women 8 times instead of 3 was €28,085 in the absence of herd immunity. At around 50% herd immunity, the ICER reached €50,000.

Conclusion

From a herd immunity level of 50% onwards, screening intensity based on the pre-vaccination risk level becomes cost-ineffective for unvaccinated women. Reducing the screening intensity of uniform screening may then be considered.     

Association between two genetic variants of CD226 gene and Cervical Squamous Cell Carcinoma: A case–control study

Cervical carcinoma is a common gynecologic tumor severely influencing the health and life quality of women worldwide. CD226, a costimulatory molecule, is mainly participated in the activation and differentiation of T cells. Recent studies have investigated the association between two genetic variants (rs763361 and rs727088) of CD226 gene and many diseases. In order to evaluate whether these two variants are associated with Cervical Squamous Cell Carcinoma (CSCC), a case–control study including 349 CSCC patients and 380 unrelated healthy controls was carried out to determine the genotypes of these two variants by using the methods of polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing methods. Significantly increased CSCC risk was observed to be associated with G allele of rs727088 locus (OR = 1.422, 95% CI = 1.129–1.792). We have also observed that increased CSCC risk was statistically associated with rs727088 polymorphism in a dominant model (OR = 1.41, 95% CI = 1.05–1.89). Results of stratified analysis revealed that both rs763361 and rs727088 polymorphisms were not associated with clinical characters. Collectively, this study supports that rs727088 polymorphism may contribute to increased CSCC susceptibility.     

Evaluation of Cervical Cancer Screening Programs in C?te d’Ivoire,Guyana, and Tanzania: Effect of HIV Status

Background

HIV infection increases a woman’s risk for cervical cancer, and cervical cancer incidence and mortality rates are higher in countries with high HIV prevalence and limited resources for screening. Visual inspection with acetic acid (VIA) allows screening and treatment of cervical lesions in a single-visit approach (SVA), but data on its performance in HIV-infected women are limited. This study’s objective was to examine cervical cancer screening using VIA/SVA in programs serving HIV-infected women.

Methods

A VIA/SVA program with cryotherapy for VIA-positive lesions was implemented in Côte d’Ivoire, Guyana, and Tanzania from 2009 to 2012. The effect of HIV status on VIA positivity and on presence of cryotherapy-eligible lesions was examined using a cross-sectional study design, with Chi-square tests for comparisons and constructed multivariate logistic regression models. A P-value of < 0.05 was significant.

Findings

VIA was performed on 34,921 women, 10% (3,580) were VIA positive; 2,508 (85%) eligible women received cryotherapy during the same visit; only 234 (52%) of those who postponed returned for treatment; 622 (17%) VIA-positive women had lesions too large to be treated with cryotherapy and were referred for excisional treatment. In multivariate analysis—controlling for HIV status, location of the screening clinic, facility location, facility type, and country—compared to HIV-uninfected/unknown women, HIV-infected women had higher odds of being VIA positive (OR 1.95, 95% CI 1.76, 2.16, P<0.0001) and of having large lesions requiring referral (OR 1.93, 95% CI 1.49, 2.51, P< 0.0001). Minor treatment complications occurred in 19 of 3,032 (0.63%) women; none required further intervention.

Conclusions

This study found that compared to HIV-uninfected/unknown women, HIV-infected women had nearly twice the odds of being VIA-positive and to require referral for large lesions. SVA was safe and resulted in significant reductions in loss to follow-up. There is increased need for excisional treatment in countries with high HIV prevalence.     

Involvement of PI3K/AKT and MAPK Pathways for TNF-α Production in SiHa Cervical Mucosal Epithelial Cells Infected with Trichomonas vaginalis

Trichomonas vaginalis; induces proinflammation in cervicovaginal mucosal epithelium. To investigate the signaling pathways in TNF-α production in cervical mucosal epithelium after T. vaginalis infection, the phosphorylation of PI3K/AKT and MAPK pathways were evaluated in T. vaginalis-infected SiHa cells in the presence and absence of specific inhibitors. T. vaginalis increased TNF-α production in SiHa cells, in a parasite burden-dependent and incubation time-dependent manner. In T. vaginalis-infected SiHa cells, AKT, ERK1/2, p38 MAPK, and JNK were phosphorylated from 1 hr after infection; however, the phosphorylation patterns were different from each other. After pretreatment with inhibitors of the PI3K/AKT and MAPK pathways, TNF-α production was significantly decreased compared to the control; however, TNF-α reduction patterns were different depending on the type of PI3K/MAPK inhibitors. TNF-α production was reduced in a dose-dependent manner by treatment with wortmannin and PD98059, whereas it was increased by SP600125. These data suggested that PI3K/AKT and MAPK signaling pathways are important in regulation of TNF-α production in cervical mucosal epithelial SiHa cells. However, activation patterns of each pathway were different from the types of PI3K/MAPK pathways.     

Disparities of Perceptions and Practices Related to Cervical Cancer Prevention and the Acceptability of HPV Vaccination According to Educational Level in a French Cross-Sectional Survey of 18–65 Years Old Women

Introduction

We aimed to study the relationships between educational level, women''s knowledge about cervical cancer (CC), and acceptance of HPV vaccination for their daughters.

Methods

We analysed data from a quantitative (self-administrated questionnaire) and qualitative (semi-structured interviews) cross-sectional study performed in 2008 among 1,229 French 18–65-year-old women recruited by general practitioners. Women were categorized into three educational level groups: low (LEL: 43.9%), medium (MEL: 33.4%) and high (HEL: 22.6%).

Results

Knowledge about CC and its prevention was lower among LEL women. In the 180 mothers of 14–18-year-old daughters (99 LEL, 54 MEL, 45 HEL), acceptance of HPV vaccine was higher in LEL (60.4%) and MEL (68.6%) than in HEL mothers (46.8%). Among LEL mothers, those who were favourable to HPV vaccination were more likely to be young (OR = 8.44 [2.10–34.00]), to be vaccinated against hepatitis B (OR = 4.59 [1.14–18.52]), to have vaccinated their children against pneumococcus (OR = 3.52 [0.99–12.48]) and to present a history of abnormal Pap smear (OR = 6.71 [0.70–64.01]).

Conclusion

Although LEL women had poorer knowledge about CC and its prevention, they were more likely to accept HPV vaccination than HEL mothers.     

Characterization of Single-Nucleotide Polymorphisms in the Tumor Necrosis Factor α Promoter Region and in Lymphotoxin α in Squamous Intraepithelial Lesions, Precursors of Cervical Cancer

Development of cervical cancer is a long process of abnormal cancerous cell growth in the cervix and is primarily the result of infection with specific high-risk types of human papillomavirus (HPV). The cytokines tumor necrosis factor α (TNFα) and lymphotoxin α (LTA) have an important role in all stages of cervical cancer and have the ability to induce the regression or promote the development of human tumors. Biologically important single-nucleotide polymorphisms (SNPs) occur within the TNFα and LTA genes. Therefore, the purpose of this study was to investigate the SNPs in the TNFα promoter region (-163, -238, -244, -308, -376, -857, -863, and -1031) and in the first intron of LTA (+252) in women with precursor lesions of cervical cancer. Overall, we studied 396 women from Mexico City. A total of 191 patients with HPV infection and precursor cervical lesions were subdivided in two groups: those with low-grade squamous intraepithelial lesions (n = 132) and those with high-grade squamous intraepithelial lesions (n = 59). Women (n = 205) negative for HPV and without cervical lesions were also included in the study. DNA was extracted from peripheral white blood cells and from cervical samples, and detection of biallelic polymorphisms of TNFα and LTA was performed using the polymerase chain reaction-sequence-specific oligonucleotide probe and restriction fragment length polymorphism techniques, respectively. We demonstrated that risk is associated with the genotype G/A (odds ratio = 2.48) and that protection is associated with the genotype G/G of SNP TNFα -376 (odds ratio = 0.37).     

Are Immigrants and Nationals Born to Immigrants at Higher Risk for Delayed or No Lifetime Breast and Cervical Cancer Screening? The Results from a Population-Based Survey in Paris Metropolitan Area in 2010

Objectives

This study aims to compare breast cancer screening (BCS) and cervical cancer screening (CCS) practices of French women born to French parents with those of immigrants and nationals born to immigrants, taking their socioeconomic status into account.

Methods

The study is based on data collected in 2010 in the Paris metropolitan area among a representative sample of 3000 French-speaking adults. For women with no history of breast or cervical cancer, multivariate logistic regressions and structural equation models were used to investigate the factors associated with never having undergone BCS or CCS.

Results

We confirmed the existence of a strong gradient, with respect to migration origin, for delaying or never having undergone BCS or CCS. Thus, being a foreign immigrant or being French of immigrant parentage were risk factors for delayed and no lifetime screening. Interestingly, we found that this gradient persisted (at least partially) after adjusting for the women’s socioeconomic characteristics. Only the level of income seemed to play a mediating role, but only partially. We observed differences between BCS and CCS which suggest that organized CCS could be effective in reducing socioeconomic and/or ethnic inequities.

Conclusion

Socioeconomic status partially explained the screening nonparticipation on the part of French women of immigrant origin and foreign immigrants. This was more so the case with CCS than with BCS, which suggests that organized prevention programs might reduce social inequalities.     

Triage of Women with Minor Cervical Lesions: Data Suggesting a “Test and Treat” Approach for HPV E6/E7 mRNA Testing

Background

Human papillomavirus (HPV) testing is included in the cervical cancer screening program in the triage of women with equivocal (ASC-US) or low-grade (LSIL) cytological lesions. These women have an increased risk for developing high grade dysplasia and cancer (CIN2+) compared to women with normal cytology. However, in order to avoid unnecessary follow-up, as well as overtreatment, a high positive predictive value (PPV) of the triage test is important.

Methodology/Principal Findings

The HPV test PreTect HPV-Proofer, detecting E6/E7 mRNA from the HPV types 16, 18, 31, 33 and 45, is used as triage test together with repeat cytology. PPV data for HPV E6/E7 mRNA testing during the period from January 2006 up to June 2009 are reported. In total, 406 of 2099 women (19.3%) had a positive HPV test result. Of the women with a positive test result and with a histological diagnosis (n = 347), 243 women had histological high-grade dysplasia or cancer (CIN2+), giving a PPV of 70.0% (95% confidence interval [CI], 65.2%–74.8%). For HPV 16 or HPV 33 positive women above 40 years of age, the PPV was 83.7% (95% CI, 73.3%–94.0%) and 84.6% (95% CI, 65.0%–100.0%) respectively. The PPV of test positive women with HSIL cytology was 94.2% (95% CI, 88.7%–99.7%).

Conclusions

When the result in triage is HPV mRNA positive, our data suggest direct treatment for women above 40 years of age or for women with a concurrent cytological HSIL diagnosis, contributing to better clinical safety for these women. In addition, by decreasing the time to treatment, thereby reducing the number of recalls, the patient management algorithm will be considerably improved, in turn reducing follow-up costs as well as unnecessary psychological stress among patients.