Natural History Of Cervical Cancer Research Articles

Development and Implementation of a Culturally Appropriate Education Program to Increase Cervical Cancer Screening among Maasai Women in Rural Tanzania.

Background:In Tanzania, the incidence of cervical cancer is nearly ten times that found in the US. Tanzanian women of the traditional Maasai tribe are financially and educationally marginalized and face a language barrier that reduces access to health care. While cervical cancer (CACX) screening programs are available locally, in our experience, Maasai women were less likely to use these services compared to local women of other tribal backgrounds.Objectives:A novel patient education program was designed to teach Maasai women about the natural history of cervical cancer and available screening and treatment. The program addressed the importance of preventative health and informed consent. Additionally, we sought to better understand the specific barriers Maasai women face in accessing and utilizing CACX screening services.Methods:The program used simple, scripted language translated into Maa language, the Maasai native language, with accompanying culturally appropriate 3D models. The effectiveness of the program was evaluated through pre and post-intervention surveys administered to Maasai and non-Maasai women as well as local healthcare providers, assessing knowledge of cervical cancer, screening, and treatment. Paired t-test analyses were used to analyze significance. Extensive question and answer sessions followed the education sessions from which additional barriers to screening were identified.Findings:Maasai women had minimal understanding of preventative health services prior to the intervention. While all groups showed an increase in knowledge following the education program, Maasai women demonstrated the greatest statistically significant improvement in knowledge. The proportion of Maasai women in attendance to CACX screening clinics increased by 18% after the intervention.Conclusions:Through a culturally sensitive and accessible patient education program, Maasai women gained knowledge of cervical cancer screening and treatment. This program serves as an adaptable model for other marginalized populations to increase patient understanding and informed consent, and to address issues that pertain to underutilization of health care services.

Telling the Truth About Caner is a Challenge

Cancer is our neighbor and is a part of our society. It has been here from the beginning of history and is still present hiding the truth about itself and being untouchable in its malevolent version: the unstoppable growth of abnormal cells attacking the body until it succumbs to the aggression.Removing all malignant cells from the body is a challenge because it is the only real cure of the affected person. But, it can be done only if the disease is detected in precancerous phase, cancer in situ, and invasive cancer in clinical stage 1A. All more advanced cancers, notwithstanding the therapy employed, have a much worse prognosis. Medicine is there only to postpone the ultimate fatal outcome.But, this is the same with life itself. It is the blessing to have it, but the challenge to live it. Cancer is the curse of our life. Therefore we have to fight against any carcinogenic and cancer promoter factor in our environments, to search for cancer indicators via surveys among healthy peoples, to put under control the groups at risk, and to conduct regular screening for detection of early signs of cancer as diligently as it has been done in the case of cervical cancer.In this fight, medicine has made many advantages but the cancer is still present. Only a small fraction, the cervical cancer natural history has been altered due to detection of an early suspect for cancer lesions and their removal. The success was achieved in the US where Pap test has helped American health care providers to reduce its mortality rate for 80% and to reverse the curves of cancer prevalence and mortality from increasing pattern to decreasing.This success was achieved in a group of 50 million women at risk, where 10% were found as suspect, subject to further diagnosis, only 1 million was confirmed as carrying on cancer indicators, and 40,000 lesions removed. Still, due to errors in sampling specimens, diagnostic errors or ineffective therapies, 12,000 joined the prevalence and 4,000 died per annum.Worldwide, this concept failed. The global outreach is below 20% of women at risk, and curves of cervical cancer prevalence and mortality are still on rise. What can be done? It was our humble challenge for more than 30 years of research. Finally, a light started to appear in the tunnel of cervical cancer destiny. It is the change of the strategy from the fight against cervical cancer to the fight to reverse the Cervical Cancer Mortality curve in a definite population and for a definite time. The new strategy needs new tools and services. All of this is described in our book, What Every Women Should Know about Cervical cancer, Second Edition (Springer, 2017)Parts were discussed at FASEB meetings in 2016 and 2017. This is a continuation of publishing the results of our research.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Human Papillomavirus (HPV) 16/18 E6 Oncoprotein Expression in Infections with Single and Multiple Genotypes.

Factors that differentiate risk of cervical cancer associated with infection with single versus multiple HPV types are yet undefined. We hypothesize that E6 oncoprotein is one determining factor. This cross-sectional, multicenter study was performed between 2013 and 2017. A total of 1,781 women were recruited from six hospitals. Samples were tested for presence of 14 types of high-risk HPV DNA. HPV16/18-positive samples were also tested for HPV16/18-E6 oncoprotein. Of 1,781 subjects, 687 (38.6%) tested positive for HPV16/18. HPV16/18 single infections were associated with higher E6 positivity rates compared with multiple infections only for cancer cases (HPV16: 92.2% vs. 76.5%; HPV18: 93.9% vs. 62.1%) but not for normal histopathology or cervical intraepithelial neoplasia. In HPV16/18 coinfection subjects, the positivity rate was 42.9% for HPV16-E6 and 42.9% for HPV18-E6. The combined positivity rate of either HPV16-E6 or HPV18-E6 among HPV16/18 coinfection subjects was 78.6%, similar with HPV16 (74.8%) and HPV18 (79.5%) single-infection subjects. The positivity rates of HPV16/18 E6 oncoprotein varied depending on the HPV-type composition in multiple infection ("clusters") including HPV types other than 16 and 18. Multiple infection clusters most likely to express HPV16-E6 and HPV18-E6 were HPV16/52 (61.5%) and HPV18/52 (66.7%), and the less were HPV16/45 (10.0%) and HPV18/51 (16.7%), respectively. Patterns of E6 oncoprotein expression varied depending on clustering types. However, expression was greatest in women with single HPV-type infections compared with those with multiple HPV types regardless of histopathology. Our findings provided new insight of natural history of cervical cancer.

Fast approximate computation of cervical cancer screening outcomes by a deterministic multiple-type HPV progression model

Cervical cancer arises differentially from infections with up to 14 high-risk human papillomavirus (HPV) types, making model-based evaluations of cervical cancer screening strategies computationally heavy and structurally complex. Thus, with the high number of HPV types, microsimulation is typically used to investigate cervical cancer screening strategies. We developed a feasible deterministic model that integrates varying natural history of cervical cancer by the different high-risk HPV types with compressed mixture representations of the screened population, allowing for fast computation of screening interventions. To evaluate the method, we built a corresponding microsimulation model. The outcomes of the deterministic model were stable over different levels of compression and agreed with the microsimulation model for all disease states, screening outcomes, and levels of cancer incidence. The compression reduced the computation time more than 1000 fold when compared to microsimulation in a cohort of 1 million women. The compressed mixture representations enable the assessment of uncertainties surrounding the natural history of cervical cancer and screening decisions in a computationally undemanding way.

Evaluating Clinical and Cost Impacts of Achieving 90% HPV Vaccination Rate Against Cervical Cancer in Canada Using the OncoSim Cancer Simulation Model

Background: Cervical cancer can be largely prevented through vaccination against the human papillomavirus (HPV). In Canada, HPV vaccination of school-aged girls started in 2008 and has reached an average rate of 67% across the country. However, this rate is below a current national target of 90%. Aim: We project the difference in lifetime clinical outcomes and health system costs of achieving a 90% HPV vaccination rate versus a 67% rate for girls vaccinated in 2015 using the OncoSim-Cervical model. Methods: The OncoSim-Cervical model (version 2.5) is a microsimulation model led by the Canadian Partnership Against Cancer, with model development by Statistics Canada, to evaluate the impacts of cervical cancer interventions in Canada. It has two parts, the first, the HPV Microsimulation Model, simulates the transmission of HPV between males and females including possible modulation by vaccination and herd immunity, and provides projections of HPV infection and prevalence for input to the cervical cancer natural history component in the second part. We simulated two cohorts of 5-10 year old girls in 2015; one receiving HPV vaccination at the rate of 67% and another at 90%. Their relative lifetime cervical cancer outcomes and costs were compared. Assumptions included: 100% efficacy of the HPV vaccine; triennial cytology screening between ages 21 and 65; 90% screening recruitment of age-eligible women with 80% rescreening; and a $500 cost for a 3-dose quadrivalent HPV vaccine regimen. Projected costs were undiscounted and are in 2016 CAD. Results: Compared with the 67%-vaccinated cohort, in the 90%-vaccinated cohort there was a lifetime reduction of 23% in cervical cancer incident cases and 21% in cervical cancer deaths. Lifetime cancer treatment costs decreased by $26 million (23%), and wart treatment costs and precervical cancer costs decreased by $3.2 million (15%) and $45 million (16%) respectively. Lifetime screening costs decreased by $47 million (2%). Conclusion: Achieving a nationally-set target of 90% HPV vaccination in Canadian girls would not only save more lives but would free up funds that could be redirected to other health system needs. Planners could aim for relatively high nation-wide rates of HPV vaccination coverage to enhance their cervical cancer control strategy.

The association between human papillomavirus 16, 18 DNA load and E6 protein expression in cervical intraepithelial neoplasia and cancer

BackgroundIt has been reported that high HPV DNA load and elevated E6 protein expression correlate with cervical cancer, but no epidemiological study has been performed. ObjectivesTo assess the association between type-specific HPV DNA load and presence of E6 protein in cervical intraepithelial neoplasia and cancer. Study designThis study was a cross-sectional multicenter study performed between 2013 and 2017. A total of 1717 women (normal histopathology: n = 916; CIN1: n = 94; CIN2: n = 63; CIN3: n = 130; SCC: n = 474; adenocarcinoma: n = 40) were included. HPV DNA load and presence of E6 protein were detected. DNA load was measured as log copies/10,000 cells. ResultsThe HPV16/18-E6 positivity rates increased from negative for DNA to the highest load grade. Compared to the HPV16 DNA negatives, women with low (RR = 31.5, 95%CI = 18.9–52.5), medium-low (RR = 133.5, 95%CI = 77.3–230.7), medium-high (RR = 247.9, 95%CI = 134.9–455.6) and high DNA loads (RR = 677.9, 95%CI = 301.6–1523.7) had increasingly higher relative ratios of HPV16-E6 expression. The association of HPV18-E6 with its DNA load was also significant for low (RR = 27.9, 95%CI = 10.4–74.9), medium-low (RR = 89.0, 95%CI = 32.8–241.3), medium-high (RR = 276.8, 95%CI = 76.7–998.9) and high grade (RR = 441.2, 95%CI = 97.7–1992.4). The positivity rates of both HPV16 DNA and E6 protein increased consistently with the severity of diseases from normal histopathology to SCC. Unlike HPV16, the trends of HPV18 DNA and E6 protein fluctuated consistently among women from normal histopathology to cancer. DNA load in E6-positive women was significantly higher than E6-negative for both types. ConclusionsThere is a type-dependent association between HPV16/18 DNA load and E6 protein; our study furthers the understanding of the natural history of cervical cancer.

Is Proflavine Exposure Associated with Disease Progression in Women with Cervical Dysplasia? A Brief Report.

Proflavine is an acridine dye used with high‐resolution microendoscopy for in vivo diagnostic evaluation of cervical epithelial cells. However, there are concerns that even short‐term exposure of cervical tissue to dilute proflavine may increase cervical cancer risk. We performed a retrospective analysis of women referred for colposcopy to Barretos Cancer Hospital comparing the risk of cervical disease progression in those whose cervical tissue was (n = 232) or was not exposed (n = 160) to proflavine. Patients in both groups underwent treatment and follow‐up based on histopathologic results and per the local standards of care. Progression of disease was evaluated by comparing histopathology from the initial visit to the worst subsequent histopathology result from all follow‐up visits. Mean duration of follow‐up was 18.7 and 20.1 months for the proflavine‐exposed and controls groups, respectively. There were no significant differences in disease progression from normal/CIN1 to CIN2/3 or from any initial diagnosis to invasive cancer between the proflavine exposed and control groups overall. Risks of cervical dysplasia progression observed in this study are in agreement with those of the natural history of cervical cancer. Our results suggest that cervical exposure to dilute proflavine does not increase the risk of cervical precancer and cancer.

NK-Cell Count and its Function in Producing Interferon Gamma Associated with the Cervical Cancer Natural History

Natural killer cell (NK-cell) has an important role in tumor immune surveillance. We investigate the NK-cell count and its function in producing IFN-I³ on normal cervix, subclinical high risk-HPV (hr-HPV) infection, precancerous lesion, and cervical cancer in order to understand the natural history of uterine cervical cancer.

Is HPV Vaccination Secure Protection of Women Without or With Cytologic Cancer Screening

Today, million of girls around the world receive vaccination against HPV hoping vaccines will protect them from the risk of getting cervical cancer if having sex with HPV positive partners.But, is it true? And, if it is true, how long the protection lasts?This dilemma has controversial documented data. Therefore, manufacturer of HPV vaccines and health care providers in charge of cervical cancer prevention, advertised, via guidelines, testing for antibody titer and for cytopathological changes of cervical specimen – similar to Pap test. The open dilemma is about scheduling: from 1‐to 5‐year periods between screening. Many studies have been published and supported with statistical data, but, indeed, this is only a guessing game.The Pap test was introduced as screening for lesions which can be developed into cervical cancer and the suspect lesions were recommended for colposcopy/biopsy/histology – finally to early removal of those lesions. This removal of lesions, not the Pap test alone, has interrupted the natural history of cervical cancer. The definition “cancer is unstoppable growth of malignant cells,” was replaced with “no lesion – no growth of cancer.”HPV vaccine protection is specific for few strains of HPV virus which have been found in developed cervical cancers. Cervical cancer has a much wider palette of risk factors including other HPV strains, and other promoters of malignancy [3]. Because of that, the cytopathologic screening must be kept regularly active. This fact returns us to the old concerns: Pap test staining has inherited 20% false negative readings. The recommended MEDYKO composite biomarker [1–3] consists of metabolic biomarker, “ME” (increasing sensitivity to include BCC category), “DY” dysplastic changes defining the level of clinical diagnosis, and “KO” (koilocytes, HPV disease indicating worse prognosis).All three markers are visible on one slide reducing false negative results of Pap test, and false positives of HPV infection testing. All are amenable for digital communication between POC and remote medical centers. Further, the specimen can be obtained at home with the Self‐sampling Kit what increases the outreach and opens the opportunity for annual testing.The concept has been tested, confirmed, but still, waits for mass applications.ConclusionCytologicl testing is still necessary for HPV vaccinated women, but Pap tests needs improvement as MEDYKO™ described above, annual home specimen sampling, collection of specimens in scattered POC, evaluation in remote specialist centers and early, the same day, intervention for removal of lesions if necessary.Support or Funding InformationNo external supportThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

What information can change the attitude of teachers toward the human papillomavirus vaccine?

We conducted a self-administered survey on the perception of teachers toward human papillomavirus (HPV) vaccine to determine the ways to increase their willingness to encourage its use. Answers were obtained both prior to and after having the teachers read five brief information articles: (i) cervical cancer knowledge, (ii) vaccine knowledge, (iii) result of a survey in Nagoya, (iv) news report of the World Health Organization statement and (v) articles written by Dr Muranaka, a journalist. Most of the respondents (180/247) did not know about the natural history of cervical cancer. Only 36% knew that HPV is the cause of cervical cancer, although 63% knew that HPV vaccine would prevent cervical cancer. Few respondents had knowledge regarding adverse events following immunization and the survey results from Nagoya. Among those who were initially negative for the HPV vaccine, only 43% revealed that they fully understood its safety and only 29% reversed their opinion to recommend vaccination to their daughters and/or students, even after reading our informational material. The most useful information for changing their attitudes was to increase their understanding of vaccines and informing them about Nagoya city survey results. They mostly wanted a proof of the preventive effects of the vaccine on cervical cancer in Japan. Gynecologists and pediatricians must proactively communicate accurate scientific information to the government and the media to spread awareness among people in Japan. Also, we must try to demonstrate the capabilities of this vaccine to prevent cervical cancer and/or its precancerous lesions.

Assessment of trends in cervical cancer screening rates using healthcare claims data: United States, 2003-2014.

Improved understanding of the natural history of cervical cancer has led to changes in screening recommendations, including the addition of the human papillomavirus (HPV) testing as an option in routine screening. Most studies of screening trends have used national self-reported survey data. To better understand recent trends in cervical cancer screening, including cytology (Papanicolaou, or Pap, tests) and human papillomavirus co-tests (HPV + Pap test), we used healthcare claims data to examine screening practices and trends. We analyzed screening among commercially-insured females ages 18–65 during 2005–2014 who were continuously enrolled during three or more contiguous calendar years, to identify those who received cervical cancer screening with a Pap test or co-test. We examined screening prevalence by age group and year. During the latter years of our study period, screening prevalence (regardless of screening method) declined significantly for women in all age groups examined. Despite declines in overall screening, the prevalence of co-testing increased in all age groups except those aged 18–20. In 2014, women aged 30–39 had the highest overall screening uptake (77.5%) and the highest use of co-testing (44.4%); this group also had the lowest overall declines in screening over the time period (−4.5%). These screening measures from healthcare claims were lower than self-reported screening from national surveys of the general population. More research to explore the reasons for these differences is needed to ensure that women are receiving appropriate screening, and to better understand why screening prevalence is declining among this population of commercially insured women.

NK-Cell Count and Its Function in Producing Interferon Gamma Associated with the Cervical Cancer Natural History

Objective: Natural killer cell (NK-cell) has an important role in tumor immunosurveilance. We investigate the NKcell count and its function in producing IFN-γ on normal cervix, subclinical high risk-HPV (hr-HPV) infection, precancerous lesion of cervix, and cervical cancer in order to understand the natural history of uterine cervical cancer. Methods: This is a descriptive comparative numerical study with more than two unpaired group with total subjects of 40 females who met the inclusion and exclusion criteria. Samples were gathered from cervical tissue using cytobrush and were processed in the laboratory to calculate NK-cell count and NK-cell expression of IFN-γ by phyta hemagglutinin (PHA) stimulation using flow cytometry. Data was analyzed using Kruskal Wallis and post hoc analysis was done to determine the difference between groups. Results: The mean NK-cell count on normal cervix, subclinical hr-HPV infection, precancerous lesion, and cervical cancer were 2.6%, 11.6%, 12%, and 7.4%. The mean NK-cell producing IFN-γ on normal cervix, subclinical hr-HPV infection, precancerous lesion, and cervical cancer were 8.1%, 3.3%, 1.1%, and 1.8%. There is significant difference of NK-cell count between 4 groups (p=0.001) but there is no significant difference of NK-cell producing IFN-γ (p=0.577). Conclusion: NK-cell count on normal cervix was significantly lower than other group but it has highest expression of IFN-γ after stimulation. On the other hand, precancerous lesion and cervical cancer has lower expression of IFN-γ after stimulation. Eventhough statistically there is no NK-cell activity difference, this study shows that NK-cell activity in disease groups were impaired. Further study is needed to understand NK-cell activity and its role in cervical cancer natural history. Nowdays, NK-cells as immunotherapy are potential tools for cancer therapy. In the future, we hope that NK-cell activity can be a parameter of cervical cancer progression and strategy to treat cervical cancer.

Expresión de EDNRB y CDX2 posibles biomarcadores en progresión al cáncer cervical

De acuerdo a la historia natural del cáncer del cuello uterino, en donde las lesiones preneoplásicas de bajo y alto grado pueden presentar fenómenos de regresión o progresión, existe gran interés en la búsqueda de biomarcadores que permita predecir la evolución de las lesiones preneoplásicas del cérvix hacia la progresión o regresión de la enfermedad. Estos biomarcadores pudieran ser de origen genético, o epigenético que alteren la expresión de los genes y que pudieran estar asociados con la carcinogénesis en diferentes tipos de tejido humano. El objetivo del estudio fue analizar la expresión del mARN de los genes SFRP1, PTPRN, CDO1, EDNRB, CDX2, EPB41L3 y HAND1 en muestras negativas para lesiones intraepiteliales cervicales (n=9), muestras con lesiones intraepiteliales de bajo grado (n=10) y alto grado (n=11). Se realizó análisis de expresión de los genes mencionados mediante qRT-PCR y el análisis de los datos se realizó mediante la prueba no paramétrica de ANOVA. La diferencia estadística se determinó en valores p< 0,05. Para los genes EDNRB y CDX2 se observó disminución 66,7% en las muestras sin alteraciones histológicas cervicales, comparado con una disminución en la expresión del 50% en muestras con LIEBG y para el grupo de LIEAG del 36,4% para el gen EDNRB y del 27,3% para el gen CDX2 dando una diferencia estadísticamente significativa p= 0,02. Sugiriendo que EDNRB y CDX2 podrían ser útiles como posibles biomarcadores en la carcinogénesis cervical.

PCN17 - Economic Evaluation of the Change from An Opportunistic Cervical Screening Program to an Organized Screening in Catalonia, Spain

Cervical cancer (CC) screening in Catalonia is opportunistic with a protocol that recommends a cytology every 3 years for women aged 25-65 years. However, evidence on the use of HPV testing as primary screening indicates that it is at least as effective as cytology, but with a greater protective effect allowing prolonged intervals of 5 years for HPV-negative women. In addition, well-organized screening programs have proven to be more effective and efficient than opportunists. The objective is to assess the cost-effectiveness and health expenditure in Catalonia of the current opportunistic screening and a hypothetical organized screening based on primary HPV testing every 5 years. Using a calibrated mathematical model to simulate the natural history of CC, we performed a cost-effectiveness and budget impact analysis. The model includes all processes and expenses derived from screening, follow-up and treatment of cases, as well as organizational expenses. Outcomes include QALYs, reduction of CC incidence and clinical procedures, total direct medical and non-medical costs (MDC & NMDC), and annual and per woman costs. The analysis was carried out from a societal perspective, with costs indexed at year 2016 and a discount rate of 3%. Sensitivity analysis was performed. An organized HPV screening would cost 13,940 €/QALY compared to non-intervention and current screening would be dominated. At the same coverage, organized HPV screening is always less expensive than the current screening. Assuming 40% coverage in the NHS in Catalonia, current screening would cost 17.8€ million annually (MDC 14.6€ and NMDC 3.2€) and an organized screening with HPV 12.2€ million annually (MDC 10.2€, NMDC 1.7€ and organization 0.3€). The same economic resources currently used in cytology-based opportunistic screening every 3 years with 40% coverage could be more efficiently utilized by covering more women (~70%) through screening with HPV testing every 5 years.

Retinol as a micronutrients related to cervical local immunity: The expression of tumor necrosis factor-alpha specifically stimulated with E6 epitope of human papillomavirus type-16 and ratio of CD4+/CD8+ T cell in natural history of cervical cancer

Retinol is one of the antioxidant micronutrients that plays essential roles in the immune system, by preventing the persistence of modulating CD4+ and CD8+ T cells and cytokines production. Tumor Necrosis Factor-Alpha (TNF-α) is an acute pro-inflammatory cytokine which has many crucial roles in controlling HPV. In contrast, when persistent infection occurs, TNF-α induces carcinogenesis. The ratio of CD4+ cells to CD8+ T cells and adequate TNF-α production in acute HPV infection are key points for clearance. The aim of this research is to analyze the sufficiency level of retinol deposit, the expression of TNF-α, and the ratio of CD4+: CD8+ T cells in a normal cervix, clearance and persistent HPV subclinical infection, and cervical cancer group. The sufficiency level of retinol deposit was analyzed from peripheral blood using the ELISA method. The cervico-vaginal secretions, which were incubated for 24 hours, were stimulated specifically by E6 epitope HPV type-16, measuring TNF-α expression semi-quantitatively by the ELISpot method and CD4+/CD8+ T cells quantitatively by flowcytometry method. The sufficient level of retinol deposit in a normal cervix, clearance HPV subclinical infection, persistent, and cervical cancer group was 85%, 75% (OR 1.89), 33.3% (OR 11.33), and 75% (OR 1.89), respectively. The expression of TNF-α in normal cervix group was 10%, while for cervical cancer it was 75% (OR 27.00; p < 0.001). There was no expression in clearance and persistent HPV subclinical infection groups. A high ratio of CD4+: CD8+ T cells in the normal cervix and cervical cancer group was 10% and 25% (OR 0.33). There was no high ratio of CD4+: CD8+ T cells in clearance (OR 1.22) and persistent (OR 0.95) HPV subclinical infection groups. This study was able to prove that the normal cervix group has the highest retinol deposit sufficiency level and the cervical cancer group has the highest TNF-α expression (OR 27; p < 0.001). The lowest of retinol deposit sufficiency level was not in cervical cancer, but in the persistent HPV subclinical infection group (OR 11.33). There was significant correlation in TNF-α expression between cervical cancer and normal cervix (p < 0.001), cervical cancer and clearance subclinical HPV infection (p = 0.024), and between clearance and persistent group (p = 0.007).

Level of Retinol Deposit and Cervical Cancer

Objective: To analyze level of retinol deposit sufficiency in the&#x0D; natural history of cervical cancer.&#x0D; &#x0D; Methods: Serum retinol level was measured by ELISA from&#x0D; peripheral blood of subjects with normal cervix, cleared and&#x0D; persistent high risk human papilloma virus (HR-HPV) subclinical&#x0D; infection, and cervical cancer who fulfilled the inclusion and&#x0D; exclusion criteria. The study was held in Dr. Cipto Mangunkusumo&#x0D; and Fatmawati Hospital, Jakarta, within 2 years (August 2013-&#x0D; 2015). Blood was taken twice, consisting of post-8-hour fasting&#x0D; blood and 2 hours after 6000 IU retinyl palmitate oral&#x0D; administration.&#x0D; &#x0D; Results: Of 47 total samples, sufficient level of retinol deposit in&#x0D; normal cervix, cleared and persistent HR-HPV subclinical infection,&#x0D; and cervical cancer group was 85.0% (reference), 75.0% (OR 1.89),&#x0D; 33.3% (OR 11.33), and 75% (OR 1.89); respectively. Statistically,&#x0D; there was no significant difference from sufficiency level of retinol&#x0D; deposit between normal cervix and clearance HR-HPV subclinical&#x0D; infection (p=0.628), normal cervix and persistent HR-HPV&#x0D; subclinical infection (p=0.078), normal cervix and cervical cancer&#x0D; (p=0.433), cervical cancer and clearance HR-HPV subclinical&#x0D; infection (p=1.000), cervical cancer and persistent HR-HPV&#x0D; subclinical infection (p=0.430), persistent and clearance HR-HPV&#x0D; subclinical infection group (p=0.740).&#x0D; &#x0D; Conclusion: This study proves that normal cervix group has the&#x0D; highest level of retinol deposit sufficiency; however, it cannot&#x0D; be stated that cervical cancer group has less sufficiency level.&#x0D; Persistent HR-HPV subclinical infection group has the lowest&#x0D; level of retinol deposit (OR 11.33). There is no association&#x0D; between sufficient level of retinol deposit and clearance of&#x0D; HR-HPV.&#x0D; &#x0D; [Indones J Obstet Gynecol 2017; 5-1: 46-54]&#x0D; &#x0D; Keywords: cervical cancer, HR-HPV clearance, retinol deposit

Age of Acquiring Causal Human Papillomavirus (HPV) Infections: Leveraging Simulation Models to Explore the Natural History of HPV-induced Cervical Cancer.

Although new human papillomavirus (HPV) infections can occur at all ages, the age at which women acquire their "causal" HPV infection that develops into cervical cancer is poorly understood and practically unobservable. We aimed to estimate the age distribution at which individuals acquired their causal HPV infection in the absence of HPV vaccination or screening to help guide the optimal use of both. Using an empirically calibrated mathematical model that simulates the natural history of cervical cancer, we estimated the cumulative number of causal HPV infections by age, stratified by HPV genotype (HPV16 vs. other HPV genotypes), and the direct age-specific reduction in cancer incidence for alternative vaccination initiation scenarios (i.e., age 9-45 years). Our model projected that among all cervical cancers, 50% and 75% of women acquired their causal HPV infection by ages 20.6 (range: 20.1-21.1) and 30.6 (range: 29.6-31.6) years, respectively. HPV16 infections were acquired at an earlier age. Assuming 95% efficacy against HPV16 and HPV18 infections, the direct reduction in lifetime risk of cervical cancer varied from 55% (53-56%) among women vaccinated at age 9 years to 6% (range: 6-7%) among women vaccinated at age 45 years. Similar patterns were observed for the second-generation vaccine. Although new HPV infections and precancers can occur throughout a woman's lifetime, only a small proportion are acquired in mid-adult women and are vaccine-preventable. Our simulations highlight the potential limitations of using surrogate endpoints for vaccine efficacy studies of mid-adult women to guide policy decisions for implementation.

Cost-effectiveness of increasing cervical cancer screening coverage in the Middle East: An example from Lebanon

BackgroundMost cervical cancer (CC) cases in Lebanon are detected at later stages and associated with high mortality. There is no national organized CC screening program so screening is opportunistic and limited to women who can pay out-of-pocket. Therefore, a small percentage of women receive repeated screenings while most are under-or never screened. We evaluated the cost-effectiveness of increasing screening coverage and extending intervals. MethodsWe used an individual-based Monte Carlo model simulating HPV and CC natural history and screening. We calibrated the model to epidemiological data from Lebanon, including CC incidence and HPV type distribution. We evaluated cytology and HPV DNA screening for women aged 25–65years, varying coverage from 20 to 70% and frequency from 1 to 5years. ResultsAt 20% coverage, annual cytologic screening reduced lifetime CC risk by 14% and had an incremental cost-effectiveness ratio of I$80,670/year of life saved (YLS), far exceeding Lebanon’s gross domestic product (GDP) per capita (I$17,460), a commonly cited cost-effectiveness threshold. By comparison, increasing cytologic screening coverage to 50% and extending screening intervals to 3 and 5years provided greater CC reduction (26.1% and 21.4, respectively) at lower costs compared to 20% coverage with annual screening. Screening every 5years with HPV DNA testing at 50% coverage provided greater CC reductions than cytology at the same frequency (23.4%) and was cost-effective assuming a cost of I$18 per HPV test administered (I$12,210/YLS); HPV DNA testing every 4years at 50% coverage was also cost-effective at the same cost per test (I$16,340). Increasing coverage of annual cytology was not found to be cost-effective. ConclusionCurrent practice of repeated cytology in a small percentage of women is inefficient. Increasing coverage to 50% with extended screening intervals provides greater health benefits at a reasonable cost and can more equitably distribute health gains. Novel HPV DNA strategies offer greater CC reductions and may be more cost-effective than cytology.

The effect of intrauterine devices on acquisition and clearance of human papillomavirus

Previous studies have shown a decrease in cervical cancer associated with intrauterine device use. It has been hypothesized that intrauterine device use may alter the natural history of human papillomavirus infections, preempting development of precancerous lesions of the cervix and cervical cancer, but the effect of intrauterine devices on the natural history of human papillomavirus infection and subsequent development of cervical cancer is poorly understood. The purpose of this study was to evaluate the association between intrauterine device use and cervical high-risk human papillomavirus acquisition and clearance. This is a prospective cohort study conducted from October 2000 through June 2014 among 676 sexually active young women and girls enrolled from family planning clinics in San Francisco, CA. Data were analyzed using a Cox proportional hazards model, including time-varying indicators of intrauterine device use, and adjusting for fixed and time-dependent predictor variables. A total of 85 women used an intrauterine device at some time during follow-up. Among 14,513 study visits, women reported intrauterine device use at 505 visits. After adjusting for potential behavioral confounders, there was no association between intrauterine device use and human papillomavirus acquisition (hazard ratio, 0.50; 95% confidence interval, 0.20-1.23; P= .13) or clearance of human papillomavirus infection (hazard ratio, 1.44; 95% confidence interval, 0.76-2.72; P=.26). Current intrauterine device use is not associated with acquisition or persistence of human papillomavirus infection. Intrauterine device use is safe among women and girls with human papillomavirus infections and at risk for human papillomavirus acquisition. Intrauterine device use may play a role further downstream in the natural history of cervical cancer by inhibiting the development of precancerous lesions of the cervix in human papillomavirus-infectedwomen, or enhancing clearance of established precancerous lesions.

Risk allelic load in Th2 and Th3 cytokines genes as biomarker of susceptibility to HPV-16 positive cervical cancer: a case control study.

BackgroundAlterations in the host cellular immune response allow persistent infections with High-Risk Human Papillomavirus (HR-HPV) and development of premalignant cervical lesions and cervical cancer (CC). Variations of immunosuppressive cytokine levels in cervix are associated with the natural history of CC. To assess the potential role of genetic host immunity and cytokines serum levels in the risk of developing CC, we conducted a case–control study paired by age.MethodsPeripheral blood samples from patients with CC (n = 200) and hospital controls (n = 200), were used to evaluate nine biallelic SNPs of six cytokine genes of the adaptive immune system by allelic discrimination and cytokines serum levels by ELISA.ResultsAfter analyzing the SNP association by multivariate logistic regression adjusted by age, CC history and smoking history, three Th2 cytokines (IL-4, IL-6 and IL-10) and one Th3 (TGFB1) cytokine were significantly associated with CC. Individuals with at least one copy of the following risk alleles: T of SNP (−590C > T IL-4), C of SNP (−573G > C IL-6), A of SNP (−592C > A IL-10), T of SNP (−819C > T IL-10) and T of SNP (−509C > T TGFB1), had an adjusted odds ratio (OR) of 2.08 (95 % CI 1.475–2.934, p = 0.0001), an OR of 1.70 (95 % CI 1.208–2.404, p = 0.002), an OR of 1.87 (95 % CI 1.332–2.630, p = 0.0001), an OR of 1.67 (95 % CI 1.192–2.353, p = 0.003) and an OR of 1.91 (95 % CI 1.354–2.701, p = 0.0001), respectively, for CC. The burden of carrying two or more of these risk alleles was found to have an additive effect on the risk of CC (p trend = 0.0001). Finally, the serum levels of Th2 and Th3 cytokines were higher in CC cases than the controls; whereas IFNG levels, a Th1 cytokine, were higher in controls than CC cases.ConclusionThe significant associations of five SNPs with CC indicate that these polymorphisms are potential candidates for predicting the risk of development of CC, representing a risk allelic load for CC and can be used as a biomarker of susceptibility to this disease.