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This study aimed to report the clinical outcomes and risk factors for survival of patients with low-risk early-stage human papillomavirus-associated (HPVA) endocervical adenocarcinoma (EAC) treated with surgery alone. This retrospective study obtained the clinicopathological data of patients with early-stage HPVA EAC who underwent surgery between 2012 and 2018. The Silva pattern of invasion was determined by reviewing pathology slides. Locoregional recurrence-free survival (RFS), RFS, and overall survival were calculated, and the risk factors for survival were analyzed. One hundred seventeen patients with a median follow-up of 5.2 years (0.5-9.7 yr) were included. The most common histologic type was usual (94/117, 80.3%). The Silva pattern was A in 79 patients (67.5%), B in 30 (25.6%), and C in 8 (6.8%). The 5-year locoregional RFS, RFS, and overall survival rates were 92.4%, 87.8%, and 97.2%, respectively. The presence of intermediate-risk factors and Silva pattern C were significantly associated with worse survival. Based on these findings, patients were categorized into 2 groups: Group 1 (Silva pattern A or Silva pattern B without intermediate-risk factors) and Group 2 (Silva pattern B with intermediate-risk factors or Silva pattern C ). Group 2 showed significantly worse outcomes than Group 1, including the 5-year locoregional RFS (98.6% vs 68.0%), RFS (96.4% vs 54.6%), and overall survival (100.0% vs 86.5%). In conclusion, surgery alone for early-stage HPVA EAC resulted in favorable outcomes. Consideration of the Silva pattern, in addition to well-known risk factors, could help in precise risk group stratification of low-risk, early-stage HPVA EAC., Competing Interests: H.S.K.’s work is supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT; 2023R1A2C2006223). The remaining authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: To identify clinicopathological factors associated with disease recurrence for patients with 2018 FIGO stage IA with lymphovascular invasion to IB1 cervical cancer treated with minimally invasive surgery (MIS)., Methods: A total of 722 patients with cervical cancer between January 2010 and February 2021 were identified. Clinicopathological factors related to disease recurrence were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. To determine prognostic factors for DFS, a Cox proportional hazard regression model was used., Results: Of 722 patients, 49 (6.8%) experienced disease recurrence (37 pelvis, 1 para-aortic lymph node, and 11 peritoneum). Five-year DFS and OS rates were 90.7% and 98.1%, respectively. In multivariate analysis, risk factors associated with disease recurrence were residual disease in the remaining cervix (OR, 3.122; 95% CI, 1.152-8.461; p = 0.025), intracorporeal colpotomy (OR, 3.252; 95% CI, 1.507-7.017; p = 0.003), and positive resection margin (OR, 3.078; 95% CI, 1.031-9.193; p = 0.044). The non-conization group had a higher percentage of stage IB1 (77.4% vs. 64.6%; p = 0.004) and larger tumor (10 mm vs. 7 mm; p < 0.001) than the conization group. Intracorporeal colpotomy and residual disease in the remaining cervix were independent variables associated with disease recurrence in patients undergoing MIS following conization., Conclusion: During MIS, patients with cervical cancer ≤2 cm in size can be vulnerable to peritoneal recurrences. Patients diagnosed with invasive cancer through conization often have low-risk pathological features, which may affect their survival outcomes., Competing Interests: Declaration of Competing Interest All the authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the 2022 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Ovarian cancer: long-term follow-up data, new poly (ADP-ribose) polymerase (PARP) inhibitors, overall survival (OS) issues with PARP inhibitor monotherapy, hyperthermic intraperitoneal chemotherapy, immunotherapy, and antibody-drug conjugate; 2) Cervical cancer: surgery in early stage disease, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Corpus cancer: follow-up regimen, immune checkpoint inhibitor, WEE1 inhibitor, selective inhibitor of nuclear export. A special note was made on the withdrawal of PARP inhibitor from the market for heavily pretreated ovarian cancer patients based on the final OS results of ARIEL-4 and SOLO-3 due to concerns of increased risk of death., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: Cervical adenocarcinoma has poorer outcomes compared with squamous cell carcinoma; however, treatment is identical irrespective of histologic sub-types. This study aimed to investigate the patterns and risk factors of recurrence following surgery alone for low-risk early-stage cervical adenocarcinoma., Methods: We retrospectively reviewed patients who underwent surgery alone for low-risk early-stage cervical adenocarcinoma between January 2001 and December 2018 in a single institution. Baseline clinicopathological characteristics were collected to identify the factors associated with recurrence-free survival., Results: A total of 252 patients met the inclusion criteria. Most patients underwent radical hysterectomy (218 patients, 86.5%) and had usual type endocervical adenocarcinoma (190 patients, 75.4%). The International Federation of Gynecology and Obstetrics 2018 stage was IA1 in 72 patients (27.4%), IA2 in 58 (22.1%), IB1 in 51 (19.4%), and IB2 in 71 patients (27.0%). With a median follow-up of 70.4 months (range 6.2-252.5 months), 5-year survival rates were as follows: locoregional recurrence-free survival, 93.0%; recurrence-free survival, 89.6%; overall survival, 94.7%. The recurrence patterns were local in nine patients (32.1%), regional in five patients (17.8%), distant in 10 patients (35.7%), local and distant in one patient (3.6%), regional and distant in two patients (7.2%), and locoregional and distant in one patient (3.6%). In multivariable analysis, negative human papillomavirus (HPV) status (HR 7.314; p<0.001) and deep cervical stromal invasion (HR 5.110; p=0.003) were associated with poor locoregional recurrence-free survival. Patients were stratified based on the number of risk factors and a statistically significant difference in locoregional recurrence-free survival was observed: 5-year survival rates of 99.0%, 84.2%, and 50.0% for patients with 0, 1, and 2 risk factors (0 vs 1, p=0.001; 1 vs 2, p=0.011)., Conclusion: Surgery alone for low-risk early-stage cervical adenocarcinoma was associated with favorable outcomes over a long follow-up period. Patients with the highest risk of recurrence were those with a negative HPV status and deep cervical stromal invasion. Additional management following surgery may be considered in patients with these risk factors., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI., Methods: We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs., Results: Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs., Conclusion: We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

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., (© 2022. The Author(s).)

In the 2021 series, we not only summarized the major clinical research advances in gynecologic oncology but also added discussions to every part, based on communications at the conference. A review of cervical cancer included adjuvant treatments such as radiation and chemoradiation (concurrent or sequential) after radical hysterectomy in early cervical cancer, and immune checkpoint inhibitors in advanced, recurrent, and metastatic disease. Ovarian cancer research included studies of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer, and various trials of immune checkpoint inhibitors with or without vascular endothelial growth factor inhibitors and conventional chemotherapy. The rechallenge of poly (ADP-ribose) polymerase inhibitor maintenance in heavily pretreated ovarian cancer were also addressed. For uterine corpus cancer, dostarlimab (anti-programmed cell death protein 1 antibody) alone, or a tyrosine kinase inhibitor in combination with pembrolizumab for advanced, metastatic, or recurrent endometrial cancer were reviewed. The survival differences between the intensive and minimalist follow-up protocols were also described. In this review, we compared salpingectomy with delayed oophorectomy and salpingo-oophorectomy in terms of quality of life in BRCA 1 and 2 pathogenic variant carriers., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Purpose: This study aimed to evaluate the effect of waiting time, from diagnosis to initiation of definitive concurrent chemoradiation (CCRT), on overall survival in cervical cancer patients., Materials and Methods: Patients with cervical cancer who were treated with definitive CCRT between 2000 and 2017 were retrospectively reviewed. Time from initial pathological diagnosis to definitive CCRT was analyzed both as a continuous variable (per day) and as a categorical variable in two groups (group 1 ≤ median, group 2 > median). Patients with a waiting time of more than 60 days were excluded., Results: The median waiting time was 14 days (0-60). There were differences between group 1 and group 2 in age and chemotherapy regimens. However, no significant difference was found in the International Federation of Gynecology and Obstetrics stage, cell type, or the number of cycles of chemotherapy received during CCRT. A longer waiting time was associated with poorer overall survival on the Kaplan-Meier curve (group 1 vs. group 2, p=0.042). On multivariate analysis, intervals as either a continuous variable (hazard ratio [HR], 1.023; 95% confidence interval [CI], 1.006 to 1.040; p=0.007) or a categorical variable (HR, 1.513; 95% CI, 1.073 to 2.134; p=0.018), FIGO stage, cell type, and the number of cycles of chemotherapy received during CCRT were significant independent prognostic factors for overall survival., Conclusion: A shorter waiting time from pathological diagnosis to definitive CCRT showed benefit on overall survival. Our findings suggest that an effort to minimize waiting times should be recommended in cervical cancer patients who are candidates for CCRT.

Objective: Unlike cervical squamous cell carcinoma, there are no consensus criteria for serum tumor markers in cervical adenocarcinoma. This study aimed to identify the prognostic value of preoperative carbohydrate antigen 125 (CA125) levels in cervical adenocarcinoma patients with adverse pathologic features., Methods: A total of 105 patients who underwent radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiation therapy were included. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Cox proportional hazard regression model., Results: Using a cutoff value of 50 U/mL, 83 and 22 patients had low- and high-CA125, respectively. Patients with high-CA125 had a larger tumor size, more frequent parametrial extension, and more frequent lymph node metastasis than those with low-CA125. During a median follow-up of 59.3 (interquartile range, 32.7-97.8) months, patients with high-CA125 showed inferior 5-year LRFS, DMFS, and OS rates compared to those with low-CA125 (38.5% vs. 70.0%; 37.0% vs. 69.4%; 43.6% vs. 78.1%, respectively, all p<0.05). In multivariable analysis, the high-CA125 remained significant prognostic factor for LRFS, DMFS, and OS (all p<0.05). Furthermore, 12 patients with high-CA125 at recurrence exhibited lower 5-year OS rates than 21 patients with low-CA125 at recurrence (0.0% vs. 51.3%, p=0.003)., Conclusion: In this retrospective analysis, the serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features. A CA125 level of ≥50 U/mL may be a prognostic surrogate marker for cervical adenocarcinoma in patients with the presence of adverse factors., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Purpose: This study aimed to identify the prognostic value of early metabolic response assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) during radiation therapy (RT) for cervical cancer., Materials and Methods: We identified 116 patients treated with definitive RT, including FDG-PET/CT-guided intracavitary brachytherapy, between 2009 and 2018. We calculated parameters including maximum (SUVmax) and mean standardized uptake values (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for baseline FDG-PET/CT (PETbase) and image-guided brachytherapy planning FDG-PET/CT (PETIGBT). Multivariable analyses of disease-free survival (DFS) and overall survival (OS) were performed., Results: We observed a time-dependent decrease in PET parameters between PETbase and PETIGBT; ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG were 65%, 61%, 78%, and 93%, respectively. With a median follow-up of 59.5 months, the 5-year DFS and OS rates were 66% and 79%, respectively. Multivariable analysis demonstrated that ΔSUVmax ≥ 50% was associated with favorable DFS (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.14 to 5.77) and OS (HR, 5.14; 95% CI, 1.55 to 17.01). Patients with ΔSUVmax ≥ 50% (n=87) showed better DFS and OS than those with ΔSUVmax < 50% (n=29) (DFS, 76% vs. 35%, p < 0.001; OS, 90% vs. 41%, p < 0.001, respectively). Adenocarcinoma was frequently observed in ΔSUVmax < 50% compared to ΔSUVmax ≥ 50% (27.6% vs. 10.3%, p=0.003). In addition, models incorporating metabolic parameters showed improved accuracy for predicting DFS (p=0.012) and OS (p=0.004) than models with clinicopathologic factors., Conclusion: Changes in metabolic parameters, especially those in SUVmax by > 50%, can help improve survival outcome predictions for patients with cervical cancer treated with definitive RT.

In 2020 series, we summarized the major clinical research advances in gynecologic oncology with providing representative figures of the most influential study for 1 of each 3 gynecologic cancers: cervix, ovary, and uterine corpus. Review for cervical cancer covered targeted agents and immune checkpoint inhibitors, adjuvant radiation therapy or concurrent/sequential chemoradiation therapy after radical hysterectomy in early cervical cancer, radical surgery in early cervical cancer; and prevention and screening. Ovarian cancer research included studies of various combinations of poly (ADP-ribose) polymerase inhibitors with chemotherapy, immune checkpoint inhibitors, and/or vascular endothelial growth factor inhibitors according to the clinical setting. For uterine corpus cancer, molecular classification upon which the decision of adjuvant treatments might be based, World Health Organization recommendation of 2-tier grading system (low grade vs. high grade), sentinel lymph node assessment and ovarian preservation in clinically early-stage endometrial cancer were reviewed. Molecular targeted agents including immune checkpoint inhibitors which showed promising anti-tumor activities in advanced/recurrent endometrial cancer were also included in this review., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: The effectiveness of paclitaxel-cisplatin-ifosfamide triplet regimen (TIP) was reported to be superior to that of paclitaxel-cisplatin doublet. However, the efficacy of paclitaxel-cisplatin-bevacizumab triplet (TPA) and TIP has not been compared. Here, we compared the efficacy and safety of TIP and TPA in patients with metastatic, recurrent, or persistent cervical cancer., Methods: We retrospectively reviewed the medical records of patients with recurrent, persistent, or metastatic cervical cancer who were at the Samsung Medical Center, Seoul, Korea between January 2005 and September 2018. Of the 161 patients included in the study, 92 had received TIP and 71 had received TPA. For the study, we compared the response rates, progression-free survival (PFS), overall survival (OS), and safety in the 2 treatment groups., Results: The response rates of patients who received TIP and TPA were comparable (64.1% vs 73.2%, P = 0.239). Histology (squamous vs nonsquamous) was the only prognostic factor that affected the response to therapy (odds ratio, 0.259; 95% confidence interval [CI], 0.119-0.562; P = 0.001). The PFS after TIP and TPA treatment was similar: 12.0 months (95%CI, 10.26-13.74) vs 11.5 months (95%CI, 10.18-12.83), respectively. In a Cox proportional hazard model, objective response to therapies was the only independent prognostic factor for both PFS and OS. However, different types of therapy (TIP vs TPA) did not affect the oncological outcomes for either PFS or OS. Although hematologic toxicity was significantly higher in the TIP-treated group than in the TPA-treated group, both regimens were safe and well-tolerated., Conclusions: The effectiveness and safety of TIP was comparable to TPA in terms of response rates, survival, and adverse effects. TIP could be an effective alternative in the treatment of cervical cancer when TPA is contraindicated or unaffordable., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Resistance to chemo-radiation therapy is a substantial obstacle that compromises treatment of advanced cervical cancer. The objective of this study was to investigate if a proteomic panel associated with radioresistance could predict survival of patients with locally advanced cervical cancer., Methods: A total of 181 frozen tissue samples were prospectively obtained from patients with locally advanced cervical cancer before chemoradiation. Expression levels of 22 total and phosphorylated proteins were evaluated using well-based reverse phase protein arrays. Selected proteins were validated with western blotting analysis and immunohistochemistry. Performances of models were internally and externally validated., Results: Unsupervised clustering stratified patients into three major groups with different overall survival (OS, P = 0.001) and progression-free survival (PFS, P = 0.003) based on detection of BCL2, HER2, CD133, CAIX, and ERCC1. Reverse-phase protein array results significantly correlated with western blotting results (R 2  = 0.856). The C-index of model was higher than clinical model in the prediction of OS (C-index: 0.86 and 0.62, respectively) and PFS (C-index: 0.82 and 0.64, respectively). The Kaplan-Meier survival curve showed a dose-dependent prognostic significance of risk score for PFS and OS. Multivariable Cox proportional hazard model confirmed that the risk score was an independent predictor of PFS (HR: 1.6; 95% CI: 1.4-1.9; P < 0.001) and OS (HR: 2.1; 95% CI: 1.7-2.5; P < 0.001)., Conclusion: A proteomic panel of BCL2, HER2, CD133, CAIX, and ERCC1 independently predicted survival in locally advanced cervical cancer patients. This prediction model can help identify chemoradiation responsive tumors and improve prediction for clinical outcome of cervical cancer patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this study to disclose., (Published by Elsevier Inc.)

Purpose: Lymph node metastasis (LNM) is the most significant prognostic factor in cervical cancer that was recently incorporated into the International Federation of Gynecology and Obstetrics (FIGO) staging system. This study was performed to evaluate whether the prognostic significance of LNM differs according to disease status., Materials and Methods: Patients with FIGO stage IB or higher cervical cancer who had pretreatment computed tomography and/or magnetic resonance imaging studies as well as long-term follow-up were enrolled in this retrospective study. The hazard ratio (HR) of Cox regression was used to determine the prognostic significance of LNM. The HRs were compared between the different tumor groups (based on stage, histology, tumor size, primary treatment, age, parametrium involvement, and lymphovascular space invasion)., Results: A total of 970 patients treated between January 1999 and December 2007 were included. The pretreatment LNM had prognostic significance in patients with stage IB1/IIA (HR for progression-free survival 2.10, p=0.001; HR for overall survival 1.99, p=0.005). However, the significance gradually decreased or disappeared with advancing stages. Similarly, the prognostic significance of the pretreatment LNM decreased with advancing disease status, including old age, parametrial involvement or lymphovascular space involvement. In contrast, the tumor size was associated with the prognostic significance of LNM with advancing status. The significance of the clinical LNM did not reflect the significance of the clinical stage. In contrast, the tumor size, parametrial involvement, and significance of the pathologic LNM reflected the clinical stage., Conclusion: In patients with cervical cancer, pretreatment LNM on imaging has different clinical significance depending on the tumor status.

Although the concurrent use of a chemotherapeutic agent and radiotherapy improves survival in patients with locally advanced or recurrent cervical cancer, severe side effects related to chemotherapy are frequent and may result in a low quality of life for the patients. In this study, we investigated the effects of a combination of Wee1 inhibitor (AZD1775) and irradiation in cervical cancer. In vitro effects of AZD1775 with irradiation in human cervical cancer cells were assessed by clonogenic survival and apoptosis assays. The effects on DNA damage response signaling and the cell cycle were also explored. Tumor growth delay was evaluated to investigate the in vivo effects of AZD1775 with irradiation in cervical cancer mouse models, including xenografts and patient-derived xenografts (PDXs). The co-treatment of AZD1775 and irradiation significantly decreased clonogenic survival and increased apoptosis in cervical cancer cells. These effects were associated with G2 checkpoint abrogation which resulted in persistent DNA damage. Both in the xenografts and the PDXs, the co-treatment significantly decreased tumor growth compared tothe irradiation alone (p < 0.05). These results demonstrate that the Wee1 inhibitor (AZD1775) can be considered as a potential alternative as a radiosensitizer in cervical cancer instead of a chemotherapeutic agent such as cisplatin.

Objective: Paclitaxel/ifosfamide/cisplatin triplet has shown a higher response rate than paclitaxel/cisplatin doublet, but the toxicity profile hindered the use of the triplet regimen. In this study, we adjusted the dosage of the triplet regimen and introduced carboplatin in cisplatin-intolerable patients. We tested the efficacy and toxicity of the modified triplet regimen in patients with recurrent or persistent cervical cancer., Materials and Methods: We retrospectively reviewed the medical records of patients with recurrent or persistent cervical cancer who were treated between 2003 and 2015 at Samsung Medical Center. Response rate, progression-free survival (PFS), overall survival (OS), and toxicity of paclitaxel/ifosfamide/platinum (TIP) and paclitaxel/platinum (TP) were compared., Results: The overall response rate of TIP was significantly higher than that of TP (52.7% vs 36.4%, P = 0.031). In the TP group, response rate was higher in patients with progression-free interval longer than 12 months (P = 0.028) and those with squamous cell histology (P = 0.028). In TIP group, patients with older than 50 years (P = 0.017), progression-free interval longer than 12 months (P = 0.046), and squamous cell carcinoma histology (P < 0.001) showed higher response rates; but TIP showed higher response on all occasions. Median OS and median PFS were similar for TP and TIP (OS, 22.43 months vs 18.5 months, P = 0.44; PFS, 6.37 months vs 8.3 months, P = 0.48)., Conclusions: Paclitaxel/ifosfamide/platinum showed a higher response rate than TP in patients with recurrent cervical cancer without an increase in severe complications. Considering the high response rate, TIP may be an option for persistent or recurrent cervical cancer.

Objective: This study aims to analyze the published literatures on the effect of less radical fertility-preserving procedures, such as conization or simple trachelectomy, on oncological outcomes in IA1 cervical cancer patients with lymphovascular space invasion (LVSI) through a systematic-review., Methods: The EMBASE and MEDLINE databases and Cochrane Library were searched for published studies reporting the oncological outcomes of conization/simple trachelectomy in these patients, through April 2017. The endpoints were recurrence and mortality rates. Data were presented as per the Meta-analysis Of Observational Studies in Epidemiology checklist. Practice guidelines were generated via the Grading of Recommendation, Assessment, Development and Evaluation system., Results: From 6,755 records, 94 full-texts articles were reviewed for eligibility, and five studies were included in this systematic review. All included studies were nonrandomized studies: two case-control studies comparing conization (n = 14) with hysterectomy (n = 24), and the other three were interrupted time series including conization (n = 20) and simple vaginal trachelectomy (n = 59). During the median follow-up duration of 43 months, no recurrence was reported in both conization and simple trachelectomy groups in IA1 patients with LVSI. From three studies reporting the fertility outcomes, the rates of pregnancy, live birth, preterm delivery, and second-trimester miscarriage were 73% (35/48), 64% (32/50), 10% (5/48), and 6% (3/48), respectively., Conclusion: Results suggest that simple trachelectomy or conization could be performed for IA1 cervical cancer patients with LVSI who want to preserve fertility, although these results are only based on a small number of nonrandomized studies (recommendation grade 2 = weak; evidence level D = very low). Further randomized trials with long-term study period are needed to address this issue.

Clinical practice guidelines for gynecologic cancers have been developed by academic society from several countries. Each guideline reflected their own insurance system and unique medical environment, based on the published evidence. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to develop the third edition of the guidelines in an advanced format based on evidence-based medicine, embracing up-to-date clinical trials and qualified Korean data. These guidelines cover strategies for diagnosis and treatment of primary and recurrent cervical cancer. The committee members and many gynecologic oncologists derived key questions through discussions, and a number of relevant scientific literature were reviewed in advance. Recommendations for each specific question were developed by the consensus conference, and they are summarized here, along with the details. The objective of these practice guidelines is to establish standard policies on issues in clinical practice related to the management in cervical cancer based on the results in published papers to date and the consensus of experts as a KSGO Consensus Statement., Competing Interests: Jae-Weon Kim, Myong Cheol Lim, Jeong-Yeol Park, and Seung-Hyuk Shim serve as editors of the Journal of Gynecologic Oncology (JGO), but have no role in the decision to publish this article. No other conflict of interest relevant to this article was reported., (Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Aim: We investigated the feasibility of dynamin 2 as a potential treatment target in cervical cancer cells., Materials and Methods: We performed tissue microarray for dynamin 2 expression in 208 patients with early cervical cancer and in vitro in HeLa cells with dynamin 2 inhibitors MiTMAB, OcTMAB, Dynasore, and DD-6., Results: Tumor size greater than 2 cm or tumor invasion of more than half of the entire cervix was associated with expression of dynamin 2 compared to no expression (p=0.013, and p=0.045, respectively). All dynamin 2 inhibitors significantly reduced proliferation, increased apoptotic activity, and reduced matrix metallopeptidase 9 expression in HeLa cells. Dynasore and DD-6 reduced migration of HeLa cells on laminin 1-coated plates and DD-6 most strongly reduced migration performance on fibronectin-coated plates., Conclusion: Targeting dynamin 2 may be a promising new approach for the treatment of cervical cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: Magnetic resonance imaging (MRI) can be used to assess parametrial invasion (PMI) in cervical cancer. Discordance between MRI findings and International Federation of Gynecology and Obstetrics (FIGO) staging is not uncommon because FIGO staging depends on physical examination. The purpose of this study was to retrospectively evaluate the long-term outcomes of MRI stage IIB cervical cancer., Methods: A total of 312 patients with MRI stage IIB cervical cancer were retrospectively found between 2002 and 2011. Of these patients, 171 (group 1) were FIGO stage IIB cervical cancers and 141 (group 2) were MRI stage IIB cervical cancers that were negative PMI on physical examination. Group 1 was treated with chemotherapy and/or radiation therapy, and group 2 was treated with radical hysterectomy and lymph node dissection. The FIGO stages and pathologic findings of group 2 were recorded. Groups 1 and 2 were compared regarding 5-year overall survival rate., Results: The FIGO stages of group 2 were IB1 in 51 (36.2%), IB2 in 28 (19.9%), and IIA in 62 (44%), whereas those of group 1 were all IIB. Group 2 showed lymphovascular space invasion in 71 (50.4%), lymph node metastasis in 48 (34.0%), PMI in 46 (32.6%), and vagina invasion in 9 (6.4%). Five-year overall survival rates of groups 1 and 2 were 73.7% and 84.5%, respectively (P = 0.013)., Conclusions: Magnetic resonance imaging stage IIB cervical cancers with negative PMI on physical examination should be surgically treated because of better survival rate than FIGO stage IIB cervical cancers.

Objective: To assess the clinical outcomes of surgical treatment for acquired vulvar lymphangioma circumscriptum in patients who received radical surgery and/or adjuvant radiation therapy for cervical cancer., Methods: A retrospective chart review of eight patients was performed to assess the demographic information, chief complaints, treatment modality for cervical cancer, location, and primary treatment modality for vulvar LC, postoperative changes in symptoms, and/or signs, the development of local recurrence and the outcome of patients., Results: All eight patients were previously diagnosed with cervical cancer FIGO clinical stage IA to IIA and received surgery, radiation therapy, or concurrent chemoradiation therapy. Microscopic examination revealed multiple, dilated, D2-40-positive dermal vascular channels containing eosinophilic proteinaceous material, consistent with LC. Most chief complaints showed considerable improvements on assessment at the outpatient clinic after the primary surgery. No patient showed aggravation of symptoms. Two patients developed local recurrences. One patient developed recurrence on the opposite side 13 months after local excision. We performed a second wide local excision. Another patient developed recurrence 47 months after the primary surgery. Since the lesion was very small and localized, we decided to manage it conservatively, but monitor it very closely. The remaining six patients remained free of recurrence., Conclusion: It is not easy for gynecologists to have an initial clinical diagnosis of LC, because there are a number of diseases that exhibit similar clinical manifestation to that of vulvar LC. Even if it is diagnosed correctly, local recurrence often occurs. Relevant symptoms associated with LC are not only distressing, but also affect patients' quality of life. Based on our data, we propose that surgical treatment could provide a more long-lasting answer compared to other treatment modalities, since it is beneficial in terms of clinical outcomes. In the future, a long-term follow-up investigation is required to assess the prognosis and to compare the efficacy and side effects of each modality.

Sphingosine kinase 1 (SPHK1), an oncogenic kinase, has previously been found to be upregulated in various types of human malignancy and to play a crucial role in tumor development and progression. Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology, its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown. SPHK1 expression was examined in 287 formalin-fixed, paraffin-embedded cervical cancer tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Cervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720, and effects on cell survival, apoptosis, angiogenesis, and invasion were examined. Moreover, the effects of FTY720 on tumor growth were evaluated using a patient-derived xenograft (PDX) model of cervical cancer. Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in cervical cancer compared with normal tissues. SPHK1 expression was significantly associated with tumor size, invasion depth, FIGO stage, lymph node metastasis, and lymphovascular invasion. Patients with high SPHK1 expression had lower overall survival and recurrence-free survival rates than those with low expression. Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in cervical cancer cells. Furthermore, FTY720 significantly decreased in vivo tumor weight in the PDX model of cervical cancer. We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of cervical cancer. Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of cervical cancer.

Objective: This study reports our initial experience of robotic high para-aortic lymph node dissection (PALND) with high port placement using same port for pelvic surgery in cervical and endometrial cancer patients., Methods: Between July 2013 and January 2014, we performed robotic high PALND up to the left renal vein during staging surgeries. With high port placement and same port usage for pelvic surgery, high PALND was successfully performed without repositioning the robotic column. All data were registered consecutively and analyzed retrospectively., Results: All patients successfully underwent robotic high PALND, followed by hysterectomy and pelvic lymph node dissection. Median age was 45 years (range, 39 to 51 years) and median body mass index was 22 kg/m² (range, 19.3 to 23.1 kg/m²). Median operative time for right PALND and left PALND was 37 minutes (range, 22 to 65 minutes) and 44 minutes (range, 36 to 50 minutes), respectively. Median number of right and left para-aortic lymph node by pathologic report was 12 (range, 8 to 15) and 13 (range, 5 to 26)., Conclusion: With high port placement and one assistant port, robotic high PALND with the same port used in pelvic surgery is feasible to non-obese patients.

Objective: This study aimed to compare the laparoscopic-assisted radical vaginal trachelectomy (LARVT) and laparoscopic radical trachelectomy (LRT) surgical approaches and provide outcome data on patients who have undergone radical trachelectomy., Methods: We identified patients who had undergone LARVT or LRT at Samsung Medical Center between January 2005 and March 2013., Results: A total of 38 patients were identified, and 21 patients had undergone LARVT, whereas 17 patients had undergone LRT. The median age was 32 years for both groups. Most of the patients had a squamous cell carcinoma (68.4%) and International Federation of Gynecology and Obstetrics stage IB1 disease (76.3%). Twenty (52.6%) of 38 patients had tumor size greater than 2 cm. There were no significant differences between groups in the baseline characteristics except for the tumor size. Patients undergoing LRT had significantly larger tumor size than patients undergoing LARVT (median tumor size, 2.7 cm [range, 1.2-3.7] vs 2.1 cm [range, 0.4-3.0], P = 0.032). Perioperative outcomes were similar between groups except for the decline of hemoglobin after surgery. The median decline of hemoglobin indicating blood loss was significantly smaller in the LRT group than in the LARVT group (1.8 g/dL [range, 0.5-3.5] vs 2.6 g/dL [range, 0.7-6.2], P = 0.017). Intraoperative complications occurred in 2 patients (9.5%, 2/21) in LARVT group. Although 52.6% of tumors were larger than 2 cm, recurrence occurred only in 3 (7.9%) patients who underwent LARVT., Conclusions: The study shows the feasibility of LRT, with the advantage of reduced blood loss. The LRT could be an alternative option for patients with large tumors. Further researches are needed to investigate the long-term outcomes.

Objective: The aim of this study was to assess the relative incidences of cervical adenocarcinoma in situ (AIS) and squamous cell carcinoma in situ (sCIS) and to determine the effect of coexisting squamous cell lesions on prognosis in patients with cervical AIS., Study Design: We performed a retrospective review of patients diagnosed with AIS or sCIS who underwent cervical conization at a University hospital between 2000 and 2011., Results: A total of 1184 patients with cervical carcinoma in situ were included. The ratio of sCIS to AIS was 16:1. Among 71 patients with AIS, AIS with coexisting squamous cell lesions and AIS alone were detected in 41 patients (58%) and 30 patients (42%), respectively. During the median follow-up of 57.1 months, 5 episodes of AIS recurrences and one episode of invasive recurrence occurred. The recurrence rate was significantly higher in patients with AIS alone than in patients with AIS and coexisting squamous cell lesions (17% versus 2%; P=0.043)., Conclusion: These results suggest that patients with cervical AIS and coexisting squamous cell lesions have a more favorable prognosis than patients with AIS alone., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma., (Published by Elsevier Inc.)

Objective: The study investigated the association between the location of transposed ovaries and posttreatment ovarian function in patients with early cervical cancer (IB1-IIA) who underwent radical hysterectomy and ovarian transposition with or without adjuvant therapies., Methods: Retrospective medical records were reviewed to enroll the patients with early cervical cancer who underwent ovarian transposition during radical hysterectomy at Samsung Medical Center between July 1995 and July 2012. Serum follicle-stimulating hormone (FSH) level was used as a surrogate marker for ovarian function., Results: Twenty-one patients were enrolled. The median age and body mass index (BMI) were 31 years (range, 24-39 years) and 21.3 kg/m² (range, 17.7-31.2 kg/m²), respectively. The median serum FSH level after treatment was 7.9 mIU/mL (range, 2.4-143.4 mIU/mL). The median distance from the iliac crest to transposed ovaries on erect plain abdominal x-ray was 0.5 cm (range, -2.7 to 5.2 cm). In multivariate analysis, posttreatment serum FSH levels were significantly associated with the location of transposed ovaries (β = -8.1, P = 0.032), concurrent chemoradiation (CCRT) as an adjuvant therapy (β = 71.08, P = 0.006), and BMI before treatment (underweight: β = -59.93, P = 0.05; overweight: β = -40.62, P = 0.041)., Conclusions: Location of transposed ovaries, adjuvant CCRT, and BMI before treatment may be associated with ovarian function after treatment. We suggest that ovaries should be transposed as highly as possible during radical hysterectomy to preserve ovarian function in young patients with early cervical cancer who might be a candidate for adjuvant CCRT and who have low BMI before treatment.

Objective: This study aimed to compare initial surgical outcomes and complication rates of patients with early-stage cervical cancer who underwent robotic radical hysterectomy (RRH) and conventional laparoscopic radical hysterectomy (LRH)., Methods: Patients diagnosed with invasive cervical cancer (International Federation of Gynecology and Obstetrics stage I-IIA) who underwent RRH (n = 23) at Samsung Medical Center from January 2008 to May 2013 were compared with matched patients who underwent LRH (n = 69) during the same period. The 2 surgical groups were matched 3:1 for variables of age, body mass index, International Federation of Gynecology and Obstetrics stage, histological subtype, tumor size, and node positivity. All patient information and surgical and postoperative follow-up data were retrospectively collected., Results: Operating time was significantly longer (317 vs 236 minutes; P < 0.001) in the RRH group compared with the LRH group but mean estimated blood loss was significantly reduced in the RRH group (200 vs 350 mL; P = 0.036). Intraoperative and postoperative complications were not significantly different between the 2 groups (4.3% for RRH vs 1.45% for LRH; P = 0.439). Recurrences were 2 (8.7%) in the RRH and 7 (10.1%) in the LRH group. The overall 3-year recurrence-free survival was 91.3% in RRH group and 89.9% in the LRH group (P = 0.778)., Conclusions: Although operating time was longer in the RRH cases because of lesser experience on robotic platform, we showed that surgical outcomes and complication rate of RRH were comparable to those of LRH. In addition, surgical skills for LRH easily and safely translated to RRH in case of experienced laparoscopic surgeon.

Objective: Tumor volume is a significant prognostic factor of cervical cancer. It is still unknown about outcome of biopsy-proven IB1 cervical cancer, which is invisible on preoperative magnetic resonance imaging (MRI). The aim was to evaluate retrospectively the postoperative outcomes of MR-invisible stage IB1 cervical cancers., Study Design: Between January 2001 and December 2007, we reviewed the medical records of 86 patients with biopsy-proven IB1 cervical cancer that was invisible on MRI. During the same period, we also reviewed the medical records of 260 patients with biopsy-proven IB1 cervical cancer that was visible on MRI. Both of these cancer groups were treated with radical hysterectomy and lymph node dissection. MR-invisible and MR-visible IB1 cancers were compared in terms of pathologic parameters and long-term survival rate., Results: The median sizes and depths of stromal invasion of MR-invisible vs MR-visible IB1 cancers were 4.5 ± 7.1 mm and 33.3% ± 20.1% vs 30 ± 14 mm and 66.7% ± 26.6%, respectively (P = .000). The incidences of lymph node metastasis, parametrial invasion, and lymphovascular invasion were 1.1% (1/86 cases) and 18.8% (49/260 cases; P = .000; odds ratio, 19.7), 0% (0/86 cases) and 6.5% (17/260 cases; P = .009; odds ratio, 12.4), and 4.7% (4/86 cases) and 26.9% (70/260 cases; P = .000; odds ratio, 7.6) in the MR-invisible and MR-visible IB1 cancers, respectively. Recurrence-free and overall 5-year survival rates of MR-invisible vs MR-visible IB1 cancers were 98.8% (85/86 cases) vs 91.2% (237/260 cases) and 100% (86/86 cases) vs 95.8% (249/260 cases), respectively (P = .011 and .045)., Conclusion: MR-invisible IB1 cancer provides better postoperative outcomes than MR-visible IB1 cancer because of the much lower tumor burden., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Recurrence is the major cause of death in early cervical cancer. We compared the prediction powers for disease recurrence between the gene set prognostic model and the clinical prognostic model., Materials and Methods: A gene set model to predict disease free survival was developed using the cDNA-mediated annealing, selection, extension, and ligation (DASL) assay data set from a cohort of early cervical cancer patients who had been treated with radical surgery with or without adjuvant therapy. A clinical prediction model was also developed using the same cohort, and the ability of predicting recurrence from each model was compared., Results: Adequate DASL assay profiles were obtained from 300 patients, and we selected 12 genes for the gene set model. When patients were categorized as having a low or high risk by the prognostic score, the Kaplan-Meier curve showed significantly different recurrence rates between the two groups. The clinical model was developed using FIGO stage and post-surgical pathological findings. In multivariate Cox regression analysis of prognostic models, the gene set prognostic model showed a higher hazard ratio than that of the clinical prognostic model., Conclusions: The genetic quantitative approach may be better in predicting recurrence in early cervical cancer patients., (© 2013 Elsevier Inc. All rights reserved.)

Aim: Adjuvant concurrent chemoradiation (CCRT) should be considered in surgically-treated patients with early-stage cervical cancer (ECC) who exhibit pelvic lymph node (LN) metastasis. Platinum-based chemotherapy is usually recommended during adjuvant CCRT, however, it is unclear which regimen has better prognostic outcomes., Patients and Methods: We reviewed the electronic medical records to find patients with primary ECC (FIGO stages IB-IIA) who underwent type III radical hysterectomy and adjuvant CCRT due to pelvic LN metastasis at the Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Korea, from November 1997 to September 2007., Results: Among 75 patients, 34 received weekly cisplatin. Combination chemotherapy was performed without consolidation in 21 patients and with consolidation in 20 patients. The mean follow-up period was 59.0 months and the five-year survival rate was 84.4%. In multivariate analysis, combination chemotherapy with and without consolidation was associated with improved disease-free survival [hazard ratio (HR)=0.23, 95% confidence interval (CI)=0.06-0.88, p=0.032, and HR=0.29, 95% CI=0.09-0.91, p=0.034, respectively]; combination chemotherapy with consolidation significantly improved overall survival (HR=0.11, 95% CI=0.02-0.87, p=0.037) when compared to weekly cisplatin., Conclusion: We found that platinum-based combination chemotherapy during adjuvant CCRT after surgery promoted better survival than a weekly cisplatin regimen in ECC patients with pelvic LN metastasis.

Objective: The purpose of this study was to describe the clinical characteristics and to assess the contributing factors in patients developing bone metastasis in uterine cervical cancer., Methods: Two thousand thirteen patients had a diagnosis of uterine cervical cancer at Samsung Medical Center between June 1994 and December 2011. During the study period, 105 patients with bone metastasis were identified, and their clinicopathologic data were investigated retrospectively., Results: Among 105 patients with bone metastasis, 14 patients were excluded and 91 patients were evaluable. The median bone metastasis-free survival was 27 months (range, 0-279 months).The time to bone metastasis was significantly shorter in patients with adenocarcinoma than in patients with squamous cell carcinoma (median duration, 12 vs 29 months; P = 0.016). In addition, it was shorter in patients with stage IIB to stage IV disease than in those with stage I to stage IIA disease (15 vs 22 months; P = 0.02). The median survival after bone metastasis was 10 months, longer in the patients who received radiotherapy (± chemotherapy) than in the patients who received chemotherapy alone as a salvage therapy (12 vs 7 months; P = 0.01). Initial stage, number of bone metastases, location of involved bone, and coexisting metastatic lesion were not associated with the overall survival of the patients., Conclusions: Our study demonstrates that adenocarcinoma, advanced stage (IIB-IV) and initial multiple bone metastases contribute to earlier bone metastasis. Once bone metastasis was recognized, the survival of these patients was poor and no factors were identified to predict survival of those patients.

Galectin 1 is a 14-kd laminin-binding lectin involved in important biologic mechanisms of tumors, including neoplastic transformation, cell survival, angiogenesis, cell proliferation, and metastasis. In this study, we investigated the role of galectin 1 in cell survival and metastasis in cervical cancer. The expression of galectin 1 was determined in 73 formalin-fixed, paraffin-embedded cervical cancer tissues using an immunohistochemical method and compared with clinicopathologic risk factors for recurrence after surgery. To evaluate the role of galectin 1 in cell proliferation and invasion, we performed proliferation and invasion assays with galectin 1 small interfering RNA (siRNA) using cervical cancer cell lines, including HeLa and SiHa cells. Immunohistochemical analysis revealed that galectin 1 expression was found in most peritumoral stroma samples (72/73; 98.6%). Galectin 1 expression was significantly correlated with the depth of invasion in the cervix (P=.015) and lymph node metastasis (P=.045) on univariate analysis. When progression-free survival of all of the patients studied was analyzed based upon galectin 1 expression, galectin 1 expression was not correlated with progression-free survival (P=.32). Down-regulation of galectin 1 using small interfering RNA resulted in the inhibition of cell growth and proliferation of HeLa and SiHa cells. Moreover, the ability of cells to invade was significantly reduced by galectin 1 small interfering RNA. Our results revealed that high galectin 1 expression in peritumoral stroma was significantly correlated with depth of invasion in cervical lesions and lymph node metastasis of cervical cancer and that galectin 1 may be functionally involved in cell proliferation and invasion., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: To determine whether the use of high-intensity focused ultrasound (HIFU) ablation combined with cisplatin, compared with HIFU ablation, and cisplatin alone, facilitates tumor necrosis and reduces tumor volume in an animal model., Materials and Methods: The cervical cancer cell line SiHa was cultured and injected subcutaneously into female BALB/c nude mice. Animals that developed tumors were randomized to four groups: treatment with HIFU ablation and cisplatin (i.p. injection, 100 mg/mouse twice per week); cisplatin treatment alone; HIFU ablation alone; and control. The dimensions of the tumor were measured transcutaneously using a vernier caliper. After mice were sacrificed, tumor excised, and triphenyl tetrazolium chloride (TTC) staining was carried out to investigate the area of coagulation necrosis in the tumors., Results: Out of the 32 animals that developed tumors, 25 had tumors able to be measured through subcutaneous palpation in the pretreatment period (control, n=7; HIFU ablation, n=7; cisplatin, n=6; combination of HIFU ablation and cisplatin, n=5). In the group receiving HIFU ablation with cisplatin, tumor volume decreased significantly when compared with the other groups. TTC staining showed that necrosis was induced in the central zone of the tumors that were ablated by HIFU, and chemotherapy enhanced the effect of HIFU ablation in the combination therapy group., Conclusion: HIFU ablation combined with cisplatin facilitates reductions in tumor volume and increases in tumor necrosis and could be useful as another option in treating patients with cervical cancer.

Background: The aim of this study was to compare the surgical and oncologic outcomes of laparoscopic-assisted radical vaginal hysterectomy (LARVH) with that of laparoscopic radical hysterectomy (LRH) for early-stage cervical cancer., Methods: Patients affected by invasive cervical cancer (FIGO stage I-IIA) who had received LARVH (n = 89) in our institute between September 2004 and December 2010 were compared with patients treated by LRH (n = 105) during the same period. All patient information, surgical and pathological data, and oncological results were prospectively collected. Patients undergoing abdominal radical hysterectomy (ARH) were included for comparison of safety, morbidity, and recurrence rate., Results: The mean estimated blood loss (EBL) and return of bowel activity were significantly reduced in the LRH group compared with the LARVH group (p = .011 and p = .002, respectively). Intraoperative complications occurred in 10 patients (11.2 %) in the LARVH group, 6 (5.7 %) in the LRH group, and 3 (3.0 %) in the ARH group. Forest plot analyses of the previous studies showed higher incidence of intraoperative complication in the LARVH group than in LRH group (p = .02). Despite the similar overall recurrence rate, stump recurrence seems to be high in the LRH group in the forest plot analysis of previous studies (p = 0.08)., Conclusions: Both LARVH and LRH are safe and effective therapeutic procedures for the management of early-stage cervical cancer, although LRH is characterized by less blood loss and shorter bowel recovery time. Possible higher stump recurrence in the LRH should be further evaluated.

Objective: Immune competence is an important prognostic factor in cancer patients. Surgical management of cancer can cause a variety of immunological disturbances, the clinical consequences of which are still unclear., Materials and Methods: Patients with clinically staged cervical carcinoma (IB to IIA) who were treated at Samsung Medical Center, Seoul, Korea from 1994 to 2007 were retrospectively enrolled. We compared peri-operative peripheral lymphocyte counts, tumor-infiltrating lymphocyte scores, and survival in patients with early cervical cancer treated by abdominal type III radical hysterectomy., Results: The sample included 756 patients. The median follow-up was 58 months with a range of 3-181 months. There was a positive correlation between pre-operative peripheral lymphocyte counts and tumor infiltrating lymphocyte score. Pre-operative peripheral lymphocyte counts decreased significantly after surgery. In multivariate analyses for recurrence, higher pre-operative peripheral lymphocyte counts and recovery of lymphocyte counts (more than 100/μL from the pre-operative level) on post-operative day 3 were independent positive prognostic factors and LN metastasis was negatively associated with post-operative recovery of peripheral lymphocyte counts., Conclusion: Peripheral lymphocyte counts after cervical cancer surgery are important prognostic factors, and management aimed at minimizing immune disturbances after surgery should be assessed, especially in patients with LN metastasis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Dynamin 2, which plays a role in endocytosis, is known to be required for HPV infection on host cells. We investigated dynamin 2 as a biomarker in grading of cervical intraepithelial neoplasia (CIN) by comparing with Ki-67 expression and the type of HPV infection (low-risk vs. high-risk)., Study Design: We performed immunohistochemical stains of dynamin 2 and Ki-67 on tumor samples of patients with CIN and the type of HPV infection was investigated., Results: All the patients with reactive changes (n=7) or normal (n=4) did not show dynamin 2 expression. There were 33, 14, and 12 cases with CIN I, II, and III, respectively, and there was a negative correlation between the degree of dynamin 2 expression and the severity of CIN lesions with statistical significance (P<0.001). Negative expression of dynamin 2 was more sensitive for the detection of CIN II/III than high expression (2+) of Ki-67 (96.2% vs. 73.1%, P=0.041). Among patients in whom HPV infection was detected, the degrees of dynamin 2 expression were not associated with the type of HPV infection (low-risk vs. high-risk). Overall, there was a negative correlation between the expression patterns of Ki-67 and dynamin 2., Conclusion: We found that dynamin 2 may be a helpful biomarker in grading of CIN lesions and a candidate biomarker for detecting low grade CIN with high sensitivity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Approximately 15% of all cervical cancers are found in women under the age of 40. Sexual function is a matter of great importance for these women. However, the impact of the surgical radicality for cervical cancer on sexual function has not been established., Aims: The aim of this study is to estimate the difference in postoperative sexual function in women with surgically treated early-stage cervical cancer according to the extent of surgical radicality., Methods: One hundred and five women with early-stage cervical cancer treated by cervical conization (CC), radical trachelectomy (RT), and radical hysterectomy (RH) between January 2006 and December 2009 were asked to answer a validated questionnaire, the Female Sexual Function Index (FSFI)., Main Outcome Measure: FSFI score., Results: Eighty-one completed questionnaires from 39 (48.2%) women in the CC group, 18 (22.2%) in the RT group, and 24 (29.6%) in the RH group were studied. The FSFI total score for the CC group was 30.72 ± 3.39, suggesting no sexual dysfunctioning. The FSFI total score for the RT and RH groups (21.78 ± 4.17 and 22.40 ± 4.09, respectively) demonstrated a globally compromised sexuality, based on a FSFI total score of 26.55 as the clinical cut-off for sexual dysfunction. The FSFI total scores in the RT and RH groups were significantly decreased compared to the CC group (P < 0.001). However, there were no significant differences between the RT and RH groups., Conclusions: The RT and RH groups, unlike the CC group, had compromised sexual function after the treatment of early-stage cervical cancer., (© 2012 International Society for Sexual Medicine.)

Aim: This study was designed to investigate the prognostic value of the neutrophil:lymphocyte ratio (NLR) in cervical cancer., Patients and Methods: Patients with clinically staged cervical carcinoma (IB to IVA) at Samsung Medical Center, Seoul, Korea, from 1996 to 2007 were retrospectively enrolled., Results: We enrolled 1061 patients with cervical cancer. The median NLR was 1.9, with a range of 0.3-27.0. When the cohort was divided according to the median NLR, poorer survival outcomes were observed in the group with higher NLR (≥1.9) than in the lower NLR group (<1.9). Patients of the higher NLR group (≥1.9) were younger in age and had more advanced staged disease when compared with those of the lower NLR group (<1.9). In multivariable analysis, higher pretreatment NLR was identified as being an independent poor prognostic factor for survival., Conclusion: Pretreatment NLR may be a cost-effective biomarker to stratify risk of recurrence and death in patients with cervical cancer.

Objective: Higher level of circulating monocyte has been reported to be related with higher cancer incidence and mortality. We investigated the role of pre-treatment circulating monocyte count for cancer specific survival in cervical squamous cell carcinoma patients comparing with pre-treatment squamous cell carcinoma-related antigen (SCC-Ag) level., Methods: We retrospectively enrolled patients with squamous cell carcinoma of the cervix (FIGO stage IB to IVA) who had complete blood cell counts with differential cell count and serum SCC-Ag level within 2 weeks before starting initial treatment and were treated at Samsung Medical Center, Seoul, Korea, from 1996 to 2007., Results: The 788 patients in our study group had a median follow-up of 53.4 months and a five-year survival rate of 87.8%. The median value for pre-treatment circulating monocyte count was 349/μl (21-1463), and the median concentration of SCC-Ag was 1.6 ng/ml (0.1-362.0). In multivariable analysis, the pre-treatment circulating monocyte count was an independent prognostic factor for progression-free survival and overall survival in locally advanced disease (P=0.007 and P=0.038) but not in case of SCC-Ag for overall survival. The combined index of monocyte count and SCC-Ag level could enhance the prognostic value of SCC-Ag alone in patients with locally advanced cervical squamous cell carcinoma., Conclusions: A higher pre-treatment circulating monocyte count is independently associated with poor prognosis in patients with locally advanced cervical squamous cell carcinoma. The pre-treatment circulating monocyte count may be considered as an adjunctive biomarker with SCC-Ag., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Patient age is one important factor used to evaluate the risk in women with ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion). This finding may be associated with atrophic changes reflecting a hypoestrogenic status and suggests that body mass index (BMI) can affect the outcome of ASC-H smears in postmenopausal women., Study Design: We investigated the outcome of 154 postmenopausal women with an ASC-H smear and assessed relationships with BMI categories and serum estradiol levels., Results: In patients with higher BMI, an underlying squamous intraepithelial lesion (SIL) was more frequent than in patients with lower BMI, and a higher BMI was also associated with increased serum estradiol levels. When samples were classified by preparation method, these findings were more pronounced in liquid-based smears than in conventional smears. Principal component analysis using three factors (BMI, age and human papilloma virus status) revealed two distinct groups: those with a negative cervical smear and those with a smear result indicating SIL+., Conclusion: Hormonal alterations can affect the outcome of ASC-H smears, and BMI is one factor that should be considered when evaluating the risk associated with ASC-H smears in postmenopausal women., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: The aim of this study was to compare the efficacy and toxicity of consolidation chemotherapy after concurrent chemoradiation (CCRT) and CCRT alone in patients with locally advanced cervical carcinoma., Methods and Materials: Using medical records from January 2001 to December 2007, 39 patients treated with consolidation chemotherapy after CCRT (Group 1) were matched to 39 patients treated with CCRT alone (Group 2). Consolidation chemotherapy consisted of three additional cycles of chemotherapy with cisplatin 60 mg/m2 (Day 1) and 5-fluorouracil 1,000 mg/m2 per day (Days 1-5) given every 3 weeks. The primary endpoint was overall survival., Results: During a median follow-up period of 35 months (range, 8-96 months), 10 (25.6%) and 16 (41.0%) patients showed disease progression in Groups 1 and 2, respectively. Distant recurrence with or without locoregional/lymphogenous recurrence occurred more frequently in Group 2 than in Group 1 (23.1% vs. 7.7%, p=0.06). By contrast, there was no difference in locoregional or lymphogenous recurrence between the two groups. The rate of overall survival was higher in Group 1 than in Group 2 (92.7% vs. 69.9%, p=0.042), whereas the difference in progression-free survival between the groups was not statistically significant (70.1% vs. 55.1%, p=0.079). Although the difference was not statistically significant, neutropenia was more common in Group 1 than in Group 2 (10.9% vs. 4.7%, p=0.07)., Conclusions: Consolidation chemotherapy after CCRT may improve survival and reduce distant recurrence without additional toxicity compared to CCRT alone in patients with locally advanced cervical carcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: This study was designed to investigate the survival difference between pure adenocarcinoma (AC) and squamous cell carcinoma (SCC) in early cervical cancer (FIGO stage IB-IIA) after radical hysterectomy with or without adjuvant therapy performed at a single institution., Methods: Patients with AC or SCC between November 1994 and September 2007 at the Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Korea were evaluated., Results: Among the 775 patients, 636 patients had SCC, and 139 patients had pure AC. In basal characteristics, preoperative FIGO stage, adjuvant therapy after surgery, as well as chemotherapeutic regimens, were not different between the two groups. However, the median age was about 5 years younger in pure AC patients than in SCC patients (44 years vs. 49 years, P=.001). In the comparison of pathological findings after surgery between the two groups, there were no differences between the two groups, except for LVSI status. The recurrence rate was higher in the pure AC group than in the SCC group (SCC; 36/636; 5.7%, AC; 20/139; 14.4%, P=<0.001, respectively). The pure AC group had a higher recurrence rate in hematogenous/distant areas than the SCC group (SCC: 8/36; 22.2%, AC; 9/20; 45.0%, P=.076, respectively). In multivariable analysis, positive for pelvic LN and the pure AC cell type were independent factors in both DFS and OS., Conclusion: We observed that pure AC of the cervix might entail a worse survival outcome than SCC in patients with early cervical cancer (IB-IIA)., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: This retrospective study evaluates the efficacy and toxicity of topotecan, followed by cisplatin, in patients with persistent or recurrent cervical cancer., Methods: Twenty-four patients were included in the study. Ninety-two cycles of chemotherapy were administered during the study period. Topotecan (0.75 mg/m(2)) was administered as a 30-minute infusion on 3 consecutive days, and cisplatin was given intravenously at a dose of 50 mg/m(2) over 1h on day 3 of every third week., Results: The median number of cycles administered was 3, with a range of 1-8 cycles per patient. There were 4 (16.7%) complete responses, 3 (12.5%) partial responses, and 5 (20.8%) stable disease. All of the patients with a complete response had received palliative radiation or surgery for pain or an isolated solitary recurrence prior to chemotherapy. There were no treatment delays of >7 days per cycle due to hematologic toxicity. There were 59 days of delay (average, 0.6 days per cycle) in 21 of 92 (22.8%) cycles and two episodes of dose reduction (cisplatin, 50% reduction) in 2 patients due to low creatinine clearance (30-60 mL/min). Overall, grade 3/4 anemia, thrombocytopenia, and neutropenia were experienced in 13.1%, 1.1%, and 18.5% of the courses, or 33.4%, 4.2%, and 45.8% of the patients, respectively., Conclusion: Combination chemotherapy, consisting of topotecan on days 1-3 and cisplatin on day 3, showed a relatively low rate of hematologic toxicity, as compared with the regimen of topotecan on days 1-3 and cisplatin on day 1, as used in previous studies., (Copyright © 2010. Published by Elsevier Inc.)

Dynamin 2 is known as a protein involved in cell migration and endocytosis. We aimed to investigate the association between dynamin 2 expressions and tumor progression in early cervical carcinoma (IB1-IIA). Dynamin 2 expression was evaluated at protein level in thirty seven paraffin-embedded, formalin-fixed tissues including four normal cervix tissues and compared with pathologic risk factors for recurrence after surgery in thirty three patients with squamous cell carcinoma of the cervix. The expression of dynamin 2 was not different according to clinical stage and lympho-vascular space invasion. However, there were inverse correlations between dynamin 2 expression and the depth of invasion in cervix (p = 0.003) and lymph node (LN) metastasis (p = 0.001). To evaluate the mechanism of dynamin 2 in tumor invasion and metastasis, we performed an in vitro experiment with dynamin 2 siRNA using several cervical carcinoma cell lines such as HeLa, MS751 and SiHa cells. We found the inhibition of dynamin 2 using specific siRNA enhanced the expression of matrix metalloproteinase-2. These results suggested that dynamin 2 might be involved in preventing tumor invasion and LN metastasis, possibly in relation with extracellular matrix degradation, and may be a prognostic marker for these risk factors in early squamous cell carcinoma of the cervix.

Aim: To better predict treatment responses for managing bulky cervical carcinoma with neoadjuvant chemotherapy (NAC)., Methods: The expression of p-STAT3 was analyzed by immunohistochemistry using paraffin-embedded pretreatment cervical biopsy tissues. The study included 29 patients with bulky IB to IIA cervical squamous cell carcinoma treated with NAC., Results: Twenty (69.0%) of 29 patients were scored as p-STAT3-positive. Pathological response to chemotherapy (complete response or residual tumor with less than 3 mm stromal invasion) was observed in eight patients (27.6%). The p-STAT3-positive patients had a longer disease-free survival compared to p-STAT3-negative patients (P = 0.03), though they had more frequent clinical nodal involvement (P = 0.046)., Conclusion: Pretreatment assessment of p-STAT3 expression may provide additional information for the identification of patients with cervical cancer who have a favorable prognosis.

Objective: The aim of this study was to evaluate the association between pretreatment random plasma glucose levels and cancer prognosis in non-diabetic women with locally advanced cervical cancer treated with CCRT (concurrent chemoradiation) or RT (radiation therapy) only., Methods: We investigated the non-fasting plasma glucose levels checked during the initial work up before treatment in 134 non-diabetic patients with locally advanced cervical cancer. Based on the survival time and the progression-free interval (PFI) recorded in the electronic medical records Cox proportional hazard regression models were used to estimate the hazard ratio (HR) for overall survival and PFI according to the various level of glucose and a cut-off level (<102 mg/dL and >or=102 mg/dL), adjusting for clinical covariates., Results: A shorter overall survival and PFI was observed in the group with higher glucose levels (HR, 1.03; p=0.002, HR, 1.02; p=0.001, respectively) and more than 102 mg/dL, by univariate analyses (HR, 3.21; p=0.012, HR, 2.20; p=0.006, respectively). Multivariate analysis, adjusting for clinical FIGO stage, performance status, treatment type (CCRT vs. RT) and chemotherapeutic regimen types showed that patients with higher glucose levels or more than >or=102 mg/dL had shorter overall survival times (HR, 1.02; p=0.015, HR, 2.54; p=0.049, respectively) and PFI (HR, 1.02; p=0.003, HR, 1.88; p=0.031, respectively)., Conclusion: This investigation provides evidence supporting the prognostic value of glucose levels in non-diabetic women with locally advanced cervical cancer treated with radiation therapy and/or concurrent chemotherapy; high glucose levels were associated with a greater risk for recurrence and mortality in these patients.

Objective: The objective of this study was to evaluate the prognostic significance of the cervical tumor uptake of fluorine-18-labeled FDG (fluorodeoxyglucose) measured as the SUVmax (maximum standardized uptake value) by PET (Positron Emission Tomography) in patients with early cervical cancer treated with surgery+/-adjuvant therapy., Methods: Forty-four patients (FIGO clinical stage IB to IIA) with biopsy-proven cervical cancer underwent PET before surgery. The SUVmax of the primary cervical tumor mass was obtained and compared with pathological prognostic factors after the initial treatment. In addition, we investigated the recurrence pattern according to the SUVmax and analyzed independent risk factors associated with the recurrence of disease., Results: According to the tumor stage, the mean SUVmax significantly differed among groups (P=0.013). The SUVmax was significantly higher in patients with deep stromal invasion (>or=1 cm, P=0.0208), LVSI (lymph-vascular space invasion) (P=0.0429) and a pathologically confirmed large tumor size of more than 4 cm (P=0.0074) when compared to controls. Patients with a high SUVmax (>or=13.4) had a significantly reduced disease-free survival rate compared to patients with a low SUVmax (P=0.021). In addition, the SUVmax (>or=13.4) was a significant independent predictor of recurrence of cervical cancer after treatment with surgery (+/-adjuvant therapy) (P=0.0207)., Conclusion: Patients with early cervical cancer showing a high SUVmax (>or=13.4) of the cervical tumor should be considered at increased risk for disease recurrence after surgery and may need more aggressive multimodal treatment.