• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6837-6842
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• 2014

Background: Northern Thailand is a region with a high cervical cancer incidence. Combined high-risk HPV (hrHPV) DNA testing and cytology (co-testing) has increasingly gained acceptance for cervical cancer screening. However, to our knowledge, data from a population-based screening using co-testing have not been available in this region. This study therefore aimed to evaluate the performance of cytology and hrHPV test in women in northern Thailand. Materials and Methods: Cervical samples were collected for hybrid capture 2 (HC2) testing and liquid-based cytology from women aged 30 to 60 years who were residents in 3 prefectures of Chiang Mai in northern Thailand between May and September 2011. Women with positive cytology were referred to colposcopy, while women with positive for HC2 only were followed for 2 years. Results: Of 2,752 women included in this study, 3.0% were positive in both tests, 4.1% for HC2 only, and 1.3% had positive cytology only. At baseline screening, positive HC2 was observed in 70.6% among cytology-positive women compared with 4.3% among cytology-negative women. The prevalence of positive HC2 or cytology peaked in the age group 35-39 years and was lowest in the age group 55-60 years. High-grade squamous intraepithelial lesion or worse lesions (HSIL+) were histologically detected in 23.5% of women with positive baseline cytology and in 9.8% of women with positive baseline HC2 only on follow-up. All women with histologic HSIL+ had positive baseline HC2. Conclusions: The hrHPV test is superior to cytology in the early detection of high-grade cervical epithelial lesions. In this study, the prevalence of histologic HSIL+ on follow-up of women with positive hrHPV test was rather high, and these women should be kept under careful surveillance. In northern Thailand, hrHPV testing has a potential to be used as a primary screening test for cervical cancer with cytology applied as a triage test.

• BMB Reports
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• 제51권11호
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• pp.584-589
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• 2018

Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of $94.3{\times}$ for WES and $35.3{\times}$ for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.3893-3900
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• 2015

It's known that having multiple sexual partners is one of the risk factors of human papillomavirus (HPV) infection which is a major cause of cervical cancer. However, it is not clear whether the number of sexual partners is an independent risk factor for cervical cancer. We identified relevant studies by searching the databases of MEDLINE, PubMed and ScienceDirect published in English from January 1980 to January 2014. We analyzed those studies by combining the study-specific odds ratios (ORs) using random-effects models. Forty-one studies were included in this meta-analysis. We observed that the number of sexual partners was associated with the occurrence of non-malignant cervical disease (OR=1.82, 95%CI 1.63-2.00) and invasive cervical carcinoma (OR=1.77, 95%CI 1.50-2.05). Subgroup analyses revealed that the association remained significant after controlling for HPV infection (OR=1.52, 95%CI 1.21-1.83 for non-malignant disease; OR=1.53, 95%CI 1.30-1.76 for invasive cervical carcinoma). We found that there was a non-linear relation of the number of sexual partners with both non-malignant cervical disease and invasive cervical carcinoma. The risk of both malignant and non-malignant disease is relatively stable in women with more than 4-7 sexual partners. Furthermore, the frequency-risk of disease remained significant after controlling for HPV infection.The study suggested that h aving multiple sexual partners, with or without HPV infection, is a potential risk factor of cervical cancer.

• 대한세포병리학회지
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• 제16권1호
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• pp.18-24
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• 2005

The objective of this study was to ascertain whether or not the high-risk human papillomavirus (HPV) test, when coupled with Papanicolaou (Pap) smears, would prove useful in the screening and management of patients in whom abnormal Pap smear results had been obtained. Concomitant high-risk HPV detection using the hybrid capture II test and colposcopy with a Pap smear were performed with 176 patients, all of whom had been screened for both cervical carcinoma and precancerous lesions. We concomitantly performed colposcopies on these patients. Upon the follow-ups, the histologic diagnoses of these patients were confirmed via either biopsy or hysterectomy. The rate of high-risk HPV detection was correlated with cytologic diagnoses and colposcopic findings. The group composed of the high-risk HPV-positive ASCUS patients exhibited a 55.7% rate of cervical intraepithelial neoplasia (CIN), a significantly higher rate than the 7.5% result obtained in the high-risk HPV-negative ASCUS group. HPV test showed high sensitivity (87%) and low specificity (62.6%) in detection of CIN and colposcopy also showed high sensitivity (88%) and low specificity (22%). Any combination of these tests improve sensitivity, but not specificity. High-risk HPV tests, when coupled with Pap smears, constituted a useful triage approach with regard to colposcopy-directed biopsies in patients in whom a cytologic diagnosis of ASCUS had been rendered.

• Asian Pacific Journal of Cancer Prevention
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• 제13권2호
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• pp.469-472
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• 2012

The present study was conducted to assess utility of $p16^{INK4a}$ immunopositivity as a surrogate marker for genomic integration of high-risk human papillomavirus infection (hrHPV). A total of 29 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSILs), 27 high-grade squamous intraepithelial lesions (HSILs) and 53 invasive squamous cell carcinomas (SCCs), histologically-diagnosed between 1st January 2006 to 31st December 2008 at the University of Malaya Medical Centre were stained for $p^{16INK4a}$ (CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany). Immunopositvity was defined as diffuse staining of the squamous cell cytoplasm and or nucleus (involving > 75% of the intraepithelial lesions or SCCs). Staining of basal and parabasal layers of intraepithelial lesions was pre-requisite. One (3.4%) LSIL, 24 (88.9%) HSIL and 46 (86.8%) SCC were $p^{16INK4a}$ immunopositive. All normal squamous epithelium did not express $p16^{INK4a}$. $p16^{INK4a}$ expression was significantly lower (p<0.05) in LSIL compared with HSIL and SCC with no difference in expression between HSIL and SCC. The increased $p16^{INK4a}$ immunopositivity in HSIL and SCC appears in line with the integrated existence of the hrHPV and may provide more insightful information on risk of malignant transformation of cervical squamous intraepithelial lesions than mere hrHPV detection.

• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2447-2451
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• 2014

Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer. Consideration of safety and non human leukocyte antigen restriction, protein vaccine has become the most likely form of HPV therapeutic vaccine, although none have so far been reported as effective. Since tumor cells consistently express the two proteins E6 and E7, most therapeutic vaccines target one or both of them. In this study, we fabricated DC vaccines by transducing replication-defective recombinant adenoviruses expressing E6/E7 fusion gene of HPV-16, to investigate the lethal effects of specific cytotoxic T lymphocytes (CTL) against CaSki cells in vitro. Mouse immature dendritic cells (DC) were generated from bone marrow, and transfected with pAd-E6/E7 to prepare a DC vaccine and to induce specific CTL. The surface expression of CD40, CD68, MHC II and CD11c was assessed by flow cytometry (FCM), and the lethal effects of CTL against CaSki cells were determined by DAPI, FCM and CCK-8 methods. Immature mouse DC was successfully transfected by pAd-E6/E7 in vitro, and the transfecting efficiency was 40%-50%. A DC vaccine was successfully prepared and was used to induce specific CTL. Experimental results showed that the percentage of apoptosis and killing rate of CaSki cells were significantly increased by coculturing with the specific CTL (p <0.05). These results illustrated that a DC vaccine modified by HPV-16 E6/E7 gene can induce apoptosis of CaSki cells by inducing CTL, which may be used as a new strategy for biological treatment of cervical cancer.

• 한국발생생물학회:학술대회논문집
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• 한국발생생물학회 2003년도 제3회 국제심포지움 및 학술대회
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• pp.106-106
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• 2003

Human papillomavirus type 16(HPV16) has been known to the major factor for the development of uterine cervical carcinomas. We have extended these studies to investigate the in vivo activities of HPV-16 E6/E7 when expressed in squamous epithelia of transgenic mice. Grossly, hK14HPV16E6/E7 transgenic mice had multiple phenotypes, including wrinkled skin that was apparent prior to the appearance of hair on neonates, thickened ears, and loss of hair in adults. In the transgenic mice, the wrinkled skin phenotype on the body and legs died at the age of 3-4 weeks. Histological analysis of demonstrated that E6/E7 causes epidermal hyperplasia in multiple transgenic lineages with high penetrance. This epithelial hyperplasia was characterized by an expansion of the proliferating compartment and an expansion of the keratinocyte and was associated with hyperkeratosis. These transgenic mice expressed E6/E7 transgene mainly in skin, heart, pancreas and kidney. Hyperplasia was found at the skin. The enzyme activities of GR, GPx and CuZnSOD were measured from the transgene cause keratinocyte at the skin. The specific enzyme activities were significantly higher in transgenic mice skin compared to the normal mice skin. Thus these transgenic mice may be useful for the develpment of antioxidant enzymes or other therapies for HPV-associated hyperkeratosis.

• Bulletin of the Korean Chemical Society
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• 제30권12호
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• pp.2999-3005
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• 2009

Among the more than 120 different types of human papillomavirus (HPV), types 16 and 18 have been known to be high risk agents that cause cervical cancer. We examined, in an immuno-chromatographic analysis, the potential of using the early gene product, E7 protein, as a diagnostic marker of cervical cancer caused by HPV. We developed monoclonal antibodies specific to HPV-16 and 18 E7 proteins that were produced from bacterial cells using gene recombinant technology. For each E7 protein, the optimal antibody pair was selected using the immuno-chromatographic sandwichtype binding system based on the lateral flow through membrane pores. Under these conditions, this rapid testing assay had a detection capability as low as 2 ng/mL of E7 protein. Furthermore, since viral analysis required the host cell to be lysed using chemicals such as detergents, it was possible that the E7 protein was structurally damaged during this process, which would result in a decrease in detection sensitivity. Therefore, we examined the detrimental effects caused by different detergents on the E7 protein using HeLa cells as the host. In these experiments, we found that the damage caused by the detergent, nonylphenylpolyethylene glycol (NP-40), was minimal relative to Triton X-100 commonly used for the cell lysis. Temperature also affected the stability of the E7 protein, and we found that the E7 protein was stabilized at 4$^{\circ}C$ for about 2 h, which was 4 times longer than at room temperature. Finally, a HPV-infected cervical cancer cell line, which was used as a real sample model, was treated using the optimized conditions and the presence of E7 proteins were analyzed by immuno-chromatography. The results of this experiment demonstrated that this rapid test could specifically detect HPV-infected samples.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8063-8067
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• 2014

Background: Cervical cancer is a major public health problem in Bangladesh. Persistence of high risk human papillomavirus (HRHPV) influences the progression of the disease, with an important role in followup for cervical intraepithelial neoplasia (CIN). Objective: To establish application of high risk HPV DNA test in the follow-up of women after treatment of CIN. Materials and Methods: This cross-sectional and hospital based study was carried out among 145 CIN treated women during the previous six months to three years at the colposcopy clinic of Bangabandhu Sheikh Mujib Medical University, Dhaka, between January 2011 and June 2012. Pap smear and HPV samples were collected and colposcopy was performed to find out the persistence of the disease. Cervical samples obtained were tested for HPV DNA using the Hybrid Capture II (HC-II) test. A cervical biopsy was collected whenever necessary. The results were compared to assess the efficacy of different methods during follow up such as Pap smear, HPV test and colposcopy. Results: Mean age of the recruited women (n=145) was 33.6 (${\pm}7.6$), mean age of marriage was 16.8 (${\pm}2.9$) and mean age of 1st delivery was 18.8 (${\pm}3.5$) years. More than half had high grade CIN before treatment and 115 (79.3%) women were managed by LEEP and 20.7% were managed by cold coagulation. Among the 145 treated women, 139 were negative for HPV DNA and six of them (4.1%) were HPV positive. Sensitivity of Pap smear (40.0) and HPV DNA test (40.0) was poor, but specificity was quite satisfactory (>93.0) for all the tests. Conclusions: The high risk HPV DNA test can be an effective method of identifying residual disease. It can be added to colposcopy and this should be applied to all treated women attending for their first or second post-treatment follow-up visit at 6 months to one year, irrespective of the grade of treated CIN.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.6857-6862
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• 2015

Background: To identify the optimal cost effective strategy for the management of women having ASC-US who attended at King Chulalongkorn Memorial Hospital (KMCH). Design: An Economical Analysis based on a retrospective study. Subject: The women who were referred to the gynecological department due to screening result of ASC-US at King Chulalongkorn Memorial Hospital, a general and tertiary referral center in Bangkok Thailand, from Jan 2008 - Dec 2012. Materials and Methods: A decision tree-based was constructed to evaluate the cost effectiveness of three follow up strategies in the management of ASC-US results: repeat cytology, triage with HPV testing and immediate colposcopy. Each ASC-US woman made the decision of each strategy after receiving all details about this algorithm, advantages and disadvantages of each strategy from a doctor. The model compared the incremental costs per case of high-grade cervical intraepithelial neoplasia (CIN2+) detected as measured by incremental cost-effectiveness ratio (ICER). Results: From the provider's perspective, immediate colposcopy is the least costly strategy and also the most effective option among the three follow up strategies. Compared with HPV triage, repeat cytology triage is less costly than HPV triage, whereas the latter provides a more effective option at an incremental cost-effectiveness ratio (ICER) of 56,048 Baht per additional case of CIN 2+ detected. From the patient's perspective, the least costly and least effective is repeat cytology triage. Repeat colposcopy has an incremental cost-effectiveness (ICER) of 2,500 Baht per additional case of CIN2+ detected when compared to colposcopy. From the sensitivity analysis, immediate colposcopy triage is no longer cost effective when the cost exceeds 2,250 Baht or the cost of cytology is less than 50 Baht (1USD = 31.58 THB). Conclusions: In women with ASC-US cytology, colposcopy is more cost-effective than repeat cytology or triage with HPV testing for both provider and patient perspectives.