Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors.

OBJECTIVE: Previously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). METHODS: We identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. RESULTS: In total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). CONCLUSIONS: LRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Impact of hemodynamic instability during cytoreductive surgery on survival in high-grade serous ovarian carcinoma.

BACKGROUND: To evaluate the impact of intraoperative hypotension and hemodynamic instability on survival outcomes in patients with high-grade serous ovarian carcinoma (HGSOC). METHODS: We retrospectively identified patients with HGSOC, who underwent primary or interval debulking surgery between August 2013 and December 2019. We collected anesthesia-related variables, including the arterial blood pressure measurements (at 1-min intervals) during the surgery of patients. The cumulative duration of mean arterial blood pressure (MAP) readings under 65 mmHg and two performance measurements (median performance error [MDPE] and wobble) were calculated. We investigated associations between the factors indicating hemodynamic instability and prognosis. RESULTS: In total, 338 patients were included. Based on the cumulative duration of MAP under 65 mmHg, we divided patients into two groups: ≥30 min and <30 min. The progression-free survival (PFS) was worse in the ≥30 min group (n = 107) than the <30 min group (n = 231) (median, 18.2 vs. 23.7 months; P = 0.014). In multivariate analysis adjusting for confounders, a duration of ≥30 min of MAP under 65 mmHg was identified as an independent poor prognostic factor for PFS (adjusted HR, 1.376; 95% CI, 1.035-1.830; P = 0.028). Shorter PFS was observed in the group with a MDPE <-4.0% (adjusted HR, 1.351; 95% CI, 1.024-1.783; P = 0.033) and a wobble ≥7.5% (adjusted HR, 1.445; 95% CI, 1.100-1.899; P = 0.008). However, no differences were observed in overall survival. CONCLUSION: This study suggests that the three intraoperative variables for hemodynamic instability, cumulative duration of MAP <65 mmHg, MDPE, and wobble, might be novel prognostic biomarkers for disease recurrence in patients with HGSOC.

Cervical conization before primary radical hysterectomy has a protective effect on disease recurrence in early cervical cancer: A two-center matched cohort study according to surgical approach.

OBJECTIVE: To ascertain whether cervical conization before radical hysterectomy (RH) has a protective effect on survival outcomes in early cervical cancer, taking into account the surgical approach. METHODS: From cervical cancer cohorts of two institutions, we identified node-negative, margin-negative, parametria-negative, 2009 FIGO stage IB1 cervical cancer patients who received primary Type C RH between July 2006 and June 2020. Patients were divided into conization group (n = 144) and control group (n = 434). We conducted three independent 1:1 propensity score matching processes for histology, lymphovascular space invasion, cervical tumor size, and surgical approach (all patients, those who underwent open surgery, and those who underwent minimally invasive surgery [MIS]). Survival outcomes were compared. RESULTS: Overall, the conization group had less cervical tumor size and received MIS more frequently (P = 0.010) and adjuvant treatment less often (P = 0.002) versus the controls. After matching, the conization group showed significantly better disease-free survival (DFS) versus control (3-year DFS rate, 94.2% vs. 86.3%; P = 0.012), but similar overall survival. Among the open RH matched patients (n = 96), no difference in DFS was observed between the conization and control groups (P = 0.984). In contrast, among the MIS RH matched patients (n = 192), the conization group showed significantly better DFS versus control (3-year DFS rate, 95.7% vs. 82.9%; P = 0.005). In multivariate analysis adjusting for cervical tumor size and adjuvant treatment, conization was identified as an independent favorable prognostic factor for DFS (adjusted HR, 0.318; 95% CI, 0.134-0.754; P = 0.009). CONCLUSIONS: Preoperative cervical conization might reduce the disease recurrence rate in early cervical cancer patients who undergo primary MIS RH.

Impact of no residual disease on postoperative computed tomography on survival in patients with optimally debulked advanced high-grade serous ovarian cancer during upfront surgery.

OBJECTIVE: We sought to investigate the impact of size of residual tumors as determined by postoperative computed tomography (CT) on survival of patients with advanced, high-grade serous ovarian carcinoma (HGSC) who achieved residual disease less than 1 cm after primary debulking surgery (PDS). METHODS: We collected data of patients with stage III HGSC who had residual tumor less than 1 cm after PDS between 2013 and 2018. Surgeon-assessed residual disease during surgery was defined as sR0 (no gross residual) or sR1 (gross residual <1 cm), and radiologist-assessed residual disease on postoperative CT was defined as rR0 (no evidence of disease) or rRany (existing residual disease). All patients were classified into the following groups: sR0/rR0, sR1/rR0, sR0/rRany, and sR1/rRany. RESULTS: A total of 436 patients was placed into the sR0/rR0 (n = 187, 42.9%), sR1/rR0 (n = 59, 13.5%), sR0/rRany (n = 79, 18.1%), or sR1/rRany group (n = 111, 25.5%). Discrepancies between surgical and radiological assessments were recorded for 176 patients (40.4%) including 38 cases of sR1/rRany group with discordant residual tumor location indicated between two methods. During multivariate analysis, patients with ascites on preoperative CT, sR0/rRany group inclusion, and sR1/rRany group inclusion showed unfavorable progression-free and overall survival. CONCLUSIONS: The incorporation of surgical and radiological evaluations for determining the size of residual tumors was more accurate than surgical evaluation only for predicting survival among patients with advanced ovarian cancer who underwent PDS to residual disease less than 1 cm.

Open versus minimally invasive radical hysterectomy for early cervical cancer: A two-center retrospective cohort study with pathologic review of usual-type adenocarcinoma and adenosquamous carcinoma.

OBJECTIVE: To compare survival outcomes of minimally invasive surgery (MIS) and open surgery for radical hysterectomy (RH) in early cervical cancer patients with histologic subtypes of usual-type adenocarcinoma and adenosquamous carcinoma. METHODS: From two centers' cervical cancer cohorts, patients with 2009 FIGO stage IB1-IB2 who underwent RH between 2007 and 2020 were retrospectively identified. Patients with usual-type adenocarcinoma and adenosquamous carcinoma were included in the analysis after pathologic review according to the updated World Health Organization Classification of Tumors. Clinicopathologic characteristics and survival outcomes were compared in terms of open surgery or MIS. RESULTS: This study included 161 patients. No significant differences were noted in overall survival (OS; P = 0.241) and disease-free survival (DFS; P = 0.156) between patients with usual-type adenocarcinoma (n = 136) and those with adenosquamous carcinoma (n = 25). MIS RH group (n = 99) had a significantly smaller tumor size (P < 0.001), lesser pathologic parametrial invasion (P = 0.001), and lesser lymph node metastasis (P < 0.001) than open RH group (n = 62). MIS and open RH groups showed similar OS (P = 0.201) and 3-year DFS rate (87.9% vs. 75.1%; P = 0.184). In multivariate analysis, worse DFS was not associated with MIS (P = 0.589) but was associated with pathologic parametrial invasion (adjusted HR, 3.41; 95% CI, 1.25-9.29; P = 0.016). Consistent results were observed among patients with usual-type adenocarcinoma; MIS was not associated with worse DFS. CONCLUSIONS: Comparable survival outcomes were found for MIS and open RH in early-stage cervical usual-type adenocarcinoma and adenosquamous carcinoma. Although MIS RH was not a poor prognostic factor, pathologic parametrial invasion was significantly associated with worse DFS in cervical usual-type adenocarcinoma and adenosquamous carcinoma.

Is increased chronological age a contraindication to debulking surgery for elderly patients with advanced ovarian cancer?

We collected data of elderly patients aged 65 years and older who underwent debulking surgery for advanced ovarian cancer in order to explore the impact of old age on surgical outcomes and complications. A total of 120 patients were classified as follows: group 1, 65-69 years (n = 58); group 2, 70-74 years (n = 38); group 3, 75-79 years (n = 17); group 4, ≥80 years (n = 7). There were no differences in most of the characteristics, surgical extent and outcomes, and postoperative complications between the four groups, whereas polypharmacy was more common (6 vs. 5-16; p=.02) and operation time was shorter (median, 194 vs. 285-330 min; p=.02) in group 4. Factors related to frailty rather than age, polypharmacy, preoperative albumin level, estimated blood loss and transfusion increased the risk of postoperative complications. Thus, the impact of old age on surgical extent, outcomes and postoperative complications may be minimal in elderly patients with advanced ovarian cancer. Impact StatementWhat is already known on this subject? Optimal debulking surgery is a significant factor in improving the prognosis of ovarian cancer but it is not easy to perform such radical surgery on elderly patients in fear of increasing surgical morbidity and mortality. Some studies suggest that underlying comorbidities may be a stronger contributing factor to increasing such risk rather than old age although there is not enough evidence yet.What do the results of this study add? Through this study, we could see that increased age is not the determining cause of increased morbidity and mortality in elderly patients who undergo optimal debulking surgery in ovarian cancer. There are other aspects describing a patient's health status that can predict prognosis better rather than age.What are the implications of these findings for clinical practice and/or further research? Old age need not be a contraindication when performing optimal debulking surgery in elderly patients with advanced ovarian cancer.

Survival impact of additional chemotherapy after adjuvant concurrent chemoradiation in patients with early cervical cancer who underwent radical hysterectomy.

BACKGROUND: To determine whether additional chemotherapy after concurrent chemoradiation (CCRT) improves survival outcomes in patients with early cervical cancer who undergo radical hysterectomy (RH). METHODS: We included high- or intermediate-risk patients from two institutions, with 2009 FIGO stage IB-IIA, who underwent primary RH and pelvic lymphadenectomy between January 2007 and June 2020, and had completed adjuvant CCRT. Survival outcomes were compared between patients who received additional chemotherapy (study group) and those who did not (control group). RESULTS: A total of 198 patients were included in this analysis. The study (n = 61) and control groups (n = 137) had similar patient age, histologic cancer type, 2009 FIGO stage, and tumor size. However, minimally invasive surgery was performed less frequently in the study group than in the control group (19.7% vs. 46.0%, P < 0.001). The presence of pathologic risk factors was similar, except for lymph node metastasis, which was more frequent in the study group (72.1% vs. 46.0%; P = 0.001). In survival analyses, no differences in the disease-free survival (DFS; P = 0.539) and overall survival (OS; P = 0.121) were observed between the groups. Multivariate analyses adjusting for surgical approach and other factors revealed that additional chemotherapy was not associated with DFS (adjusted HR, 1.149; 95% CI, 0.552-2.391; P = 0.710) and OS (adjusted HR, 1.877; 95% CI, 0.621-5.673; P = 0.264). The recurrence patterns did not differ with additional chemotherapy. Consistent results were observed in a subset of high-risk patients (n = 139). CONCLUSIONS: Additional chemotherapy after CCRT might not improve survival outcomes in patients with early cervical cancer who undergo RH.

Survival impact of extended cycles of second-line chemotherapy in platinum-sensitive relapsed ovarian cancer patients with residual tumor after six cycles.

BACKGROUND: To determine if extended chemotherapy improves survival outcomes in patients with platinum-sensitive relapsed epithelial ovarian cancer (EOC) who have residual disease after six cycles of second-line chemotherapy. METHODS: In this study, 135 EOC patients who experienced platinum-sensitive recurrence after primary treatment between 2008 and 2018, and had a residual tumor ≥0.5 cm (detected on CT scans) after completing six cycles of second-line, platinum-based chemotherapy, were retrospectively reviewed. Based on the number of main therapy cycles (second-line chemotherapy), we divided patients into an extended group (>6 cycles, n = 52) or a standard group (6 cycles, n = 83) and compared patient characteristics and survival outcomes between these groups. RESULTS: The extended group had a shorter platinum-free interval after primary treatment than the standard group (median, 11.0 vs. 13.1 months; P = 0.018). Secondary debulking surgery was less frequently performed in the standard group (1.9% vs. 19.3%; P = 0.003). After six chemotherapy cycles, the extended and standard groups showed similar serum CA-125 levels (P = 0.122) and residual tumor sizes (P = 0.232). There was no difference in overall survival (OS) between the groups (P = 0.382), although the extended group had significantly worse progression-free survival (PFS) than the standard group (median, 13.9 vs. 15.1 months; P = 0.012). Multivariate analyses revealed that platinum-free interval was an independent prognostic factor for PFS and OS, but extended chemotherapy was not (PFS: HR, 1.25; 95% CI, 0.84-1.85; P = 0.279; and OS: HR, 1.36; 95% CI, 0.72-2.56; P = 0.342). We observed consistent results in the subset of patients who did not undergo secondary debulking surgery. CONCLUSIONS: More than six cycles of platinum-based chemotherapy might not improve survival outcomes in patients with platinum-sensitive recurrent EOC who had a residual tumor ≥0.5 cm after six cycles of second-line chemotherapy.

Recurrence patterns after bevacizumab in platinum-sensitive, recurrent epithelial ovarian cancer.

OBJECTIVE: Evidence on recurrence patterns after bevacizumab in epithelial ovarian cancer is still insufficient. The aim of this study was to evaluate recurrence patterns after treatment with bevacizumab as second-line treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer. METHODS: We retrospectively identified epithelial ovarian cancer patients who relapsed ≥6 months after primary treatment consisting of surgery and platinum-based chemotherapy between January 2008 and June 2019. Only those who received platinum-based doublet chemotherapy with bevacizumab or without bevacizumab as second-line treatment were included (n=192). To adjust confounders, we conducted 1:2 propensity score matching for platinum-free interval and secondary debulking surgery. Imaging studies were performed to locate newly developed or enlarged pre-existing tumors. Recurrence patterns were compared between bevacizumab users (study group) and non-users (control group). RESULTS: After matching, the study group (n=52) and control group (n=104) showed similar baseline clinicopathologic characteristics including platinum-free interval (median (range) 15.3 (6.2-87.3) vs 14.0 (6.2-143.5) months; p=0.29) and patient age at the time of first recurrence (median (range) 55.5 (33.7-72.4) vs 55.0 (35.7-84.2) years; p=0.56). Initially, FIGO stage III disease was the most common in both two groups (55.8% vs 66.3%; p=0.20). Bevacizumab users were less likely to develop disease recurrence in the retroperitoneal lymph nodes (13.5% vs 34.6%; p=0.005), pelvis (17.3% vs 35.6%; p=0.018), and abdomen (40.4% vs 61.5%; p=0.012). However, no difference in distant metastasis was observed between the groups (23.1% vs 24.0%; p>0.99). Multivariate analyses adjusting for stage, histologic type, grade, platinum-free interval, and secondary debulking surgery revealed that the use of bevacizumab significantly reduced risks of nodal (adjusted HR (aHR) 0.24; 95% CI 0.10 to 0.56; p=0.001), pelvic (aHR 0.32; 95% CI 0.15 to 0.68; p=0.003), and abdominal recurrences (aHR 0.43; 95% CI 0.26 to 0.71; p=0.001). Nevertheless, use of bevacizumab did not influence risk of distant metastasis (aHR 0.70; 95% CI 0.35 to 1.40; p=0.32). CONCLUSIONS: In patients with platinum-sensitive, recurrent epithelial ovarian cancer, second-line chemotherapy with bevacizumab is associated with reduced risks of nodal, pelvic, and abdominal recurrences, but similar risks of distant metastases.

Comparison of survival outcomes between minimally invasive surgery and conventional open surgery for radical hysterectomy as primary treatment in patients with stage IB1-IIA2 cervical cancer.

OBJECTIVE: To compare survival outcomes of minimally invasive surgery (MIS) and conventional open surgery for radical hysterectomy (RH) among patients with early-stage cervical cancer (CC). METHODS: We retrospectively identified stage IB1-IIA2 CC patients who underwent either laparoscopic or open Type C RH between 2000 and 2018. Patients' clinicopathologic characteristics and survival outcomes were compared according to the surgical approach. For a more robust statistical analysis, we narrowed the study population down to the patients with stage IB1 who underwent pre-operative MRI. RESULTS: In total, 435 and 158 patients were assigned to open surgery and MIS groups, respectively. MIS group had significantly less parametrial invasion (6.3% vs. 15.4%; P = 0.004). Despite similar proportions of patients received adjuvant treatment, concurrent chemoradiation therapy was performed less frequently in MIS group. After a median follow up of 114.8 months, the groups showed similar overall survival; however, MIS group displayed poorer progression-free survival (PFS; 5-year rate, 78.5% vs. 89.7%; P < 0.001). Multivariate analyses identified MIS as an independent poor prognostic factor for PFS (adjusted HR, 2.883; 95% CI, 1.711-4.859; P < 0.001). Consistent results were observed among 349 patients with stage IB1: MIS was associated with higher recurrence rates (adjusted HR, 2.276; 95% CI, 1.039-4.986; P = 0.040). However, MIS did not influence PFS of stage IB1 patients with cervical mass size ≤2 cm on pre-operative MRI (adjusted HR, 1.146; 95% CI, 0.278-4.724; P = 0.850). CONCLUSIONS: Overall, MIS RH was associated with higher recurrence rates than open RH in patients with early-stage CC. However, MIS was not a poor prognostic factor among those with stage IB1 and cervical mass size ≤2 cm on pre-operative MRI.

Impact of laparoscopic radical hysterectomy on survival outcome in patients with FIGO stage IB cervical cancer: A matching study of two institutional hospitals in Korea.

OBJECTIVE: To compare survival outcomes of primary laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in patients with FIGO stage IB cervical cancer. METHODS: We retrospectively identified stage IB1-IB2 cervical cancer patients who received either LRH (n = 343) or ORH (n = 222) at two tertiary institutional hospitals between 2000 and 2018. To adjust for confounders, we conducted Mahalanobis distance-based sample matching for stage, histology, cervical mass size, parametrial invasion, and lymph node metastasis. Then, survival outcomes were compared between the matched groups. Through the independent matching processes, we narrowed the study population to stage IB1 patients and stage IB1 patients with tumor size ≤2 cm on pre-operative MRI. RESULTS: After matching, LRH group showed poorer progression-free survival (PFS) than ORH group (3-year: 85.4% vs. 91.8%; P = 0.036), whereas no significant difference in overall survival (OS) was found. Regarding recurrence patterns, no significant differences in the incidences of pelvic, retroperitoneal lymph node and abdominal recurrences, or distant metastasis were observed between the two groups. Among the matched patients with stage IB1 who had cervical mass size ≤2 cm, the LRH and ORH groups showed similar PFS (3-year: 90.0% vs. 93.1%; P = 0.8) and OS (5-year: 98.6% vs. 96.4%; P = 0.6). CONCLUSIONS: Despite the retrospective design, our matched cohort study suggests that ORH might be preferable for the surgical treatment of FIGO stage IB cervical cancer. However, in stage IB1 patients with tumor size ≤2 cm, LRH might be applicable, as equivalent outcomes were found regardless of the surgical approach. Further prospective studies are warranted.

Prognostic value of lymph node-to-primary tumor standardized uptake value ratio in endometrioid endometrial carcinoma.

PURPOSE: To determine whether the relative metabolic activity of pelvic or para-aortic LN compared with that of primary tumor measured by preoperative [18F]FDG PET/CT scan has prognostic value in patients with endometrioid endometrial carcinoma. METHODS: We retrospectively reviewed patients with endometrioid endometrial carcinoma who underwent preoperative [18F]FDG PET/CT scans. Prognostic values of PET/CT-derived metabolic variables such as maximum standardized uptake value (SUV) of the primary endometrial carcinoma (SUVTumor) and LN (SUVLN), and the LN-to-endometrial carcinoma SUV ratio (SUVLN / SUVTumor) were assessed. RESULTS: Clinico-pathological data, imaging data, and treatment results were reviewed for 107 eligible patients. Median post-surgical follow-up was 23 months (range, 6-60), and 7 (6.5%) patients experienced recurrence. Regression analysis showed that SUVLN / SUVTumor (P < 0.001), SUVLN (P = 0.003), International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.006), and tumor grade (P = 0.011) were risk factors of recurrence. Multivariate regression analysis revealed that FIGO stage (P = 0.034) was the independent risk factor of recurrence. SUVLN / SUVTumor showed significant correlation with FIGO stage (P < 0.001), LN metastasis (P < 0.001), lymphovascular space invasion (P < 0.001), recurrence (P = 0.001), tumor grade (P < 0.001), and deep myometrial invasion of tumor (P = 0.022). Patient groups categorized by SUVLN / SUVTumor showed significant difference in progression-free survival (Log-rank test, P = 0.001). CONCLUSIONS: Preoperative SUVLN / SUVTumor measured by [18F]FDG PET/CT was significantly associated with recurrence, and may become a novel prognostic factor in patients with endometrioid endometrial carcinoma.

LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data.

BACKGROUND: Somatic amplifications of the LYL1 gene are relatively common occurrences in patients who develop uterine corpus endometrial carcinoma (UCEC) as opposed to other cancers. This study was undertaken to determine whether such genetic alterations affect survival outcomes of UCEC. METHODS: In 370 patients with UCEC, we analysed clinicopathologic characteristics and corresponding genomic data from The Cancer Genome Atlas database. Patients were stratified according to LYL1 gene status, grouped as amplification or non-amplification. Heightened levels of cancer-related genes expressed in concert with LYL1 amplification were similarly investigated through differentially expressed gene and gene set enrichment analyses. Factors associated with survival outcomes were also identified. RESULTS: Somatic LYL1 gene amplification was observed in 22 patients (5.9%) with UCEC. Patients displaying amplification (vs. non-amplification) were significantly older at the time of diagnosis and more often were marked by non-endometrioid, high-grade, or advanced disease. In survival analysis, the amplification subset showed poorer progression-free survival (PFS) and overall survival (OS) rates (3-year PFS: 34.4% vs. 79.9%, P = 0.031; 5-year OS: 25.1% vs. 84.9%, P = 0.014). However, multivariate analyses adjusted for tumor histologic type, grade, and stage did not confirm LYL1 gene amplification as an independent prognostic factor for either PFS or OS. Nevertheless, MAPK, WNT, and cell cycle pathways were significantly enriched by LYL1 gene amplification (P < 0.001, P = 0.002, and P = 0.004, respectively). CONCLUSIONS: Despite not being identified as an independent prognostic factor in UCEC, LYL1 gene amplification is associated with other poor prognostic factors and correlated with upregulation of cancer-related pathways.

Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing.

OBJECTIVE: To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. METHODS: We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC. RESULTS: OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups. CONCLUSION: We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy.

Prognostic importance of peritoneal lesion-to-primary tumour standardized uptake value ratio in advanced serous epithelial ovarian cancer.

OBJECTIVES: Using preoperative PET/CT, we evaluated the prognostic value of preoperative [18F]FDG uptake ratio between various metastatic lesions and primary tumour in patients with advanced serous epithelial ovarian cancer (EOC). METHODS: We retrospectively reviewed patients with International Federation of Gynecology and Obstetrics (FIGO) stage III, IV serous EOC who underwent preoperative [18F]FDG PET/CT scans. Clinico-pathological variables and PET/CT parameters such as maximum standardized uptake value of the ovarian cancer (SUVovary), pelvic or para-aortic LN (SUVLN), peritoneal (SUVperit) and distant extra-peritoneal (SUVdist) metastatic lesions, and the metastatic lesion-to-ovarian cancer standardized uptake value ratio were assessed. RESULTS: Clinico-pathological data were retrospectively reviewed for 97 eligible patients. The median progression-free survival (PFS) was 18 months (range, 6-90 months) and 59 (60.8 %) patients experienced recurrence. In multivariate regression analysis, older age (p = 0.035, hazard ratio (HR) 1.032, 95 % CI 1.002-1.062), and high SUVperit/SUVovary (p = 0.046, HR 1.755, 95 % CI 1.011-3.047) were independent risk factors of recurrence. Patient group categorized by SUVperit/SUVovary showed significant difference in PFS (Log-Rank test, p = 0.001). CONCLUSIONS: In patients with advanced serous EOC, preoperative SUVperit/SUVovary measured by [18F]FDG PET/CT provides significant incremental performance for prediction of recurrence. KEY POINTS: • PET/CT data from advanced serous epithelial ovarian cancer patients were analysed. • Prognostic value of SUV ratio between metastatic and primary tumour was investigated. • SUV perit /SUV ovary provides incremental performance for prediction of recurrence.

Prognostic importance of lymph node-to-primary tumor standardized uptake value ratio in invasive squamous cell carcinoma of uterine cervix.

PURPOSE: Using integrated PET/CT, we evaluated the prognostic value of [18F]FDG uptake ratio between pelvic lymph node (LN) and primary tumor in invasive squamous cell carcinoma (SCCA) of the uterine cervix. METHODS: We retrospectively reviewed patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB to IIA cervical SCCA who underwent preoperative [18F]FDG PET/CT scans. PET/CT parameters such as maximum standardized uptake value (SUV) of the primary cervical cancer (SUVcervix) and LN (SUVLN), and the LN-to-cervical cancer SUV ratio (SUVLN/SUVcervix) were assessed. Prognostic values of PET/CT-derived metabolic and volumetric variables and clinicopathology parameters were analyzed to predict progression-free survival (PFS) in regression analyses. RESULTS: Clinical data, treatment modalities, and results were reviewed for 103 eligible patients. Median post-surgical follow-up was 29 months (range, 6-89), and 19 (18.5%) patients experienced recurrence. Multivariate logistic regression analysis showed that SUVLN / SUVcervix > 0.1747(P = 0.048) was the independent risk factor of recurrence. Patient group categorized by SUVLN/SUVcervix showed significant difference in PFS (log-rank test, P < 0.001). CONCLUSIONS: Preoperative SUVLN/SUVcervix measured by [18F]FDG PET/CT was significantly associated with recurrence, and has an incremental prognostic value for PFS in patients with cervical SCCA.

Predictive value of circulating tumor cells (CTCs) captured by microfluidic device in patients with epithelial ovarian cancer.

OBJECTIVE: To test an electrically conductive chip, incorporating a nanoroughened microfluidic platform for the capture of circulating tumor cells (CTCs), and assess its clinical merit in instances of epithelial ovarian cancer (EOC). METHODS: A total of 54 patients with EOC recruited between August 2014 and May 2015 were enrolled in this prospective study. CTCs in peripheral blood were detected in advance of primary tumor resection and before initiating adjuvant chemotherapy for recurrent disease. We identified CTCs as EpCAM-positive and DAPI-positive, and CD45-negative feature. RESULTS: Twenty-four patients with primary disease and 30 patients with recurrences were included in the study. CTCs were detected in 98.1% (53/54). In newly diagnosed patients, median counts of single CTCs and CTC clusters were 4 (0-13) and 1(0-14), respectively. In those with recurrences, median counts were 3 (1-9) and 1(0-24), respectively. Such counts did not differ significantly by tumor stage or by serum CA125 level; but progression-free survival declined at a cutpoint of ≥3 CTCs, and CTC-cluster positivity correlated with platinum resistance. Isolated CTCs (successfully cultured ex vivo in two patients) showed greater sensitivity to anticancer drugs and proliferated more rapidly than did established cell lines. CONCLUSION: Proof-of-concept was provided for an electrically conductive and nanoroughened microfluidic platform-based chip designed to capture CTCs in patients with EOC. A larger patient sampling and longer duration of follow-up are needed to determine its suitability for clinical use.

Prognostic implication of the metastatic lesion-to-ovarian cancer standardised uptake value ratio in advanced serous epithelial ovarian cancer.

OBJECTIVES: To evaluate the prognostic value of metabolic activity of metastatic lesions measured by 18F-flurodeoxyglucose (18F-FDG) uptake on preoperative positron emission tomography/computed tomography (PET/CT) in patients with advanced serous epithelial ovarian cancer (EOC). METHODS: Clinico-pathological variables and PET/CT parameters such as the maximum standardised uptake value of the ovarian cancer (SUVovary), metastatic lesions (SUVmeta), and the metastatic lesion-to-ovarian cancer standardised uptake value ratio (SUVmeta/SUVovary) were assessed in International Federation of Gynaecology and Obstetrics (FIGO) stage III, IV patients. RESULTS: Clinico-pathological data were retrospectively reviewed for 94 eligible patients. The median progression-free survival (PFS) was 18.5 months (range, 6-90 months), and 57 (60.6%) patients experienced recurrence. Older age [P = 0.017, hazard ratio (HR) 1.036, 95% CI 1.006-1.066], residual disease after surgery (P = 0.024, HR 1.907, 95% CI 1.087-3.346), and high SUVmeta/SUVovary (P = 0.019, HR 2.321, 95% CI 1.148-4.692) were independent risk factors of recurrence. Patients with high SUVmeta/SUVovary showed a significantly worse PFS than those with low SUVmeta/SUVovary (P = 0.007, log-rank test). CONCLUSIONS: Preoperative SUVmeta/SUVovary was significantly associated with recurrence and has an incremental prognostic value for PFS in patients with advanced serous EOC. KEY POINTS: • The prognostic value of the metabolic activity of metastatic lesions was investigated. • SUVmeta/SUVovary was significantly associated with recurrence of serous EOC. • Preoperative SUVmeta/SUVovary can be a predicator of serous EOC recurrence.