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.

Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.

Ovarian cancer is a lethal gynecologic cancer mostly diagnosed in an advanced stage with an accumulation of ascites. Interleukin-6 (IL-6), a pro-inflammatory cytokine is highly elevated in malignant ascites and plays a pleiotropic role in cancer progression. Mitochondria are dynamic organelles that undergo fission and fusion in response to external stimuli and dysregulation in their dynamics has been implicated in cancer progression and metastasis. Here, we investigate the effect of IL-6 on mitochondrial dynamics in ovarian cancer cells (OVCs) and its impact on metastatic potential. Treatment with IL-6 on ovarian cancer cell lines (SKOV3 and PA-1) led to an elevation in the metastatic potential of OVCs. Interestingly, a positive association was observed between dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, and IL-6R in metastatic ovarian cancer tissues. Additionally, IL-6 treatment on OVCs was linked to the activation of Drp1, with a notable increase in the ratio of the inhibitory form p-Drp1(S637) to the active form p-Drp1(S616), indicating enhanced mitochondrial fission. Moreover, IL-6 treatment triggered the activation of ERK1/2, and inhibiting ERK1/2 mitigated IL-6-induced mitochondrial fission. Suppressing mitochondrial fission through siRNA transfection and a pharmacological inhibitor reduced the IL-6-induced migration and invasion of OVCs. This was further supported by 3D invasion assays using patient-derived spheroids. Altogether, our study suggests the role of mitochondrial fission in the metastatic potential of OVCs induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach to suppress the metastasis of ovarian cancer.

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.

A multicentre, randomised, open-label, parallel-group Phase 2b study of belotecan versus topotecan for recurrent ovarian cancer.

BACKGROUND: This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer. METHODS: Patients with platinum-sensitive recurrent or platinum-resistant recurrent ovarian cancer (PRROC) were randomised 1:1 to receive belotecan 0.5 mg/m2 or topotecan 1.5 mg/m2 for five consecutive days every 3 weeks. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: A total of 140 (belotecan, n = 71; topotecan, n = 69) and 130 patients (belotecan, n = 66; topotecan, n = 64) were included in the intention-to-treat (ITT) and per-protocol (PP) populations. ORR did not differ significantly between the belotecan and topotecan groups (ITT, 29.6% versus 26.1%; PP, 30.3% versus 25%). Although PFS did not differ between the groups, belotecan was associated with improved OS compared with topotecan in the PP population (39.7 versus 26.6 months; P = 0.034). In particular, belotecan showed longer OS in PRROC and non-high-grade serous carcinoma (non-HGSC; PP, adjusted hazard ratios, 0.499 and 0.187; 95% confidence intervals 0.255-0.977 and 0.039-0.895). Furthermore, there were no differences in toxicities between the two groups. CONCLUSIONS: Belotecan was not inferior to topotecan in terms of overall response for recurrent ovarian cancer. CLINICAL TRIAL REGISTRATION: NCT01630018.

Computational modeling of malignant ascites reveals CCL5-SDC4 interaction in the immune microenvironment of ovarian cancer.

Fluid accumulation in the abdominal cavity is commonly found in advanced-stage ovarian cancer patients, which creates a specialized tumor microenvironment for cancer progression. Using single-cell RNA sequencing (scRNA-seq) of ascites cells from five patients with ovarian cancer, we identified seven cell types, including heterogeneous macrophages and ovarian cancer cells. We resolved a distinct polarization state of macrophages by MacSpectrum analysis and observed subtype-specific enrichment of pathways associated with their functions. The communication between immune and cancer cells was predicted through a putative ligand-receptor pair analysis using NicheNet. We found that CCL5, a chemotactic ligand, is enriched in immune cells (T cells and NK cells) and mediates ovarian cancer cell survival in the ascites, possibly through SDC4. Moreover, SDC4 expression correlated with poor overall survival in ovarian cancer patients. Our study highlights the potential role of T cells and NK cells in long-term survival patients with ovarian cancer, indicating SDC4 as a potential prognostic marker in ovarian cancer patients.

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.

Prognostic implications of body composition change during primary treatment in patients with ovarian cancer: A retrospective study using an artificial intelligence-based volumetric technique.

OBJECTIVE: To investigate the impact of changes in body composition during primary treatment on survival outcomes in patients with epithelial ovarian cancer (EOC). METHODS: We retrospectively identified patients diagnosed with EOC between 2010 and 2019. Using an artificial intelligence-based tool, the volumes of skeletal muscle, visceral fat, and subcutaneous fat were measured automatically at the waist level from pre-treatment and post-treatment computed tomography scans. Associations between changes in body mass index (BMI) and volume of each body composition component and survival outcomes were evaluated. RESULTS: A total of 208 patients were included. A significant decrease in BMI and waist volumes of skeletal muscle and visceral fat was observed during the primary treatment. Patients with BMI loss ≥5% showed significantly worse progression-free survival (PFS) and overall survival (OS) than those with BMI loss <5%. In multivariate analyses adjusting for clinicopathologic factors, BMI loss ≥5% was identified as an independent poor prognostic factor for PFS (adjusted HR, 1.565; 95% CI, 1.074-2.280; P = 0.020) and OS (adjusted HR, 2.754; 95% CI, 1.382-5.488; P = 0.004). Meanwhile, both muscle loss ≥10% and visceral fat loss ≥20% were associated with an increased mortality rate but did not affect disease recurrence. In multivariate analyses, muscle loss ≥10% (adjusted HR, 2.069; 95% CI, 1.055-4.058; P = 0.034) and visceral fat loss ≥20% (adjusted HR, 2.292; 95% CI, 1.023-5.133; P = 0.044) were poor prognostic factors for OS. Consistent results were observed in the advanced-stage disease subgroup (n = 173). CONCLUSIONS: Changes in BMI and waist volume of skeletal muscle and visceral fat were associated with survival outcomes in patients with EOC.

Increasing serum gamma-glutamyltransferase level accompanies a rapid increase in the incidence of endometrial cancer in Korea: A nationwide cohort study.

OBJECTIVE: This study aimed to determine the association of serum GGT levels with the risk of developing endometrial cancer. Women's obesity and menopausal status were also taken into account in our analysis. METHODS: We used a nationwide cohort to examine the association between serum GGT levels and endometrial cancer development in Korean women. Data were retrieved from the Korean National Health Insurance Service (NHIS) healthcare system. Women aged over 19 years who participated in the Korea National Health Screening Examination in 2009 and were not diagnosed with endometrial cancer 1-year post-examination were included in our study (n = 2,736,588). RESULTS: Obese (BMI, ≥25 kg/m2) women with increased GGT levels were at high risk of endometrial cancer (HR = 1.415, 95% CI: 1.236-1.621). Interestingly, in pre-menopausal women, high GGT level (Q4) was associated with the increased endometrial cancer risk only for obese women (HR = 1.482, 95% CI: 1.205-1.821). In post-menopausal women, only a high GGT level (Q4) was also associated with the increased cancer risk for obese women (HR = 1.313, 95% CI: 1.096-1.573). We observed a significant association between high GGT levels and increased risk of endometrial cancer in pre-menopausal women with abdominal obesity (WC, ≥85 cm) (HR = 1.647, 95% CI: 1.218-2.227). CONCLUSIONS: Increased GGT level is an independent risk factor of endometrial cancer, especially for post-menopausal women and obese pre-menopausal women. These results may suggest that serum GGT levels might be useful in the risk stratification of endometrial cancer. Adopting a healthy lifestyle for lowering serum GGT level is warranted, especially for women with a higher risk of developing endometrial cancer.

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.

Resveratrol as a Tumor-Suppressive Nutraceutical Modulating Tumor Microenvironment and Malignant Behaviors of Cancer.

Tumor-suppressive effects of resveratrol have been shown in various types of cancer. However, regulation of tumor microenvironment by resveratrol is still unclear. Recent findings suggest resveratrol can potentiate its tumor-suppressive effect through modulation of the signaling pathways of cellular components (fibroblasts, macrophages and T cells). Also, studies have shown that resveratrol can suppress malignant phenotypes of cancer cells acquired in response to stresses of the tumor microenvironment, such as hypoxia, oxidative stress and inflammation. We discuss the effects of resveratrol on cancer cells in stress environment of tumors as well as interactions between cancer cells and non-cancer cells in this review.

Ovarian cancer therapeutic potential of glutamine depletion based on GS expression.

Amino acids (AAs) are biologically important nutrient compounds necessary for the survival of any cell. Of the 20 AAs, cancer cells depend on the uptake of several extracellular AAs for survival. However, which extracellular AA is indispensable for the survival of cancer cells and the molecular mechanism involved have not been fully defined. In this study, we found that the reduction of cell survival caused by glutamine (Gln) depletion is inversely correlated with the expression level of glutamine synthetase (GS) in ovarian cancer (OVC) cells. GS expression was downregulated in 45 of 316 OVC cases (14.2%). The depletion of extracellular Gln by treatment with l-asparaginase, in addition to inhibiting Gln uptake via the knockdown of a Gln transporter, led to the inhibition of cell growth in OVC cells with low expression of GS (GSlow-OVC cells). Furthermore, the re-expression of GS in GSlow-OVC cells induced the inhibition of tumor growth in vitro and in vivo. Thus, these findings provide novel insight into the development of an OVC therapy based on the requirement of Gln.