Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis.

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.

Cervical Cancer Screening Beliefs and Prevalence of LSIL/HSIL Among a University-Based Population in Cameroon.

OBJECTIVE: The aim of the study was to determine beliefs and utilization of cervical cancer screening and prevalence of low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion among a university-based population in the Southwest region of Cameroon. MATERIALS AND METHODS: A public-private partnership was established between the University of Arizona, University of Buea, and the Cameroon Baptist Convention Health Services. A single-day screening clinic using visual inspection with acetic acid and Lugol's iodine solution (VILI) was provided at the University of Buea. Screening results were documented as negative, low-grade, high-grade, or suspicious for cancer. Thermocoagulation and loop electrosurgical excisional procedure was available for low- and high-grade lesions, respectively. A survey was conducted before screening and factors associated with screening practices were evaluated. RESULTS: Of 120 clinic participants, 107 (89.2%) believed that treatment of precancerous lesions helped prevent cervical cancer, but most (67.5%) had never been screened. Eighty women (66.7%) were aware of the human papillomavirus (HPV) vaccine, and only 2 had received vaccination. Among 115 patients screened, the prevalence of abnormal screening was 6.09%. Low-grade lesions were treated with thermocoagulation and high-grade lesions were treated with loop electrosurgical excisional procedure. CONCLUSIONS: Despite knowledge of cervical cancer screening benefits, the majority had not been screened or vaccinated. This study suggests a desire for additional screening services in this population and validates the utility of public-private partnerships in low-income regions.

Assessing the hierarchical structure of titanium implant surfaces.

The physical texture of implant surfaces are known to be one important factor in creating a stable bone-implant interface. Simple roughness parameters (for e.g., Sa or Sz) are not entirely adequate when characterizing surfaces possessing hierarchical structure (macro, micro, and nano scales). The aim of this study was to develop an analytical approach to quantify hierarchical surface structure of implant surfaces possessing nearly identical simple roughness. Titanium alloys with macro/micro texture (MM) and macro/micro/nano texture (MMN) were chosen as model surfaces to be evaluated. There was no statistical difference (p > 0.05) in either Sa (13.56 vs. 13.43 µm) or Sz (91.74 vs. 92.39 µm) for the MM and MMN surfaces, respectively. However, when advanced filtering algorithms were applied to these datasets, a statistical difference in roughness was found between MM (Sa = 0.54 µm) and MMN (Sa = 1.06 µm; p < 0.05). Additionally, a method was developed to specifically quantify the density of surface features appearing similar in geometry to natural osteoclastic pits. This analysis revealed a significantly greater numbers of these features (i.e., valleys) on the MMN surface as compared to the MM surface. Finally, atomic force microscopy showed a rougher nano-texture on the MMN surface compared with the MM surface (p < 0.05). The results support recent published studies that show a combination of appropriate micron and nano surface results in a more robust cellular response and increased osteoblast differentiation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1083-1090, 2016.

Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia.

OBJECTIVE: In vitro data and pilot data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and precursor lesions. We conducted a randomized, double-blind, placebo-controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low-grade cervical intraepithelial neoplasia (CIN1) to evaluate the potential of Polyphenon E for cervical cancer prevention. METHODS: Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. RESULTS: Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high-risk HPV and normal histopathology, was noted in 7 (17.1%) and 6 (14.6%) women in the Polyphenon E and placebo arms, respectively. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group than in the placebo group [6 (14.6%) vs. 3 (7.7%)]. CONCLUSION: Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that 4 months of Polyphenon E intervention did not promote the clearance of persistent high-risk HPV and related CIN1. Further studies may be necessary to better delineate the risk factors for persistent HPV infection and biology of the disease to facilitate the evaluation of chemopreventive strategies.

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion: review of ancillary testing modalities and implications for follow-up.

OBJECTIVE: To review the cytology category atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), with human papillomavirus (HPV) and other ancillary testing results and according to age group. METHODS: A literature search was performed on the ASC-H category, and studies analyzing ASC-H according to ancillary testing modalities or patient age groups during the past 4 years were emphasized. RESULTS: The ASC-H category accounts for less than 1% of cytology reports, and 33% to 84% will test positive for oncogenic HPV. The number of patients with cervical intraepithelial neoplasia 2/3 and cancer on biopsy is quite variable, from about 12% to more than 70%, averaging about 40%. The variation reflects patient population as well as local laboratory practices, but older subgroups are more likely to have negative HPV results and negative follow-up. Both the sensitivity of HPV testing for cervical intraepithelial neoplasia 2/3 detection and the negative predictive value for a patient with ASC-H and negative HPV testing average more than 95%. Additional studies evaluating other types of ancillary testing for the ASC-H category are needed. CONCLUSIONS: Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, is an uncommon cytology result, and HPV testing results and biopsy follow-up show variation according to patient age group and local laboratory practices. A negative HPV result in ASC-H offers a high negative predictive value and could be considered as a management strategy in mature women as well as women 30 years and older receiving combined cytology and HPV screening.

NovaMin and dentin hypersensitivity--in vitro evidence of efficacy.

OBJECTIVE: The objective of this study was to determine the ability of a calcium sodium phosphosilicate (NovaMin) particulate to occlude dentin tubules, and to characterize the nature of the occlusion through a number of in vitro studies. METHODS: Four experiments were designed to demonstrate the ability of NovaMin to 1) rapidly occlude tubules, 2) remain on the dentin surface in the face of acid challenges, and 3) form a biologically stable hydroxycarbonate apatite layer on the surface of dentin. Bovine dentin samples, polished to 1200 grit silicon and etched in 40% w/w o-phosphoric acid solution for 15 minutes to remove the smear layer, were employed in all four experiments. Four different experimental techniques were used to evaluate the effects of NovaMin and other marketed calcium-based products on tubule occlusion in 1) a single-treatment model, 2) a 10-day acid challenge cycling model to evaluate tubule occlusion, 3) a 10-day acid challenge cycling model to evaluate changes in surface hardness, and 4) a calcium-release model. Samples were assessed for tubule occlusion by scanning electron microscopy, surface mineralization by microhardness, and calcium release by inductively coupled mass spectroscopy. RESULTS: For the single-treatment model, statistical analysis showed that all treatment groups had statistically fewer open tubules than the control group (untreated; p < 0.001), and that the NovaMin group occluded significantly more tubules than the Quell group (p < 0.001). For the cycling models, after a one-time brushing with the NovaMin (SootheRx) dentifrice, significantly fewer open tubules were visible compared to the untreated control (p < 0.001). After the 10-day cycle, there were few visible open tubules on the samples treated with SootheRx, a significant reduction when compared to the control samples (p < 0.001). The hardness of dentin treated with NovaMin during the 10-day cycle was significantly greater than sound and demineralized dentin (p < 0.001). The calcium-release model demonstrated NovaMin-based dentifrices released less calcium initially compared to the other treatment groups. After four hours, a higher release of calcium was observed that was sustained over 24 hours. CONCLUSION: NovaMin adheres to an exposed dentin surface and reacts with it to form a mineralized layer. The layer formed is resistant to acid challenges and is mechanically strong. The continuous release of calcium over time is suggested to maintain the protective effects on dentin, and provide continual occlusion of the dentin tubules.

The role of ionic release from NovaMin (calcium sodium phosphosilicate) in tubule occlusion: an exploratory in vitro study using radio-labeled isotopes.

OBJECTIVE: The primary objective of this work was to develop a method of quantifying the levels and source of calcium and phosphate deposited on dental hard tissue from a novel calcium phosphosilicate (NovaMin) material using neutron activation analysis (NAA). A second objective was to explore the utility of radiotracing to determine dentin porosity following exposure to calcium phosphosilicate. METHODS: Neutron activation was used to create isotopes of Ca and P in the calcium phosphosilicate particles. Gamma radiation emitted from these isotopes was used to identify and measure their uptake (concentration) onto dental hard tissue. Three experiments were conducted to explore calcium and phosphate uptake to dental hard tissue: 1) a dose response to quantify the relative levels of calcium and phosphate deposited on dental hard tissue as a function of calcium phosphosilicate dose; 2) the effect of calcium phosphosilicate particle size on the relative levels of calcium and phosphate uptake; and 3) the permeability of calcium phosphosilicate-treated dentin by employing the radiotracer technetium. For all experiments, extracted bovine incisors were employed as the test substrate. RESULTS: The results indicate there is a strong dose relationship between the wt% and particle size of calcium phosphosilicate in the dentifrice formulation and new Ca and P deposition. At above 5.0 wt% calcium phosphosilicate, there appears to be an exponential increase in the number of counts from the tooth surface. Finer particle size calcium phosphosilicate appears to deposit much higher levels of Ca and P than the larger range of particle sizes. The results from the technetium study show that when treated with the dentifrice slurry containing calcium phosphosilicate, dentin shows only a slight amount of technetium infiltration, indicating a lowering of dentin permeability. CONCLUSION: This exploratory study has demonstrated that NAA and the use of radio isotopes have utility in monitoring the uptake of Ca and P into both dentin and enamel tooth structure. The data generated from these studies have shown that there is a dose dependence and particle size effect for calcium phosphosilicate on the deposition of calcium and phosphate to dental hard tissue.

A clinical study of the effect of calcium sodium phosphosilicate on dentin hypersensitivity--proof of principle.

OBJECTIVE: NovaMin is technically described as amorphous sodium calcium phosphosilicate, and has been shown in laboratory studies to rapidly occlude dentin tubules through the deposition of particles that react to form a protective layer, similar to bone mineral, on the dentin surface. NovaMin was originally developed as a bone regenerative material and is highly biocompatible. The objective of this pilot study was to compare the safety and effectiveness of two prototype formulations containing 2.5% and 7.5% w/w NovaMin to a placebo dentifrice for the treatment of dentin hypersensitivity. METHODS: This was a randomized, double-blind, placebo-controlled pilot study. Sixty-six subjects with a confirmed diagnosis of dentin hypersensitivity were randomized to one of three treatments: 2.5% NovaMin, 7.5% NovaMin, or placebo. Two standard test stimuli, tactile and thermal air, were applied to sensitive cervical dentin surfaces. Subjects recorded the intensity of sensitivity in response to each stimulus on a visual analog scale at baseline, and after two, four, and eight weeks of twice-daily product use. Oral soft tissues were examined and spontaneous reports of adverse experiences were also monitored. RESULTS: Comparison of the mean change from baseline among the three treatment groups indicated a meaningful reduction in sensitivity scores in the 7.5% group that was significant compared to reductions observed in the placebo control group at all time points. CONCLUSION: The results of this study are supportive of the incorporation of NovaMin into products intended for the reduction of dentin hypersensitivity.

A clinical study comparing oral formulations containing 7.5% calcium sodium phosphosilicate (NovaMin), 5% potassium nitrate, and 0.4% stannous fluoride for the management of dentin hypersensitivity.

UNLABELLED: To determine and compare the clinical performance of formulations containing 7.5% calcium sodium phosphosilicate (NovaMin), 5% potassium nitrate, and 0.4% stannous fluoride for the management of dentin hypersensitivity. METHODS: This was a single-center, randomized, double-blind, parallel-group design with a duration of 12 weeks. The study included a total of 120 subjects and measured sensitivity to cold water and air blast by the use of a visual analogue scale. Measurements were taken at baseline, two, four, and 12 weeks. RESULTS: All three products significantly reduced sensitivity versus baseline at each time point, although the calcium sodium phosphosilicate (NovaMin) dentifrice reduced sensitivity significantly more than the others at the two- and four-week time points. At the two-week time point, for air and water, respectively, the dentifrice containing NovaMin reduced sensitivity 45% and 49%, the stannous fluoride gel 30% and 26%, and the potassium nitrate dentifrice 35% and 34%. At the 12-week time point, the dentifrice containing NovaMin reduced sensitivity 87% and 91%, stannous fluoride gel 87% and 85%, and potassium nitrate dentifrice 84% and 79%. CONCLUSION: In this study, all three products were effective. Compared to the potassium nitrate and stannous fluoride formulations, the dentifrice containing NovaMin provided more substantial and significant improvements at the early time points.

Clinical evaluation of a dentifrice containing calcium sodium phosphosilicate (novamin) for the treatment of dentin hypersensitivity.

PURPOSE: To evaluate the efficacy of a dentifrice containing calcium sodium phosphosilicate (NovaMin) study versus a placebo and a commercially-available SrCl2 containing dentifrice for the treatment of dentin hypersensitivity. METHODS: This was a 6-week, randomized, parallel-arm, double-blind clinical study. 71 subjects ranging in age from 21 to 56 years old completed the study. Evaporative and thermal stimuli were used to measure pain using a VAS scale. Measurements were obtained at baseline, 2 weeks and 6 weeks. RESULTS: The placebo and the NovaMin groups showed a statistically significant decrease in sensitivity by both measures after 6 weeks (P < 0.05). The SrCl2 group showed a statistically significant decrease from baseline at the 2-week time point, but not at the 6-week time point for the evaporative stimulus. The percent reduction in sensitivity at 6 weeks for the NovaMin test group was 35% for air and 39% for cold water stimulus, versus 11% for air and 22% for cold water for the SrCl2 paste. The reductions for the placebo paste were 21% for the air stimulus and 18% for water. A cross tabulation measure of the reduction in sensitivity at each time point for all three treatments showed that the NovaMin product was more effective than either of the other products. For the air stimulus in the NovaMin group, 58% of subjects improved at each time point compared with 26% for the SrCl2 group and 20% for the placebo group. These results demonstrate that the NovaMin dentifrice was more effective at reducing sensitivity compared with a commercial dentifrice and placebo control.

The effect of the ionic products of Bioglass dissolution on human osteoblasts growth cycle in vitro.

In this study, in order to observe the effect of Bioglass and its ionic products on human esteoblasts growth cycle in vitro, the ionic products of Bioglass have been introduced to a cell culture medium by dissolving Bioglass particles in Dulbecco's modified Eagle's medium (DMEM) at 37 degrees C for 24 h; this was used as the experimental medium, while DMEM without Bioglass modification was used as the control medium. Human osteoblasts isolated from trabecular bone were treated by the two media and the timing of the osteoblast growth cycle was examined. Cell growth curves were derived after 7 days. Also, human osteoblasts were treated for 1-6 days by the two media, and the G(1), S, G(2) phase percentages of osteoblasts were recorded by flow cytometry every day, resulting in the cell proliferation activity index: SPF (S-phase fraction) and PI (proliferation index). The difference in cell growth was shown after the second day of culture (p < 0.01), and cell growth in the experimental groups was greater than in control groups. The SPF and PI of the experimental groups were also higher than the control groups in 2 days of culture (p < 0.05 and p < 0.01), which indicates that the growth cycle of the human osteoblasts in experimental medium is about 2 days. In conclusion, Bioglass can promote osteoblast proliferation, reducing the human osteoblast growth cycle to pass through G(1) and S phase and then enter G(2) phase quickly.

Compliance after loop electrosurgical excision procedure or cold knife cone biopsy.

OBJECTIVE: To examine rates and predictors of compliance with follow-up recommendations in low-income women from a county hospital clinic undergoing loop electrosurgical excision procedure (LEEP) and cone knife cone biopsy. METHODS: A retrospective cohort study of 135 patients who underwent LEEP or cold knife cone biopsy was performed. Demographic data, results of cytology, colposcopy biopsy, excision specimen pathology, and indication for the LEEP or cold knife cone biopsy were collected. Compliance was determined by whether the patient adhered to the recommended follow-up within 1 year from the date of the procedure. Multivariable analysis was performed by using logistic regression. RESULTS: A total of 135 patients were included for analysis (81 LEEP and 54 cold knife cone cases). Type of procedure was significant in predicting compliance: 74.1% of cold knife cone patients were compliant compared with 43.2% of LEEP patients (adjusted relative risk 1.64, 95% confidence interval 1.30-1.87). There was a trend for older patients to be more compliant than younger patients in the univariable analyses but not in multivariable analysis. After adjusting for age, LEEP patients were still significantly less compliant than cold knife cone patients. Pathologic indication (severity of disease), race, payor source, and gravidity were not significant predictors of compliance and not included in the multivariable analysis. CONCLUSION: Compared with LEEP, cold knife cone patients were significantly more compliant with follow-up. Because LEEP is a less invasive in-office procedure, it may convey to patients the idea that their condition is less severe. LEVEL OF EVIDENCE: II.

Endometrial cells in cervical cytology: review of cytological features and clinical assessment.

The 2001 Bethesda System for Reporting Cervical Cytology recommends reporting benign exfoliated endometrial cells in women age 40 and older, and a review of the literature supports this recommendation. Stromal cells and histiocytes do not need to be reported. The effect of hormonal therapy on endometrial shedding is reviewed. Clinical information should be provided to the laboratory so that appropriate educational notes can be appended to the cytology report. Benign endometrial cells in premenopausal women in the first half of the cycle are not associated with significant pathology and such women do not need additional evaluation. Significant pathology is also unlikely in the second half of the cycle and evaluation may not be required unless clinically indicated. Initial evaluation of other women with benign endometrial cells may include either endometrial sampling or transvaginal ultrasound. Atypical endometrial cells are associated with a higher rate of significant pathology and should lead to additional evaluation. Additional prospective studies on the management of patients with endometrial cells on Pap tests are needed.

Bone augmentation with bioactive glass in three cases of dental implant placement.

This study reports the clinical use of a bioactive bone graft material, PerioGlas, in the treatment of dental extraction sites before dental implant placement, to effect bone regeneration and to give early fixation to the implant.PerioGlas, granules, ranging from 90 to 710 mm, are implanted after tooth extraction in three patients; after 6 months bone biopsies were performed in the site of the glass implantation and observed under Electron Scanning Microscopy. All the granules showed a biodegradation involving precipitation of calcium phosphate that worked as a scaffold for osteoblasts colonization. All cases examined showed the bioactivity of PerioGlas granules resulting in new bone formation and biodegradation of the glass. After a two-year clinical follow-up all the implants were successfully loaded and appeared stable.

Anti-gingivitis effect of a dentifrice containing bioactive glass (NovaMin) particulate.

BACKGROUND: The objective of this pilot clinical trial was to evaluate the anti-gingivitis and anti-plaque effects of a dentifrice containing bioactive glass (NovaMin) compared with a placebo control dentifrice in a 6 weeks clinical study. METHODS: The study design was a randomized, double-blinded, controlled clinical trial. One hundred volunteers took part in the study and were matched for plaque index (PLI), gingival bleeding index (GBI), age and gender. The protocol was reviewed and approved by the Ethical Committee of the University. The subjects received a supragingival prophylaxis to remove all plaque, calculus and extrinsic stain. Following the baseline examination, subjects were instructed to brush with their assigned dentifrice and toothbrush. The PLI and GBI were determined for the baseline and 6 weeks. The data were analysed using a repeated-measures anova conducted on the two dependent measures to compare the effect between the test and control group. RESULTS: Ninety-five subjects finished the study. The results showed that the PLI (baseline=1.54, 6 weeks=1.29) and GBI (baseline=1.14, 6 weeks=0.47) were significantly reduced, respectively, over the 6 weeks period in the test group (p<0.001 for each measure). There was a 58.8% reduction in gingival bleeding and a 16.4% reduction in plaque growth. There was no difference of the PLI (baseline=1.60, 6 weeks=1.57) and GBI (baseline=1.18, 6-week=1.02) over the 6 week period in the control group. CONCLUSION: This study demonstrated that a dentifrice containing NovaMin significantly improves oral health as measured by a reduction in gingival bleeding and reduction in supragingival plaque compared with a negative dentifrice over the 6 weeks study period.

An analytical model for the dissolution of different particle size samples of Bioglass in TRIS-buffered solution.

We analyzed the early stages of reactivity of three different particle size samples of Bioglass 45S5 and a bulk sample in TRIS-buffered solution at pH 8. Ion release, measured with ion-coupled plasma emission spectroscopy, and pH variations are reported. It was demonstrated that differences in the initial surface area influence the increase in pH, the rate of elemental release, and the rate of calcium phosphate reprecipitation. In particular, a thicker Ca/P layer was obtained on larger particles. The equilibrium value of Si in solution was independent of sample form and amount of sample dissolved, and was always close to the value observed when bulk silica is dissolved at pH 8. An analytical model is proposed for cation release, based on a two-step mechanism. It was found that the early stage of dissolution was nearly diffusion controlled for larger particles and bulk samples. The second stage was similar to a first-order homogeneous dissolution. The influence of sample surface area/solution volume ratio seemed to be more complex than that proposed in the early works presented in the literature. It is suggested that variation of surface area has a significant impact on the course of the dissolution.