• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3851-3864
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• 2014

Cytokine research is currently at the forefront in cancer research. Deciphering the functions of these multiple small molecules, discovered within the cell and in intercellular spaces, with their abundance and pleotrophism, was initially a great challenge. Advances in analytical chemistry and molecular biology have made it possible to unravel the pathophysiological functions of these polypeptides/proteins which are called interleukins, chemokines, monokines, lymphokines and growth factors. With more than 5 million women contracting cervical cancer every year this cancer is a major cause of mortality and morbidity the world over, particularly in the developing countries. In more than 95% of cases it is associated with human papilloma virus (HPV) infection which is persistent, particularly in those with a defective immune system. Although preventable, the mere magnitude of prevalence of HPV in the world population makes it a dominating current health hazard. The discovery of cytokine dysregulation in cervical cancer has spurted investigation into the possibility of using them as biomarkers in the early diagnosis of cases at high risk of developing cancer. Their critical role in carcinogenesis and progression of cervical cancer is now being revealed to a great extent. From diagnostics to prognosis, and now with a possible role in therapeutics and prevention of cervical cancer, the cytokines are being evaluated in all anticancer approaches. This review endeavours to capture the essence of the astonishing journey of cytokine research in cervical neoplasia.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.339-342
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• 2012

Background: About one third of the human population suffer cancer during their lifetime and more than 20% of total morbidity is related to neoplasia. Cervical cancer is generally the most common cancer in developing countries and the second most common in women globally. The role of human papilloma viruses viruses in its induction is clear. However, the involvement of hepres simplex virus type 2 (HSV-2) is controversial. Therefore a survey was conducted of the prevalence of HSV-2 in patients with cervical cancer and also healthy people with sensitive and quantitative Taq Man real-time PCR assay. Materials and methods: Seventy six formaldehyde fixed paraffin embedded tissue specimens from patients with histologically proven history of cervical cancer as well as 150 control blocks were sectioned for deparaffinization and DNA extraction. Results: There was no HSV-2 DNA in our patient specimens but four control samples were positive, all with a history of hysterectomy. Conclusion: Considering the absence of any positive viral HSV-2 DNA in our patients and also the presence of four positive specimens among our controls, we did not find any relationship between the presence of HSV-2 DNA and cervical cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.305-308
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• 2012

Objective: To assess the health and economic burden of human papillomavirus (HPV)-related diseases (cervical cancer, cervical intraepithelial neoplasia (CIN) 1/2/3, and genital warts) in Singapore over a period of 25 years beginning in 2008. Methods: Incidence-based modeling was used to estimate the incidence cases and associated economic burden, with the assumption that age-stratified incidence rates will remain the same throughout the period of 25 years. The incidence rates in 2008 were projected based on data obtained from the National Cancer Registry for cervical cancer, and from a combination of published data and hospital registry review for CIN1/2/3 and genital warts. The population growth rate was factored into the projection of incidence cases over time. Direct cost data per cervical cancer and per CIN1/2/3 case were obtained from the financial database of large local hospitals while cost data for genital warts were obtained from the National Skin Center; these costs were multiplied by the number of incidence cases to produce an aggregate estimate of the economic burden over the 25-year period (in 2008 Singapore dollars) using a 3% discount rate. Results: The total number of incidence cases of HPV-disease over 25 years beginning in 2008 was estimated to be 60,183, including 8,078 for cervical cancer, 11,685 for CIN 2/3, 8,849 for CIN1, and 31,572 for genital warts. The estimated total direct cost was 83.2 million Singapore Dollars over 25 years: 57.6 million attributable to cervical cancer, 13.0 million to CIN2/3, 6.83 million to CIN1, and 5.70 million to genital warts. Conclusion: HPV-related diseases are expected to impose significant health and economic burden on the Singapore healthcare resources in the next 25 years.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6257-6261
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• 2014

Background: HPV related cervical cancer as one of the most common women cancers in developing countries. Regarding accessibility of commercial vaccines, any long or short term modality for integrating preventive immunization against HPV in a national program needs comprehensive information about HPV prevalence and its genotypes. The important role of selecting most accurate diagnostic technologies for obtaining relevant data is underlined by different assays proposed in the literature. The main objective of the present study was to introduce an in-house HPV typing assay using multiplex real time PCR with reliable results and affordable cost for molecular epidemiology surveys and diagnosis. MATERIALS AND METHODS: 112 samples of formalin fixed paraffin embedded tissues and liquid based cytology specimens from patients with known different grades of cervical dysplasia and invasive cancer, were examined by this method and the result were verified by WHO HPV LabNet proficiency program in 2013. RESULTS: HPV was detected in 105 (93.7%) out of 112 samples. The dominant types were HPV 18 (61.6%) and HPV 16 (42.9%). Among the mixed genotypes, HPV 16 and 18 in combination were seen in 12.4% of specimens. CONCLUSIONS: According to acceptable performance, easy access to primers, probes and other consumables, affordable cost per test, this method can be used as a diagnostic assay in molecular laboratories and for further planning of cervical carcinoma prevention programs.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5007-5010
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• 2013

Heat shock proteins are molecular chaperones that may be constitutively present in cells protecting them from various stresses, such as extreme temperature, anoxia or chemical agents. Cervical cancer is the second most prevalent malignancy of women. In this study, we analyzed the expression of Hsp27 by immunohistochemistry in cervical intraepithelial lesions of Brazilian women, along with samples from non neoplasic lesions (NN). Cervical intraepithelial neoplasia I (CIN I), II (CIN II) and III (CIN III)/in situ carcinoma and squamous cell carcinoma (SCC) were included. Immunostaining was observed in 30 (100%) samples of NN, 46 (92%) in CIN I, 50 (100%) in CIN II, 52 (98.11%) in CIN III/CIS, and 46 (98.11%) in SCC. In group NN Hsp27 immunostaining was heterogeneous, more intense in basal and parabasal layers of the epithelium and less or absent in the intermediate and superficial layer. The majority of the samples of CIS and SCC presented strong staining in all epithelial layers. Metaplasic cells, when present, were strongly stained. In this study, Hsp27 protein was found to be commonly expressed in cervical epithelial cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6639-6641
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• 2014

Background: To evaluate the clinical significance of atypical squamous cells of undetermined significance (ASCUS) in PAP test in post-menopausal women and compare with reproductive age women. Materials and Methods: A total of 367 patients who referred to our gynecologic oncology clinic were included to the study between September 2012 and August 2013. Data for 164 post-menopausal (group 1) and 203 pre-menopausal (group 2) women with ASCUS cytology were evaluated retrospectively. Immediate colposcopy and endocervical curettage was performed for both groups and conization for all women with a result suggestive of CIN2-3. Histopathological results and demographic features of patients were compared between the two groups. Results: Mean age of the patients was $54.6{\pm}6.5$ years in group 1 and $38{\pm}6.6$ years in group 2. Some 14 (8.5%) of post-menopausal women and 36 (17.7%) of pre-menopausal women were current smokers (p=011). Totals of 38 (23.2%) post-menopausal and 64 (31.5%) pre-menopausal women were assessed for HPV-DNA. High risk HPV was detected in 7 (4.3%) and 21 (10.3%), respectively (p=0.029). Final histopathological results recorded were normal cervix, low grade cervical intra-epithelial neoplasia (CIN 1), and high grade cervical intra-epithelial neoplasia (CIN2-3). In group 1 results were 84.8%, 12.2% and 1.8%, respectively, and in group 2 were 71.9%, 23.2% and 4.9%. There were no cases of micro invasive or invasive cervical carcinoma in either group. Two cases were detected as endometrial carcinoma in the menopausal group (1.2%). Conclusions: In current study we found that preinvasive lesions were statistically significantly higher in pre-menopausal women than post-menopausal women with ASCUS. Cervicitis was more common in menopausal women. Therefore, we think that in case of ASCUS in a post-menopausal woman there is no need for radical management.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4353-4356
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• 2016

Purpose: To study the prevalence of CIN2+ diagnosis in women with atypical Papaniculoau (Pap) smears to suggest appropriate management option for Thai health care. Materials and Methods: Data from all patients with liquid based cytology with human papillomavirus (HPV) testing between May 2013 - May 2016 were collected from medical records. Women with atypical cervical Pap smears were recruited. Results for age, HPV testing, HPV 16, 18, 45 and other genotypes tested, colposcopic examination and histopathological assessment were all collected. Atypical smears were defined as atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells cannot be exclude high grade squamous intraepithelial lesion (ASC-H). Results: A total of 2,144 cases were recruited. Twenty six women with ASC-US on cytology had high risk (HR) HPV detection while eight cases with ASC-H had HR-HPV (40.0% VS 72.7%, p=0.005). Among the 26 women with ASC-US cytology and positive HR-HPV, HPV type 16 (n=8, 30.8%), type 18 (n=1, 3.8%), type 45 (n=1, 3.8%) and other HPV types (n=17, 65.4%) were found. Eight women with ASC-H and positive HR-HPV demonstrated type 16 (n=6, 75%) and other HPV types (n=2, 25%). Fifty seven women with ASC-US had normal colposcopy, CIN1 and CIN2+ at percentages of 80.7 (46/57), 14.0 (8/57) and 5.3 (3/57), respectively. In the ASC-H group, 7 out of 10 women had normal colposcopy and three (30%) had CIN2+ results. Conclusions: In women with ASC-US cytology, immediate colposcopy is highly recommended. HPV testing can be performed if colposcopy is not an available option because there was high prevalence (5.3%) of CIN2+ in our findings. ASCCP recommendations for ASC-H that colposcopy should be performed on all ASC-H cases regardless of HPV result are thereby supported by the findings of this investigation.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5271-5276
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• 2014

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important protein kinase and a member of the MAPK family, which regulates cellular responses to environmental stress and serves as key integration points along the signal transduction cascade that not only link diverse extracellular stimuli to subsequent signaling molecules but also amplify the initiating signals to ultimately activate effector molecules and induce cell proliferation, differentiation and survival. To explore the relationship between MEKK3 and cell apoptosis, clinicopathology and prognosis, we characterize the expression of MEKK3 and survivin in cervical cancer. MEKK3 and survivin expression was measured by RT-PCR and Western blotting of fresh surgical resections from 30 cases of cervical cancer and 25 cases of chronic cervicitis. Protein expression was detected by tissue microarray and immunochemistry (En Vision) in 107 cases of cervical cancer, 86 cases of cervical intraepithelial neoplasia (CIN), and 35 cases of chronic cervicitis. Expression patterns were analyzed for their association with clinicopathological factors and prognosis in cervical cancer. Expression of MEKK3 and survivin mRNA was significantly higher in cervical cancer than in the controls (p<0.05). MEKK3 and survivin expression differed significantly between cervical carcinoma, CIN, and cervicitis (p<0.05) and correlated with clinical stage, infiltration depth, and lymph node metastasis (p<0.05). MEKK3 expression was positively correlated with survivin (p<0.05). Kaplan-Meier survival analysis showed that MEKK3 and survivin expression, lymph node metastasis, depth of invasion, and FIGO stage reduce cumulative survival. Cox multivariate regression analysis showed that MEKK3, survivin, and clinical staging are independent prognostic factors in cervical cancer (p<0.05). Expression of MEKK3 and survivin are significantly increased in cervical cancer, their overexpression participating in the occurrence and development of cervical cancer, with protein expression and clinical staging acting as independent prognostic factors for patients with cervical cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6935-6939
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• 2015

Background: Currently, a comprehensive program for screening and early detection of cervical cancer does not exist in Iran. This study aimed to determine the prevalence of abnormal Papanicolaou (Pap) smears and some related factors among women living in Zanjan, Iran. Materials and Methods: This cross-sectional study was conducted in 2012 in Zanjan on 4274 married women aged 20-65 years. The study participants were selected through two-stage cluster sampling. After obtaining written consent, demographic and fertility questionnaires were completed. Samples from cervix were obtained through a standard method using the Rover Cervex- Brush. Evaluation and interpretation of the samples were reported using the Bethesda 2001 method. Data were statistically analyzed using chi-square and logistic regression models. Results: Most inflammatory changes in the samples were mild (37.4%). Abnormal atypical changes in the epithelial cells were found in 4.04%. The highest percentage of abnormal changes in the epithelial cells was atypical squamous cells of undetermined significance (ASCUS) (1.9%). Abnormal results of Pap smear was significantly and independently associated with age, papillomavirus infection, and lack of awareness about Pap smear tests. Conclusions: Given the high prevalence of inflammatory and precancerous changes in this study, compared to other studies in Iran and other Muslim countries, and the effect of demographic variables and individual factors on abnormal results, increasing the awareness of women and their families regarding the risk factors for cervical cancer, preventive measures such as screening, and timely treatment seem necessary.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9313-9317
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• 2014

Fragile histidine triad (FHIT) is a suppressor gene related to cervical cancer through CpG island hypermethylation. Folate is a water-soluble B-vitamin and an important cofactor in one-carbon metabolism. It may play an essential role in cervical lesions through effects on DNA methylation. The purpose of this study was to observe effects of folate and FHIT methylation and HPV 16 on cervical cancer progression. In this study, DNA methylation of FHIT, serum folate level and HPV16 status were measured using methylation-specific polymerase chain reaction (MSP), radioimmunoassay (RIA) and polymerase chain reaction (PCR), respectively, in 310 women with a diagnosis of normal cervix (NC, n=109), cervical intraepithelial neoplasia (CIN, n=101) and squamous cell carcinoma of the cervix (SCC, n=101). There were significant differences in HPV16 status (${\chi}^2=36.64$, P<0.001), CpG island methylation of FHIT (${\chi}^2=71.31$, P<0.001) and serum folate level (F=4.57, P=0.011) across the cervical histologic groups. Interaction analysis showed that the ORs only with FHIT methylation (OR=11.47) or only with HPV 16 positive (OR=4.63) or with serum folate level lower than 3.19ng/ml (OR=1.68) in SCC group were all higher than the control status of HPV 16 negative and FHIT unmethylation and serum folate level more than 3.19ng/ml (OR=1). The ORs only with HPV 16 positive (OR=2.58) or with serum folate level lower than 3.19ng/ml (OR=1.28) in CIN group were all higher than the control status, but the OR only with FHIT methylation (OR=0.53) in CIN group was lower than the control status. HPV 16 positivity was associated with a 7.60-fold increased risk of SCC with folate deficiency and with a 1.84-fold increased risk of CIN. The patients with FHIT methylation and folate deficiency or with FHIT methylation and HPV 16 positive were SCC or CIN, and the patients with HPV 16 positive and FHIT methylation and folate deficiency were all SCC. In conclusion, HPV 16 infection, FHIT methylation and folate deficiency might promote cervical cancer progression. This suggests that FHIT may be an effective target for prevention and treatment of cervical cancer.