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PurposeThis study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H) in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers according to MMR/MSI status.Materials and MethodsWe conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.ResultsAmong 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%, 164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and 25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129–8.144; p=0.028).ConclusionThe frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could be effective predictive biomarkers in gynecologic cancers of any type.

Purpose While the risk of lower limb lymphedema (LLE) after radical surgery for gynecologic malignancies is multifactorial, the limited assessment of lymph nodes (LNs), such as sentinel LN biopsy, has been incorporated into a standard procedure. We assessed the relationship between the number of LNs retrieved from the hemipelvis and the incidence of ipsilateral LLE (iLLE). Methods This retrospective study included 103 women with gynecologic cancer who had LNs removed with minimally invasive surgery between January 2014 and December 2018. For early detection of LLE, the patients were followed up by a lymphedema specialist who complied with the International Society of Lymphedema criteria. Potential risk factors for LLE were collected, and the risk factors were further investigated according to the number of LNs removed in a side-specific manner. Results LLE was diagnosed in 32 (31.1%) patients, and most of them were diagnosed with unilateral (n = 22) LLE rather than bilateral (n = 10). The number of pelvic LNs removed (p = 0.018), no lymphatic mapping (p = 0.034), and radiation (p = 0.020) were associated with the development of one or both LLEs. A side-specific analysis revealed that the incidence of iLLE increased significantly when four or more LNs were removed from the hemipelvis compared with three or fewer LNs (22.9% vs. 8.3%, p = 0.048). Conclusions The number of pelvic LNs retrieved was associated with the incidence of LLE in patients with early gynecologic cancer. We identified the cutoff number per hemipelvis through side-specific analysis that could minimize the risk of iLLE. Further studies are needed to validate our results.

We aimed to investigate the prevalence and relative contributions of LS and non-LS mutations in patients with endometrial cancer in Korea. We retrospectively reviewed the medical records of 204 patients diagnosed with endometrial cancer who underwent a germline next generation sequencing multigene panel test covering MLH1, MSH2, MSH6, PMS2, and EPCAM at three tertiary centers. Thirty patients (14.7%) with pathogenic mutations (12 MLH1; 6 MSH2; 10 MSH6; 2 PMS2) and 20 patients (9.8%) with 22 unclassified variants (8 MLH1; 8 MSH2; 2 MSH6; 3 PMS2; 1 EPCAM) were identified. After excluding four close relatives of a proband, the prevalence of LS was 13.0% (26/200). Patients with LS were more likely than those with sporadic cancer to be younger at diagnosis (48 vs. 53 years, p = 0.045) and meet the Amsterdam II criteria (66.7 vs. 3.5%, p < 0.001). Non-endometrioid histology was more prevalent in patients with MSH6 or PMS2 mutations (41.7%) than those with MLH1 or MSH2 mutations (5.6%, p = 0.026). In this pre-selected cohort of endometrial cancer patients who underwent next generation sequencing, the prevalence of LS was 13%, thus supporting the use of gene panel testing for endometrial cancer patients.

Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this study, we performed in silico analyses using The Cancer Genome Atlas data to discover novel Notch-related lncRNAs and validated our transcriptome data via NOTCH1/3 silencing in serous ovarian cancer cells. The expression of novel Notch-related lncRNAs was down-regulated by a Notch inhibitor and was upregulated in high-grade serous ovarian cancers, compared to benign or borderline ovarian tumors. Functionally, Notch-related lncRNAs were tightly linked to Notch-related changes in diverse gene expressions. Notably, genes related to DNA repair and spermatogenesis showed specific correlations with Notch-related lncRNAs. Master transcription factors, including EGR1, CTCF, GABPα, and E2F4 might orchestrate the upregulation of Notch-related lncRNAs, along with the associated genes. The discovery of Notch-related lncRNAs significantly contributes to our understanding of the complex crosstalk of Notch signaling with other oncogenic pathways at the transcriptional level.

PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.ResultsBRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Simple Summary Recurrent patients with gynecologic cancer experience a difficult situation when using immune checkpoint inhibitors based on mismatch repair gene immunohistochemistry and microsatellite instability. Six machine learning algorithms were used to create predictive models with seven prospective features (four MMR IHC [MLH1, MSH2, MSH6, and PMS2], MSI, Age 60, and tumor size). The experimental results showed that the RF-based model performed best at predicting gynecologic cancer recurrence, with AUCs of 0.818 and 0.826 for the 5-fold cross-validation (CV) and 5-fold CV with 10 repetitions, respectively. This provides novel and baseline results of patients with recurrent gynecologic cancer using immune checkpoint inhibitors by using machine learning methods based on Lynch syndrome-related screening markers. Abstract To support the implementation of genome-based precision medicine, we developed machine learning models that predict the recurrence of patients with gynecologic cancer in using immune checkpoint inhibitors (ICI) based on clinical and pathologic characteristics, including Lynch syndrome-related screening markers such as immunohistochemistry (IHC) and microsatellite instability (MSI) tests. To accomplish our goal, we reviewed the patient demographics, clinical data, and pathological results from their medical records. Then we identified seven potential characteristics (four MMR IHC [MLH1, MSH2, MSH6, and PMS2], MSI, Age 60, and tumor size). Following that, predictive models were built based on these variables using six machine learning algorithms: logistic regression (LR), support vector machine (SVM), naive Bayes (NB), random forest (RF), gradient boosting (GB), and extreme gradient boosting (EGB) (XGBoost). The experimental results showed that the RF-based model performed best at predicting gynecologic cancer recurrence, with AUCs of 0.818 and 0.826 for the 5-fold cross-validation (CV) and 5-fold CV with 10 repetitions, respectively. This study provides novel and baseline results about predicting the recurrence of gynecologic cancer in patients using ICI by using machine learning methods based on Lynch syndrome-related screening markers.

Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas, this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy.

Objective To investigate the therapeutic efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) as consolidation treatment after completing first-line treatment in patients with advanced ovarian cancer.Methods A retrospective chart review was conducted on patients treated at the Comprehensive Gynecologic Cancer Center between January 2014 and 2019. Based on the inclusion criteria, 24 eligible patients who received HIPEC (paclitaxel 175 mg/m2, for 90 minutes, at 42°C) (HIPEC group) as consolidation treatment after terminating the adjuvant chemotherapy were identified. Another 24 patients who met the inclusion criteria and did not receive HIPEC were matched, representing the non-HIPEC group. Disease-free survival (DFS) and overall survival (OS) were examined between the two groups.Results The median DFS was 28.7 and 24.2 months in the HIPEC and non-HIPEC groups, respectively (P=0.688). The 3-year DFS rates in the HIPEC and non-HPEC groups were 39.5% and 32.6%, respectively. However, the median OS was not determined. The 5-year OS rates in the HIPEC and non-HIPEC groups were 86.2% and 81.3%, respectively (P=0.850). One patient developed grade 3 neutropenia. Other patients experienced mild adverse events after HIPEC.Conclusion This study suggests that consolidation HIPEC could not support the survival benefit after completing the first-line treatment for patients with advanced ovarian cancer, although no severe specific safety issues were found. Therefore, randomized trials evaluating consolidation HIPEC for the management of ovarian cancer are warranted.

Purpose We evaluated the efficacy and safety of pembrolizumab in patients with recurrent gynecologic cancers in real-world practice. Materials and methods We conducted a retrospective, single-institution study of patients with recurrent gynecologic malignancies treated with pembrolizumab. The primary endpoints were the objective response rate (ORR) and safety. Results Thirty-one patients treated with pembrolizumab were included. The primary disease sites were the uterine cervix (n=18), ovaries (n=8), and uterine corpus (n=5). Fifteen of the 31 patients (48%) had an Eastern Cooperative Oncology Group performance status of ≥2. The median number of prior chemotherapy lines was 2 (range, 1-6), and 14 of 31 patients (45%) had received ≥ 3 prior lines of chemotherapy. The overall ORR was 22.6%: specifically, 22.3% (4 of 18 patients), 12.5% (1 of 8 patients), and 40% (2 of 5 patients) for cervical, ovarian, and endometrial cancers, respectively. During a median follow-up of 4.7 months (range, 0.2-35.3), the median time to response was 1.9 months (range, 1.4-5.7). The median duration of response was not reached (range, 8.8-not reached). The median progression-free survival was 2.5 months (95% confidence interval, 1.7-not reached). Adverse events occurred in 20 patients (64.5%), and only 3 (9.7%) were grade ≥3. There was one case of suspicious treatment-related mortality, apart from which most adverse events were manageable. Conclusion In real-world practice, pembrolizumab was feasible and effective in heavily treated recurrent gynecologic cancer patients with poor performance status who may not be eligible for enrollment in clinical trials.

Background Cancer stem cells (CSCs) can self-renew, proliferate into differentiated cells, or enter a quiescent state and are regarded to cause chemoresistance and recurrence. An integrative analysis of transcription factors (TF) and miRNAs was performed in ovarian CSC-enriched spheroid-forming cells (SFCs) to identify factors relevant to ovarian CSCs. Methods Fresh tumor cells from three ovarian cancer patients were cultured in standard and in selective medium. The mRNAs and miRNAs that exhibited significant differential expression between SFCs and adherent cells were identified using mRNA and miRNAs microarrays. Target genes of miRNAs were further selected if predicted with TargetScan by half of the miRNAs or more. Gene enrichment analysis was performed on over- or under-expressed mRNAs and target genes of miRNAs using DAVID tools. Complex regulatory networks were combined from TF-genes and miRNA-genes interactions using the MAGIA webtool. Results A total of 1245 mRNA and 55 miRNAs were differentially expressed (p-value Conclusions MYC, EGR1, and miR-130a-3p were hubs in our integrative analysis of ovarian CSC-enriched SFCs, suggesting that ovarian cancer SFCs display a stem cell identity with the quiescent phenotype where adhesion- and cell cycle-related genes were suppressed.

Aim 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. Methods Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review. Results Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review. Conclusion The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified.

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.

Background and objectives Surgical smoke contains various malodorous and hazardous combustion byproducts. We aimed to analyze hydrocarbons accumulated in the abdominal cavity during laparoscopic gynecologic surgery and determine the efficiency of a built-in-filter port. Methods We prospectively followed seven patients with benign uterine pathology. Surgical smoke was generated using laparoscopic or robotic electrocautery. The smoke was collected twice for each patient using a built-in-filter port and a conventional port. The concentrations of volatile organic compounds and aldehydes were determined using gas chromatography with mass spectrometry and high-performance liquid chromatography with ultraviolet visible light detection and compared using the paired-sample Wilcoxon signed-rank test. Results Five volatile organic compounds and five aldehydes had toxic effects or unpleasant odors. The median concentration of formaldehyde before filtration (0.870 ppm) exceeded the time-weighted average concentration (0.75 ppm) of the Occupational Safety and Health Administration. Built-in-filter ports significantly reduced the concentration of five volatile organic compounds and two aldehydes but not that of formaldehyde, acetaldehyde, and propionaldehyde. Formaldehyde concentration decreased by 50% after filtration but remained above the recommended exposure limit (0.016 ppm) of the National Institute of Occupational Safety and Health. Conclusions Surgical smoke in minimally invasive gynecologic procedures contains several hazardous hydrocarbons including formaldehyde. Built-in-filter ports have the potential to reduce the exposure of surgical smoke to surgeons and operating room personnel; nevertheless, development of built-in-filter ports is necessary to improve the filtering efficiency for highly concentrated formaldehydes.

ObjectivesThe aim of this study was to evaluate the clinicopathologic features of placental site trophoblastic tumors (PSTTs) in Korea.Methods/MaterialsTwenty patients given a diagnosis of PSTT in Korea (1990–2013) were evaluated retrospectively, including 14 patients identified through a literature review and 6 patients identified through a medical chart review of a single institution. The analysis included patient age, antecedent pregnancies, time since antecedent pregnancy, presenting symptoms, serum β-human chorionic gonadotropin level, International Federation of Gynecology and Obstetrics stage, treatment, outcome, and follow-up.ResultsThe mean age of the 20 patients was 32 years (range, 25–53 years). The antecedent pregnancies included 8 term pregnancies, 8 abortions, and 2 molar pregnancies. The time since the antecedent pregnancy was less than 1 year in 16 patients (80%). Nineteen patients (95%) presented with abnormal vaginal spotting or amenorrhea. Serum β-human chorionic gonadotropin levels ranged from normal to 13,480 mIU/mL, although most patients (80%) had a level less than 1000 mIU/mL. Seventeen patients (85%) presented with stage I disease. Ten patients (50%) underwent hysterectomy, and 14 patients (70%) were treated with chemotherapy with or without hysterectomy. In 11 evaluated patients, the median mitotic count index was 3.4 (0.4–10) per 10 high-power fields. The median follow-up time was 17 months (range, 1–68 months). There was no recurrence or death from disease.ConclusionsKorean patients with PSTT often have early-stage disease, which has a favorable prognosis even with fertility-preserving therapy. However, international studies are necessary to determine the optimal treatment and prognostic factors.

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.

Objectives The present study aimed to analyze the clinicopathologic features and treatment of uSTUMP in a single institution. In addition, we described the obstetric outcomes after uterine-preserving surgery for uSTUMP. Methods and materials A retrospective chart review was performed of patients diagnosed with uSTUMP between January 2000 and February 2018 at the Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center. We obtained data on the patients' demographics, treatment, therapeutic results, time to recurrence, disease-free and overall survival, and subsequent obstetric outcomes. The central pathology reviews were carried out by two pathologists specializing in gynecologic oncology. Result A total of 19 patients diagnosed with uSTUMP were identified and included in the study. The mean age at diagnosis was 41 years (range 28–49 years). Frozen sections were performed in 11 patients including five patients during surgery. Nine of the 19 patients (47.4%) were treated by hysterectomy and 10 patients were initially treated by myomectomy. The mean follow-up period was 47 months (range 6–209 months). Two patients (10.5%; 2/19) experienced recurrence. Although not defined as recurrence in the present study criteria, one patient had a secondary diagnosis of atypical leiomyoma one year after the initial diagnosis of uSTUMP. Seven patients requested uterine-preserving treatment, five of whom wanted to become pregnant. Three of them (3/5; 60%) successfully delivered live birth to full term by Cesarean section without complications such as abortion, preterm delivery or uterine rupture, and tumor recurrence. Conclusions The present study describes the clinicopathologic data of uSTUMP patients. Our results suggest a uSTUMP recurrence of 10.5%, comparable to previous reports. Although there is a possibility of malignant recurrence, fertility-preserving management is worth attempting because of relatively low affected age with careful close follow-up.

Since after 2006 when the first edition of practice guidelines for gynecologic oncologic cancer treatment was released, the Korean Society of Gynecologic Oncology (KSGO) has published the following editions on a regular basis to suggest the best possible standard care considering updated scientific evidence as well as medical environment including insurance coverage. The Guidelines Revision Committee was summoned to revise the second edition of KSGO practice guidelines, which was published in July 2010, and develop the third edition. The current guidelines cover strategies for diagnosis and treatment of primary and recurrent ovarian cancer. In this edition, we introduced an advanced format based on evidence-based medicine, collecting up-to-date data mainly from MEDLINE, EMBASE, and Cochrane Library CENTRAL, and conducting a meta-analysis with systematic review. Eight key questions were raised by the committee members. For every key question, recommendations were developed by the consensus meetings and provided with evidence level and strength of the recommendation.

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.

Background and Objective 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. Study Design/Materials and Methods Fifteen patients received PDT for vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), or vulvar Paget's disease between January 2003 and December 2013. Patients underwent colposcopy and/or vulvoscopy for assessment of lesions. Surface photoillumination with a 630-nm red laser light was applied to the lesions 48 hours after intravenous injection of 2 mg/kg photosensitizer (PSZ; Photogem®). The light dose to the lesions was 150 J/cm2. Results The median age of the 15 patients (VIN II: 3, VIN III: 4, VAIN II: 2, VAIN III: 3, Paget's disease: 3) was 42.3 years. The complete response (CR) rate was 80% (12/15) at the 3-month follow-up and 71.4% (10/14) at the 1-year follow-up. There were two cases of persistent disease at the 3-month follow-up. One patient with persistent disease underwent partial vulvectomy three times for repetitive recurrence, and the other received secondary PDT with topical 5-aminolevulinic acid (5-ALA) and subsequently showed no evidence of disease (NED). Another patient achieved 90% remission through a combination of additional alternative treatments after showing partial response (PR). In two cases of CR, recurrence was observed at the 1-year follow-up. Regarding adverse events, photosensitivity reactions such as facial edema and urticaria occurred in 13.3% (2/15) and perineal pain occurred in one patient. Conclusions PDT may be an effective alternative treatment for premalignant lesions of the female lower genital tract to preserve normal anatomy and sexual function without therapeutic impairment. Lasers Surg. Med. 47:566–570, 2015. © 2015 Wiley Periodicals, Inc.

A patient with early-stage endometrial cancer may possibly have microscopic metastasis in the omentum, which is associated with a poor prognosis. The purpose of this study was to identify risk factors for microscopic omental metastasis in patients with clinical stage I endometrial cancer to establish the indications for selective omentectomy. We searched the PubMed, EMBASE, and Cochrane Library databases for published studies from inception to August 2014, using terms such as ‘endometrial cancer’ or ‘uterine cancer’ for disease, ‘omentectomy’ or ‘omental biopsy’ for intervention, and ‘metastasis’ for outcome. Two reviewers independently identified the studies that matched the selection criteria. We calculated the pooled risk ratios (RRs) with 95 % confidence intervals (CI) of each surgicopathologic finding for microscopic omental metastases in clinical stage I endometrial cancer. We also calculated the prevalence of microscopic omental metastases. Among 1163 patients from ten studies, 22 cases (1.9 %) of microscopic omental metastases were found, which accounted for 26.5 % of all omental metastases. Positive lymph nodes (RR 8.71, 95 % CI 1.38–54.95), adnexal metastases (RR 16.76, 95 % CI 2.60–107.97), and appendiceal implants (RR 161.67, 95 % CI 5.16–5061.03) were highly associated with microscopic omental metastases. Microscopic omental metastases were not negligible in patients with clinical stage I endometrial cancer. Those with a risk factor of microscopic omental metastases were recommended for selective omentectomy.

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as "Personalized Medicine", are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells.

Objective To compare the oncologic and obstetric outcomes in reproductive-age females with borderline ovarian tumors (BOTs) treated with cyst enucleation (CE) or unilateral salpingo-oophorectomy (USO). Methods The medical records of patients with BOTs treated between 1998 and 2014 were retrospectively reviewed. The recurrence rates in the USO and CE groups were compared, and the postoperative obstetric outcomes were assessed via telephone survey. Results Eighty-nine patients with BOTs underwent USO, and 19 underwent CE. Of these, six patients had recurrent BOTs. The recurrence rate was significantly lower in the USO group (3/89, 3.4%) than in the CE group (3/19, 15.8%) (P=0.032). All patients with recurrent disease were successfully treated with further surgery. Of the 76 patients interviewed by telephone, 71 (93.4%) resumed regular menstruation after surgery. Twenty-six of the 32 patients (81.3%) who attempted to conceive had successful pregnancies. USO (19/24, 79.2%), like CE (7/8, 87.5%), resulted in favorable pregnancy rates for patients with BOTs. Conclusion USO is a suitable fertility-preserving surgery for women with BOTs. CE is also an acceptable option for select patients.

We examined the involvement of peroxiredoxin 6 (Prdx 6) in providing chemoprotection against cisplatin cytotoxicity in SKOV-3 ovarian cancer cells. Treatment of SKOV-3 cells with cisplatin-induced cytotoxicity that was associated with increased accumulation of intracellular reactive oxygen species (ROS) and apoptosis mediated by proteolytically activated caspase 3 and 9. Overexpression of Prdx 6 protein or exposure to N-acetylcysteine (NAC) reversed the apoptotic effect of cisplatin by reducing ROS levels and suppressing the caspase signaling pathway. These results indicate that targeting Prdx 6 may sensitize cancer cells to ROS-producing therapeutic treatments, such as anticancer drugs and radiation.

The aims of this study were to assess the surgical outcomes and to also determine the prognostic factors in patients with surgically resectable liver metastases for recurrent ovarian cancer. Between 1991 and 2008, 18 patients with recurrent ovarian cancer who underwent hepatic resection as part of secondary cytoreductive surgery were identified from the tumor registry pathology database. Parameters for safety, efficacy, and survival data were considered as primary endpoints. Hepatic resections included wedge resection (n = 4), unisegmentectomy (n = 13), and bisegmentectomy (n = 1). There were no surgery-related deaths. Only one patient (5.6%) had postoperative major complications. The median postoperative hospitalization was 15.5 days (range 11–46 days). The prognostic factors associated with improved survival were less abdominal than pelvic disease (38 vs. 11 months, P = 0.032), optimal cytoreduction (40 vs. 9 months, P = 0.0004), and negative margin status of the hepatic resection (40 vs. 9 months, P = 0.0196). The overall median survival after hepatic resection was 38 months (range 3–78 months). Hepatic resection for recurrent ovarian cancer is safe and is associated with a favorable outcome. Parenchymal liver metastases should not exclude attempts at optimal secondary cytoreductive surgery, and especially, patients with solitary liver metastases should be considered for hepatic resection.

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.

Objective: Ectrodactyly is a rare malformation with various presentations. The current report describes a case of ectrodactyly detected using 2-dimensional (2D) and 3-dimensional (3D) ultrasonography at 16 weeks’ gestation. Methods and Results: The 2D ultrasonographic findings were ectrodactyly in the right hand and monodactyly in the left hand, and these results were confirmed and further clarified using 3D imaging. The postmortem X-ray findings were consistent with the ultrasonography. Conclusion: We conclude that 3D ultrasonography can assist in clarifying 2D ultrasonography findings of hand malformations during the second trimester of pregnancy.

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.

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.Fifteen patients received PDT for vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), or vulvar Paget's disease between January 2003 and December 2013. Patients underwent colposcopy and/or vulvoscopy for assessment of lesions. Surface photoillumination with a 630-nm red laser light was applied to the lesions 48 hours after intravenous injection of 2 mg/kg photosensitizer (PSZ; Photogem®). The light dose to the lesions was 150 J/cmThe median age of the 15 patients (VIN II: 3, VIN III: 4, VAIN II: 2, VAIN III: 3, Paget's disease: 3) was 42.3 years. The complete response (CR) rate was 80% (12/15) at the 3-month follow-up and 71.4% (10/14) at the 1-year follow-up. There were two cases of persistent disease at the 3-month follow-up. One patient with persistent disease underwent partial vulvectomy three times for repetitive recurrence, and the other received secondary PDT with topical 5-aminolevulinic acid (5-ALA) and subsequently showed no evidence of disease (NED). Another patient achieved 90% remission through a combination of additional alternative treatments after showing partial response (PR). In two cases of CR, recurrence was observed at the 1-year follow-up. Regarding adverse events, photosensitivity reactions such as facial edema and urticaria occurred in 13.3% (2/15) and perineal pain occurred in one patient.PDT may be an effective alternative treatment for premalignant lesions of the female lower genital tract to preserve normal anatomy and sexual function without therapeutic impairment. Lasers Surg. Med. 47:566-570, 2015. © 2015 Wiley Periodicals, Inc.

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.

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).

// Ayesha B. Alvero 1 , Michele K. Montagna 1 , Natalia J. Sumi 1 , Won Duk Joo 1 , Emma Graham 1 and Gil Mor 1 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA Correspondence: Gil Mor, email: // Keywords : ovarian cancer, cancer stem cells, oxidative phosphorylation, Warburg effect, maintenance treatment Received : June 29, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract Survival rate in ovarian cancer has not improved since chemotherapy was introduced a few decades ago. The dismal prognosis is mostly due to disease recurrence where majority of the patients succumb to the disease. The demonstration that tumors are comprised of subfractions of cancer cells displaying heterogeneity in stemness potential, chemoresistance, and tumor repair capacity suggests that recurrence may be driven by the chemoresistant cancer stem cells. Thus to improve patient survival, novel therapies should eradicate this cancer cell population. We show that in contrast to the more differentiated ovarian cancer cells, the putative CD44+/MyD88+ ovarian cancer stem cells express lower levels of pyruvate dehydrogenase, Cox–I, Cox-II, and Cox–IV, and higher levels of UCP2. Together, this molecular phenotype establishes a bioenergetic profile that prefers the use of glycolysis over oxidative phosphorylation to generate ATP. This bioenergetic profile is conserved in vivo and therefore a maintenance regimen of 2-deoxyglucose administered after Paclitaxel treatment is able to delay the progression of recurrent tumors and decrease tumor burden in mice. Our findings strongly suggest the value of maintenance with glycolysis inhibitors with the goal of improving survival in ovarian cancer patients.

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.

Adenocarcinoma (ACA) of the uterine cervix is increasing in incidence and currently accounts for approximately 20% of all cervical malignancies. MicroRNAs (miRNAs) have been investigated as potential biomarkers of cervical cancer; however, their role in ACA remains unknown. Here, we characterized miRNA expression profiles and investigated miRNAs as diagnostic and prognostic factors in ACA.Evaluation of genome-wide miRNA expression profiles in ACA by microarray led to the identification of ten candidate miRNAs, whose expression patterns were validated by qRT-PCR in 45 ACA, 10 normal control, and 15 squamous cell carcinoma samples. The association between miRNA expression and prognosis was analyzed in patients with ACA.Microarray analysis identified 86 miRNAs that were dysregulated more than 2.0-fold (p0.05) in ACA relative to normal tissues of the uterine cervix. Five most over- and underexpressed miRNAs were selected respectively and their expression patterns were confirmed in the validation set. MiR-135b, miR-192, and miR194 were overexpressed in ACA, and miR-363-3p, miR-195 and miR-199b were significantly associated with conventional prognostic factors. Overexpression of miR-363-3p by more than 2.5-fold relative to the normal control was a strong predictor of favorable prognosis (hazard ratio, 0.1; 95% confidence interval, 0.009-0.779) after adjusting for confounders.MiR-135b, miR-192, and miR-194 are altered in uterine cervical ACA, and miR-363-3p is an independent favorable prognostic factor in ACA. These miRNAs could be of value as biomarkers for the diagnosis and prognosis of ACA.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP+/CD44+/MyD88+ EOC stem cells and mCherry+/CD44−/MyD88− EOC cells. The in vivo model consists of mCherry+/CD44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction (qPCR) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD44+/MyD88+ EOC stem cells. However, we observed that the surviving CD44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer.

Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3′-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3′-UTR. This suggests that the TTP-mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells.

Background/Aims: To evaluate the feasibility and safety of single-port access total laparoscopic hysterectomy (SPA-TLH) for large uterus (>500 g). Methods: A prospective data collection was performed in 21 consecutive patients in March 2010 and August 2011. Surgical outcome including operative time (OT) and estimated blood loss (EBL) were analyzed. Results: SPA-TLH procedures were successfully performed in 16 cases (76.2%). Of the 5 failed cases, 4 were converted to multiport TLH because of distorted uterine contours and pelvic adhesions and 1 was converted to laparotomy for bleeding control. The median OT, uterine weight, and EBL were 110 (65–165) min, 600 (502–980) g, and 200 (100–800) ml, respectively. Spearman’s correlation analysis demonstrated that OT and blood loss increased with increasing uterine weight (p = 0.003 and p = 0.033, respectively). No operative complications were observed during the hospital stay and 3-month follow-up following discharge. Conclusion: SPA-TLH for large uterus is a feasible and safe technique.

Ectrodactyly is a rare malformation with various presentations. The current report describes a case of ectrodactyly detected using 2-dimensional (2D) and 3-dimensional (3D) ultrasonography at 16 weeks' gestation.The 2D ultrasonographic findings were ectrodactyly in the right hand and monodactyly in the left hand, and these results were confirmed and further clarified using 3D imaging. The postmortem X-ray findings were consistent with the ultrasonography.We conclude that 3D ultrasonography can assist in clarifying 2D ultrasonography findings of hand malformations during the second trimester of pregnancy.