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1.  Clinical significance of human papillomavirus genotyping 
Cervical cancer is the fourth most common cancer in women worldwide, and the human papillomavirus (HPV) is the main causative agent for its development. HPV is a heterogeneous virus, and a persistent infection with a high-risk HPV contributes to the development of cancer. In recent decades, great advances have been made in understanding the molecular biology of HPV, and HPV’s significance in cervical cancer prevention and management has received increased attention. In this review, we discuss the role of HPV genotyping in cervical cancer by addressing: clinically important issues in HPV virology; the current application of HPV genotyping in clinical medicine; and potential future uses for HPV genotyping.
doi:10.3802/jgo.2016.27.e21
PMCID: PMC4717226  PMID: 26768784
DNA Tests; Genotype; Human Papillomavirus; Uterine Cervical Neoplasms; Vaccine
2.  Methylation of Cervical Neoplastic Cells Infected With Human Papillomavirus 16 
Objective
This study was conducted to evaluate the role of methylation of adenylate cyclase activating peptide 1 (ADCYAP1), paired box gene 1 (PAX1), cell adhesion molecule 1 (CADM1), and T-lymphocyte maturation–associated protein (MAL) during carcinogenesis.
Methods
We evaluated the methylation of 4 genes by using the cervical carcinoma cell lines (CaSki, SiHa, HeLa, and C33A) and cervical neoplastic cells from 56 subjects with human papillomavirus 16 (HPV16)–infected low-grade squamous intraepithelial lesions (LSILs), 50 subjects with HPV16-infected high-grade squamous intraepithelial lesions (HSILs), and 24 subjects with HPV16-infected invasive cervical cancer who attended Seoul St. Mary’s Hospital. Methylation of the 4 genes was evaluated using quantitative bisulfate pyrosequencing.
Results
The ADCYAP1 promoter was hypermethylated in the 4 cell lines (CaSki, 97.40 ± 1.39; SiHa, 82.04 ± 17.02; HeLa, 96.14 ± 2.08; and C33A, 78 ± 10.18). PAX1 and CADM1 were hypermethylated in the HPV16/18-infected cell lines CaSki (PAX1, 91.18 ± 9.91; CADM1, 93.5 ± 7.33), SiHa (PAX1, 96.14 ± 2.08; CADM1, 93.15 ± 8.81), and HeLa (PAX1, 82.04 ± 17.02; CADM1, 92.43 ± 9.95). MAL was hypermethylated in the CaSki cell line (96.04 ± 4.74). Among human cervical neoplastic cells, the methylation indices of ADCYAP1 were 7.8 (95% confidence interval [95% CI], 7.0–8.6) in subjects with LSILs and 39.8 (95% CI, 29.0–54.7) in those with cervical cancer (P < 0.001); for PAX1, 7.2 (95% CI, 6.1–8.5) and 37.8 (95% CI, 27.1–52.7), respectively; for CADM1, 3.5 (95% CI, 3.0–4.0) and 17.7 (95% CI, 10.8–29.1), respectively; for MAL, 2.7 (95% CI, 2.5–3.0) and 13.0 (95% CI, 7.6–22.0), respectively (P < 0.001 for each). Immunohistochemical staining results were positive in the cytoplasm of subjects with low methylation of the 4 gene promoters; however, they were negative in the cytoplasm of those with hypermethylation of the 4 gene promoters.
Conclusions
The results of this study suggest that the methylation of ADCYAP1, PAX1, CADM1, and MAL may be highly associated with the development of cervical cancer, and that gene expression can be suppressed by gene promoter hypermethylation.
doi:10.1097/IGC.0000000000000582
PMCID: PMC4679343  PMID: 26552048
DNA methylation; Cervical cancer; Human papillomavirus
3.  Selective cyclooxygenase inhibitors increase paclitaxel sensitivity in taxane-resistant ovarian cancer by suppressing P-glycoprotein expression 
Journal of Gynecologic Oncology  2013;24(3):273-279.
Objective
The purpose of this study was to investigate whether selective cyclooxygenase (COX) inhibitors promote paclitaxel-induced apoptosis in taxane-resistant ovarian cancer cells by suppressing MDR1/P-glycoprotein (P-gp) expression.
Methods
Taxane-resistant ovarian cancer cells were cultured with paclitaxel alone or combined with a selective COX inhibitors. The expression patterns of MDR1/P-gp and the ability of COX inhibitors to inhibit growth of taxane-resistant ovarian cancer cells were measured. The efficacy of prostaglandin E2 (PGE2) supplementation was measured to evaluate the mechanisms involved in suppressing MDR1 gene expression.
Results
P-gp was upregulated in taxane-resistant ovarian cancer cells compared to paired paclitaxel-sensitive ovarian cancer cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that selective COX inhibitors significantly enhanced the cytotoxic effects of paclitaxel in taxane-resistant ovarian cancer cells via a prostaglandin-independent mechanism. These increased apoptotic effects were further verified by measuring an increased percentage of cells in sub-G1 stage using flow cytometry. Selective COX inhibitors suppressed MDR1 and P-gp expression. Moreover, combined treatment with paclitaxel and selective COX inhibitors increased poly (ADP-ribose) polymerase (PARP) cleavage in taxane-resistant ovarian cancer cells.
Conclusion
Selective COX inhibitors significantly promote paclitaxel-induced cell death in taxane-resistant ovarian cancer cells in a prostaglandin-independent manner. COX inhibitors could be potent therapeutic tools to promote paclitaxel sensitization of taxane-resistant ovarian cancers by suppressing MDR1/P-gp, which is responsible for the efflux of chemotherapeutic agents.
doi:10.3802/jgo.2013.24.3.273
PMCID: PMC3714466  PMID: 23875078
Chemosensitizer; Cyclooxygenase inhibitor; Ovarian cancer; Paclitaxel; P-glycoprotein
4.  Establishment of a Korea HPV cohort study 
We have designed a five-year multicentre prospective cohort study in women who are both human papillomavirus (HPV)-positive with either atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) of cervix. This study aimed to analyze the risk of developing a high-grade squamous intraepithelial lesion (HSIL) from either ASCUS or LSIL in HPV-positive women, so called 'progression' rate, to investigate differences in the progression rates according to HPV type-specific infection, and to evaluate the various factors associated with the persistence or clearance of HPV infection in the Korean population. At present, the study protocol composed of cervical cytology, HPV DNA testing, and questionnaire have been conducted actively since the first participant was enrolled in 2010. This study is the first nationwide Korea HPV cohort study. Our data will provide valuable information about not only the ambiguous cytology results of ASCUS and LSIL but also the effect of the specific HPV type and other various factors on the progression to HSIL. Finally, the results of our study will be helpful and applicable to determine the primary cervical cancer prevention strategies.
doi:10.3802/jgo.2013.24.1.59
PMCID: PMC3549509  PMID: 23346315
Cervical intraepithelial neoplasms; Cohort studies; Human papillomavirus; Uterine cervical neoplasms
5.  What Questions do People Ask on a Human Papillomavirus Website? A Comparative Analysis of Public and Private Questions 
Objective: In 2004, we launched the question and answer (Q&A) section on a human papillomavirus (HPV) website (www.hpvkorea.org) that provides ample and regularly updated information about HPV. The purpose of this study is to collect data pertaining to questions posed on this website about HPV and its related diseases and analyze the type of questions and frequency before and after introduction of HPV vaccine in Korea. Using these results, we intend to determine the clinical and practical implications for doctors treating HPV and for HPV website providers.
Method: Data were collected from March 2004 to July 2011. This study analyzed all the questions that were asked on the website during this period. The questions were categorized into 2 groups, according to whether they were asked publicly or privately. The 10 categories for classification were determined on the basis of the contents of the questions by 4 researchers with medical degrees (Ph.D.) related to HPV research. The frequency of the questions was separately determined for the public and private question formats. Also, we compared the type of questions and frequency before and after introduction of HPV vaccine in Korea and evaluated the changes in the 2 groups over the 2 periods studied.
Results: Of the 3,062 subjects who visited the HPV website, 2,330 subjects asked public questions and 732 asked private questions. The most frequent question was “I have been infected with HPV, and I want to know about the treatment options for HPV infection and cervical dysplasia” (n = 1156, 37.8%), and the second most common question was “What are the transmission routes of HPV?” (n = 684, 22.3%). The third most common question was “How long does it take for HPV infection to spontaneously remit?” (n = 481, 15.7%).
Of the 2,330 public questions, the most common question types pertained to the treatment of HPV and cervical dysplasia, HPV transmission, HPV remission, and risk of cervical cancer (in that order). Of the 732 private questions, the most frequent question types pertained to the HPV transmission, treatment of HPV and cervical dysplasia, genital warts, and HPV & pregnancy (in that order). The type and frequency of public and private questions showed statistical differences between the 2 groups (p < 0.001).
Conclusion: Our results show that when people consult an internet site about HPV, they actually want to seek about “treatment of HPV and cervical dysplasia”, “HPV transmission”, “HPV remission”, “genital warts”, and “risk of cervical cancer” (in this order). Also, our results showed that “genital warts” and “HPV & pregnancy” may have been considered embarrassing topics. Thus, these findings can be used to make informed recommendations for future clinical or internet-based communications with patients and the general public.
doi:10.7150/ijms.3420
PMCID: PMC3258556  PMID: 22253561
human papillomavirus; cervix; genital warts; dysplasia
6.  Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women 
Objective
The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15-25 years.
Methods
Phase IIIB, double-blind, randomised (2:1), multi-centre trial was conducted in Korea from June 2007 to March 2008. The study enrolled 225 women in the HPV (N=149) and placebo (N=76) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo (aluminium hydroxide) administered intramuscularly at 0, 1, and 6 months and were followed until one month post-dose 3. Serum samples were collected pre-vaccination and one month post-dose 3. Safety and reactogenicity data were collected throughout.
Results
In this trial, 208 women completed the study (141 in HPV group; 67 in placebo group). At month 7, all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El.U/mL (95% CI, 8,145.5 to 10,735.8) and 4204.1 El.U/mL (95% CI, 3,626.5 to 4,873.6), respectively. Initially seropositive women showed similar increase in geometric mean titre levels. Compliance to the three dose vaccination course was 95.3% in HPV and 89.5% in placebo group. Solicited local (pain) and general (fatigue, myalgia or headache) symptoms were commonly reported in both groups. Three serious adverse events were reported (two in HPV group; one in placebo group), all unrelated to vaccination by the investigator; all recovered.
Conclusion
The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinically acceptable safety profile in Korean women. This study was in line with previous global studies in Europe, North America, and Brazil. (ClinicalTrials.gov number, NCT 00485732.)
doi:10.3802/jgo.2011.22.2.67
PMCID: PMC3152758  PMID: 21860731
AS04-adjuvanted; Cervical cancer; Geometric mean titres; Human papillomavirus-16/18; Immunogenicity; Seroconversion
7.  DNA methylation in human papillomavirus-infected cervical cells is elevated in high-grade squamous intraepithelial lesions and cancer 
Objective
DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population.
Methods
A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves.
Results
Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively).
Conclusion
DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies.
doi:10.3802/jgo.2016.27.e14
PMCID: PMC4717219  PMID: 26768780
Cervical Cancer Screening; Cervical Cytology; Cervical Intraepithelial Neoplasia; DNA Methylation; Uterine Cervical Neoplasms
8.  Clinical analysis of intra-operative frozen section proven borderline tumors of the ovary 
Journal of Gynecologic Oncology  2009;20(3):176-180.
Objective
We have assessed the accuracy of frozen section diagnosis and the outcomes of misdiagnosis in borderline tumors of the ovary (BTO) according to frozen section.
Methods
All pathology reports with BTO in both frozen and permanent section analyses between 1994 and 2008 at Seoul St. Mary's Hospital were reviewed. Frozen section diagnosis and permanent section histology reports were compared. Logistic regression models were conducted to evaluate the correlation of patient and tumor characteristics with diagnostic accuracy. The clinical outcomes of misdiagnosis were evaluated.
Results
Agreement between frozen section diagnosis and permanent histology was observed in 63 of 101 patients (62.4%). Among the 76 patients with frozen section proven BTO, under-diagnosis and over-diagnosis occurred in 8 of 76 (10.5%) and 5 of 76 patients (6.6%), respectively. Mean diameter of under-diagnosed tumor was larger than matched BTO (21.0±11.4 vs. 13.7±7.1; p=0.021). Tumor size 20 cm was determined as the optimal cut-off for under-diagnosis (50% sensitivity, 87.3% specificity). Among 8 under-diagnosed patients, no patient relapsed. Among 5 over-diagnosed patients, 2 patients < 35 years of age had fertility-preserving surgery.
Conclusion
Although frozen section diagnosis is an important and reliable tool in the clinical management of patients with ovarian tumors, over-diagnosis and under-diagnosis are relatively frequent in frozen proven BTO. Surgical decision-making for BTO based on frozen section diagnosis should be done carefully, especially in large tumors.
doi:10.3802/jgo.2009.20.3.176
PMCID: PMC2757563  PMID: 19809552
Borderline tumors of the ovary; Frozen section diagnosis; Accuracy
9.  Clinical Characteristics of Metastatic Tumors to the Ovaries 
Journal of Korean Medical Science  2009;24(1):114-119.
Approximately 5-30% of the ovarian cancers are metastatic malignancies. The prevalence of metastatic ovarian tumors varies with the incidence rates and spread patterns of primary malignancies. We evaluated the prevalence, pre- and postoperative characteristics of metastatic ovarian cancer in Korean women. We reviewed the records for 821 ovarian malignancies with pathological consultation from 1996-2006 and recorded patient demographical, radiological, histopathological, and survival data. The study included 112 cases of histologically confirmed metastatic ovarian cancer. Metastatic ovarian cancer accounted for 13.6% of all ovarian malignancy, primarily arising from the gastrointestinal tract. The preoperative detection rate with imaging was 75%, and none of the radiological or serological features were useful for differential diagnosis. In multivariate analysis for prognostic variables, the only significant factor was the primary tumor site (p=0.004). Furthermore, extensive resection increased survival for some patients. The differential diagnosis of metastatic ovarian cancer can be problematic, so multiple diagnostic approaches are necessary. The extent of cytoreductive surgery for this type of tumor must be decided on a case-by-case basis.
doi:10.3346/jkms.2009.24.1.114
PMCID: PMC2650975  PMID: 19270823
Metastasis; Ovary; Prevalence; Diagnostic Imaging; Surgical Procedures
10.  Adjuvant therapy in high-risk early endometrial carcinoma: a retrospective analysis of 46 cases 
Journal of Gynecologic Oncology  2008;19(4):236-240.
Objective
We assessed the prognostic factors and the efficacy of adjuvant therapy and reviewed randomized studies carried out on patients receiving adjuvant therapy with early endometrial carcinoma.
Methods
One hundred and five patients that received primary surgical treatment for stage IB, IC and II endometrial cancer were enrolled in this study. The clinical outcomes were compared among the patients with variable prognostic factors and adjuvant treatments.
Results
One hundred and five patients fulfilled the eligibility criteria and 46 patients (43.8%) underwent adjuvant therapy. Disease recurrence occurred in nine patients within a median time of 24 months. Cervical involvement was an independent prognostic factor for the disease-free survival rates. Eight of 16 patients with FIGO stage II disease received adjuvant chemotherapy consisting of cisplatin and etoposide (or cyclophosphamide) or combined chemoradiation. The 5-year disease-free survival rate for these patients was 87.5%, a value significantly higher than for patients that received radiation therapy alone (30%).
Conclusion
Adjuvant chemotherapy or combination chemo-radiotherapy might be superior to radiation therapy alone in high-risk early endometrial cancer patients.
doi:10.3802/jgo.2008.19.4.236
PMCID: PMC2676478  PMID: 19471649
Endometrial carcinoma; Adjuvant therapy; Prognostic factor
11.  The Increasing Frequency of Cervical Cancer in Korean Women under 35 
Purpose
The goal of this study was to determine the clinical and epidemiological trends of cervical cancer in young Korean women. Social behavior including sexual habits has changed in Korean women, with sexual activity commencing at a younger age. These changes are likely to influence certain risk factors of cervical cancer, resulting in changing trends in the occurrence of the disease.
Materials and Methods
The incidence of cervical cancer in women less than 35 years-old between January 1990 and December 2006 was analyzed, and available medical records from January 1996 to December 2006 were reviewed. The clinical, pathological and epidemiologic characteristics and changing trends among these young patients were analyzed.
Results
Over the last two decades, the incidence of young (< 35 years) cervical cancer patients increased, more patients had an aggressive form of the disease, and there was a higher rate of women with more advanced education. Human papillomavirus (HPV) infection was detected in 94.0% of the women (63/67) tested. HPV 16 (82.5%) and HPV 18 (12.7%) were the two most common viral infections detected throughout the study period.
Conclusions
The changing trends and risk factors identified suggest a need for more active education of young women about cervical cancer prevention strategies. In addition, young women are strongly recommended to undergo a regular screening test and HPV vaccination.
doi:10.4143/crt.2008.40.1.1
PMCID: PMC2699086  PMID: 19688057
Uterine cervical neoplasms; Incidence; Epidemiology; Sexual behavior; Human papillomavirus (HPV); Young patients
12.  Biomarkers in Cervical Cancer 
Biomarker Insights  2007;1:215-225.
Cervical cancer, a potentially preventable disease, remains the second most common malignancy in women worldwide. Human papillomavirus (HPV) is the single most important etiological agent in cervical cancer, contributing to neoplastic progression through the action of viral oncoproteins, mainly E6 and E7. Cervical screening programs using Pap smear testing have dramatically improved cervical cancer incidence and reduced deaths, but cervical cancer still remains a global health burden. The biomarker discovery for accurate detection and diagnosis of cervical carcinoma and its malignant precursors (collectively referred to as high-grade cervical disease) represents one of the current challenges in clinical medicine and cytopathology.
PMCID: PMC2716791  PMID: 19690652
Cervical cancer; Human papillomavirus (HPV); biomarker
13.  The Role of HPV E6 and E7 Oncoproteins in HPV-associated Cervical Carcinogenesis 
Cervical cancer is one of the leading world causes of cancer morbidity and mortality in woman, with more than 98% related to a human papillomavirus (HPV) infection origin. Infection with specific subtypes of HPV has been strongly implicated in cervical carcinogenesis. The identification and functional verification of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information in understanding cervical carcinogenesis and the development of cervical cancer-specific markers. The advent of functional genomics and proteomics has provided hope of discovering novel biological markers for use in the screening, early diagnosis, prognostication and prediction of response to therapy. Herein, we review the studies where the profiles of host proteins associated with HPV E6 and E7 oncoproteins in cervical cancer were generated.
doi:10.4143/crt.2005.37.6.319
PMCID: PMC2785934  PMID: 19956366
Cervix neoplasms; HPV; E6; E7; Genomics; Proteomics
14.  Proteome Analysis of Differential Protein Expression in Cervical Cancer Cells after Paclitaxel Treatment 
Purpose
It is well known that infection with HPV (human papillomavirus) is the main cause of cervical cancer and certain types of HPV are recognized as carcinogens. At present, there is little information regarding the antineoplastic mechanism of paclitaxel against cervical carcinoma cells. We thus tried to analyze differential protein expression and antineoplastic mechanism-related proteins after paclitaxel treatment on cervical cancer cells by using a proteomic analysis and to investigate the mechanism of action.
Materials and Methods
Using proteomics analysis including 2-DE and MALDI-TOF-MS, we detected the antineoplastic mechanism-related proteins. Then, we performed western blot analysis for apoptosis- and transformation-related proteins to confirm expression patterns derived from proteome analysis after paclitaxel treatment.
Results
We identified several cellular proteins that are responsive to paclitaxel treatment in HeLa cells using proteomics methods. Paclitaxel treatment elevated mainly apoptosis, immune response and cell cycle check point-related proteins. On the other hand, paclitaxel treatment diminished growth factor/oncogene-related proteins and transcription regulation-related proteins. Also, in the HPV-associated cervical carcinoma cells, paclitaxel demonstrated anti-proliferative activity through the membrane death receptor-mediated apoptotic pathway and the mitochondrial-mediated pathway.
Conclusion
Identification and characterization of functionally modulated proteins involved in anti-cancer regulatory events should lead to a better understanding of the long-term actions of paclitaxel at the molecular level and will contribute to the future development of novel therapeutic drug treatments based upon current therapies.
doi:10.4143/crt.2004.36.6.395
PMCID: PMC2843878  PMID: 20368835
Paclitaxel; HPV; Cervical carcinoma; Proteomics; Apoptosis
15.  A Clinicopathological Review of Pulmonary Metastasis from Uterine Cervical Cancer 
Purpose
The purpose of this study was to investigate the clinicopathological features of pulmonary metastasis from cervical cancer.
Materials and Methods
We reviewed the medical records of 56 patients with cervical cancer who developed pulmonary metastasis after radical hysterectomy, postoperative concurrent chemoradiation or systemic chemotherapy between January 1990 and March 2014.
Results
Fifty-six patients were diagnosed with pulmonary metastasis from cervical cancer. The prevalence of pulmonary metastasis was 3.6%. The mean event-free duration was 12 months. Twelve patients underwent surgical removal of metastatic lesions. The overall survival (OS) of patients with ≤ 3 metastatic lung lesions was 40.7 months, longer than those with > 4 lesions (25 months, p=0.034). The OS of patients who underwent surgical resection was 53.8 months, longer than that of those who did not (p=0.006). In addition, the OS of patients with adjuvant platinum-based chemotherapy was 32.6 months (p=0.027).
Conclusion
In this study, we found that the number of metastatic nodules, surgical resection, and postoperative platinum-based chemotherapy can influence clinical outcome. Further studies on prognostic factors and successful treatment modalities are warranted.
doi:10.4143/crt.2014.206
PMCID: PMC4720087  PMID: 25715766
Uterine cervical neoplasms; Pulmonary metastasis; Prognosis
16.  Identification of Daxx interacting with p73, one of the p53 family, and its regulation of p53 activity by competitive interaction with PML 
Nucleic Acids Research  2003;31(18):5356-5367.
We performed a yeast two-hybrid screen using p73α, which is a member of the p53 family, as bait. We found that the p53 family members were functionally associated with Daxx, which was described originally as a cytoplasmic mediator of Fas signaling, but has been identified recently as a nuclear protein that co-localizes with the promyelocytic leukemia (PML) protein and regulates transcription. Extensive yeast two-hybrid assays indicated a physical interaction between a region including the oligomerization domain (OD) of p73α (amino acids 345–380) or p53 (amino acids 319–360) and amino acids 161–311 and 667–740 (C-terminal S/P/T-rich domain) of hDaxx, which is the common binding region of Fas, ASK1 and PML. This interaction was further confirmed by in vitro GST pull-down and in vivo immunoprecipitation assays. Both Daxx and p73/p53 co-localized in nuclear dot-like structures, which are probably nuclear PML oncogenic domains (PODs) or the nuclear domain NB10. Transient co-expression of Daxx resulted in strong inhibition of p73- and p53-mediated transcriptional activation of the synthetic p53-responsive and p21WAF1 promoters. Consequently, Gal4-Daxx repressed basal transcription in a dose-dependent manner. Treatment with trichostatin A, which is an inhibitor of histone deacetylase, or PML over-expression relieved Daxx-mediated transcriptional repression of p53. The mechanism underlying PML-mediated derepression appears to be competitive binding between Daxx, p53 and PML. Taken together, these findings delineate a transcriptional regulatory network that is modulated by differential Daxx–p53–PML interactions in the nuclear PODs. Therefore, Daxx is implicated in the regulation of the cell cycle and apoptosis through transcriptional regulation of p53 and possibly its family members.
doi:10.1093/nar/gkg741
PMCID: PMC203324  PMID: 12954772
17.  Geographical Distribution and Risk Association of Human Papillomavirus Genotype 52–Variant Lineages 
The Journal of Infectious Diseases  2014;210(10):1600-1604.
Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%–5.5%; Pcorrected < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name “Asian lineage” be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.
doi:10.1093/infdis/jiu310
PMCID: PMC4539913  PMID: 24879800
HPV; cervical cancer; phylogeny; oncogenic risk; Asia
18.  Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients 
Nature Communications  2014;5:5317.
Here, we demonstrate that electroporation-enhanced immunization with a rationally designed HPV DNA vaccine (GX-188E), preferentially targeting HPV antigens to dendritic cells, elicits a significant E6/E7-specific IFN-γ-producing T-cell response in all nine cervical intraepithelial neoplasia 3 (CIN3) patients. Importantly, eight out of nine patients exhibit an enhanced polyfunctional HPV-specific CD8 T-cell response as shown by an increase in cytolytic activity, proliferative capacity and secretion of effector molecules. Notably, seven out of nine patients display complete regression of their lesions and viral clearance within 36 weeks of follow up. GX-188E administration does not elicit serious vaccine-associated adverse events at all administered doses. These findings indicate that the magnitude of systemic polyfunctional CD8 T-cell response is the main contributing factor for histological, cytological and virological responses, providing valuable insights into the design of therapeutic vaccines for effectively treating persistent infections and cancers in humans.
While several human papilloma virus (HPV) vaccines exist, a highly effective vaccine that mediates regression of HPV-induced tumours is lacking. Here the authors show that a therapeutic DNA vaccine-induced HPV-specific polyfunctional CD8 T cell in 7 out of 9 patients who all exhibited complete regression of lesions and viral clearance.
doi:10.1038/ncomms6317
PMCID: PMC4220493  PMID: 25354725
19.  Large cell neuroendocrine carcinoma of the ovary: a case report and a brief review of the literature 
Large cell neuroendocrine carcinoma (LCNC) of the ovary, or ovarian undifferentiated non-small cell carcinoma of neuroendocrine type, is a rare entity that is frequently associated with ovarian surface epithelial tumors. Few cases have been reported in the literature. LCNC is an aggressive tumor with tendency to present at advanced stages and to cause death after a short postoperative duration. We report three cases of LCNC diagnosed histopathologically. Immunohistochemically, the tumor cells were positive for chromogranin A, NSE, CD56, and pancytokeratin. The patients were treated postoperatively with combination chemotherapy. Due to the rarity of LCNC, the general consensus on standard therapy is not established. Although most patients are at stage I, the biological aggressiveness and poor prognosis of the tumors have been reported in previous reports despite extensive surgery and chemotherapy.
doi:10.1186/1477-7819-12-314
PMCID: PMC4210534  PMID: 25314924
Ovary; Neuroendocrine carcinoma; Non-small cell; Large cell
20.  Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations 
Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.
doi:10.1002/ijc.27932
PMCID: PMC3962828  PMID: 23136059
HPV; variant; cervical cancer; phylogeny; oncogenic risk
21.  Clinicopathological Implications of Human Papilloma Virus (HPV) L1 Capsid Protein Immunoreactivity in HPV16-Positive Cervical Cytology 
Background: The objective of this study was to investigate the expression of human papilloma virus (HPV) L1 capsid protein in abnormal cervical cytology with HPV16 infection and analyze its association with cervical histopathology in Korean women.
Material and Methods: We performed immunocytochemistry for HPV L1 in 475 abnormal cervical cytology samples from patients with HPV16 infections using the Cytoactiv® HPV L1 screening set. We investigated the expression of HPV L1 in cervical cytology samples and compared it with the results of histopathological examination of surgical specimens.
Results: Of a total of 475 cases, 188 (39.6%) were immunocytochemically positive and 287 (60.4%) negative for HPV L1. The immunocytochemical expression rates of HPV L1 in atypical squamous cells of unknown significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cancer were 21.8%, 59.7%, 19.1%, and 0.0%, respectively. LSIL exhibited the highest rate of HPV L1 positivity. Of a total of 475 cases, the multiple-type HPV infection rate, including HPV16, in HPV L1-negative cytology samples was 27.5%, which was significantly higher than that in HPV L1-positive cytology samples (p = 0.037). The absence of HPV L1 expression in ASCUS and LSIL was significantly associated with high-grade (≥cervical intraepithelial neoplasia [CIN] 2) than low-grade (≤CIN1) histopathology diagnoses (p < 0.05), but was not significantly different between HPV16 single and multiple-type HPV infections (p > 0.05). On the other hand, among 188 HPV L1-positive cases, 30.6% of multiple-type HPV infections showed high-grade histopathology diagnoses (≥CIN3), significantly higher than the percentage of HPV16 single infections (8.6%) (p = 0.0004)
Conclusions: Our study demonstrates that the expression of HPV L1 is low in advanced dysplasia. Furthermore, the absence of HPV L1 in HPV16-positive low-grade cytology (i.e., ASCUS and LSIL) is strongly associated with high-grade histopathology diagnoses. The multiplicity of HPV infections may have an important role in high-grade histopathology diagnoses (≥CIN3) in HPV L1-positive cases.
doi:10.7150/ijms.5585
PMCID: PMC3880994  PMID: 24396289
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; immunocytochemistry; cervical cytology
22.  High-Dose-Rate Brachytherapy for the Treatment of Vaginal Intraepithelial Neoplasia 
Purpose
Vaginal intraepithelial neoplasia (VAIN), a rare premalignant condition, is difficult to eradicate. We assess the effectiveness of high-dose rate intracavitary brachytherapy (HDR-ICR) in patients with VAIN or carcinoma in situ (CIS) of the vagina after hysterectomy.
Materials and Methods
We reviewed 34 patients treated for posthysterectomy VAIN or CIS of the vagina by brachytherapy as the sole treatment. All patients underwent a coloposcopic-directed punch biopsy or had abnormal cytology, at least 3 consecutive times. All patients were treated with a vaginal cylinder applicator. The total radiation dose was mainly 40 Gy in 8 fractions during the periods of 4 weeks at a prescription point of the median 0.2 cm (range, 0 to 0.5 cm) depth from the surface of the vaginal mucosa.
Results
Acute toxicity was minimal. Seven patients had grade 1/2 acute urinary and rectal complications. There were 15 cases of late toxicity, predominantly vaginal mucosal reaction in 12 patients. Of these patients, two patients suffered from grade 3 vaginal stricture and dyspareunia continuously. After a median follow-up time of 48 months (range, 4 to 122 months), there were 2 recurrences and 2 persistent diseases, in which a second-line therapy was needed. The success rate was 88.2%. The average prescription point in failure patients was 1.1 mm from the surface of the vagina compared to an average of 2.6 mm in non-recurrent patients (p=0.097).
Conclusion
HDR-ICR is an effective treatment method in VAIN patients. In spite of high cure rates, we should consider issues regarding vaginal toxicity and radiation techniques to reduce the occurrence of failure and toxicity.
doi:10.4143/crt.2014.46.1.74
PMCID: PMC3918530  PMID: 24520226
Vaginal neoplasms; Carcinoma in situ; Radiotherapy; Brachytherapy
23.  Benign metastasizing leiomyoma of the lung 
Benign leiomyomas of the uterus are uncommonly found in association with benign smooth muscle tumors beyond the confines of the uterus. Benign metastasizing leiomyoma (BML) is a rare disease in which the lung is described to be the most afflicted extrauterine organ. We present a brief review of the literature, along with case reports for four patients who were followed up after resection of a pulmonary lesion or after pathological confirmation by biopsy. The clinical course of BML varies from chronic asymptomatic appearance to rapid progression, leading to respiratory failure and death. Our BML patients did not complain of pulmonary symptoms, such as cough, dyspnea, or chest tightness. Pathology revealed benign leiomyomas with no atypia and mitotic activity <5 per 10 high-power field. Immunohistochemical staining was positive for actin and desmin. A standard treatment for BML has not yet been established. Because of the hormone-sensitive characteristics of BML, treatments are based on hormonal manipulation along with either surgical or medical oophorectomy. Benign metastasizing leiomyoma can be observed in postmenopausal women. We observed four patients who did not receive adjuvant hormonal therapy because they were postmenopausal or perimenopausal. All patients are still healthy and show no evidence of recurrence or progression of the disease.
doi:10.1186/1477-7819-11-279
PMCID: PMC3842688  PMID: 24134076
Benign metastasizing leiomyoma; Lung; Uterine leiomyoma
24.  Adenoma malignum of the uterine cervix: report of four cases 
Adenoma malignum (AM) of the cervix is a rare disease and it is difficult to diagnose due to the deceptively benign appearance of the tumor cells. These lesions have mucin-rich cystic lesions and are usually situated deep in the cervix. Since AM is very rare, standard screening tests, diagnostic tools and treatments have not yet been established. Radiologically, it mimics multiple nabothian cysts as a benign-looking tumor. Histologically, AM is a well-differentiated adenocarcinoma and could be misdiagnosed as a benign lesion. These findings make a preoperative diagnosis of AM difficult and can result in surgery being performed based on a misdiagnosis. We report here on four cases of pathologically confirmed AM.
doi:10.1186/1477-7819-11-168
PMCID: PMC3733704  PMID: 23885647
Adenoma malignum; Minimal-deviation adenocarcinoma; Uterine cervix
25.  Laparoscopic upper vaginectomy for post-hysterectomy high risk vaginal intraepithelial neoplasia and superficially invasive vaginal carcinoma 
Background
The aim of this study is to describe the feasibility and efficacy of the laparoscopic upper vaginectomy (LUV) in vaginal intraepithelial neoplasia(VAIN) and superficially invasive vaginal carcinoma.
Methods
We studied patients with vaginal intraepithelial neoplasia (VAIN) 2, VAIN 3, and superficially invasive vaginal carcinoma after hysterectomy who have been under laparoscopic upper vaginectomy between March 2010 and March 2012.
Results
Four patients underwent LUV after hysterectomy for high risk VAIN and early vaginal cancer. The mean age was 50.8 (range 40–56) years; the mean operation time was 162.5 (range 145–205) minutes; and the mean estimated blood loss was 55 (range 20–100) ml. All the patients restituted bladder function after the removal of the foley catheter. Mean hospital stay was 2 days. Two patients had postoperative complications. One patient with warfarin administration had vaginal stump bleeding and another developed vesico-vaginal fistula. Three of the patients had no residual lesion, but 1 patient had VAIN 1 in the resection margin. Colposcopy was followed on all patients and cytology proved no recurrence.
Conclusions
LUV after hysterectomy is a feasible procedure and attentively applicable to high risk VAIN or superficially invasive vaginal carcinoma.
doi:10.1186/1477-7819-11-126
PMCID: PMC3680043  PMID: 23725440
Vaginal carcinoma; Vaginal intraepithelial neoplasia; Vaginectomy

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