Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

The Combination of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) is an Effective Prognostic Biomarker in Cervical Cancer.

Transient receptor potential vanilloid type 1 (TRPV1) has been reported to play an important role in human cancers. However, the knowledge about TRPV1 in cervical cancer is sparse. Therefore, we evaluated the expression and clinical significance of TRPV1 in cervical cancer. Immunohistochemical analyses were performed for TRPV1 and phosphatase and tension homolog (PTEN) to delineate clinical significance using 150 cervical cancers, 230 cervical intraepithelial neoplasias, and 312 normal cervical epithelial tissues in a tissue microarray. Furthermore, the role of TRPV1 in cell growth was assessed in a cervical cancer cell line. The TRPV1 expression was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasias, and normal epithelial tissues (P<0.001). In cervical cancer tissues, TRPV1 expression negatively correlated with PTEN expression (Spearman ρ=-0.121, P=0.009). Multivariate survival analysis revealed high TRPV1 expression (hazard ratio=3.41, 95% confidence interval: 1.25-9.27, P=0.016) as an independent prognostic factor for overall survival. Notably. the high TRPV1/low PTEN expression showed the highest hazard ratio (5.87; 95% confidence interval: 2.18-15.82, P<0.001) for overall survival. In vitro results demonstrated that the overexpression of TRPV1 was associated with increased cell viability and colony formation. Overexpression of TRPV1 could be a good biomarker for the prediction of chemoradiation response. Our result suggested promising potential of high TRPV1/low PTEN as prognostic and survival makers. The possible link between the biologic function of TRPV1 and PTEN in cervical cancer warrants further studies.

Tetraspanin 1 promotes endometriosis leading to ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) reportedly develops from endometriosis. However, the molecular mechanism underlying its malignant progression to OCCC remains elusive. This study aimed to identify an essential gene in the malignant transformation of endometriosis to OCCC. We performed RNA sequencing in formalin-fixed, paraffin-embedded (FFPE) tissues of endometriosis (n = 9), atypical endometriosis (AtyEm) (n = 18), adjacent endometriosis to OCCC (AdjEm) (n = 7), and OCCC (n = 17). We found that tetraspanin 1 (TSPAN1) mRNA level was significantly increased by 2.4- (DESeq2) and 3.4-fold (edgeR) in AtyEm and by 80.7- (DESeq2) and 101-fold (edgeR) in OCCC relative to endometriosis. We confirmed that TSPAN1 protein level was similarly overexpressed in OCCC tissues and cell lines. In immortalized endometriosis cell lines, TSPAN1 overexpression enhanced cell growth and invasion. Mechanistically, TSPAN1 triggered AMP-activated protein kinase (AMPK) activity, promoting endometriosis and cell growth. Upregulated levels of TSPAN1 are considered an early event in the development of high-risk endometriosis that could progress to ovarian cancer. Our study suggests the potential of TSPAN1 as a screening candidate for high-risk endometriosis.

Prognostic Significance of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) in Epithelial Ovarian Cancer.

BACKGROUND: Transient receptor potential vanilloid type 1 (TRPV1) has been studied in human malignancies, but has not been studied in epithelial ovarian cancer (EOC). We, therefore, investigated the significance of TRPV1 and correlation with phosphatase and tension homolog (PTEN) in EOC. MATERIALS AND METHODS: Immunohistochemical analyses for TRPV1 and PTEN were performed using a tissue microarray. Moreover, the role of TRPV1 in cell growth was assessed in a EOC cell line. RESULTS: High TRPV1 expression and the combination of high TRPV1 and low PTEN expression were an independent prognostic factor for overall survival and disease-free survival. In vitro results demonstrated that knockdown of TRPV1 was associated with decreased cell viability and colony formation. CONCLUSION: There is a strong association between TRPV1 and PTEN and the combination of TRPV1 and PTEN is a strong indicator of prognostic predictor in EOC.

Prognostic implications of forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) in epithelial ovarian cancer.

BACKGROUND: Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC. METHODS: Immunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines. RESULTS: FOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p < 0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearman's rho = 0.118, p = 0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratio = 2.77 [95% CI, 1.48-5.18], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00-10.55], p < 0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation. CONCLUSIONS: This study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer.

BACKGROUND/AIM: The prognostic role of USP10 in epithelial ovarian cancer has been studied in various human cancers. Our aim was to evaluate the clinical and pathological significance of USP10 in epithelial ovarian cancer. MATERIALS AND METHODS: Immunohistochemical analyses of the expression of USP10 and p14ARF by using tissue microarrays were performed in 336 ovarian tumours and the data were compared with clinicopathological variables. We examined their level of DNA methylation around the putative transcriptional start site in 5' CpG islands in fresh frozen tissues and ovarian cancer cells. RESULTS: Expression of USP10 and p14ARF was significantly lower in cancer tissues than in normal epithelium. Low USP10 expression and a combined USP10/p14ARF low expression were revealed to be independent prognostic factors. A high degree of methylation in USP10 and p14ARF CpG islands was found by methylation specific PCR analysis in cancer than in normal tissues and cells. CONCLUSION: Decreased expression of USP10 or combined USP10/p14ARF decreased expression is a strong indicator of poor prognosis in patients with ovarian cancer.

Forkhead box protein O1 (FOXO1) and paired box gene 3 (PAX3) overexpression is associated with poor prognosis in patients with cervical cancer.

PURPOSE: Forkhead box protein O1 (FOXO1) and paired box gene 3 (PAX3) have been reported to play an imported role in human cancers, but their role in cervical cancer has not yet been clarified. In this study, we evaluated the functional role of FOXO1 in cervical cancer cells and investigated the expression and clinical significance of FOXO1 and PAX3 in cervical lesions. METHODS: In vitro assessment of cell function by cell viability, migration, and invasion assays were performed on FOXO1-knockdown cervical cancer cells. Immunohistochemical (IHC) staining analyses of FOXO1 and PAX3 were performed with a tissue microarray (TMA). The clinical significance was evaluated by comparing the data with various clinicopathologic characteristics, including survival of patients with cervical cancer. RESULTS: In vitro results revealed that knockdown of FOXO1 is associated with decreased cell viability (p < 0.001), migration (p < 0.001), and invasion (p < 0.05), supporting the oncogenic role of FOXO1 in cervical cancer. FOXO1 and PAX3 expression was significantly higher in CIN (both p < 0.001) and cancer tissue (both p < 0.001) than in normal tissue. Multivariate analysis indicated that FOXO1 expression (hazard ratio 4.01 [95% CI 1.22-13.10], p = 0.021) and an advanced FIGO stage (hazard ratio 3.89 [95% CI 1.35-11.19], p = 0.012) were independent prognostic factors for overall survival. CONCLUSIONS: This study reveals increased FOXO1 and PAX3 expression in cervical cancers and indicates an oncogenic role of FOXO1 in cervical cancer cells that correlates with poor patient survival.

Combined treatment with modulated electro-hyperthermia and an autophagy inhibitor effectively inhibit ovarian and cervical cancer growth.

PURPOSE: Modulated electro-hyperthermia (mEHT), known as oncothermia, is an anticancer therapy that induces radiofrequency thermal damage to the cancer tissues. This study aimed to evaluate the potential effectiveness of mEHT as a therapeutic tool in ovarian and cervical cancer. MATERIALS AND METHODS: We used both tumor-bearing mice and ovarian and cervical OVCAR-3, SK-OV-3, HeLa and SNU-17 cancer cell lines to investigate the effects of mEHT in vivo and in vitro, respectively, and determine whether it was enhanced by cotreatment with an autophagy inhibitor. RESULTS: We discovered that phosphorylation of p38, a stress-dependent kinase, was induced at the Thr180/Tyr182 residue in cancer cells exposed to mEHT. Apoptotic markers such as cleaved caspase-3 and poly-ADP ribose polymerase (PARP) were increased in OVCAR-3 and SNU-17 cells. Fluorescence-activated cell sorting (FACS) analysis showed a significant increase in the population of sub-G1 mEHT-exposed cells, which are dying and apoptotic cells. mEHT also reduced both weight and volume of xenograft tumors in mice transplanted with ovarian and cervical cancer cells and patient-derived cancer tissues. We determined that mEHT-induced cellular damage recovery was mediated by autophagy and, therefore, expectedly, cotreatment with mEHT and 3-methyladenine (3-MA), an autophagy inhibitor, more effectively inhibited cancer cell growth than individual treatment did. CONCLUSIONS: mEHT treatment alone was sufficient to inhibit cancer growth, while a combined treatment with mEHT and an autophagy inhibitor amplified this inhibition effect.

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.

DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer.

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer.

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 manufacturer's 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.

OBJECTIVE: Monoclonal 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. METHODS: We 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). RESULTS: In 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. CONCLUSIONS: The 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.

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. CONCLUSIONS: Tumorigenicity 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.

API5 induces cisplatin resistance through FGFR signaling in human cancer cells.

Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5high cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.

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.

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.

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

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 . 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 HPV + MKRN1 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 cytology + HPV (60.6%, 81.8%, 75.4%, and 69.2%) and cytology + MKRN1 (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 HPV + MKRN1 combination performed best by above measures (100%, 72.7%, 73.9%, and 100%), followed by cytology + MKRN1 (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, MKRN1 + HPV showed the highest sensitivity and specificity levels. The MKRN1 biomarker may be a useful adjunct in primary cervical cytology screening.

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.

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.

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.