Changes in the tumor immune microenvironment during disease progression in clear cell ovarian cancer.

OBJECTIVE: The tumor immune microenvironment in ovarian clear cell carcinoma has not been clearly defined. We analyzed the immunological changes from treatment-naive to recurrence to correlate them with clinical outcomes. METHOD: We compared the changes in immune infiltration of advanced-stage ovarian clear cell carcinoma samples before treatment and at the time of recurrence via immunohistochemistry (Programmed Cell Death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8+), forkhead box P3 (Foxp3+)), tumor-infiltrating lymphocytes (TIL), and next-generation sequencing (54 patients). We analyzed the association between platinum sensitivity status and tumor immune microenvironment. RESULTS: Immunohistochemistry revealed significantly increased PD-L1 (p=0.048) and CD8+T cells (p=0.022) expression levels after recurrence. No significant differences were observed in TIL density or Foxp3+T cells. There was no significant correlation between TIL, PD-L1, CD8+T cell, and Foxp3+T cell levels in treatment-naive tumors and survival outcomes. The most common genomic alterations were PIK3CA (41.7%) and ARID1A (41.7%) mutations. There were no differences in the immunological changes or survival outcomes according to PIK3CA and ARID1A mutations. Patients with recurrent platinum-sensitive disease showed higher TIL expression levels. There were no significant differences in PD-L1, CD8+T cells, or Foxp3+T cells between platinum-sensitive and platinum-resistant diseases. CONCLUSION: We characterized the tumor immune microenvironment in patients with advanced-stage ovarian clear cell carcinoma. PD-L1 and CD8+T cell expression significantly increased after recurrence. Whether this could be used to select patients for immunotherapy in the recurrence setting should be investigated.

Comparison of oncological outcomes between sentinel lymph node biopsy and complete lymphadenectomy for endometrial cancer.

AIM: Sentinel lymph node (SLN) mapping allows node-negative patients to be spared from the surgical comorbidities associated with total lymphadenectomy. This study aimed to evaluate the oncological outcomes of SLN biopsy versus complete lymph node dissection in patients with early-stage endometrial carcinoma. METHODS: Retrospective analyses were performed in patients with pathologically confirmed endometrioid endometrial carcinoma, who underwent minimally invasive surgical staging with SLN biopsy or complete lymph node dissection at Yonsei Cancer Center between 2015 and 2019. RESULTS: A total of 301 patients were included in this study. Eighty-two patients underwent SLN biopsy, while 219 underwent complete lymph node dissection. There were no significant differences in patient characteristics between the two groups. In terms of operative characteristics, the SLN biopsy-only group had a significantly shorter surgical duration (p < 0.001) than the lymphadenectomy group. The mean follow-up period was 41.4 months. There were no differences in progression-free survival (PFS) and overall survival (OS) between the two groups (SLN biopsy vs. complete lymph node dissection; p = 0.798 and 0.301, respectively). Multivariate analysis revealed that SLN biopsy was not an independent prognostic factor for PFS or OS. CONCLUSION: Our results showed that SLN biopsy provided oncological outcomes similar to those of lymphadenectomy.

Safety and efficacy study of laparoscopic or robotic radical surgery using an endoscopic stapler for inhibiting tumour spillage of cervical malignant neoplasms evaluating survival (SOLUTION): a multi-centre, open-label, single-arm, phase II trial protocol.

BACKGROUND: The Laparoscopic Approach to Cervical Cancer trial and Surveillance, Epidemiology, and End Results program database study demonstrated that minimally invasive radical hysterectomy was inferior to abdominal radical hysterectomy in terms of disease recurrence and survival. Among risk factors related to poor prognosis after minimally invasive surgery (MIS), tumour spillage during intracorporeal colpotomy became a significant issue. Thus, we designed this trial to evaluate the efficacy and safety of minimally invasive radical hysterectomy using an endoscopic stapler for early-stage cervical cancer. METHODS: This trial is a prospective, multi-centre, open-label, single-arm, non-inferiority phase II study. The nine organisations will participate in this trial after the approval of the institutional review board. Major eligibility criteria include women aged 20 years or older with cervical cancer stage IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma according to the revised 2009 FIGO staging system who will undergo type B2 or C hysterectomy by MIS. The primary endpoint is the 4.5-year disease-free survival (DFS) rate between abdominal radical hysterectomy and MIS using an endoscopic stapler. For calculating the sample size, we hypothesised that the 4.5-year DFS rate after MIS using an endoscopic stapler is assumed to be the same after abdominal radical hysterectomy at 90.9%, and the non-inferiority margin was 7.2%. When we consider a three-year accrual and 4.5-year follow-up, at least 13 events must happen, requiring a total of 111 patients assuming a statistical power of 80% and the one-tailed test of 5% significance. A total of 124 patients is needed, considering a drop-out rate of 10%. DISCUSSION: We expect intracorporeal colpotomy using an endoscopic stapler may prevent tumour spillage during MIS for stage IB1 cervical cancer, showing a comparable prognosis with abdominal radical surgery. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04370496 ; registration date, May 2020.

Usefulness and potential pitfalls of pre-operative PET-CT in patients with endometrial cancer undergoing one- and two-step sentinel lymph node mapping: Do negative findings on PET-CT negativity really indicate node negativity?

OBJECTIVE: We investigated the utility of Positron emission tomography-Computed tomography (PET-CT) in the setting of two different sentinel lymph node (SLN) mapping techniques; the conventional cervical injection method (one-step) and the two-step method, which involves fundal injection followed by cervical injection. METHODS: Patients with endometrial cancer undergoing FDG PET-CT followed by laparoscopic or robotic surgical staging with SLN mapping at the Yonsei Cancer Center between July 2014 and April 2021 were stratified into the PET-positive group (with suspected or likely lymph nodes metastasis) and PET-negative group. A chart review was performed for the number of harvested SLNs, patterns of SLN metastases, and recurrence. RESULTS: Among 466 patients undergoing one-step (n = 276) and two-step (n = 190) SLN mapping, LN metastasis was identified in 21 of 434 PET-negative and 18 of 32 PET-positive patients. The sensitivity and specificity of PET-CT for diagnosing lymph node metastasis were 46.2% and 96.7%, respectively. Among PET-positive patients with LN metastasis, anatomical distribution was concordant in 14/18 patients (77.8%). Among PET-negative patients, four (2.3%) had metastatic para-aortic SLNs, including three (1.7%) with isolated para-aortic metastases; metastatic para-aortic SLNs were exclusively found in the two-step group. Among PET-positive patients, para-aortic SLN metastasis was identified in 35.7% of two-step and 16.7% of one-step group. Among the 21 PET false-negative patients, recurrence was seen in four patients (19%) after a median follow-up of 34 months (range: 7-70 months). CONCLUSIONS: PET-CT served as a useful guide to clinicians with high anatomical concordance rate in patients with LN metastasis. However, despite high specificity, sensitivity was limited. SLN metastasis pattern, especially at the para-aortic level, indicates that the two-step SLN technique might be useful in PET-negative and PET-positive patients.

Incidence of postoperative thrombotic events in ovarian cancer patients with a de-escalated prophylactic strategy: A retrospective cohort study.

OBJECTIVE: This study aimed to determine the incidence of thrombotic events in ovarian cancer patients following a de-escalated prophylactic strategy and to stratify risk groups. METHODS: We reviewed the records of patients who underwent debulking surgery for ovarian cancer at a single institution between January 2007 and May 2019. We identified clinically diagnosed and radiologically confirmed cases of thrombotic events-classified as pulmonary thromboembolism (PE), deep vein thrombosis (DVT), and other thrombotic events-within 6 months of debulking surgery. RESULTS: After excluding 13 patients diagnosed with thromboembolism at the baseline or during neoadjuvant chemotherapy, 799 were analyzed. Since the introduction of medical prophylaxis at our institution in 2009, 482 patients (60%) received medical prophylaxis with subcutaneous injection of low molecular weight heparin for 5 days with mechanical prophylaxis, whereas 317 (40%) received mechanical prophylaxis only. After debulking surgery, thrombotic events occurred in 28 patients (3.5%) including PE (n = 11), DVT (n = 10), and other thrombotic events (n = 7). Multivariable analysis identified age, body mass index (BMI), and operative duration as independent risk factors associated with thrombotic events. A thrombotic event was an independent prognostic factor for overall survival (HR 2.17, 95% CI 1.16-4.1). A cut-off analysis for pre-operative identifiable risk factors showed age < 57 years and BMI < 21 could help define low-risk groups. One patient from 172 low-risk patients (0.58%) experienced a thrombotic event. CONCLUSIONS: The thrombotic event incidence was low in our cohort. A de-escalated prophylaxis strategy may be considered in young (age < 57 years) and lean (BMI < 21) patients.

Immunohistochemical and genetic characteristics of HPV-associated endocervical carcinoma with an invasive stratified mucin-producing carcinoma (ISMC) component.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described entity of human papillomavirus (HPV)-associated endocervical adenocarcinoma with phenotypic plasticity and aggressive clinical behavior. To identify the cell of origin of ISMC, we investigated the immunohistochemical expression of cervical epithelial cell markers (CK7, PAX8, CK5/6, p63, and CK17), stemness markers (ALDH1 and Nanog), and epithelial-mesenchymal transition (EMT) markers (Snail, Twist, and E-cadherin) in 10 pure and mixed type ISMCs with at least 10% of ISMC component in the entire tumor, seven usual type endocervical adenocarcinomas (UEAs), and seven squamous cell carcinomas (SCCs). In addition, targeted sequencing was performed in 10 ISMCs. ISMC was significantly associated with larger tumor size (p = 0.011), more frequent lymphovascular invasion and lymph node metastasis (p < 0.001), higher FIGO stage (p = 0.022), and a tendency for worse clinical outcomes (p = 0.056) compared to other HPV-associated subtypes. ISMC showed negative or borderline positivity for PAX8, CK5/6, and p63, which were distinct from UEA and SCC (p < 0.01). Compared to UEA and SCC, ISMC showed higher expression for ALDH1 (p = 0.119 for UEA and p = 0.009 for SCC), Snail (p = 0.036), and Twist (p = 0.119), and tended to show decreased E-cadherin expression (p = 0.083). In next-generation sequencing analysis, ISMC exhibited frequent STK11, MET, FANCA, and PALB2 mutations compared to conventional cervical carcinomas, and genes related to EMT and stemness were frequently altered. EMT-prone and stemness characteristics and peripheral expression of reserve cell and EMT markers of ISMC suggest its cervical reserve cell origin. We recommend PAX8, CK5/6, and p63 as diagnostic triple biomarkers for ISMC. These findings highlight the distinct biological basis of ISMC.

The preventive effect of breastfeeding against ovarian cancer in BRCA1 and BRCA2 mutation carriers: A systematic review and meta-analysis.

OBJECTIVE: A recent study showed that even a few months of breastfeeding is associated with a significant decrease in the risk of ovarian cancer in the general population. This study aimed to perform a systematic review and meta-analysis to determine the significance of the length of the breastfeeding period on ovarian cancer risk in BRCA1/2 mutation carriers. METHODS: PubMed, EMBASE, and Cochrane databases were searched up to June 1, 2021. We included case-control and cohort studies that contained information on breastfeeding and the risk of ovarian cancer in BRCA1/2 mutation carriers. Odds ratios (OR) were meta-analytically pooled using a fixed-effects model.dd RESULTS: Five studies, including one cohort study and four case-control studies, were included in this meta-analysis. Of the 14,601 BRCA1/2 mutation carriers, the overall pooled OR of ever having performed breastfeeding in patients who had ovarian cancer was 0.767 (95% confidence interval [CI], 0.688-0.856) and 0.817 (95% CI, 0.650-1.028) for patients with BRCA1 and BRCA2 mutation, respectively. Breastfeeding for >1 year acted as a protective factor in both BRCA1 [OR: 0.787 (95% CI, 0.682-0.907)] and BRCA2 [OR: 0.567 (95% CI, 0.400-0.802)] mutation carriers. No significant heterogeneity was present (I2 = 0%), and the funnel plot was also properly distributed, showing no publication bias. CONCLUSIONS: Breastfeeding is a preventive, modifiable factor for ovarian cancer in BRCA1/2 mutation carriers. Ever having performed breastfeeding was significantly preventive for ovarian cancer in the BRCA1 mutation carriers, however a period of 1 year or more of breastfeeding is required for a reduced ovarian cancer risk in BRCA2 mutation carriers.

Mismatch repair status influences response to fertility-sparing treatment of endometrial cancer.

BACKGROUND: Patients younger than 40 years usually present with early-stage endometrial cancer with favorable prognosis. However, such patients are usually in their childbearing age and may desire fertility-sparing options. The identification of biomarkers may improve the clinical outcomes in these patients and aid in fertility-sparing management; however, there has been no reports on biomarker analysis so far. OBJECTIVE: This study aimed to evaluate the prognostic significance of Proactive Molecular Risk Classifier for Endometrial Cancer in the fertility-sparing management of endometrial cancer. STUDY DESIGN: A total of 57 endometrial biopsy specimens obtained before hormone therapy were evaluated, and patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes (mismatch repair deficiency, DNA polymerase epsilon mutation, wild-type p53, and abnormal p53). The primary endpoint was the response rate after hormone therapy. The secondary endpoint was the recurrence rate after the complete response, hysterectomy rate owing to treatment failure, and upstaged diagnosis rate after hysterectomy. RESULTS: Of 57 patients, 9 (15.8%) had mismatch repair deficiency, 2 (3.5%) had DNA polymerase epsilon mutation, 45 (78.9%) had wild-type p53, and 1 (1.8%) had abnormal p53. Overall, the complete response rate was 75.4% after hormone therapy. Patients with mismatch repair deficiency had a significantly lower complete response or partial response rate than those with wild-type p53 in terms of the best overall response (44.4% [95% confidence interval, 4.0-85.0] vs 82.2% [95% confidence interval, 71.0-94.0]; P=.018) and complete response rate at 6 months (11.1% [95% confidence interval, 0.2-37.0] vs 53.3% [95% confidence interval, 38.0-68.0]; P=.010). Among patients with mismatch repair deficiency, 4 underwent immediate hysterectomy because of treatment failure and 3 presented upstaged diagnosis after hysterectomy. CONCLUSION: The Proactive Molecular Risk Classifier for Endometrial Cancer molecular classification has prognostic significance in the fertility-sparing management of endometrial cancer, thereby enabling early stratification and risk assignment to direct care. Mismatch repair status could be used as a predictive biomarker for selecting patients who could benefit from hormone therapy. These findings need to be validated in larger studies.

Impact of subcutaneous negative pressure drains on surgical wound healing in ovarian cancer.

INTRODUCTION: Subcutaneous negative pressure wound drains have been used to reduce wound complication rates in various surgical procedures. However, research on the benefits of subcutaneous drains on wound healing after ovarian cancer surgery is limited. The aim of this study was to assess the effects of subcutaneous negative pressure drains on wound healing after abdominal surgery for ovarian cancer. METHODS: Patients who underwent surgery with a midline incision for ovarian cancer between February 2015 and May 2019 were retrospectively examined. Patients were divided into two groups according to the presence (group 1; n=99) or absence (group 2; n=213) of subcutaneous wound drains. The primary endpoint was the incidence of wound complications within 8 weeks after abdominal surgery. The secondary endpoints were time interval from surgery to adjuvant chemotherapy and survival. RESULTS: Patients in group 1 were older (mean 58.5 vs 55.4 years; p=0.02), and had higher rates of previous abdominal surgery (66.7% vs 47.9%; p=0.002), bowel surgery (47.5% vs 34.3%; p=0.026), and had a high surgical complexity score (53.5% vs 33.8%; p<0.001) compared with patients in group 2. Median body mass index was not different between the two groups: group 1, 22.9 kg/m2 (range 16.0 to 33.3) and group 2, 22.8 kg/m2 (range 16.4 to 37.5) (p=0.858). A higher rate of clear wound healing (82.8% vs 71.8%; p=0.036) and a lower rate of seroma formation (6.1% vs 16.0%; p=0.015) were observed in group 1 compared with group 2. After multivariate analysis, subcutaneous wound drain placement was identified as an independent predictive factor for preventing wound complications (adjusted odds ratio 0.43; 95% confidence interval 0.21 to 0.87). Time interval from surgery to adjuvant treatment was significantly longer in patients with wound complications than in those with clear wound healing (mean 23.6 vs 19.2 days; p=0.003). Kaplan-Meier analysis, however, showed no significant differences in progression free or overall survival between the two groups (p=0.35 and p=0.96, respectively). CONCLUSION: The prophylactic use of subcutaneous negative pressure drains after abdominal surgery for ovarian cancer significantly reduced the incidence of wound complications in this study.

The institutional learning curve is associated with survival outcomes of robotic radical hysterectomy for early-stage cervical cancer-a retrospective study.

BACKGROUND: Despite recent advances in diagnosis and treatment, cervical cancer continues to be a significant health problem worldwide. Whereas robot-assisted surgery has advantages over the abdominal approach, and minimally invasive techniques are being used increasingly, these may be associated with a higher recurrence rate and lower overall survival than the abdominal approach. The objective of this study was to compare the surgical and survival outcomes between abdominal radical hysterectomy (ARH) and robotic radical hysterectomy (RRH). METHODS: A retrospective cohort of patients undergoing radical hysterectomy for cervical cancer from 2006 to 2018 was identified. Patients with stage IA to IB cervical cancer were included and grouped: ARH vs. RRH. The RRH group was further divided into two groups based on the year of enrollment: RRH1 (2006-2012) and RRH2 (2013-2018). Tumor characteristics, recurrence rate, progression-free survival (PFS), and overall survival (OS) were compared between the groups. P-values < 0.05 (two-sided) were considered statistically significant. RESULTS: A total of 310 patients were identified: 142 and 168 underwent ARH and RRH, respectively. RRH1 and RRH2 had 77 and 91 patients, respectively. Interestingly, RRH2 was more likely to have a larger tumor size (1.7 ± 1.4 vs. 2.0 ± 1.1 vs. 2.4 ± 1.7 cm, P = 0.014) and higher stage (P < 0.001) than RRH1. However, RRH2 showed significantly favorable PFS in contrast to RRH1. There was no difference between ARH and RRH2 in PFS (P = 0.629), whereas overall, the RRH group showed significantly shorter PFS than the ARH group. In the multivariate analysis, the institutional learning curve represented by the operation year was one of the significant predictors for PFS (hazard ratio [HR] 0.065, P = 0.0162), along with tumor size (HR 5.651, P = 0.0241). CONCLUSIONS: The institutional learning curve, represented by the operation year, is one of the most significant factors associated with outcomes of RRH for early-stage cervical cancer.

Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors. METHODS: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel. RESULTS: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98). CONCLUSIONS: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.

Germline BRCA, chemotherapy response scores, and survival in the neoadjuvant treatment of ovarian cancer.

BACKGROUND: To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). METHODS: We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated. RESULTS: BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients. CONCLUSION: In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.

Comparison of outcomes between the one-step and two-step sentinel lymph node mapping techniques in endometrial cancer.

INTRODUCTION: Fluorescence image-guided sentinel lymph node (SLN) biopsy using a two-step mapping technique incorporates sequential injection of indocyanine green into the bilateral uterine cornus, followed by cervical injection. Outcomes were compared with the conventional cervical (one-step) method . METHODS: Patients with FIGO stage I-III endometrial cancer who underwent laparoscopic or robotic staging, including SLN biopsy, from May 2014 to December 2018, were retrospectively reviewed. Patient characteristics, pre-operative imaging, SLN detection pattern, pathologic result, adjuvant, and recurrence locations were analyzed. RESULTS: A total of 199 patients received one-step (n=123) and two-step (n=76) SLN biopsy. Para-aortic SLN were more frequently identified in the two-step group. Lower and upper para-aortic SLN were identified in 67.1% and 38.2%, respectively, in the two-step group and in 18.7% and 5.7% in the one-step group (p<0.001). The number of para-aortic SLN harvested was superior in the two-step group (p<0.001). Metastatic para-aortic SLN were found in 7.9% of the two-step group and 2.4% of the one-step group (p=0.070). In detecting nodal metastasis, the sensitivities of the one- and two-step methods were 91.7% and 100.0%, negative predictive values were 99.0% and 100.0%, false-negative rates were 8.3% and 0%, and accuracy rates were 99.1% and 100.0%, respectively. The one-step method identified only three out of eight para-aortic lymph node metastases and missed five para-aortic lymph node metastases. There was no missed para-aortic lymph node metastasis in the two-step group. Recurrence was observed in two patients (2.6%; vaginal vault and adrenal gland) in the two-step group and seven patients (5.7%) including three nodal recurrences in the one-step group (p=0.307). DISCUSSION: Two-step SLN mapping improved the para-aortic SLN detection rate, a known pitfall of conventional cervical injection. Proper evaluation of aortic nodal status will assist in the tailoring of adjuvant and prevent undertreatment of patients with isolated para-aortic metastasis.

Adenosine triphosphate-based chemotherapy response assay predicts long-term survival of primary epithelial ovarian cancer.

OBJECTIVE: The aim of this study is to analyze the long-term relapse-free survival and overall survival outcomes of primary ovarian cancer patients using adenosine triphosphate-based chemotherapy response analysis. METHODS: In total, 162 primary epithelial ovarian cancer patients who underwent chemotherapy response assay for carboplatin, cisplatin, and paclitaxel by adenosine triphosphate-based chemotherapy response analysis prior to chemotherapy between December 2006 and November 2016 were retrospectively reviewed. Chemosensitivity with single or combined three agents and clinical characteristics of patients were studied to understand their correlation with long-term relapse-free survival and overall survival. RESULTS: Median follow-up time was 61.4 (range 1 - 130) months. Univariate analysis showed the paclitaxel-sensitive group (HR = 0.625, 95%CI = 0.393 to 0.994), combined carboplatin and paclitaxel-sensitive group (HR = 0.574, 95%CI = 0.352 to 0.937), and combined carboplatin, cisplatin, and paclitaxel-sensitive group (HR = 0.489, 95%CI = 0.295 to 0.810) were highly associated with better relapse-free survival than their corresponding non-sensitive groups. The carboplatin-sensitive group (HR = 0.533, 95%CI = 0.303 to 0.939), cisplatin-sensitive group (HR = 0.433. 95%CI = 0.251 to 0.748), and combined carboplatin- and cisplatin-sensitive group (HR = 0.286, 95%CI = 0.142 to 0.576) were highly associated with better overall survival than their corresponding non-sensitive groups. Combined carboplatin, cisplatin, and paclitaxel chemosensitivity, together with International Federation of Gynecology and Obstetrics (FIGO) stage were independent predictors for relapse-free survival. Single or combined chemosensitivity of cisplatin and/or carboplatin, together with residual tumor size and FIGO stage, were significant independent predictors for overall survival on a multivariate hazard model. CONCLUSION: Paclitaxel sensitivity is a prognostic factor of long-term relapse-free survival in patients with epithelial ovarian cancer, but platinum sensitivity is a more important prognostic factor for long-term overall survival.

MicroRNA-630 inhibitor sensitizes chemoresistant ovarian cancer to chemotherapy by enhancing apoptosis.

MicroRNA-630 (miR-630) has been implicated in the development and progression of multiple cancers. The current study aimed to investigate the role of miR-630 in chemoresistant epithelial ovarian cancer. MiR-630 expression levels were detected in ovarian cancer cell line SKOV3 and paclitaxel-resistant SKOV3 (SKOV3-TR) via microarray and qRT-PCR. MiR-630 inhibitors and negative controls were transfected into SKOV3 and SKOV3-TR cells. Wound healing, invasion, chemosensitivity, and cell apoptosis assays were performed to determine proliferation and migration rates. Chemoresistant patient-derived xenograft (PDX) models were established and utilized to verify the effect of miR-630 on chemoresistant ovarian cancer. Inhibition of miR-630 decreased cell proliferation and enhanced the sensitivity of SKOV3-TR and SKOV3 cells to paclitaxel. In the chemosensitivity assay, we observed that the miR-630 inhibitor exhibited a synergistic effect with paclitaxel on SKOV3-TR cells. Inhibition was correlated with enhanced expression of apoptosis-related proteins. APAF-1 was predicted to be a potential target of miR-630. An in vivo PDX study showed that the miR-630 inhibitor sensitized chemoresistant ovarian cancer to paclitaxel. Thus, miR-630 inhibitor sensitizes chemoresistant epithelial ovarian cancer to chemotherapy by enhancing apoptosis. Our findings suggest that miR-630 might be a potential therapeutic target for chemotherapy-resistant ovarian cancer.

Prediction of perioperative complications after robotic-assisted radical hysterectomy for cervical cancer using the modified surgical Apgar score.

BACKGROUND: Although there has been marked development in surgical techniques, there is no easy and fast method of predicting complications in minimally invasive surgeries. We evaluated whether the modified surgical Apgar score (MSAS) could predict perioperative complications in patients undergoing robotic-assisted radical hysterectomy. METHODS: All patients with cervical cancer undergoing robotic-assisted radical hysterectomy at our institution between January 2011 and May 2017 were included. Their clinical characteristics were retrieved from their medical records. The surgical Apgar score (SAS) was calculated from the estimated blood loss, lowest mean arterial pressure, and lowest heart rate during surgery. We modified the SAS considering the lesser blood loss typical of robotic surgeries. Perioperative complications were defined using a previous study and the Clavien-Dindo classification and subdivided into intraoperative and postoperative complications. We analyzed the association of perioperative complications with low MSAS. RESULTS: A total of 138 patients were divided into 2 groups: with (n = 53) and without (n = 85) complications. According to the Clavien-Dindo classification, 49 perioperative complications were classified under Grade I (73.1%); 13, under Grade II (19.4%); and 5, under Grade III (7.5%); 0, under both Grade IV and Grade V. Perioperative complications were significantly associated with surgical time (p = 0.026). The MSAS had a correlation with perioperative complications (p = 0.047). The low MSAS (MSAS, ≤6; n = 52) group had significantly more complications [40 (76.9%), p = 0.01]. Intraoperative complications were more correlated with a low MSAS than were postoperative complications [1 (1.2%) vs. 21 (40.4%); p < 0.001, 13 (15.1%) vs. 25 (48.1%); p = 0.29, respectively]. We also analyzed the risk-stratified MSAS in 3 subgroups: low (MSAS, 7-10), moderate (MSAS 5-6), and high risks (MSAS, 0-4). The prevalence of intraoperative complications significantly increased as the MSAS decreased p = 0.01). CONCLUSIONS: This study was consistent the concept that the intuitive and simple MSAS might be more useful in predicting intraoperative complications than in predicting postoperative complications in minimally invasive surgeries, such as robotic-assisted radical hysterectomy for cervical cancer.

Variants of cancer susceptibility genes in Korean BRCA1/2 mutation-negative patients with high risk for hereditary breast cancer.

BACKGROUND: We evaluated the incidence and spectrum of pathogenic and likely pathogenic variants of cancer susceptibility genes in BRCA1/2 mutation-negative Korean patients with a high risk for hereditary breast cancer using a comprehensive multigene panel that included 35 cancer susceptibility genes. METHODS: Samples from 120 patients who were negative for BRCA1/2 mutations, but had been diagnosed with breast cancer that was likely hereditary, were prospectively evaluated for the prevalence of high-penetrance and moderate-penetrance germline mutations. RESULTS: Nine patients (7.5%) had at least one pathogenic or likely pathogenic variant. Ten variants were identified in these patients: TP53 in two patients, PALB2 in three patients, BARD1 in two patients, BRIP1 in two patients, and MRE11A in one patient. We also identified 30 types of 139 variants of unknown significance (VUS). High-penetrance germline mutations, including TP53 and PALB2, tended to occur with high frequency in young (< 35 years) breast cancer patients (4/19, 21.1%) than in those diagnosed with breast cancer at ≥35 years of age (1/101, 1.0%; p = 0.003). CONCLUSIONS: These combined results demonstrate that multigene panels offer an alternative strategy for identifying veiled pathogenic and likely pathogenic mutations in breast cancer susceptibility genes.

Prognostic significance of supradiaphragmatic lymph node metastasis detected by 18F-FDG PET/CT in advanced epithelial ovarian cancer.

BACKGROUND: Supradiaphragmatic lymph node metastases (SdLNM) are frequently identified using 18F-FDG positron emission tomography/computed tomography (PET/CT) in advanced epithelial ovarian cancers (AEOC). This study aimed to determine the prognostic significance of SdLNM detected by PET/CT in patients with AEOC. METHODS: Medical records of patients diagnosed with AEOC were retrospectively registered from January 2009 to July 2015. Patients were categorized according to PET/CT stage: PET/CT stage III, PET/CT stage IV with SdLNM, and PET/CT stage IV with other metastases. Clinicopathologic characteristics, recurrence patterns, survival outcomes were compared according to PET/CT stage. Anatomical distribution of SdLNM and effect of thoracic debulking surgery were estimated. RESULTS: A total of 295 patients were identified, including 176 patients who underwent primary debulking surgeries (PDS). Progression-free (P = 0.671) and overall (P = 0.525) survival did not differ significantly between patients with PET/CT IV with SdLNM and PET/CT IV with other metastases; however, patients with PET/CT IV with SdLNM had significantly poorer progression-free (P < 0.001) and overall (P = 0.016) survival than those with PET/CT stage III. Recurrence patterns were similar in all groups; intraperitoneal metastasis was the most common (78.8%) and thoracic recurrence alone accounted for less than 10%. Debulking of SdLNM lesions did not improve progression-free survival (P = 0.425) or overall survival (P = 0.465) of patients with AEOC. CONCLUSIONS: SdLNM detected using preoperative PET/CT are a negative prognostic factor in AEOC. Resection of suspicious SdLNM may not have effect to survival of patients with AEOC.

Impact of the time interval from completion of neoadjuvant chemotherapy to initiation of postoperative adjuvant chemotherapy on the survival of patients with advanced ovarian cancer.

OBJECTIVE: To investigate the relationship of the time interval from the completion of neoadjuvant chemotherapy (NAC) to the initiation of postoperative adjuvant chemotherapy (POAC) with the survival outcomes in patients with ovarian cancer. METHODS: We retrospectively investigated 220 patients with pathologically confirmed epithelial ovarian cancer who received NAC at Yonsei Cancer Hospital between 2006 and 2016. The time interval was defined as the period from the completion of NAC, spanning interval debulking surgery (IDS), to the initiation of POAC. RESULTS: The median time interval was 42 (range 16-178) days; 103 patients (53.1%) received POAC within 42days after NAC while 91 patients (46.9%) received it after 42days. There were no significant differences in patient characteristics between these 2 groups. Kaplan-Meier analysis showed that patients with longer time intervals (>42days) had poorer progression-free survival and overall survival (P=0.039 and 0.005, respectively). In the multivariate analysis, patients with longer time intervals had significantly poorer progression-free (hazard ratio, 1.41; 95% confidence interval, 0.98-2.03; not significant) and overall survivals (hazard ratio, 2.03; 95% confidence interval, 1.16-3.54). When the patients were categorized according to time interval quartiles (≤37, 38-42, 43-50, and >50days), longer time intervals were associated with higher risks of recurrence and death (P for trend: 0.006 and <0.001, respectively). CONCLUSION: The time interval from the completion of NAC to the initiation of POAC appears to influence survival. Efforts to reduce the time interval might improve the outcomes in ovarian cancer patients undergoing NAC.

Expression of programmed cell death ligand 1 and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade serous ovarian cancer.

OBJECTIVE: To investigate the prognostic value of the expressions of programmed cell death ligand 1 (PD-L1) and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy (NAC) for advanced high-grade serous ovarian cancer (HGSOC). METHODS: We collected pre- and post-NAC tumor samples from patients with advanced HGSOC between 2006 and 2017. Post-NAC tumor tissue samples were available for immunostaining from 131 patients. The expressions of PD-L1 and immune checkpoint markers were assessed by immunohistochemical staining and the status of tumor-infiltrating lymphocytes (TILs) was also evaluated. We examined whether there are significant associations between protein expression status and patient outcomes and whether significant changes in protein expression levels occurred in response to NAC. RESULTS: PD-L1 expression in the tumor cells was evaluated in 113 patients, 12 (10.6%) of whom had high PD-L1 expression (≥25%) in post-NAC tissues. However, these high levels were not associated with progression-free survival (PFS; P = 0.348) or overall survival (OS; P = 0.699). Similarly, high stromal TILs [≥50%; n = 16 (15.0%)] among the 107 patients evaluated did not show any significant impact on PFS (P = 0.250) or OS (P = 0.800). Moreover, an abundance of TILs (intraepithelial, CD8+, and Foxp3+) and the expression of immune checkpoint markers (PD-1, ICOS, and LAG-3) in residual tumors did not confer any significant survival benefit. The impact of NAC on PD-L1 expression and stromal TILs varied considerably among individual patients. CONCLUSION: Although the expression of PD-L1 and immune checkpoint markers in residual tumors after NAC had no prognostic impact on survival in patients with HGSOC, post-NAC evaluation of these proteins in chemoresistant tumors may help select patients for immunotherapy trials.