Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.

Clinical outcome of pulmonary lymphangitic carcinomatosis in gynecologic malignancy: A single-institution experience.

OBJECTIVE: Pulmonary lymphangitic carcinomatosis (PLC) is a rare event of metastatic lung disease in advanced gynecologic malignancy. Nonspecific symptoms of patients and difficulties in detection of PLC often result in a delayed diagnosis. In this study, we evaluated the clinical outcomes of PLC in patients with gynecologic cancer. MATERIALS AND METHODS: We retrospectively reviewed electronic medical records of patients with gynecologic cancer who received care from January 1, 2008 through December 31, 2018 in Samsung Medical Center, Seoul, Republic of Korea. We based diagnosis of PLC on chest CT scan and analyzed clinical parameters of cancer type, International Federation of Gynecology and Obstetrics (FIGO) stage, histology, and patient survival. RESULTS: During the study period, 27 cases of PLC in patients with gynecologic malignancy were identified, including 11 cervical, 12 ovarian, and four uterine cancers. The most common histologic type at initial diagnosis was squamous cell in cervical (6/11, 55%), serous in ovarian (1/11, 92%), and serous in endometrial (2/4, 50%) cancer. The average survival time from diagnosis of PLC to death was a mean of 5.7 months (0.7-23.6 months) in all patients and 6.3, 6.6, and 3.6 months for cervical, endometrial, and ovarian cancer, respectively. CONCLUSION: This study showed that PLC results in extremely poor survival, from several days to a few months, in patients with gynecologic cancer. Clinicians must be aware of these clinical characteristics and consider other novel therapeutic strategies in the future.

Effect of Waiting Time from Pathological Diagnosis to Definitive Concurrent Chemoradiation for Cervical Cancer on Overall Survival.

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.

Single-port access (SPA) laparoscopic myomectomy with uterine artery ligation via a retroperitoneal approach is feasible in women with large uterine leiomyoma.

OBJECTIVE: Uterine artery ligation (UAL) at the time of myomectomy has shown to decrease blood loss during the operation. However, little is known about the efficacy and feasibility of UAL during single-port access (SPA) myomectomy. The present study was performed to investigate the clinical benefits of UAL in SPA myomectomy and to provide details of the surgical techniques. MATERIALS AND METHODS: A retrospective and comparative review on the surgical outcomes of the patients who underwent SPA myomectomy with UAL and those who underwent SPA myomectomy without UAL was conducted. UAL was performed at its origin from the internal iliac artery via a retroperitoneal approach. RESULTS: A total of 56 women who received SPA myomectomy were reviewed (24 patients received SPA myomectomy with UAL while 32 patients received SPA myomectomy only). The median weight of total resected leiomyomas was heavier for the patients who received UAL than those who did not receive UAL [210.0 g (range: 171.5-335.0 g) vs. 119.0 g (62.5-265.0 g), p = 0.023]. However, no differences in total operative time, estimated blood loss, perioperative hemoglobin changes, use of postoperative analgesics and postoperative complications between the two groups were seen. CONCLUSION: Obtaining similar surgical outcomes between the patients who received UAL with larger leiomyomas and those who did not receive UAL with smaller leiomyomas suggests that UAL is a feasible surgical approach to reduce blood loss during SPA myomectomy. Detailed descriptions of the surgical techniques are provided in the present report.

Significance of serum CA125 level in surgically resected cervical adenocarcinoma with adverse features.

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.

Minimally-Invasive Versus Abdominal Hysterectomy for Endometrial Carcinoma With Glandular or Stromal Invasion of Cervix.

The purpose of the study was to evaluate the feasibility of laparoscopic approach versus laparotomy in endometrial cancer that extends to the cervix in the form of glandular extension and/or stromal invasion. A retrospective, single-center cohort study was conducted using data between 1995 and 2017 at an urban tertiary academic medical center. We identified patients who were diagnosed with endometrial cancer whose tumor involved the uterine cervix on final pathology. Operative and oncologic outcomes were compared between the patients who underwent minimally-invasive surgery (MIS) versus those who underwent laparotomy. A total of 282 patients with endometrial cancer were reviewed for the study. Among these patients, 76 patients underwent hysterectomy and surgical staging via MIS. There was no conversion from MIS to laparotomy. In the MIS group, shorter hospital stay (4.4 ± 2.3 days for MIS group vs. 7.1 ± 4.7 days for laparotomy group; p-value = 0.002) and less blood loss during the operations (228 mL vs. 478 mL, p-value < 0.001) were observed compared to the laparotomy group. The multivariate Cox regression analysis revealed that age at diagnosis, FIGO stage, histology grades, tumor size, lymph-vascular space invasion were independent prognostic markers for poor oncologic outcomes but the types of surgical approach (MIS vs. laparotomy) were not associated with it. The means by which colpotomy was performed (either intracorporeal or transvaginal) among the MIS group also did not affect patient survivals. Among the women with endometrial cancer that involved the uterine cervix, surgical treatment via MIS compared to laparotomy showed no difference in survival outcomes but better perioperative results. These findings support the use of MIS for these patient group.

Metabolic syndrome and persistent cervical human papillomavirus infection.

OBJECTIVE: Few studies have been conducted on the relationship between metabolic syndrome (MetS) and persistent human papillomavirus (HPV) infection. We investigated whether MetS and associated factors can predict the persistence of HPV infection. PATIENTS AND METHODS: We performed a retrospective cohort study of 80,993 female cases undergoing general medical screenings at Samsung Medical Center and 51,140 cases were included in final analysis. MetS and associated factors were used to develop a model predicting the persistence of HPV infection which was defined as HPV positivity for at least one year. The performance of the model was internally validated using bootstrapping and externally validated by testing the risk score against the test set. RESULTS: Of the 51,140 cases, there were 5833 (11.4%) cases diagnosed with MetS and 7682 (15.0%) cases diagnosed with HPV infection at baseline. The 12- to 24-month persistence rates of HPV were 50.0% (2846/5691). MetS (OR 1.34, 95% CI 1.04-1.71), globulin (by quintile; OR 1.70, 95% CI 1.25-2.30), fibrinogen (x100 value by quintile; OR 1.07, 95% CI 1.02-1.14), total protein (by quintile; OR 0.91, 95% CI 0.84-0.99) and prothrombin time (by quintile; OR 0.94, 95% CI 0.89-0.99) were significantly associated with the persistence of HPV in multivariate analysis. For validation, a prediction model showed good performance for a range of risk scores and categorized cases into low-, intermediate- and high-risk, which were also correlated with HPV persistence (45.8%, 51.9%, and 60.2% respectively, P < 0.001). CONCLUSION: MetS and associated factors were associated with an increased risk of persistent HPV infection.

Early Metabolic Response Assessed Using 18F-FDG-PET/CT for Image-Guided Intracavitary Brachytherapy Can Better Predict Treatment Outcomes in Patients with Cervical Cancer.

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.

Prognostic Significance of Tumor Regression Rate during Concurrent Chemoradiotherapy in Locally Advanced Cervix Cancer: Analysis by Radiation Phase and Histologic Type.

This study aimed to evaluate the prognostic significance of tumor regression rate according to radiation phase and histologic subtype in patients with locally advanced cervical cancer (LACC) treated with chemoradiation. We retrospectively reviewed the medical records of 398 patients with FIGO stage IIB-IVA cervical cancer treated with concurrent chemoradiotherapy (CCRT) between 2001 and 2019. Tumor response was assessed using serial magnetic resonance imaging (MRI) at three time points: pre-treatment, post-external beam radiotherapy (EBRT), and post-intracavitary radiotherapy (ICR). Tumor regression pattern according to histologic subtype and radiation phase (EBRT and ICR) was evaluated. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes. Of 398 patients, 44 patients had adenocarcinoma/adenosquamous carcinoma (AC/ASC) and 354 patients had squamous cell carcinoma (SCC). AC/ASC was associated with significantly worse PFS and OS than SCC (p < 0.001). AC/ASC had a relatively poorer regression rate in response to EBRT than SCC (p < 0.001), whereas there was no significant difference in overall tumor regression rate after completion of RT (EBRT and ICR) between the two histologic subtypes. Multivariable analysis demonstrated AC/ASC histology to be an independent prognostic factor of decreased PFS and OS. Moreover, tumor regression rate after completion of EBRT (post-EBRT tumor regression rate (EBRTregression ≤ 26%) and proportion of tumor regression during EBRT to overall tumor regression (EBRTproportion ≤ 40%) were independent predictors of poor survival in patients with LACC. Tumor regression pattern of LACC in response to CCRT differs according to histologic subtype. AC/ASC histology and poor tumor response to EBRT are independent prognostic factors for worse survival in patients with LACC. Further studies are needed to develop a CCRT protocol that is specialized for patients with AC/ASC.

Feasibility of Single-Port Access (SPA) Laparoscopy for Large Ovarian Tumor Suspected to Be Borderline Ovarian Tumor.

OBJECTIVES: To compare the surgical, pathological and oncological outcomes of single-port access (SPA) laparoscopy against laparotomy for large ovarian tumor (>15 cm) suspected to be a borderline ovarian tumor (BOT) on preoperative imaging. METHODS: A retrospective review of the patients who underwent SPA laparoscopy (SPA Group) or laparotomy (Laparotomy Group) for suspected BOT was performed. Surgical outcomes, including the rates of iatrogenic spillage of tumor contents, and oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS), were compared between the two groups. Correlation between intraoperative frozen section analysis and permanent pathology results was also assessed. RESULTS: A total of 178 patients underwent surgical treatment for suspected large BOT. Among them, 105 patients with a mean tumor diameter of 20.9 ± 6.5 cm underwent SPA laparoscopy, and the other 73 patients, with a mean tumor diameter 20.2 ± 5.9 cm, underwent laparotomy. The mean operation time did not differ between the two groups (99.1 ± 41.9 min for SPA Group vs. 107.3 ± 35.7 min for Laparotomy Group, p = 0.085). There was no difference in the occurrence of iatrogenic spillage of tumor contents between the groups either (11.4% in the SPA Group vs. 6.8% in the Laparotomy Group, p = 0.381). However, the postoperative complication rates were significantly higher in the Laparotomy Group compared with SPA Group (16.4% vs. 5.7%, p = 0.025). The surgical approach was not associated with the misdiagnosis rates of frozen section analysis (19% in the SPA Group vs. 26% in the Laparotomy Group, p = 0.484). The most common histologic type of the tumors was mucinous in both groups. CONCLUSION: SPA laparoscopy is feasible, safe, and not inferior to laparotomy for surgical treatment of large ovarian tumors that suspected to be BOT on preoperative imaging.

Comparison of Laparoscopy and Laparotomy for Para-Aortic Lymphadenectomy in Women With Presumed Stage I-II High-Risk Endometrial Cancer.

Objective: To compare laparoscopic surgery to laparotomy for harvesting para-aortic lymph nodes in presumed stage I-II, high-risk endometrial cancer patients. Methods: Patients with histologically proven endometrial cancer, presumed stage I-II with high-risk tumor features who had undergone hysterectomy, bilateral salpingoophorectomy, or pelvic and para-aortic lymphadenectomy by either laparoscopy or laparotomy in Samsung Medical Center from 2005 to 2017 were retrospectively investigated. The primary outcome was para-aortic lymph node count. Secondary outcomes were pelvic lymph node count, perioperative events, and postoperative complications. Results: A total of 90 patients was included (35 for laparotomy, 55 for laparoscopy) for analysis. The mean (±SD) para-aortic lymph node count was 10.66 (±7.596) for laparotomy and 10.35 (±5.848) for laparoscopy (p = 0.827). Mean pelvic node count was 16.8 (±6.310) in the laparotomy group and 16.13 (±7.626) in the laparoscopy group (p = 0.664). Lower estimated blood loss was shown in the laparoscopy group. There was no difference in perioperative outcome between the groups. Additional multivariate analysis showed that survival outcome was not affected by surgical methods in presumed stage I-II, high-risk endometrial cancer patients. Conclusions: Study results demonstrate comparable para-aortic lymph node count with less blood loss in laparoscopy over laparotomy. In women with presumed stage I-II, high-risk endometrial cancer, laparoscopy is a valid treatment modality.

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis.

Ovarian clear cell adenocarcinoma (Ov-CCA) has a higher prevalence in the Japanese ancestry than other populations. The ancestral disparities in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations and may provide an opportunity to identify the novel genes associated with Ov-CCA tumorigenesis. Using 94 previously reported genes as the phenotypic trait, we conducted multistep expression quantitative trait loci (eQTL) analysis with the HapMap3 project datasets. Four single-nucleotide polymorphisms (SNPs) (rs4873815, rs12976454, rs11136002, and rs13259097) that had different allele frequencies in the Japanese ancestry and seven genes associated in cis (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified. In silico functional annotation analysis and in vitro promoter assay validated the regulatory effect of rs4873815-TT on ZNF707 and rs11136002-TT on TNFRSF10B. Furthermore, ZNF707 was highly expressed in Ov-CCA and had a negative prognostic value in disease recurrence in our sample cohort. This prognostic power was consistently observed in The Cancer Genome Atlas (TCGA) clear cell renal cell carcinoma dataset, suggesting that ZNF707 may have prognostic value in clear cell histology regardless of tissue origin. In conclusion, rs4873815-TT/ZNF707 may have clinical significance in the prognosis and tumorigenesis of Ov-CCA, which may be more relevant to clear cell histology. Besides, this study may underpin the evidence that cis-eQTL analysis based on ancestral disparities can facilitate the discovery of causal genetic alterations in complex diseases, such as cancer.

Long-term outcomes of single-port laparoscopic myomectomy using a modified suture technique.

OBJECTIVE: To evaluate the long-term outcomes, including the pregnancy outcome and recurrence rate after single-port laparoscopic myomectomy (LM) using a modified suture technique with a Hem-o-lok clip (Choi's LM) and conventional 4-port LM. METHODS: A retrospective study of patients who underwent Choi's LM (n=55) and 4-port LM (n=102) in a single institutional hospital was conducted. Patients with <3 symptomatic myomas sized <10 cm each and operated on by a single surgeon were included. Recurrence was confirmed when a myoma measuring ≥3 cm was detected. RESULTS: The patients in both groups had similar demographic characteristics. Single (76.4% vs. 62.7%) and intramural (52.7% vs. 56.9%) tumors were commonly detected in both groups in the mean diameter (6.8±1.5 cm vs. 7.0±1.6 cm; P=0.40). In Choi's LM, 16 patients (29.1%) needed an additional port; those who were nulliparous and/or had a large leiomyoma more frequently required an additional port (P=0.023 and 0.04, respectively). During a median follow-up period of 69 months, 17 patients (7.1% vs. 14.6%) had recurrence. The size of dominant myomas at recurrence was significantly smaller in patients who underwent Choi's LM (3.4±0.7 cm vs. 5.7±2.4 cm; P=0.004). All 13 patients in both groups who successfully conceived had a full-term delivery. No major complications occurred during pregnancy. CONCLUSION: Although an additional port was frequently used, the long-term outcomes of patients who experienced recurrence and pregnancy after Choi's LM were acceptable. Considering its usability, Choi's LM is feasible for the treatment of uterine leiomyoma.

Combination of a pulmonary recruitment maneuver and intraperitoneal bupivacaine for the reduction of postoperative shoulder pain in gynecologic laparoscopy: a randomized, controlled trial.

OBJECTIVE: To compare the efficacy of a pulmonary recruitment maneuver using lower airway pressure (30 cm H2O) and intraperitoneal bupivacaine, alone or in combination, for reducing shoulder pain after gynecologic laparoscopy. METHODS: A prospective controlled study was performed in a teaching hospital with patients who underwent elective gynecologic laparoscopic surgery. Two hundred eighty-seven patients were randomized into 1 of 4 groups: group A, placebo; group B, intraperitoneal instillation of bupivacaine; group C, CO2 removal by a pulmonary recruitment maneuver; group D, combination of intraperitoneal bupivacaine and pulmonary recruitment maneuver. The interventions were performed at the end of surgery. Shoulder pain was recorded on a visual analog scale (VAS) at 1, 6, 12, and 24 hours postoperatively. RESULTS: The overall incidence of shoulder pain was 49.8% and the incidence tended to gradually decrease from group A to group D (59.0% in group A, 54.8% in group B, 44.4% in group C, and 41.5% in group D; P=0.026). In addition, the VAS scores gradually decreased from group A to D, although a statistically significant difference was only found at 6 hours postoperatively (P=0.03). There were no complications related to the interventions. CONCLUSION: The combination of a pulmonary recruitment maneuver with intraperitoneal bupivacaine significantly reduced shoulder pain after gynecologic laparoscopy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01039441.

Preclinical assessment of the VEGFR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer.

Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.

Chemoradiotherapy response prediction model by proteomic expressional profiling in patients with locally advanced cervical cancer.

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 (R2 = 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.

Triplet chemotherapy vs doublet chemotherapy plus bevacizumab in metastatic, recurrent, and persistent cervical cancer.

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.

In Vivo Comparison of MONOFIX, A Novel Barbed Suture with a Triangular Stopper, with Pre-existing Products in a Porcine Model.

STUDY OBJECTIVE: MONOFIX, a new absorbable barbed suture device, has a triangular stopper at the end to hold the suture to the tissue without hooking the looped end or knotting. The aim of this study was to compare the biomechanical strength and histologic features of MONOFIX with other barbed suture devices using a porcine model. DESIGN: Well-designed, controlled trial without randomization. SETTING: Animal laboratory in university hospital. SUBJECTS: Sixteen, 60-kg, mature female domestic pigs (skin closure group) and 5, 60-kg, mature female domestic pigs (fascial closure group). INTERVENTIONS: In the skin closure group, 3-0 MONOFIX versus 2 widely used 3-0 absorbable barbed sutures (3-0 V-Loc 180 or Stratafix). In the fascial closure group, 2-0 MONOFIX versus 1 widely used 2-0 absorbable barbed sutures (2-0 Stratafix). MEASUREMENTS AND MAIN RESULTS: In the skin closure group, the biomechanical wound strength of skin sutured with size 3-0 MONOFIX, V-Loc 180, or Stratafix was evaluated by postoperative day assessment (days 0, 3, 7, 14, and 28). In the fascial closure group, pigs underwent 2 paramedian incisions and were sutured with 2-0 MONOFIX or with 2-0 Stratafix to evaluate histologic reaction. At 6 weeks the tissues around the suture line were excised and microscopically evaluated. The biomechanical strength of the MONOFIX had similar tissue tensile strength compared with the control, regardless of postoperative day. In the fascial closure model, there was no significant difference in the average tissue reaction score between MONOFIX and Stratafix (1.2 ± .3 vs 1.3 ± .3, p = .478). CONCLUSION: This study demonstrated that MONOFIX has equivalent tensile strength and histologic reaction when compared with commonly used barbed suture devices. Accordingly, this preclinical study suggests that the use of MONOFIX is a safe alternative to other barbed suture devices.

CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer.

OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.

Pretreatment Lymph Node Metastasis as a Prognostic Significance in Cervical Cancer: Comparison between Disease Status.

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.