Won Duk Joo

Ovulation and extra-ovarian origin of ovarian cancer

The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies.

Photodynamic therapy for premalignant lesions of the vulva and vagina: A long-term follow-up study.

We aimed to evaluate responses to photodynamic therapy (PDT) and its long‐term efficacy in preserving normal anatomy and function in women with premalignant lesions of the lower genital tract.

Germline Mutations of BRCA1 and BRCA2 in Korean Ovarian Cancer Patients: Finding Founder Mutations

Objectives To investigate and analyze the BRCA mutations in Korean ovarian cancer patients with or without family history and to find founder mutations in this group. Methods/Materials One hundred two patients who underwent a staging operation for pathologically proven epithelial cancer between January 2013 and December 2014 were enrolled. Thirty-two patients declined to analyze BRCA1/2 gene alterations after genetic counseling and pedigree analysis. Lymphocyte specimens from peripheral blood were assessed for BRCA1/2 by direct sequencing. Results BRCA genetic test results of 70 patients were available. Eighteen BRCA1/2 mutations and 17 unclassified variations (UVs) were found. Five of the BRCA1/2 mutations and 4 of the UVs were not reported in the Breast Cancer Information Core database. One BRCA2 UV (8665_8667delGGA) was strongly suspicious to be a deleterious mutation. BRCA1/2 mutations were identified in 11 (61.1%) of 18 patients with a family history and in 7 (13.5%) of 52 patients without a family history. Candidates for founder mutations in Korean ovarian cancer patients were assessed among 39 BRCA1/2 mutations from the present study and from literature reviews. The analysis showed that 1041_1043delAGCinsT (n = 4; 10.2%) and 3746insA (n = 4; 10.2%) were possible BRCA1 founder mutations. Only one of the BRCA2 mutations (5804_5807delTTAA) was repeated twice (n = 2; 5.1%). Conclusions The prevalence of BRCA1/2 mutations in Korean ovarian cancer patients irrespective of the family history was significantly higher than previously reported. Possible founder mutations in Korean ovarian cancer patients were identified.

Comparison of diagnostic accuracy between endometrial curettage and pipelle aspiration biopsy in patients treated with progestin for endometrial hyperplasia: a Korean Gynecologic Oncology Group Study (KGOG 2019).

A prospective multicenter trial has been started in Korea to evaluate the diagnostic accuracy of endometrial aspiration biopsy compared with dilatation and curettage in patients treated with progestin for endometrial hyperplasia. For conservative treatment of endometrial hyperplasia, orally administered progestins are most commonly used method with various treatment regimens and more recently, the levonorgestrel-releasing intrauterine system also has been used successfully to treat endometrial hyperplasia. However, there is no report about the accuracy of endometrial sampling during hormonal treatment for follow-up evaluation of endometrial hyperplasia. Patients with histologically confirmed endometrial hyperplasia are offered hormonal treatment with any one of the following three options: oral medroxyprogesterone acetate 10 mg/day for 14 days per cycle, continuous oral medroxyprogesterone acetate 10 mg/day or insertion of levonorgestrel-releasing intrauterine system. Histological surveillance is performed at 3 months or 6 months following initial treatment. Endometrial tissues are obtained via endometrial aspiration biopsy using a pipelle and dilatation and curettage. In the case of levonorgestrel-releasing intrauterine system, endometrial aspiration biopsy will be done with levonorgestrel-releasing intrauterine system in uterus and then, after the removal of levonorgestrel-releasing intrauterine system, dilatation and curettage will be done. The biopsy findings will be compared. The primary endpoint is to compare the pathological outcome of endometrial aspiration with dilatation and curettage. The secondary endpoint is the response rate with three types of progestin treatment at 6 months.

Case Report of Menopausal Woman Diagnosed with Endometrial Cancer after Colon Cancer with Germline Mutation in MSH6 in Korea

We present a case of an endometrial cancer patient with germline mutation in MutS homolog 6 (MSH6), associated with Lynch syndrome. A 60-year-old Korean woman had a personal history of colon cancer 23 years ago. She also had a family history of endometrial cancer and colon cancer of her sisters and brothers. Immunohistochemistry was negative for MutL homolog 1 (MLH1) and positive for MutS homolog 2 (MSH2). Based on these findings, she underwent genetic counseling and testing that revealed a frameshift germline mutation at MSH6 (c. 3261dupC).

Unclassified Variants of BRCA1 and BRCA2 in Korean Patients With Ovarian Cancer

Objective The aim of the present study was to investigate unclassified variants (UVs) in BRCA1 and 2 of Korean patients with ovarian cancer. Methods We retrospectively analyzed 138 patients diagnosed with ovarian/fallopian tubal/peritoneal cancer between January 2013 and January 2016, whose BRCA genetic test results and clinical characteristics were available for review. Patient peripheral blood lymphocyte specimens were assessed for BRCA mutations and variations by direct sequencing. Identified UVs were classified according to several algorithms. Results The results of genetic testing revealed 31 (22.5%, 31/138) pathogenic BRCA mutations (24 BRCA1, 7 BRCA2 mutations). The BRCA1 c.390C>A mutation was observed in 4 patients (12.9%, 4/31). Thirty-four (24.6%, 34/138) BRCA UVs were identified in 33 patients. Of these, the BRCA1 c.4883T>C and BRCA2 c.8187G>T variants were each detected in 4 patients (4/34, 11.8%). According to the used algorithms and cosegregation test, the BRCA1 c.5339T>C and BRCA2 c.8437_8439delGGA variants were both predicted to be likely pathogenic. Conclusions The 2 identified likely pathogenic UVs require further verification with clinical evidence. Clarifying the clinical significance of UVs is an increasingly important step for cancer treatment in the current era of precision medicine.

Abstract LB-286: ME-344 delays tumor kinetics in an ovarian cancer in vivo recurrence model.

Background: Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite initial responsiveness to first-line standard of care, consisting of surgical debulking and chemotherapy, 8 out of 10 patients recur. In the recurrence setting, the presentation of widespread micrometastasis, which limits the usefulness of surgery, is complicated by concurrent presentation of chemoresistance. Currently, no adequate therapy is able to prevent or treat recurrence. Consequently, therapies directed against control of tumor burden can improve prognosis in EOC patients. Recently we reported the characterization of CD44+/MyD88+ EOC cells with tumor-initiating properties and inherent chemoresistance. In addition, we have identified ME-344, a novel isoflavone derivate, with potent capacity to induce cell death in these cells. Furthermore, we have developed an intra-peritoneal (i.p.) in vivo model of EOC recurrence based on the capacity of these cells to survive chemotherapy and renew the tumor. Using this model, we show the potential efficacy of ME-344 in delaying carcinomatosis and decreasing tumor burden. Methods: CD44+/MyD88+/mCherry+ EOC stem cells are injected i.p. in nude mice. Tumors are detected and consequently followed by live in vivo imaging using In Vivo FX System. Once tumors are detected, mice received 4 doses of 12 mg/kg i.p. Paclitaxel q3d or until the animals are free of disease. Mice were then randomized to maintenance with Vehicle or ME-344 (100 mg/kg i.p. q3d) and further monitored for recurrence. Recurrence is defined as appearance of tumors with ROI interior area > 2000. Tumor growth delay is defined as the difference in days when treated and control groups reach the maximal tumor burden set at ROI interior area = 10,000. Results: Mice exhibited recurrence with an average time of 6 days in the Vehicle group and 7 days in the ME-344 group. However, a significant delay in tumor kinetics was observed in the group maintained with ME-344. Maximal tumor burden, defined as ROI interior area = 10,000, was reached in the control group within 24 days and in the ME-344 group within 39 days. Thus, tumor growth was delayed for 15 days. Conclusion: Maintenance with ME-344 is able to decrease tumor burden in this very aggressive in vivo model of EOC recurrence. In this study, we show a significant delay in tumor kinetics in mice that were maintained with ME-344 following initial response to Paclitaxel. Decreasing and delaying metastatic load will allow more optimal surgical debulking and may improve survival in EOC patients. These results suggest the potential value of ME-344 therapy after 1st line standard of care in EOC patients. Citation Format: Ayesha B. Alvero, Natalia Sumi, Vinicius Craveiro, Won Duk Joo, Yang Yang-Hartwich, Gil Mor. ME-344 delays tumor kinetics in an ovarian cancer in vivo recurrence model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-286. doi:10.1158/1538-7445.AM2013-LB-286

Minimal deviation adenocarcinoma (adenoma malignum) of the uterine cervix: clinicopathological analysis of 17 cases

Objective The aim of this study was to evaluate the clinicopathological features of minimal deviation adenocarcinoma (MDA) and to analyze its prognostic factors. Methods We retrospectively analyzed the medical records of 17 patients who were diagnosed with MDA at a single institution between January 2005 and December 2015. Results The median age of the patients was 47.7 years (33–75 years). MDA was diagnosed in 7 patients (41.2%) before performing definitive surgery. Stage IB disease was diagnosed in 12 patients (70.6%) and advanced stage disease (stage II: 3, stage III: 2) in 5. MDA was incidentally diagnosed following hysterectomy for benign conditions in 6 patients. Adjuvant therapy was administered to 13 patients (76.5%). During median follow-up over 33.6 months (7–99 months), 11 patients (64.7%) showed no evidence of disease, 6 (35.3%) showed persistent or recurrent disease and 5 died of the disease. Peutz-Jeghers syndrome was not suspected in any patient, and no mutation was detected in the 3 patients who underwent genetic testing. Univariate analysis showed that advanced stage disease (P=0.016) and lymphovascular space invasion (P=0.002) demonstrated a statistically significant association with poor overall survival (OS) rates. Advanced stage disease continued to show a significant association with poor OS rates (hazard ratio, 2.92; 95% confidence interval, 1.097–7.746; P=0.032) even after multivariate analysis. Conclusion Early diagnosis is important to manage MDA. Clinicians should consider MDA among the differential diagnoses in patients with a suspicious clinical presentation even with negative cervical screening tests.

Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution

To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea.

Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube

Objective The aim of the present study was to assess the frequency of germline mutations in patients with peritoneal carcinoma (PC) or the fallopian tube carcinoma (FTC), using a multi-gene panel. Methods Twenty-six patients diagnosed with either PC or FTC between January 2013 and December 2016 were recruited consecutively. Germline DNA was sequenced using a 6-gene next generation sequencing (NGS) panel following genetic counseling. Surgico-medical information was obtained from hospital records. Genetic variations were detected using the panel and were cross-validated by Sanger direct sequencing. Results Germline BRCA1/2 mutations were identified in 6 patients (23.1%). Four were detected in patients with PC and 2 were in FTC patients. No mutations were detected in TP53, PTEN, CDH1, or PALB2. We identified 11 variant of uncertain significance (VUS) in 9 patients; 2 in BRCA1, 3 in BRCA2, 2 in TP53, and 4 in CDH1. We also detected a CDH1 c.2164+16->A VUS in 3 patients. Conclusion The prevalence of germline BRCA1/2 mutations in patients with PC or FTC is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.