Enhanced disease progression due to persistent HPV-16/58 infections in Korean women: a systematic review and the Korea HPV cohort study.

BACKGROUND: Persistent human papillomavirus (HPV) infection is a key factor for the development and progression of cervical cancer. We sought to identify the type-specific HPV prevalence by cervical cytology and assess disease progression risk based on high-risk persistent HPV infection in South Korea. METHODS: To investigate the HPV prevalence by Pap results, we searched seven literature databases without any language or date restrictions until July 17, 2019. To estimate the risk of disease progression by HPV type, we used the Korea HPV Cohort study data. The search included the terms "HPV" and "Genotype" and "Korea." Studies on Korean women, type-specific HPV distribution by cytological findings, and detailed methodological description of the detection assay were included. We assessed the risk of disease progression according to the high-risk HPV type related to the nonavalent vaccine and associated persistent infections in 686 HPV-positive women with atypical squamous cells of uncertain significance or low-grade squamous intraepithelial lesions from the Korea HPV Cohort Study. Type-specific HPV prevalence was the proportion of women positive for a specific HPV genotype among all HPV-positive women tested for that genotype in the systematic review. RESULTS: We included 23 studies in our review. HPV-16 was the most prevalent, followed by HPV-58, -53, -70, -18, and -68. In women with high-grade squamous intraepithelial lesions, including cancer, HPV-16, -18, and -58 were the most prevalent. In the longitudinal cohort study, the adjusted hazard ratio of disease progression from atypical squamous cells of uncertain significance to high-grade squamous intraepithelial lesions was significantly higher among those with persistent HPV-58 (increase in risk: 3.54-5.84) and HPV-16 (2.64-5.04) infections. CONCLUSIONS: While HPV-16 was the most prevalent, persistent infections of HPV-16/58 increased the risk of disease progression to high-grade squamous intraepithelial lesions. Therefore, persistent infections of HPV-16 and -58 are critical risk factors for cervical disease progression in Korea. Our results suggest that equal attention should be paid to HPV-58 and -16 infections and provide important evidence to assist in planning the National Immunization Program in Korea.

Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial.

BACKGROUND: Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer. METHODS: In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov, NCT03444376. FINDINGS: Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5-8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3-4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported. INTERPRETATION: Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing. FUNDING: National OncoVenture.

Dedifferentiated endometrioid carcinoma of the uterus : report of four cases and review of literature.

BACKGROUND: Dedifferentiated endometrioid adenocarcinoma (DEAC) is rare and is known to be more aggressive than high-grade endometrioid carcinoma. Differentiating between the two is important to provide appropriate treatment for patients. CASE PRESENTATION: This is a retrospective study including four cases of DEAC of the uterus, which was diagnosed and treated in our Obstetrics and Gynecology department between January 2013 and December 2015. Clinical, pathological, and immunohistochemical staining features are discussed. Each tumor was composed of undifferentiated carcinoma (UC) and low-grade endometrioid carcinoma with abrupt transition between them. Two patients showed recurrence or progression within one month postoperatively and died at the last follow-up. An immunohistochemical study showed PAX-8, ER, PR, and E-cadherin expression in UC component. CONCLUSIONS: DEAC should not be underdiagnosed as conventional endometrioid adenocarcinoma due to its fulminant clinical course. Therefore, UC, including DEAC, should be further categorized to provide intensive treatment to improve patient survival.

Multi-institution, Prospective, Randomized Trial to Compare the Success Rates of Single-port Versus Multiport Laparoscopic Hysterectomy for the Treatment of Uterine Myoma or Adenomyosis.

STUDY OBJECTIVE: To compare the operative outcomes of patients undergoing either single-port or multiport laparoscopic hysterectomy (LH). METHODS: Two hundred fifty-six women scheduled for LH for symptomatic myoma and/or adenomyosis from 8 tertiary teaching hospitals were randomized to single-port or multiport groups. Primary outcome was conversion and/or complication proportion of the planned procedure to determine whether the success proportion of the single-port approach was not inferior to that of the multiport approach. Secondary outcomes were postoperative pain and operative scar. RESULTS: Demographic parameters including age, body mass index, parity, and history of vaginal and cesarean delivery were comparable between the 2 groups. The primary outcome of a combined conversion and/or complication rate was similar between the single-port and multiport groups at 8% and 10.3%, respectively. Conversions were similar between the groups with 4% of single-port cases and .8% of multiport cases. Transfusions were the most frequent complication required in 4.0% of single-port cases and 7.9% of multiport cases, with no difference between the groups. Concerning secondary outcomes, postoperative pain score and patient and observer scar assessment were not different between the 2 groups. Although not a specific outcome measure, there was no difference between the groups in blood loss, operative time, and postoperative hospital stay. CONCLUSION: Single-port LH is not inferior to multiport LH in terms of conversion and/or complications rates, including transfusion. However, the single-port approach did not have any advantage over multiport LH with regard to pain or cosmetic outcomes. These findings were demonstrated by multi-institutional surgeons in Korea.

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.

HPV vaccination status and effectiveness in Korean women with HPV16/18 infection (2010-2021): a retrospective study.

OBJECTIVE: To evaluate human papillomavirus (HPV) vaccine effectiveness in a cohort of Korean women infected with HPV. METHODS: From 2010 to 2021, Korean women aged 20-60 years who diagnosed HPV-positive atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion were recruited from 6 hospitals. HPV vaccine effectiveness was estimated by observing the differences in pathological and clinical information and experimental results-prevalence, viral load (VL), physical state (PS), and HPV16/18 infection duration-between the vaccinated and unvaccinated groups. RESULTS: HPV16/18 prevalence declined from 18.5% to 11.8% as vaccination rates increased from 14.3% to 60.7% in the 1,757 registered cohort women. DNA analysis from 96 samples collected from the participants, indicated that HPV vaccination reduced HPV16 VL by 6 times and increased E2/E6 ratio for both HPV16 and HPV18 by 1.4 and 5 times, respectively. The HPV16 infection rate-lasting more than 18 months from 31.0% to 21.6%-and the HPV18 infection rate-lasting more than 12 and less than 24 months from 35.5% to 21.1%-were reduced by vaccination. We found VL and the infection duration to be directly proportional. Moreover, HPV vaccination reduced not only the VL to 1/4 in both the persistence and clearance groups but also the persistence rate from 90% (27/30) to 70.6% (12/17) in HPV16. CONCLUSION: HPV vaccination reduced the prevalence and duration of infection and kept the PS in an episomal form for both HPV16 and HPV18. The tendency of persistence VL to be higher than clearance in the unvaccinated group implies that the vaccine's effect of reducing VL in HPV16 may lower the risk of progression to cervical cancer by shortening the infection duration.

Correlation between the digital cervicography and pathological diagnosis performed at private clinics in Korea.

OBJECTIVE: To evaluate the correlation tendency between abnormal findings of digital cervicography and cervical pathology at private clinics in Korea. METHODS: Abnormal finding of digital cervicography performed at private clinics in Korea between January 1, 2010 and May 31, 2012 were analysed retrospectively. The patient's age, abnormal findings of digital cervicography, cervical cytology, human papillomaviru (HPV) test and cervical pathology were investigated and the rate of agreement between abnormal finding of digital cervicography and cervical pathology results was calculated. Abnormal findings of digital cervicography were divided into 4 categories: atypical, compatible with CIN1, compatible with CIN2/3 and compatible with cancer. RESULTS: The study group was composed of 1547 women with a mean (range) age of 37.4 (14-91 years). The agreement rate between abnormal findings of digital cervicography and cervical pathology was 52.0% in "compatible with CIN1", 78.9% in "compatible with CIN2/3", and 90.2% in "compatible with cancer". CONCLUSIONS: Abnormal findings of digital cervicography were highly concordant with cervical intraepithelial neoplasia (CIN) and cancer examined at outpatient clinics in Korea. Therefore, abnormal interpretations of digital cervicography can be used as an excellent auxiliary technique with cervical cytology for CIN and cancer.

Health-Related Quality of Life of Patients with Cervical Cancer According to the Duration of Treatment and Cancer Progression.

OBJECTIVE: The purpose of this study was to assess health-related quality of life (HRQoL) in Korean patients with cervical cancer according to the duration of treatment and cancer progression of cervical cancer. METHODS: This study included 452 outpatients with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer from six tertiary hospitals in South Korea. The questionnaire included the EQ-5D-3L instrument, patients' age, cancer progression (CIN or invasive cervical cancer), treatment duration (<1 year, ≥1 year but <2 years, and ≥2 years), treatment method (surgery, chemotherapy, radiation therapy), and presence of recurrence. HRQoL indices were calculated for these independent factors, and the mean was compared using ANOVA. Multiple regression analysis was performed to analyze factors affecting HRQoL in patients with cervical cancer. RESULTS: The EQ-5D index was 0.93 for patients with CIN, 0.87 for patients with invasive cervical cancer, and 0.78 for patients with recurrent invasive cervical cancer. HRQoL was significantly lower as the CIN progresses to cervical cancer. HRQoL of patients with invasive cervical cancer was lowest within 1 year of treatment in all stages. In addition, the HRQoL of patients with CIN or invasive cervical cancer who received chemotherapy and radiotherapy was lower than that of patients who underwent surgery. Multiple regression analysis showed that the HRQoL decreased significantly as increasing age, the first year of treatment after diagnosis, cancer recurrence, or chemotherapy. CONCLUSION: The HRQoL of patients with cervical cancer is affected not only by the stage of cancer progression but also by the duration of treatment and the type of treatment. As a result, when trying to apply the quality of life of patients with cervical cancer to cost-utility analysis, it is necessary to consider the duration and the type of treatment they receive.

Peripheral blood BRCA1 methylation profiling to predict familial ovarian cancer.

OBJECTIVE: Familial cancer appears at a young age and its incidence is increasing. About 12% of familial ovarian cancer cases are associated with BRCA1/2 mutations (BRCAm). In this study, we investigated BRCA1 methylation may predict ovarian cancer in those with a family history of cancer (FHC) but without BRCA1/2 mutations (BRCAwt). METHODS: Using peripheral blood DNA from 55 subjects without a history of cancer [cancer(-)] and 52 ovarian cancer patients, we examined BRCA1 promoter methylation through bisulfite sequencing of the promoter and expressed the results as the cumulative methylation index. Then, we evaluated the BRCA1 promoter methylation according to BRCA1/2 germline mutations. RESULTS: BRCA1 methylation was more prevalent in the BRCAm cancer(-) group than in the BRCAwt cancer(-) group and ovarian cancer patients (p=0.031 and p=0.019, respectively). In the BRCAwt cancer(-) group, BRCA1 methylation was more prevalent in those with an FHC than in those without one and in the BRCAm cancer(-) group with an FHC (p=0.001 and p<0.001, respectively). CONCLUSION: Our data suggest a predictive role of BRCA1 methylation profile for ovarian cancer in those without a history of cancer but with an FHC. BRCA1 methylation has important implications for diagnostic and predictive testing of those with BRCAwt cancer(-) status with FHC.

Clearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia.

The natural history of high-risk human papillomavirus (HRHPV) infection after successful treatment of cervical intraepithelial neoplasia (CIN) is not well known. This study was performed to evaluate the rate and pattern of HRHPV infection clearance after successful conization for CIN and to analyze factors associated with such clearance. A total of 287 patients who underwent loop electrosurgical excision procedures (LEEP) owing to HRHPV-associated CIN were included. All patients had negative resection margins on LEEP specimens and underwent HPV testing with the hybrid capture II system at 3-, 6-, 9-, 12-, 18- and 24-month follow-up visits after LEEP. Persistent HPV infections were detected in 45.6%, 14.3%, 6.3%, 2.2%, 1.5% and 1.1% of patients at 3, 6, 9, 12, 18 and 24 months after LEEP, respectively. Clearance rates did not differ by age, parity or severity of cervical lesion. However, clearance rates were significantly slower in patients with HPV DNA loads >500 RLU/PC before LEEP (p = 0.040). During 2 years of follow-up after LEEP, 24 patients had recurrent disease revealed by biopsy. The odds ratios for recurrent disease in patients with persistent HRHPV infection increased gradually from 5.17 at the 3-month follow-up visit to 12.54, 15.69 and 25.90 at 6-, 9-, 12- and 24-month follow-up visits, respectively. We conclude that HRHPV infection cleared gradually in most patients within 6 months of treatment. Clearance rates were significantly slower in patients with HPV DNA loads >500 RLU/PC. Persistent HPV infection was a significant positive predictor of recurrence.

The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women.

The purpose of the study was to investigate the association between cervical cancer risk and single-nucleotide polymorphisms (SNPs) in three one-carbon metabolism genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) in Korean women. Twelve SNPs were identified in MTHFR, MTR, and MTRR in the 927 case-control samples, which included 165 cervical intraepithelial neoplasia 1 (CIN1), 167 cervical intraepithelial neoplasia 2 and 3 (CIN2/3), 155 cervical cancer patients, and 440 normal controls. The frequencies of the genotypes and haplotypes were assessed in the controls, CINs, and cervical cancers. Individual carriers of the variant allele C of MTHFR A1298C (rs1801131) had a 0.64-fold [95% confidence interval (CI): 0.42-0.98] decreased risk for CIN2/3 compared with common homozygotes. However, no significant association was found between most other variants and cervical cancer risk. The results also identified an increased CIN1 risk in carriers with at least one copy of haplotype 3 in the MTHFR gene (odds ratio, 1.88; 95% CI: 1.03-3.42). In conclusion, there was no significant association between most SNPs in MTHFR, MTR, or MTRR and the risk of CIN and cervical cancer in Korean women. In addition, there was no significant association of MTHFR haplotypes with risk of CIN2/3 and cervical cancer.

Incidence and clinical course of septic shock in neutropenic patients during chemotherapy for gynecological cancers.

OBJECTIVE: To identify the incidence and clinical course of septic shock combined with neutropenia during chemotherapy in gynecological cancer patients. METHODS: We retrospectively reviewed the medical records of all gynecological cancer patients who received intravenous chemotherapy between March 2009 and March 2018. Patients diagnosed with neutropenic septic shock (NSS) during the course of chemotherapy were identified. We calculated the overall incidence and mortality rate of NSS, and analyzed risk factors and clinical course. RESULTS: A total of 1,009 patients received 10,239 cycles of chemotherapy during the study period. Among these, 30 (3.0%) patients had 32 NSS events, of which 12 (1.2%) died. With respect to patient age during the first course of chemotherapy, the incidence of NSS after the age of 50 was significantly higher than that in patients under 50 (3.9% vs. 1.4%, p=0.034). As the number of chemotherapy courses increased, the incidence of NSS increased, and linear-by-linear association analysis showed a positive correlation (p=0.004). NSS events occurred on average 7.8 days after the last cycle of chemotherapy, and the median duration of vasopressor administration was 23.3 hours. The median age (64.0 vs. 56.5, p=0.017) and peak heart rate (149.5 min-1 vs. 123.5 min-1, p=0.015) were significantly higher in the group of patients who subsequently died of NSS than in those who survived. CONCLUSION: The overall incidence of NSS in gynecological cancer patients receiving chemotherapy was 3.0%, which is higher than previously estimated. Peak heart rate during NSS events may be an indicator for predicting survival.

Comparison of human papillomavirus detection and typing by hybrid capture 2, linear array, DNA chip, and cycle sequencing in cervical swab samples.

Although the Hybrid Capture II (HC II) assay can detect 13 high-risk human papillomavirus (HPVs), it does not yield any genotype-specific information. We evaluated the performance of 4 HPV DNA tests, namely, HC II, Linear Array (LA), DNA chip, and cycle sequencing for their capacity to detect the presence of high-risk HPV DNA and HPV-associated cervical lesions. Seventy-six women who were referred to the colposcopy clinic for abnormal cytology were enrolled. The women were examined using liquid-based cytology, colposcopy-directed biopsy, and HPV DNA tests. After DNA extraction from a single sample, HPV DNA tests were performed by all 4 methods on the same specimen. The LA test has higher HPV-positive rates than HC II for cervical intraepithelial neoplasia I (83.3% vs 61.1%; P < 0.01) and for cervical intraepithelial neoplasia II and more severe lesions (100.0% vs 80.0%; P < 0.01). The concordance between the DNA chip and LA tests was 89.5%, confirming substantial agreement (kappa coefficient = 0.73), and the concordance between HC II and the DNA chip was 80.3%, also showing substantial agreement (kappa coefficient = 0.738). The concordance for 15 high-risk HPV genotypes between LA and sequencing was 82.5% with a kappa value of 0.536. Furthermore, the LA test was more sensitive in the detection of high-grade cervical lesions than HC II (100% vs 92.3%, P < 0.01). The LA test showed superior sensitivity in the detection of clinically relevant HPV infections and has proven to be an accurate tool for identifying individual HPV types, especially in cases of multiple HPV infections.

Plasma carotenoids, retinol and tocopherol levels and the risk of ovarian cancer.

OBJECTIVE: We investigated the relation between plasma carotenoids, retinol and tocopherol levels and ovarian cancer risk in Korean women. DESIGN: Hospital-based case-control study. SETTING: Six tertiary medical institutes in Korea. POPULATION: Forty-five epithelial ovarian cancers and 135 age-matched controls. METHODS: Preoperative plasma concentrations of beta-carotene, lycopene, zeaxanthin plus lutein, retinol, alpha-tocopherol, and gamma-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. MAIN OUTCOME MEASURES: Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated by tertiles to evaluate the effect of micronutrients on endometrial cancer risk after adjustment for body mass (BMI) index, menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status. RESULTS: Women in the highest tertile for beta-carotene had 0.12-times the risk of ovarian cancer of in the lowest tertile (OR 0.12; 95%CI 0.04-0.36). Women with the highest tertiles of lycopene (OR 0.09; 95%CI 0.03-0.32), zeaxanthin/lutein (OR 0.21; 95%CI 0.09-0.52), retinol (OR 0.45; 95%CI 0.21-0.98), alpha-tocopherol (OR 0.23; 95%CI 0.10-0.53) and gamma-tocopherol (OR 0.28; 95%CI 0.11-0.70) had lower risk of ovarian cancer than women in the lowest tertiles. Results were consistent across strata of socio-epidemiologic factors. CONCLUSIONS: Micronutrients, specifically ss-carotene, lycopene, zeaxanthin, lutein, retinol, alpha-tocopherol, and gamma-tocopherol, may play a role in reducing the risk of ovarian cancer.

Preoperative levels of plasma micronutrients are related to endometrial cancer risk.

OBJECTIVE: To examine the relation between the plasma concentration of antioxidant micronutrients and endometrial cancer risk in Korean women. DESIGN: Hospital-based case-control study. SETTING: Seven tertiary medical institutes in Korea. POPULATION: Incidence of 28 endometrial cancer cases were identified and 140 age-matched controls selected for the same period. METHODS: Preoperative plasma concentrations of beta-carotene, lycopene, zeaxanthin plus lutein, retinol, alpha-tocopherol, and gamma-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. Conditional logistic regression was used to evaluate micronutrient effect after adjustment for body mass index (BMI), menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status. MAIN OUTCOME MEASURES: Effect of micronutrients on endometrial cancer risk. RESULTS: The mean concentration of plasma beta-carotene (p=0.001), lycopene (p=0.008), zeaxanthin plus lutein (p=0.031), retinol (p=0.048), and gamma-tocopherol (p=0.046) were significantly lower in endometrial cancer patients than in controls. Plasma levels of beta-carotene (p for trend=0.0007) and lycopene (p for trend=0.007) were inversely associated with endometrial cancer risk across tertiles. Women in the highest tertile of plasma beta-carotene and lycopene had a 0.12-fold (95% confidence intervals (CIs) 0.03-0.48) and 0.15-fold (95% CIs 0.04-0.61) decreased risk of endometrial cancer compared to women in the lowest tertile, respectively. Other micronutrients such as zeaxanthin plus lutein (p for trend=0.142), retinol (p for trend=0.108), alpha-tocopherol (p for trend=0.322), and gamma-tocopherol (p for trend=0.087) showed no association with endometrial cancer risk. CONCLUSIONS: Plasma levels of beta-carotene and lycopene are inversely associated with the risk of endometrial cancer in Korean women.

Cost-Utility of a Two-Dose Human Papillomavirus Vaccination Programme Added to Cervical Cancer Screening Compared with Cervical Cancer Screening Alone in Korea

Background: Cervical cancer is caused by the human papillomavirus and is a leading cause of cancer death among young Korean women. Current screening programmes could benefit from the addition of HPV vaccination into their schedule to help reduce disease burden. Two-dose vaccination schedules targeting HPV types 16 and 18, which are responsible for most cervical cancer cases, have recently been approved. Of the two available vaccines, AS04-adjuvanted HPV16/18 vaccine (AS04-HPV16/18v) provides greater protection against non-vaccine oncogenic HPV, while HPV-6/11/16/18 vaccine (4vHPVv) provides protection against genital warts. Methods: The health and economic consequences of introducing a two-dose HPV vaccination programme in 12-year-old girls together with screening were assessed in the Korean healthcare setting using a previously-published Markov model. Results: Compared with screening alone, AS04-HPV16/18v was cost-effective (incremental cost-effectiveness ratio below and within the Korean Won [KRW] 20-30 million treshold). When comparing the two vaccines, at 3% discount rate, AS04-HPV16/18v dominated 4vHPVv (i.e., provided 174 more quality-adjusted life-years (QALYs), 304 more life-years (LYs) and cost-savings of KRW 980 million). At a 5% discount rate, AS04-HPV16/18v provided comparable QALYs (albeit 5 fewer), 105 more LYs and cost-savings of KRW 292 million compared with 4vHPVv. Results were particularly sensitive to the discount rate used, as the health benefits of preventing cervical cancer are observed much later than those of preventing genital warts. Conclusion: For the Korean setting, HPV vaccination with a two-dose schedule is a cost-effective option, and AS04-HPV16/18v is likely to offer better health outcomes at a cost-saving compared with 4vHPVv.

Risk of cervical dysplasia among human papillomavirus-infected women in Korea: a multicenter prospective study.

OBJECTIVE: Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, which progresses from precursor lesions with no symptom if left untreated. We compared the risk of cervical dysplasia among HPV-positive Korean women based on HPV types and infection patterns. METHODS: We observed participants of a 5-year multicenter prospective cohort study, comprising HPV-positive women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion of the cervix at their enrollment. Follow-ups, comprising cytology and HPV DNA testing results, were included in the final analysis. Incidence was calculated for each infection pattern (persistent infection, incidental infection, and clearance). To investigate cervical dysplasia risk, we used Cox proportional hazard models adjusted for variables that were significantly different among infection patterns. From April 2010 to September 2017, 71 of 1,027 subjects developed cervical dysplasia more severe than high-grade squamous intraepithelial lesion of the cervix. RESULTS: Of these 71 subjects, persistent infection, incidental infection, and clearance were noted in 30, 39, and 2 individuals, respectively. Based on changes in DNA results during follow-up, cumulative incidence was 27.2%, 10.4%, and 0.5% for persistent infection, incidental infection, and clearance, respectively. Compared to clearance, the adjusted hazard ratios for cervical dysplasia were 51.6 and 24.1 for persistent and incidental infections, respectively (p<0.001). CONCLUSION: Individuals persistently infected with the same HPV types during the follow-up period had the highest risk of severe cervical dysplasia. Hence, it is necessary to monitor HPV types and infection patterns to prevent severe cervical precancerous lesions.

Human papillomavirus (HPV) type distribution in Korean women: a meta-analysis.

The aim of the present study is to estimate the overall prevalence and type distribution of human papillomavirus (HPV) in Korean women, through literature review and meta-analysis. We searched published data for the period between 1995 and 2007 using the following inclusion criteria; (1) studies using type-specific HPV tests, (2) data from Korean female, (3) with cytologic or pathologic results, (4) having more than 20 cases for each subgroup classified by cytologic results, and (5) HPV detection including types 16, 18, and at least one other type. In total, 18 studies (13,842 cases) published up to April 2007 were identified and selected. Adjusted overall HPV prevalence was 23.9% (95% CI: 23.8-24.1%) in women with normal cytology and 95.8% (95% CI: 95.4-96.2%) in women with cervical cancer. Type 16 was predominant regardless of cervical disease status, and type 58 occupied a significantly larger proportion in high-grade cervical intraepithelial lesions and cervical cancer in Korean women. HPV types 58, 33, and 52 together accounted for about 20% of infections in cervical cancer and high-grade intraepithelial lesions. After introduction of HPV prophylactic vaccines, extended protection, especially against types 58, 33, and 52, will be an important issue for cervical cancer prevention in Korea. The future dominant genotypes will require follow-up epidemiological studies with a large-scale, multicentered, and prospective design.

Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients.

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.

Up to date: comprehensive knowledge of human papillomavirus.

The 28th International Papillomavirus Conference, hosted by the University of Puerto Rico Comprehensive Cancer Center, attracted approximately 1500 participants from 75 countries. The purpose of the meeting was mainly to provide a forum for the exchange of new knowledge; the status of HPV research and its future direction and the impact of current strategies for the prevention and control of HPV burden and HPV-related conditions. The meeting program consisted of a clinical workshop and a public health workshop followed by the main conference program. The main conference featured five breakfast sessions, four plenary sessions and 22 satellite symposia. Over 800 posters, 167 oral presentations and 53 poster-oral presentations were presented. This article highlights the most important issues discussed in HPV, which will be of interest to those working in the field of HPV vaccines.