Doo Byung Chay

Prevalence and seroprevalence of high-risk human papillomavirus infection.

OBJECTIVE: To estimate the prevalence and seroprevalence of high-risk human papillomavirus (HPV) in Korean girls and women. METHODS: We estimated the seroprevalence of HPV subtypes 16 and 18 among 1,094 girls and women aged 9-59 years and the prevalence of genital high-risk HPV among 902 women aged 20-59 years who visited our institution for a medical checkup. Genital high-risk HPV DNA was measured using liquid hybridization and polymerase chain reaction assays. Serum antibodies to HPV subtypes 16 and 18 were measured using a multiplexed competitive luminex technique. RESULTS: The prevalence of genital high-risk HPV was 12.6% among Korean women aged 20-59 years. It reached a peak of 23.2% at 20-29 years of age, decreasing thereafter but increasing again to 12.4% at 50-59 years of age. Human papillomavirus 56 was the most common subtype followed by HPV 18, HPV 52, and HPV 16. The seroprevalence of HPV subtypes 16 and 18 was 8.7% among Korean girls and women aged 9-59 years. It reached its highest peak of 13.4% at 25-29 years of age and decreased thereafter. It then reached a second peak of 10.9% at 40-49 years of age and plateaued thereafter. The seroprevalences of HPV subtypes 16 and 18 were 7.4% and 2.7%, respectively. In multivariable analysis, the prevalence and seroprevalence of high-risk HPV were correlated only with the number of lifetime sexual partners. CONCLUSION: High-risk HPV infection is common among Korean women. Our epidemiological data on high-risk HPV infection will help to assess vaccine policy and to establish a baseline for estimating vaccine efficacy. LEVEL OF EVIDENCE: III

Association of isolated single umbilical artery with perinatal outcomes: Systemic review and meta-analysis

Objective The aim of this study was to evaluate the association between prenatally diagnosed isolated single umbilical artery (iSUA) and perinatal outcomes. Methods We searched Medline, Embase, the Cochrane Library, and KoreaMed from inception to January 2016, with no language or regional restrictions, for cohort and case-control studies reporting on the relationship of iSUA and perinatal outcomes. We assessed the odds ratios (ORs) and 95% confidence intervals (CIs) for the occurrence of small for gestational age, preterm birth, pregnancy-induced hypertension, neonatal intensive care unit admission, and perinatal mortality in fetuses with iSUA compared with those in fetuses with three vessel cord. Results Eleven articles totaling 1,731 pregnancies with iSUA met the selection criteria. Studies varied in design, quality, outcome definition, and results. Meta-analysis carried out within predefined groups showed that the presence of an iSUA was associated with small for gestational age (OR, 2.75; 95% CI, 1.97 to 3.83; P<0.00001), preterm birth (OR, 2.10; 95% CI, 1.72 to 2.57; P<0.00001), pregnancy-induced hypertension (OR, 1.62; 95% CI, 1.00 to 2.63; P=0.05), neonatal intensive care unit admission (OR, 2.06; 95% CI, 1.33 to 3.19; P=0.001), and perinatal mortality (OR, 2.29; 95% CI, 1.32 to 3.98; P=0.003). Conclusion Pregnancies complicated by iSUA are at increased risk for small for gestational age, preterm birth, pregnancy-induced hypertension, neonatal intensive care unit admission and perinatal mortality. Further, large prospective cohort studies are required to improve the quality of prenatal counseling and the neonatal care for pregnancies with iSUA.

Transabdominal embryofetoscopy for the detection of short rib-polydactyly syndrome, type II(Majewski), in the first trimester.

Our aim was to demonstrate the potential of first-trimester embryofetoscopy for prenatal diagnosis in a continuing pregnancy. A patient at risk for giving birth to an infant with short rib-polydactyly syndrome, type II (Majewski), presented for prenatal diagnosis at 9 weeks of gestation. A 1 mm semirigid fiberoptic endoscope with an 18 gauge examination sheath and a single-chip digital camera were used for transabdominal embryofetoscopy. Transabdominal embryofetoscopy was performed at 13 weeks of gestation. Direct visualization of the fetus was achieved and no gross limb or facial abnormalities were seen. This case shows that embryofetoscopy is a useful tool for early diagnosis in high-risk patients in the first trimester for continuing pregnancies.

Clinical significance of CA125 level after the first cycle of chemotherapy on survival of patients with advanced ovarian cancer

Purpose To determine the most powerful cancer antigen 125 (CA125)-related prognostic factor for advanced epithelial ovarian cancer (EOC) and to identify cut-off values that distinguish patients with a poor prognosis from those with a good prognosis. Materials and Methods We included 223 patients who received staging laparotomy and were diagnosed with stage IIC–IV serous EOC. Cox regression analysis was used to determine the most significant prognostic factor among the following variables: serum CA125 before surgery and after the first, second, and sixth cycles of chemotherapy; the nadir CA125 value; the relative percentage change in CA125 levels after the first and second cycles of chemotherapy compared to baseline CA125; CA125 half-life; time to nadir; and time to normalization of the CA125 level. Results The CA125 level after the first chemotherapy cycle was the most significant independent prognostic factor for overall survival (OS). Time to normalization (p=0.028) and relative percentage change between CA125 levels at baseline and after the first chemotherapy cycle (p=0.021) were additional independent prognostic factors in terms of OS. The CA125 level after the first chemotherapy cycle (p=0.001) and time to normalization (p<0.001) were identified as independent prognostic factors for progression free survival (PFS). Conclusion Among well-established CA125-related prognostic factors, serum CA125 levels after the first cycle of chemotherapy and time to normalization were the most significant prognostic factors for both OS and PFS.

Clinical Significance of Serum Anti-human Papillomavirus 16 and 18 Antibodies in Cervical Neoplasia

OBJECTIVE: To estimate the clinical significance of serum anti-human papillomavirus (HPV) antibodies and high-risk cervical HPV DNA in cervical neoplasia. METHODS: The study population comprised patients who were histopathologically diagnosed with cervical intraepithelial neoplasia (CIN) 1 (n=64), CIN 2 and 3 (n=241), cervical cancer (n=170), and normal control participants (n=975). Cervical HPV DNA tests were performed through nucleic acid hybridization assay tests, and serum anti-HPV 16 and 18 antibodies were measured by competitive immunoassay. The associations of HPV DNA and anti-HPV antibodies were evaluated with demographic characteristics and compared according to the levels of disease severity. Anti-HPV antibodies were also investigated with clinicopathologic parameters, including survival data. RESULTS: Among various demographic characteristics, factors involving sexual behavior had a higher tendency of HPV DNA positivity and HPV seropositivity. Human papillomavirus DNA mean titer and positivity were both increased in patients with cervical neoplasia compared with those with normal control participants, but there was no statistical difference among types of cervical neoplasia. Serum anti-HPV 16 antibodies were also able to differentiate cervical neoplasia from a normal control participant and furthermore distinguished CIN 1 from CIN 2 and 3 (odd ratio 2.87 [1.43–5.78], P=.002). In cervical cancer, HPV 16 seropositivity was associated with prolonged disease-free survival according to the univariable analysis (hazard ratio=0.12 [0.01–0.94], P=.044). CONCLUSION: Serum anti-HPV 16 antibodies can distinguish cervical neoplasia from a normal control and has the advantage of identifying high-grade CIN. Moreover, in cervical cancer, HPV 16 seropositivity may be associated with a more favorable prognosis. LEVEL OF EVIDENCE: II

Comparison of Clinical Features and Outcomes in Epithelial Ovarian Cancer according to Tumorigenicity in Patient-Derived Xenograft Models

Purpose Although the use of xenograft models is increasing, few studies have compared the clinical features or outcomes of epithelial ovarian cancer (EOC) patients according to the tumorigenicity of engrafted specimens. The purpose of this study was to evaluate whether tumorigenicity was associated with the clinical features and outcomes of EOC patients. Materials and Methods Eighty-eight EOC patients who underwent primary or interval debulking surgery from June 2014 to December 2015 were included. Fresh tumor specimens were implanted subcutaneously on each flank of immunodeficient mice. Patient characteristics, progression-free survival (PFS), and germline mutation spectra were compared according to tumorigenicity. Results Xenografts were established successfully from 49 of 88 specimens. Tumorigenicity was associated with lymphovascular invasion and there was a propensity to engraft successfully with high-grade tumors. Tumors from patientswho underwent non-optimal (residual disease ≥ 1 cm) primary orinterval debulking surgery had a significantly greater propensity to achieve tumorigenicity than those who received optimal surgery. In addition, patients whose tumors became engrafted seemed to have a shorter PFS and more frequent germline mutations than patients whose tumors failed to engraft. Tumorigenicity was a significant factor for predicting PFS with advanced International Federation of Gynecology and Obstetrics stage and high-grade cancers. Conclusion sTumorigenicity in a xenograft model was a strong prognostic factor and was associated with more aggressive tumors in EOC patients. Xenograft models can be useful as a preclinical tool to predict prognosis and could be applied to further pharmacologic and genomic studies on personalized treatments.

Makorin Ring Finger Protein 1 as Adjunctive Marker in Liquid-based Cervical Cytology.

Abstract To assess the utility of makorin ring finger protein 1 (MKRN1) as a marker of cervical pathology. A PROspective specimen collection and retrospective Blinded Evaluation study was conducted. Liquid-based cytology samples were collected from 187 women, embedding all residuals as cell blocks for immunohistochemical staining of MKRN1 and P16 INK4a. Results of liquid-based cervical cytology, immunostained cell block sections, and human papillomavirus (HPV) hybrid capture (with real-time polymerase chain reaction) were analyzed. Clinical outcomes were analyzed overall and in subsets of specimens yielding atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions. Makorin ring finger protein 1 positivity and grades (1–3) of cervical intraepithelial neoplasia (CIN) increased in tandem (CIN1, 32.4%; CIN2, 60.0%; and CIN3, 80.0%), reaching 92.3% in invasive cancer. Sensitivity, specificity, positive predictive value, and negative predictive value in detecting CIN2+ via MKRN1 were 73.8%, 76.8%, 75.6%, and 75.0%, respectively. The performance of liquid-based cytology was poorer by comparison (61.3%, 69.5%, 66.2%, and 64.8%, respectively), and HPV assay (versus MKRN1 immunohistochemical staining) displayed lower specificity (67.7%). Combined HPVu200a+u200aMKRN1 testing proved highest in sensitivity, specificity, positive predictive value, and negative predictive value (71.8%, 85.5%, 82.3%, and 76.5%, respectively), whereas corresponding values for cytologyu200a+u200aHPV (60.6%, 81.8%, 75.4%, and 69.2%) and cytologyu200a+u200aMKRN1 (58.8%, 84.1%, 78.3%, and 67.7%) were all similar. In instances of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions, the HPVu200a+u200aMKRN1 combination performed best by above measures (100%, 72.7%, 73.9%, and 100%), followed by cytologyu200a+u200aMKRN1 (100%, 50.0%, 60.7%, and 100%). Makorin ring finger protein 1 displayed greater sensitivity and specificity than liquid-based cytology and proved more specific than HPV assay. In combination testing, MKRN1u200a+u200aHPV showed the highest sensitivity and specificity levels. The MKRN1 biomarker may be a useful adjunct in primary cervical cytology screening.

Establishment of five immortalized human ovarian surface epithelial cell lines via SV40 T antigen or HPV E6/E7 expression

Background Human ovarian surface epithelial (HOSE) cells are a critical cell source for ovarian cancer research; however, they are difficult to obtain and maintain under standard laboratory conditions in large quantities. The aim of this study was to generate immortalized HOSE (IHOSE) cells with maintained properties to the original cell source, thereby guaranteeing a sufficiently large cell quantity for ovarian cancer research. Methods HOSE cells isolated from four non-cancer patients and five IHOSE cell lines were established by induction of HPV-E6/E7 expression or SV40 large T antigen using a lenti-viral system. Each of IHOSE cells was confirmed to be distinct by STR profiling. RNA-sequencing was used to compare gene expression profiles in HOSE, IHOSE and ovarian cancer cells. Results RNA-sequencing results revealed a stronger linear correlation in gene expression between IHOSE and HOSE cells (R2 = 0.9288) than between IHOSE or HOSE cells and ovarian cancer cells (R2 = 0.8562 and R2 = 0.7982, respectively). The gene expression pattern of 319 differentially expressed genes revealed minimal differences between HOSE and IHOSE cells, while a strong difference between ovarian cancer cells and HOSE or IHOSE cells was observed. Furthermore, the five IHOSE cell lines displayed morphological characteristics typical of epithelial cells but showed a lower level of EpCAM, CD133 and E-cadherin, as cancer stem marker, than ovarian cancer cells. Moreover, unlike cancer cells, IHOSE cells could not form colonies in the anchorage-independent soft agar growth assay. Conclusion These findings demonstrate that five newly established IHOSE cell lines have characteristics of progenitor HOSE cells while exhibiting continuous growth, and thus, should be highly useful as control cells for ovarian cancer research.

Preoperative serum levels of cancer antigen 125 and carcinoembryonic antigen ratio can improve differentiation between mucinous ovarian carcinoma and other epithelial ovarian carcinomas

Objective The main aim of this study was to evaluate cancer antigen 125 (CA125)/carcinoembryonic antigen (CEA) ratio (CCR), as a reliable marker to differentiate ovarian mucinous carcinoma from other epithelial ovarian carcinomas (EOCs), namely serous, clear cell, and endometrioid carcinomas. Methods Female patients suffering from different kinds of EOCs whom were subjected to elective surgery at the Gangnam Severance Hospital between January 2008 and December 2016, were included in this study. The serum levels of CA125 and CEA were assayed using commercially available kits per the manufacturers instructions. Results The CCR in mucinous carcinoma (mean 32.1) was significantly lower than that of clear cell (mean 235.0) and endometrioid carcinoma (mean 427.0) in stage I (all P<0.05). In stage II–IV, CCR in mucinous carcinoma (mean 37.6) was significantly lower than that of serous carcinoma (mean 148.0) (P<0.01). The sensitivity and specificity of CCR in detecting mucinous carcinoma from other types of EOC was 75.0% and 77.5%, respectively in stage I and 100.0% and 84.4%, respectively in stage II–IV (both cut-off value <90.7). Conclusion The present results suggest that pretreatment CCR might provide higher specificity and clinically relevant information as a criterion for the differentiation between ovarian mucinous carcinoma and other types of EOC.

Prognostic implication of programmed cell death 1 protein and its ligand expressions in endometrial cancer

OBJECTIVEnMonoclonal antibodies targeting programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) demonstrated promising clinical response. The predictive/prognostic value of PD-1/PD-L1 immunohistochemistry (IHC) has been evaluated in many cancer types. However, the prognostic value of PD-1/PD-L1 IHC has not been evaluated in endometrial cancer.nnnMETHODSnWe conducted a retrospective study to quantify the IHC CD8, PD-1, and PD-L1 expressions in immune cells at center of tumor (CT), invasive margin (IM), and/or tumor cell in 183 primary endometrial cancer samples from a single cohort, followed by their reciprocal combinations, including compartmental differences, and correlated them with overall survival (OS) and progression-free survival (PFS).nnnRESULTSnIn repeated Cox multivariable models adjusted by clinicoimmunopathologic factors, high CT-PD-L1 was an independent adverse prognostic factor for PFS in all patients and in the microsatellite-stable subgroup. Immune marker ratios revealed independently shorter PFS for high CT-PD-L1/CT-CD8 and CT-PD-L1/CT-PD-1 ratios. Classification of endometrial cancer into four groups based on CT-CD8 and CT-PD-L1 revealed significantly different survival among groups.nnnCONCLUSIONSnThe high PD-L1/CD8 ratio and the high expression of PD-L1 on immune cells were independent poor prognostic factors for PFS in endometrial cancer, providing insights into the tumor microenvironment.