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.

Next-generation Sequencing of an Ovarian Spindle Cell Tumor Identified an Ovarian Low-grade Endometrial Stromal Sarcoma: A Rare Entity.

Ovarian spindle cell tumors comprise a heterogeneous group of ovarian neoplasms from benign to malignant. Since this morphologic finding describes a broad category of ovarian neoplasms, it is not easy to determine an accurate diagnosis. Low-grade endometrial stromal sarcoma (LG-ESS) is a rare gynecological malignancy that presents with spindle cell lesions. To identify ovarian LG-ESS, we performed whole-exome sequencing and transcriptome sequencing of a spindle cell tumor. The tumor harbored JAZF1-SUZ12, a well-known gene fusion commonly found in uterine LG-ESS. Moreover, 28 non-silent somatic mutations (13 frameshift, 12 missense, 2 nonsense and 1 splicing mutations) with five cancer-related genes (ACSL3, ATM, DST, HGF and PKHD1) were detected. Our results indicate that next-generation sequencing combined with conventional immunohistochemical analysis may be a better strategy than conventional analysis alone to identify ovarian LG-ESS with spindle cell lesions. Moreover, our data suggest that ovarian LG-ESS can harbor genetic characteristics similar to those of uterine LG-ESS.

Utility of human papillomavirus L1 capsid protein and HPV test as prognostic markers for cervical intraepithelial neoplasia 2+ in women with persistent ASCUS /LSIL cervical cytology.

Objective: Efficient and highly predictive biomarkers reflecting the prognosis of persistent atypical squamous cells of unknown significance(ASCUS) and low grade squamous intraepithelial lesion(LSIL)s are unavailable and need to be developed urgently. We aimed to develop a predictive model for diagnosis of cervical intraepithelial neoplasia(CIN)2+ by analyzing the immunocytochemical expression of the HPV L1 capsid protein in patients with persistent ASCUS and LSIL with a high risk of HPV infection. Methods: Cervical cytology samples comprising (70 ASCUS and 215 LSIL Pap smears) were analyzed. Immunocytochemical identification of the HPV L1 capsid protein in cervical cytology samples was performed. Expression levels of HPV L1 capsid protein in cervical cytology samples were measured, and the correlation between HPV L1 expression and cervical pathologic diagnosis was evaluated. The risk for CIN2+ was calculated using the results of immunocytochemistry and the HPV DNA test. Results: Negative results for HPV L1 immunochemistry test were more frequently observed in CIN2+, and expression of the HPV L1 capsid protein was higher in CIN1 or cervicitis (Fisher's exact test, p<0.05). Diagnosis rates for CIN2+ were highest for the combination of HPV L1 capsid protein immunocytochemistry, cytology and HPV test when compared with other combinations (Akaike information criterion (AIC): 191.7, Schwarz criterion(SC): 206.3, p<0.001). Conclusion: Absence of HPV L1 capsid expression and presence of HPV type 16 or 18 infection are reliable predictors of progression to CIN2+ in patients showing persistent ASCUS and LSIL.

Six-year multi-centre, observational, post-marketing surveillance of the safety of the HPV-16/18 AS04-adjuvanted vaccine in women aged 10-25 years in Korea.

PURPOSE: To evaluate the safety of HPV-16/18 AS04-adjuvanted vaccine when administered as per the PI in Korea. METHODS: A total of 3084 women aged 10-25 years were enrolled in this post-marketing surveillance from 2008 to 2014. Subjects were invited to receive three doses of the vaccine (0, 1 and 6 months), and participants who received at least one dose were included in the analysis. Adverse events (AEs), adverse drug reactions (ADRs) and serious AEs (SAEs) were recorded after each dose. All AEs, ADRs and SAEs were presented with exact 95% confidence intervals (CI) (NCT01101542). RESULTS: Injection-site pain was the most frequent AE and ADR reported by 322 subjects (10.4% [95%CI: 9.4-11.6]); the local pain was transient and lasted 4-7 days in most cases. Dysmenorrhoea and vaginitis were the most common unexpected AEs reported by 30 (1.0% [95%CI: 0.7-1.4]) and 16 subjects (0.7% [95%CI: 0.3-0.8]), respectively. Pain (toe pain, leg pain and body pain [one case each]; foot pain [two cases]) was the most common unexpected ADR reported by five subjects (0.2% [95%CI: 0.1-0.4]). Four subjects reported a single SAE (one case each of exostosis, gastroenteritis, abortion and tonsillitis); none were fatal. All SAEs were assessed as unlikely to be related to vaccination; gastroenteritis, exostosis and tonsillitis resolved during the study period. CONCLUSIONS: This is the first post-marketing surveillance study in Korea that provides 6-year safety data for HPV-16/18 AS04-adjuvanted vaccine. The vaccine showed an acceptable safety profile and favourable benefit/risk ratio when given to women aged 10-25 years in Korea. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Incidence and Risk Factors of Lower Extremity Lymphedema After Gynecologic Surgery in Ovarian Cancer.

OBJECTIVE: There is no standard method to establish an early diagnosis of lower extremity lymphedema (LEL). Lower extremity lymphedema can be diagnosed by physical examination and laboratory tests when patients complain of typical clinical symptoms. The objective of this study was to investigate the incidence and risk factors of LEL in patients with ovarian cancer. METHODS: The medical records were reviewed retrospectively in patients with ovarian cancer treated at Seoul St. Mary's Hospital from January 2000 to July 2014. RESULTS: A total of 413 patients with epithelial ovarian cancer were analyzed. Forty-six patients (11.1%) developed LEL, and 67.4% of these patients had LEL within 1 year after surgery. The mean number of resected lymph nodes (LNs) was larger in patients with LEL (43.1 ± 16.7; range, 12-80) than in those without (32.3 ± 19.8; range, 0-99) (P < 0.0001). The number of resected LNs was significantly associated with the occurrence of LEL (odds ratio, 1.025; 95% confidence interval, 1.005-1.045; P < 0.05). CONCLUSION: A significant proportion of patients with ovarian cancer could develop LEL after surgery. This study suggests that the occurrence of LEL is associated with the number of resected LNs.

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.

Toll-like receptor 2 gene polymorphisms in Korean women with human papillomavirus-related cervical neoplasia.

INTRODUCTION: The aim of this study was to investigate the association between Toll-like receptor 2 (TLR2) gene polymorphisms and human papillomavirus (HPV)-related cervical neoplasia in Korean women. MATERIAL AND METHODS: Peripheral blood samples collected from 127 patients with HPV-related cervical neoplasia and 175 healthy women were genotyped for the TLR2 -16934, +1350, intron1, and 3' untranslated region (UTR) polymorphisms using the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: The TLR2 -16934 A/A, intron1 A/A, and +1350 T/C genotypes were more frequent in patients than in controls [odds ratio (OR) = 2.1, 95% CI = 1.302-3.475, p = 0.002; OR = 1.9, 95% CI = 1.168-3.169, p = 0.010; and OR = 1.9, 95% CI = 1.211-3.123, p = 0.006, respectively]. The frequencies of the TLR2 + 1350 C and 3'UTR G alleles were also higher in patients (OR = 2.0, 95% CI = 1.236-3.121, p = 0.004 and OR = 1.7, 95% CI = 1.005-3.076, p = 0.046, respectively). The genotype frequencies of TLR2 -16934 A/A and intron1 A/A increased with increasing oncogenic risk of the HPV genotype, as follows. low-risk type < high-risk type < HPV-16 and/or HPV-18 type (p = 0.008). CONCLUSIONS: Our study provides the first evidence that TLR2 gene polymorphisms are associated with high-risk type HPV-related cervical neoplasia and may play an important role in susceptibility to HPV infection. Further large-scale and functional studies are needed to confirm the role of TLR2 gene polymorphisms in HPV-related cervical neoplasia.

Differences in the lipid profile and hormone replacement therapy use in Korean postmenopausal women: the Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012.

PURPOSE: Hormonal changes after menopause can cause dyslipidemia by the cessation of endogenous estrogen. We analyzed the lipid profile of the Korean healthy menopausal women according to the use of hormone replacement therapy (HRT). METHODS: Data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012 were analyzed. The study included 428 healthy postmenopausal women with HRT (HRT group) and 1804 healthy postmenopausal women without HRT (NHRT group). RESULTS: After adjustment for confounding factors, total cholesterol (TC) and low-density lipoprotein (LDL) were lower in the HRT group than in the NHRT group (TC: 200.1 ± 2.0 vs. 204.9 ± 1.1, P = 0.04; LDL: 120.3 ± 1.0 vs. 124.5 ± 1.0 mg/ml, P = 0.033). Triglycerides (TG) were lower in the HRT group than in the NHRT group [106.8, (95 % CI 99.8-114.3) vs. 115.1 (95 % CI 111.8-118.5), P = 0.04]. Non-high-density lipoprotein (HDL) was lower in the HRT group than in the NHRT group (145.4 ± 1.9 vs. 151.2 ± 1.0 mg/ml, P = 0.008). Patients with HRT were lower in the LDL cholesterol level (OR 0.601, 95 % CI 0.397-0.917, P = 0.018), the total cholesterol to high-density lipoprotein ratio (OR 0.787, 95 % CI 0.617-0.997, P = 0.016), and the non-HDL level (OR 0.68, 95 % CI 0.509-0.907, P = 0.009). CONCLUSION: The results of this study suggest that the use of HRT may have a positive effect on dyslipidemia in postmenopausal women.

Does diabetes mellitus have an impact on the prognosis for patients with cervical cancer?

OBJECTIVE: To evaluate the impact of comorbid diabetes mellitus (DM) on prognoses among patients with cervical cancer. METHODS: We analyzed cervical cancer outcomes in patients who treated in two hospitals retrospectively. Patients were divided into those with DM and those without. Clinicopathologic parameters, disease-free survival (DFS), and overall survival (OS) rates were evaluated. RESULTS: Of the 494 patients, 50 had DM. These were more likely to be older than those in the non-DM group and their body mass index (BMI) was higher. They showed higher levels of tumor markers and had more combined diseases. They were less likely to have had surgical treatment. Among these patients, 12 (24%) experienced a recurrence (hazard ratio, HR, 1.484; 95% confidence interval, CI, 0.746-2.951). Differences in DFS did not show statistical significance. In the OS analysis, 11 (22%) in the DM group and 62 (14%) in the non-DM group died (HR, 1.239; 95% CI, 0.606-2.533). No statistically significant differences were also observed for cancer-specific death (HR, 1.246; 95% CI, 0.567-2.737). Those with DM and an adenocarcinoma tended to have an increased risk of dying compared with the non-DM patients with an adenocarcinoma (HR, 3.673; 95% CI, 0.990-13.625), but this difference was not statistically significant (p=0.0518). CONCLUSION: Diabetes mellitus did not have an impact on the prognosis for patients with cervical cancers. In those with an adenocarcinoma, patients with diabetes tended to have an increased risk of dying compared with the non-DM group, but this difference was not statistically significant.

A Pilot Study to Investigate the Efficacy of Fibrin Sealant (Tisseel®) in the Loop Electrosurgical Excision Procedure.

AIMS: The objective of the current study was to evaluate the efficacy and feasibility of fibrin sealant (Tisseel®) in the loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN 2 or 3). METHODS: We designed a single-blind, prospective, randomized study in 40 consecutive women undergoing LEEP for CIN 2 or 3 at our institute. Two milliliters of fibrin sealant (Tisseel) was applied to the uterine cervix of 20 women immediately after LEEP surgery (treatment group). We evaluated abdominal pain, vaginal bleeding, vaginal discharge and impairment in daily living after 1 week using visual analogue scale questionnaires and compared the results with those of 20 women who did not receive fibrin sealant (control group). RESULTS: Among 40 women who returned for a follow-up 1 week after LEEP, 25 women (62.5%) reported at least one moderate to severe postprocedural symptom. The mean duration of moderate to severe vaginal bleeding and impairment in daily living during postoperative week 1 for the treatment group and the control group was 0.3 ± 0.80 versus 1.7 ± 2.36 days (p = 0.015) and 0.9 ± 1.37 versus 3.00 ± 2.62 days (p = 0.060), respectively. CONCLUSION: Intraoperative application of fibrin sealant (Tisseel) in LEEP can decrease postoperative vaginal bleeding and impairment in daily living.

Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages.

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%; P(corrected) < .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.

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.

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.

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.

Prevalence and type distribution of human papillomavirus in cervical adenocarcinoma in Korean women.

BACKGROUND: An increase in incidence of cervical adenocarcinoma (CADC) has been reported in many countries, including Korea. However, few studies describe human papillomavirus (HPV) type distribution among CADC in Asia. OBJECTIVE AND METHODS: This was a retrospective, hospital-based observational study between 2005 and 2010 to estimate the overall prevalence and distribution of HPV types among CDAC in Korean women. The study used hematoxylin & eosin and immunohistochemical staining (for the two biomarkers p16 and progesterone receptor [PR]) to diagnose and subtype CADC samples. HPV DNA was amplified by polymerase chain reaction (PCR) and HPV genotypes were identified using reverse hybridization. RESULTS: Of 196 cases submitted, 89.3% of the cases were confirmed as CADC. The mean age at diagnosis was 47.1 (standard deviation [SD] 11.9) years. No statistically significant differences in mean age at diagnosis by histological subtype were found. HPV DNA was detected in 90.3% (177/196) of CADC. HPV-18 was the most prevalent type (54.2%), followed by HPV-16 (44.1%) and HPV-45 (3.4%). Infection with any high-risk HPV type was identified in 97.7% of HPV-DNA-positive CADC. The biomarker p16 was positive in 92% of CADC cases and PR was positive in 19.6% of CADC. CONCLUSION: HPV DNA was found in the large majority of CADC in Korean women, with HPV-18 being the most common type followed by HPV-16 and HPV-45. This study is among the first in Asia to specifically report HPV type distribution in CADC. This information will help inform policy decisions concerning HPV vaccination for the prevention of CADC.

Is neoadjuvant chemotherapy followed by radical surgery more effective than radiation therapy for stage IIB cervical cancer?

OBJECTIVE: The primary objective of the study was to compare the survival rate of patients who had received neoadjuvant chemotherapy with that of patients who had received radiation therapy for stage IIB cervical cancer. The secondary objective was to analyze the effect of neoadjuvant chemotherapy on pathological prognostic factors. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who had received therapy for stage IIB cervical cancer. Based on the primary therapy, 192 patients were divided into 2 groups; patients in the neoadjuvant chemotherapy group (n =103) underwent a type III radical hysterectomy after completion of the neoadjuvant chemotherapy. Patients in the other group (n = 89) were treated with radiation alone or a combination of chemotherapy and radiotherapy. RESULTS: After neoadjuvant chemotherapy, the level of squamous cell carcinoma antigen, tumor size, lymph node involvement, and parametrium involvement were significantly decreased. However, 90.3% of the patients who had received neoadjuvant chemotherapy needed to have adjuvant therapy after radical surgery because of poor pathological prognostic factors. The rate of disease-free survival did not differ significantly between the 2 groups. However, the overall survival rate was significantly lower in the neoadjuvant chemotherapy group for patients who were 60 years or older (P = 0.03). The rates of disease-free survival and overall survival for patients who had a good (complete or partial) response to the neoadjuvant chemotherapy were not significantly higher than the rates for patients in the radiation therapy group. CONCLUSIONS: Although neoadjuvant chemotherapy improved pathological prognostic factors in patients with stage IIB cervical cancer, it was not sufficiently effective to decrease adjuvant therapy. Neoadjuvant chemotherapy also did not improve the rate of patient survival compared to the rate of patient survival in the radiation therapy group.

Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia across 5 countries in Asia.

OBJECTIVE: Independent, prospective, multicenter, hospital-based cross-sectional studies were conducted across 5 countries in Asia, namely, Malaysia, Vietnam, Singapore, South Korea, and the Philippines. The objectives of these studies were to evaluate the prevalence of human papillomavirus (HPV) types (high risk and others including coinfections) in women with invasive cervical cancer (ICC) and high-grade precancerous lesions. METHODS: Women older than 21 years with a histologic diagnosis of ICC and cervical intraepithelial neoplasia [CIN 2 or 3 and adenocarcinoma in situ (AIS)] were enrolled. Cervical specimens were reviewed by histopathologists to confirm the presence of ICC or CIN 2/3/AIS lesion and tested with short PCR fragment 10-DNA enzyme immunoassay-line probe assay for 14 oncogenic HPV types and 11 non-oncogenic HPV types. The prevalence of HPV 16, HPV 18, and other high-risk HPV types in ICC [including squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (ADC/ASC)] and CIN 2/3/AIS was estimated. RESULTS: In the 5 Asian countries, diagnosis of ICC was confirmed in 500 women [SCC (n = 392) and ADC/ASC (n = 108)], and CIN 2/3/AIS, in 411 women. Human papillomavirus DNA was detected in 93.8% to 97.0% (84.5% for the Philippines) of confirmed ICC cases [94.0%-98.7% of SCC; 87.0%-94.3% (50.0% for the Philippines) of ADC/ASC] and in 93.7% to 100.0% of CIN 2/3/AIS. The most common types observed among ICC cases were HPV 16 (36.8%-61.3%), HPV 18 (12.9%-35.4%), HPV 52 (5.4%-10.3%), and HPV 45 (1.5%-17.2%), whereas among CIN 2/3/AIS cases, HPV 16 (29.7%-46.6%) was the most commonly observed type followed by HPV 52 (17.0%-66.7%) and HPV 58 (8.6%-16.0%). CONCLUSIONS: This article presents the data on the HPV prevalence, HPV type distribution, and their role in cervical carcinogenesis in 5 Asian countries. These data are of relevance to public health authorities for evaluating the existing and future cervical cancer prevention strategies including HPV-DNA testing-based screening and HPV vaccination in these Asian populations.

Immunostaining of p16(INK4a)/Ki-67 and L1 capsid protein on liquid-based cytology specimens obtained from ASC-H and LSIL-H cases.

BACKGROUND: Atypical squamous cell cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and low-grade intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion (LSIL-H) are ambiguous diagnostic entities for the prediction of high-grade cervical lesion. Objective and reproducible tests for predicting high-grade cervical lesions are needed to reduce unnecessary colposcopic referrals or follow-ups. OBJECTIVE: We aimed to identify an adequate set of adjunctive markers to predict cervical intraepithelial neoplasia grade 2+ (CIN2+) in residual liquid-based cytology specimens (LBCS). METHODS: We conducted p16 (INK4a)/Ki-67 and L1 capsid protein immunostaining and human papillomavirus (HPV) DNA typing on 56 LBCS diagnosed with ASC-H or LSIL-H, all of which were subjected to histologic confirmation or follow-up cytologic examination. RESULTS: Positivity for p16 (INK4a)/Ki-67 was associated with a histology of CIN2+ (P=0.047) and CIN3+ (P=0.002). Negativity for L1 capsid protein was associated with CIN2+ confirmed at follow-up (P=0.02).Positivity for high-risk HPV (HR-HPV) was associated with CIN2+ confirmed at follow-up (P=0.036) and a histology of CIN2+ (P=0.037). The sensitivity, specificity, positive predictive value, and negative predictive value for predicting follow-up CIN2+ were 76.2%, 51.4%, 48.5%, and 78.3%, respectively, for p16 (INK4a)/Ki-67 immunostaining; 95.2%, 34.3%, 46.5%, and 92.3%, respectively, for L1 capsid protein; and 66.7%, 67.7%, 54.5%, and 77.8%, respectively, for HR-HPV. The classification and regression tree analysis showed that the combined results of p16 (INK4a)/Ki-67 andL1 capsid protein immunostaining and the HR-HPV test, conducted sequentially, correctly classified 81.8% of samples (27/33)in the prediction of a histology of CIN2 + in ASC-H or LSIL-H. For determination of the histology of cervical intraepithelial neoplasia grade 3+ (CIN3+)in ASC-H or LSIL-H, we found that the combined results of p16 (INK4a)/Ki-67 and L1 capsid protein immunostaining correctly classified 78.8% (26/33) of samples. CONCLUSIONS: p16(INK4a)/Ki-67 and L1 capsid protein immunostaining and HR-HPV testing of residual LBCS diagnosed with ASC-H or LSIL-H are useful objective biomarkers for predicting CIN2+. Immunostaining for p16(INK4a)/Ki-67 and L1 capsid protein are sufficient to predict CIN3+.

Comparison of the Cobas 4800 HPV test and the Seeplex HPV4A ACE with the hybrid capture 2 test.

BACKGROUND: It is well-known that persistent cervical infections with high-risk human papillomavirus (HPV) are related to the development of high-grade cervical intraepithelial neoplasia and invasive cervical cancer and that infection with HPV 16 and HPV 18 accounts for approximately 70% of all cases of invasive cervical cancer. METHODS: We performed 3 HPV molecular tests-the Cobas 4800 HPV test, the Seeplex HPV4A ACE, and the hybrid capture 2 (HC2) test-in 146 cervical swab samples to compare between these three tests. RESULTS: There was a concordance rate of 82.8% between the results of the Cobas 4800 HPV and the HC2 test and a concordance rate of 84.9% between the results of the Seeplex HPV4A ACE and the HC2 test. Between the Cobas 4800 HPV test and the Seeplex HPV4A ACE, there was a concordance rate of 89.6% in the detection of high-risk HPV between the results and a concordance rate of 98.7% in the detection of HPV 16 or 18. When an abnormal Pap test was defined as ≥ low grade squamous intraepithelial lesion (LSIL), the sensitivity of the Cobas 4800 HPV test, the Seeplex HPV4A ACE and the HC2 test were 71.1%, 80.0%, and 88.9%, respectively, while their specificities were 76.4%, 74.5%, and 67.9%, respectively. CONCLUSIONS: The results of this study suggest that the Cobas 4800 HPV test and the Seeplex HPV4A ACE may be as effective as the HC2 test in detecting HR HPV and that the concordance between the results of the Cobas 4800 HPV test and the Seeplex HDV4A ACE may be higher in the detection of HPV 16 and HPV18 than concerning high-risk HPV.

Clinicopathologic review of ovarian masses in Korean premenarchal girls.

OBJECTIVE: To review the clinicopathological characteristics of ovarian masses in Korean premenarchal girls. DESIGN: The data collected from hospital medical records were reviewed retrospectively regarding age, presentation, diagnosis, treatment, and outcome. PARTICIPANTS: There were 65 premenarcheal girls who underwent surgery at Seoul St. Mary's Hospital between January 1990 and March 2012. RESULTS: The most common presenting symptom was abdominal pain (n=31, 47.7%), followed by palpable abdominal masses 16 (n=16, 24.6%), abdominal distension (n=8, 12.3%), vaginal bleeding (n=4, 6.2%), incidental finding (n=3, 4.6%), difficulty in urination or defecation (n=2, 3.1%), and prenatal sonographic findings (n=1, 1.5%). Of the patients with benign tumors, including non-neoplastic lesions and benign cysts, 26 (51%) underwent cystectomy, 6 (11.8%) underwent oophorectomy, 17 (33.3%) underwent unilateral salpingo-oophorectomy and none underwent bilateral salpingo-oophorectomy. Of the patients with malignant tumors, 2 (14.3%) underwent bilateral salpingo-oophorectomy, 7 (50%) underwent unilateral salpingo-oophorectomy, 2 (14.3%) underwent oophorectomy, and 2 (14.3%) underwent cystectomy. CONCLUSION: Abdominal pain was the most common symptom. However, the incidence of abdominal distension was higher in patients with malignant tumors than in those with benign tumors. We assessed clinical features, operative outcomes, and histological classifications of Korean prememarchal girls with ovarian masses. Further studies with a larger number of subjects are needed to confirm our results.