Background In an interim analysis of this phase 2 trial, adding the GX-188E vaccine to pembrolizumab resulted manageable toxicity with antitumor activities in patients with recurrent or advanced cervical cancer. Here, we report the fi nal safety and ef fi cacy results after a long-term follow-up at the study ' s completion. Methods This open-label, single-arm, phase II trial was conducted in nine hospitals in South Korea (ClinicalTrials.gov identi fi er, NCT03444376). Eligible patients were aged >= 18 years with recurrent or advanced inoperable cervical cancer, Eastern Cooperative Oncology Group Performance status of 0 or 1, and positivity for HPV 16/18, who failed the available standard-of-care therapy. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, 19, and 46 and intravenous 200 mg pembrolizumab every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the objective response rate (ORR) within 24 weeks. Findings Between June 19, 2018, and December 24, 2021, 65 patients were enrolled and received at least one dose the study treatment. Sixty patients received combination treatment with GX-188E and pembrolizumab and underwent ef fi cacy analysis. After a median follow-up of 14.72 months, the con fi rmed ORR was 35.0% (95% CI, 23.1 - 48.4). Five patients (8.3%) had a complete response, and 16 (26.7%) had a partial response. In addition, patients with PD-L1-positive and PD-L1-negative tumors had an ORR of 38.9% (95% CI, 23.1 - 56.5) and 29.2% (95% CI, 12.6 - 51.1), respectively. The median duration of response of all the patients was 12.3 months (95% CI, 5.3 - not reached [NR]). For those with PD-L1-positive tumors, it was 12.3 months (95% CI, 3.5 - NR), and for those with PD-L1-negative tumors, it was NR (95% CI, 2.4 - NR). The median progression-free survival of the 60 patients was 4.4 months (95% CI, 2.1 - 8.3), and the median overall survival was 23.8 months (95% CI, 14.0 - NR). 22 (33.8%) of 65 patients had treatment-related adverse events (TRAEs) of any grade and four (6.2%) had grade 3 - TRAEs. No treatment-related deaths occurred. Interpretation The GX-188E vaccine combined with pembrolizumab in recurrent or advanced HPV-positive cervical cancer was safe and showed a promising overall survival and clinical response rate. This combination therapy might provide a new potential treatment option for patients with recurrent or advanced cervical cancer.

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Supplementary Data Table S1. Characteristics of the patients who participated the clinical trial Table S2. IFN-γ ELISPOT responses. Table S3. List of HPV16 nucleotide variations among 52 patients included at V8 visit Table S4. Association between "average sum of IFN-γ ELISPOT responses/ baseline IFN-γ ELISPOT responses (fold-change)" and HPV variations (Cutoff p-value <0.05)

Figure S1 Clinical efficacy according at V7 and V8.

Figure S2. Clinical efficacy according to does difference (1 mg and 4 mg).

5511 Background: Pembrolizumab was approved for the treatment of recurrent or metastatic cervical cancer, based on 14.3% of objective response rate (ORR) in patients with PD-L1 expression (CPS≥1). GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6- and E7-specific T-cell responses. We aimed to investigate whether a combination of GX-188E (Tirvalimogene teraplasmid) therapeutic DNA vaccine plus pembrolizumab showed antitumor activity against recurrent or advanced cervical cancer. Methods: In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced cervical cancer, who were aged over 18 years with ECOG PS of 0 or 1, HPV-16 or HPV-18 and histologically confirmed positive cervical cancer, and who had progressed after standard-of-care therapy were recruited from nine hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, 19, and optional dose at week 46, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the Best Overall Response Rate assessed by the investigator using RECIST version 1.1. Results: To date, a total of 52 patients have been enrolled and received at least one study treatment, and this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 48 patients. Median age was 52 (range, 27-79) years and 46.2% had ECOG PS 1. At the data cutoff date on January 11, 2021, median follow-up duration was 6.2 months (range; 1.7- 24.2 months). According to investigator evaluation, 15 (31.3%) of 48 patients achieved best overall response; 5 (10.4 %) patients had a complete response (CR) and 10 (20.8 %) had a partial response (PR). Especially, this combination treatment showed higher response rate, 48.0 %, in patients with PD-L1 positive, HPV-16 and squamous cell carcinoma. Median PFS was 4.1 months (range; 1.3-24.2) and median OS was 16.7 months (range; 1.7-24.2). In this clinical trial with cervical cancer patients, GX-188E in combination with pembrolizumab has shown an improved median PFS and OS than the monotherapy of pembrolizumab (KEYNOTE-158). 17 (32.7%) of 52 patients had treatment-related adverse events of any grade and two (3.8%) had grade 3 or 4 treatment-related adverse events; increased aspartate aminotransferase or alanine aminotransferase. No treatment-related deaths were reported. Conclusions: GX-188E vaccine combined with pembrolizumab in recurrent/advanced cervical cancer was safe and tolerable, and showed an enhanced clinical response rate compared with pembrolizumab alone in particular in patients with PD-L1 positive, HPV-16 and squamous cell carcinoma. The combination therapy could represent a new potential treatment option for this patient population. Clinical trial information: NCT03444376.

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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

AbstractPurpose: To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. Patients and Methods: We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV-sequencing analysis and an ex vivo IFNγ ELISpot assay were performed using the collected cervical biopsy and blood samples from patients. Results: In total, 72 patients were enrolled and underwent randomization. Of them, 64 patients were included in per-protocol analysis (V7) and 52 in extension analysis (V8). Our data showed 52% (33/64) of patients at V7 and 67% (35/52) of patients at V8 presented histopathologic regression after receiving the GX-188E injection. We found that 73% (V7) and 77% (V8) of the patients with histologic regression showed HPV clearance. HPV clearance and histopathologic regression were significantly associated at V7 and at V8. Compared with the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold changes in their IFNγ ELISpot responses compared with those without HPV clearance. The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E, V83L, and N29S were inversely associated with histopathologic regression at V8. Conclusions: GX-188E is an effective therapeutic vaccine against a cohort containing only CIN3 patients.

Purpose: Pembrolizumab was approved for the treatment of patients with relapsed or metastatic cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (CPS≥1), with a 14.3% objective response rate (ORR) by the U.S. FDA in 2018 (KEYNOTE-158). Combination of pembrolizumab with GX-188E, a DNA vaccine targeting HPV 16 and 18 types is expected to show synergistic anti-tumor effects presumably by antigen-specific CD8+ T cell responses induced by GX-188E DNA vaccine. The objectives of this interim analysis are to assess preliminary anti-tumor efficacy, safety and tolerability. Patients and Design: This is a prospective, open-label, phase II study in patients with advanced, inoperable or metastatic cervical cancer, ECOG PS 0-1, positivity for HPV 16 and/or 18 types who have failed all available standard-of-care (SoC) therapies including surgery, chemotherapy and radiotherapy or who have refused those (≥2 lines). Patients received GX-188E 2 mg intramuscularly, seven times at weeks 1, 2, 4, 7, 13, 19, and 46, with pembrolizumab 200 mg IV every three weeks for up to 2 years or until progression. This interim analysis was performed after obtaining at least one post baseline tumor assessment data from 22 patients (approximately 50% of total patients to be enrolled in Phase II). Results: Among 24 patients treated, 22 patients were evaluable for anti-tumor efficacy. Median age was 52 (range, 27-68) years and 37.5% had ECOG PS 1. As of the Dec 11, 2019 data cutoff, the median follow-up duration was 5.3 months (range; 0.9-16.3 months). ORR was 45.5%, with 5 CRs and 5 PRs. Additionally, one patient had SD at week 14. Median PFS was 4.1 months (range; 1.7-not reached). Median DoR and OS have not been reached. Treatment related AEs occurred in 54.2% of patients with grade 1 or 2 and 12.5% of patients with grade 3-4. The most common treatment related AEs classified by system organ class were gastrointestinal disorders (20.8%) and respiratory, thoracic and mediastinal disorders (16.7%), which were similar to those of pembrolizumab monotherapy. In contrast to pembrolizumab monotherapy, combined therapy showed therapeutic effect in PD-L1 negative tumor. Conclusions: Pembrolizumab combined with GX-188E demonstrated a higher response rate than pembrolizumab monotherapy in patients with cervical cancer showing great synergy regardless of PD-L1 expression. The safety profile was manageable and similar to that of pembrolizumab monotherapy. Further evaluation of anti-tumor response and antigen specific immune response is ongoing in a larger number of patients with and without PD-L1 expression. Citation Format: Sooyoung Hur, Jong Sup Park, Yong-Man Kim, Myong Cheol Lim, Jae Hong No, Byoung-Gie Kim, Jae-Kwan Lee, Chi Heum Cho, Yoon-Jeong Choi, You Suk Suh, Jung Won Woo, Young Chul Sung. Efficacy and safety results of pembrolizumab combined with GX-188E, a therapeutic DNA vaccine administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT033.

Objectives: Since 2007, human papillomavirus (HPV) vaccines have been administered for the prevention of cervical cancer in Korea. We investigated the status of HPV vaccination among HPV-infected adult women with abnormal cervical cytology before the introduction of National Immunization Program. Methods: From 2010 to 2016, HPV-positive women (age, 20-60 years) with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion (LSIL) were enrolled from five hospitals across Korea. Their HPV genotype, epidemiologic, and clinical data, including HPV vaccination history, were obtained. We compared the epidemiological characteristics and prevalence of HPV-16/18 genotypes between vaccinated and unvaccinated women. Results: Among the 1,300 women, approximately 26% had a history of vaccination. Vaccinated patients were significantly younger, unmarried, and had a higher education level than unvaccinated women. For HPV-vaccinated individuals by vaccine dose, there was a significant younger age at vaccination initiation (p=0.025), longer duration from HPV vaccination to Pap test date (p=0.001), and lower proportion of HPV-16/18 (p=0.028) in the women with three doses. There was a significantly lower prevalence of HPV-16/18 genotypes in women who were vaccinated at least 12 months prior than in unvaccinated women (adjusted prevalence ratio [aPR]=0.51; 95% confidence interval [CI]=0.29-0.88). For women with LSIL, the prevalence of the HPV-16/18 genotypes was significantly lower in women who were vaccinated more than 12 months prior than in unvaccinated women (aPR=0.35; 95% CI=0.13-0.96). Conclusion: This study highlighted the status of HPV vaccination and the prevalence of HPV-16/18 genotypes among HPV-infected women with abnormal cervical cytology according to HPV vaccination. It provides preliminary information regarding the status of HPV vaccination among Korean adult women.

Introduction/Background Little is known about risk factors for persistent high-risk infection after cervical conization. We compared the duration of high risk HPV among women with cervical conization by exposure to sexually transmitted infections(STIs) using a real time PCR methods. Methodology This study was conducted on 28 patients who received conization due to persistent CIN-1, CIN-2,3 and CIS at the St Paul9s Hospital of the Catholic University of Korea from Jul, 2014 until Feb, 2018. They all were positive for high risk HPV at initial visit. A specimens were tested using realtime based assay, Anyplex II STI-7 (Seegene, Korea). tients were followed in 4–6 month interval with Pap smear and Anyplex TM Real time PCR HPV 28 detection method which detect 19 high-risk HPV genotype, 9 low-risk genotypes Results The mean age was 39.3 years (Min-Max : 26–50) and mean follow-up month was 20.2 month(Min-Max :3–41 month). ASCUS, LSIL,ASCH and HSIL were 8,6,3 and 11 women. Single and multiple HPV detection was 14 and 14 (50%). Of the women received conization, median clearance time of those multiple type HPV was 26 month and that was slightly longer than single type HPV(24.5 month, P>0.05). Mycoplasma, Chlamydia and Ureaplasma positive cases were 10(35.7%),1(3.6%) and 18(64.3%).The median clearance of women infected with Mycoplasma and Ureaplasma were 22.4 and 29.8 months. Ureaplasma positive women had longer clearance time compared with negative women(29.8 month vs 24.8 month p>0.05). HPV types were related with clearance time. Mean clearance of alpha-9 group HPV(HPV-16,31,33,35,52,58) was shorter than alpha-7(HPV-18,39,45,59,68,70) and alpha-6(HPV-53,56,66). (20.9 month vs 28.8 month p<0.05). Conclusion In a follow-up after conization, women with Ureaplasma showed relatively long time persistence. Management of this STI could reduces risk for high risk HPV persistence. Disclosure Nothing to disclose

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.

Objective: Cervical intraepithelial neoplasia (CIN) 3 is a pre-malignant lesion that may progress to cervical cancer. This phase 2 clinical trial was designed to determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of HPV type 16/18-associated CIN3. Methods: We conducted a prospective, randomized, multicenter, open-label, phase 2 clinical trial of GX-188E in CIN3 patients positive for HPV type 16/18. The therapeutic vaccine was administered as an intramuscular injection by electroporation. Patients were randomly assigned to receive either 1-mg or 4-mg doses of GX-188E. The primary endpoint was to determine the histopathological regression to ＜CIN1 at visit 7 (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV sequencing analysis and an ex vivo IFN-γ ELISPOT assay were performed using the collected cervical biopsy and blood samples from patients, respectively. Results: In total, 72 patients were enrolled and underwent randomization. Among them, 52% (33/64) at V7 and 67% (35/52) of patients at V8 presented histopathological regression after receiving the GX-188E injection. We found that 73% (24/33) of the patients at V7 and 77% (27/35) of the patients at V8 showed histopathological regression with HPV clearance. HPV clearance and histopathological regression were significantly associated at V7 (odds ratio=13.867, 95% CI: 4.070-47.249, p＜0.001) and at V8 (odds ratio=25.313, 95% CI: 4.750- 14.883, p＜0.001). Compared to the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold-changes in their IFN-γ ELISPOT responses compared to those without HPV clearance (t-test, p=0.002). The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E (T178G), V83L (G350T), and N29S (A647G) were associated with histopathological regression at V8. Conclusions: GX-188E is the first therapeutic vaccine to show greater than 50% efficacy against a cohort containing only CIN3 patients with HPV type 16/18 in a phase 2 clinical trial. Thus, this vaccine may be a clinically feasible, non-surgical therapy for treating cervical pre-malignancy in the near future.

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.

ObjectiveThe aim of this study was to investigate the short-term efficacy and safety of Poly-gamma-glutamic acid (γ-PGA) and the immunologic changes in patients with CIN 1.MethodsParticipants were randomly assigned to one of two groups and orally treated with placebo or 1,500 mg of γ-PGA for 4 weeks. The primary endpoint of the study was histologic regression rate of CIN 1 at 12 weeks between γ-PGA and control groups. The secondary endpoints were HPV clearance and change in immune responses.ResultFrom April 2013 to December 2015, 195 patients participated in the study. In the intention-to-treat analysis, 42 (42.4%) of the women who received γ-PGA experienced histologic remission versus 26 (27.1%) in the control group, with a statistically significant difference (p = 0.018). In the γ-PGA group, HPV clearance was found in 37 (43.5%) of 85 patients infected with high-risk HPV, showing a significant difference compared to the control group, in which 20 (26.7%) of 75 patients exhibited HPV clearance (p = 0.026). However, there was no significant difference between the two groups in the change of NK cell activity, major histocompatibility complex (MHC) class II CD8 count, and CD56 count.Conclusionγ-PGA showed a short-term therapeutic effect on CIN 1 and high-risk HPV infection. It is a non-invasive, promising oral medication for women with these conditions.Trial registrationClinical Trials NCT01826045.

Objective: Solitary lymph node recurrence means that recurrent tumor is detected only in lymph nodes with no evidence of recurrence at other sites. Secondary Cytoreductive Surgery (SCS) for Isolated Lymph Node Recurrence (ILNR) is an acceptable modality, but the survival benefit of surgery remains controversial. The aim of this study was to evaluate the survival outcome of SCS for ILNR in gynecologic cancer. Methods: We reviewed the medical records of 18 patients with solitary lymph node recurrence between January 2009 and September 2014 at Seoul St. Mary’s Hospital. Demographic, diagnostic, operative, pathologic, and follow-up data were retrospectively reviewed. Survival outcome was calculated using the Kaplan-Meier method. Results: The mean age at the time of initial diagnosis of gynecologic malignancy was 49.8±6.7 (40-67) years. Two patients (11.1%) were diagnosed with vulvar cancer, 4 patients (22.2%) were diagnosed with cervical cancer, 1 patient (5.6%) was diagnosed with endometrial cancer, and 11 patients (61.1%) were diagnosed with ovarian cancer. The Disease Free Interval (DFI) was 41.3±34.0 (7.0-119.0) months. Eight patients underwent SCS. The mean time of follow up after recurrence was 23.2±17.0 (3.061.0) months. The overall survival time of ILNR patients was 49.0 months. The overall survival time of patients who underwent SCS was 34.8 months and that of patients who did not was 53.8 months (P=0.285). Conclusion: In selected patients with ILNR, SCS can be an effective treatment with low perioperative morbidity. More data are needed to understand the roll of SCS in ILNR patients.

OBJECTIVE:Persistent infection of HPV increases the chance of carcinoma in situ of cervix through stages of cervical intraepithelial neoplasia (CIN) 1, 2, and 3, and finally progresses into cervical cancer. We aimed to explore the safety and efficacy of BLS-M07 which is orally administered agent expressing human papillomavirus (HPV) 16 E7 antigen on the surface of Lactobacillus casei in patients with CIN 3. METHODS:Patients with CIN 3 were recruited in our clinical trial. Reid Colposcopic Index (RCI) grading and serum HPV16 E7 specific antibody production were used to evaluate efficacy of BLS-M07. In phase 1, BLS-M07 was administered orally, 5 times a week, on weeks 1, 2, 4, and 8 with dosages of 500 mg, 1,000 mg, and 1,500 mg. In phase 2a, patients were treated with 1,000 mg. The primary endpoints were the safety and the pathologic regression on colposcopic biopsy. RESULTS:Nineteen patients were enrolled in the CIN 3 cohort. In phase 1, no patients experienced dose limiting toxicity. No grade 3 or 4 treatment-related adverse events or deaths were observed. At 16 weeks after treatment, RCI grading was improved and serum HPV16 E7 specific antibody production increased (p<0.05). Six of 8 (75%) patients with CIN 3 were cured in phase 2a. CONCLUSIONS:Oral immunization with BLS-M07 increases production of serum HPV16 E7 specific antibody which induces protective humoral immunity. The safety of this oral vaccine was proved and could be a competitive non-surgical therapeutic agent of CIN 3. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02195089.

Concurrence of both endometrial adenocarcinoma and ovarian adult granulosa cell tumor (aGCT) is believed to be related to high estrogen milieu, but genomic alterations of the concurrent endometrial adenocarcinoma and aGCT are not known. For this, we analyzed an uterine endometrial adenocarcinoma and an ovarian aGCT in a same patient by a targeted next generation sequencing (NGS). We found a germline mutation in STK11 (p.L113fs). The endometrial adenocarcinoma harbored FGFR2 and TP53 mutations and the aGCT harbored a FOXL2 (p.C134 W) mutation. These germline and somatic mutations have been reported in non-concurrent tumors. These two tumors harbored 20 CNAs but only one CNA was exactly overlapped in the tumors. Our findings indicate that the concurrent endometrial adenocarcinoma and aGCT in this patient might not be genetically related to each other at germline or somatic level and suggest that such concurrence might be originated from non-genetic backgrounds including stimulated estrogen milieu.

Purpose: This study aimed to evaluate the performance of the PANArray human papilloma virus (HPV) test, a PCR-based DNA microarray assay, in detecting INV from patient samples and its concordance with the cobas 4800 HPV and Hybrid Capture 2 (HC2) tests. Materials and Methods: The PANArray HPV, cobas 4800 HPV, and HC2 tests were performed on 504 cervical swab samples from patients with atypical cells of undetermined significance at five hospitals. The samples that were interpreted as 'HPV-other' type positive in the PANArray HPV test were confirmed by direct sequencing. Results: 'the concordance rates were 80.8% between the cobas 4800 HPV and PANArray HPV tests [kappa=0.59, 95% confidence interval (CI) 0.52-0.66] and 80.2% (kappa=0.6, 95% CI 0.55-0.68) between the HC2 and PANArray HPV tests. Among the 62 patients negative on PANArray HPV (defined as the absence of high risk HPV), but positive on both cobas 4800 HPV and HC2 tests, 42 (67.7%) tested positive for HPV-other' types on the PANArray I I PV test, and 31(50.0%) had gray zone results [relative light unit/control (RLU/CO), 1.4-9.25] in the HC2 test Of the patients deemed positive by the PANArray HPV test, 43 tested positive for high-risk (HR) HPV in cobas 4800 HPV and HC 2 tests. Among them, 58.2% showed HR HPV, including HPV 16, by direct sequencing, of which 25% had gray results. Conclusion: Results classified as 'HPV-other' type by the PANArray HPV test, or gray one results by HC2 (RLU/CO ratio level 1-10) should be carefully interpreted using comprehensive clinical information.