Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer

PURPOSE: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. MATERIALS AND METHODS: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). RESULTS: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). CONCLUSION: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.ope

Impact of the Learning Curve on the Survival of Abdominal or Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer

Purpose: The objective of this study was to define the learning curve required to attain satisfactory oncologic outcomes of cervical cancer patients who were undergoing open or minimally invasive surgery for radical hysterectomy, and to analyze the correlation between the learning curve and tumor size. Materials and methods: Cervical cancer patients (stage IA-IIA) who underwent open radical hysterectomy (n=280) or minimal invasive radical hysterectomy (n=282) were retrospectively reviewed. The learning curve was evaluated using cumulative sum of 5-year recurrence rates. Survival outcomes were analyzed based on the operation period ("learning period," P1 vs. "skilled period," P2), operation mode, and tumor size. Results: The 5-year disease-free and overall survival rates between open and minimally invasive groups were 91.8% and 89.0% (p=0.098) and 96.1% and 97.2% (p=0.944), respectively. The number of surgeries for learning period was 30 and 60 in open and minimally invasive group, respectively. P2 had better 5-year disease-free survival than P1 after adjusting for risk factors (hazard ratio, 0.392; 95% confidence interval, 0.210 to 0.734; p=0.003). All patients with tumors < 2 cm had similar 5-year disease-free survival regardless of operation mode or learning curve. Minimally invasive group presented lower survival rates than open group when tumors ≥ 2 cm in P2. Preoperative conization improved disease-free survival in patients with tumors ≥ 2 cm, especially in minimally invasive group. Conclusion: Minimally invasive radical hysterectomy required more cases than open group to achieve acceptable 5-year disease-free survival. When tumors ≥ 2 cm, the surgeon's proficiency affected survival outcomes in both groups.ope

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

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

Survival outcomes of single-port access laparoscopic radical hysterectomy for early-stage cervical cancer

Background: Emerging data from the Laparoscopic Approach to Cervical Cancer trial (NCT00614211) suggested that minimally invasive surgery (MIS) for cervical cancer is correlated with worse survival outcomes than open surgery. This finding could be attributed to the different learning curves for laparoscopic surgery among surgeons. This study aimed to assess the feasibility, safety, and survival outcomes of single-port access (SPA) laparoscopic radical hysterectomy (LRH) for treating early cervical cancer. Methods: This was a retrospective cohort study of consecutive patients with early-stage cervical cancer who underwent SPA LRH between 2009 and 2018 performed by a single surgeon with expertise in SPA laparoscopy using conventional instrumentation and a homemade glove port system. Results: Type C (93.2%) and B (6.8%) radical hysterectomy were performed in 59 women with cervical cancer classified as IA (3.4%), IB (94.9%), and IIA (1.7%). Forty-one patients (69.5%) had squamous cell carcinoma and 32 patients (52.5%) had tumors < 2 cm. The median operative time was 235 (125-382) minutes. There were no perioperative complications or cases of conversion to open surgery. Postoperative complications, including chylous ascites, low hemoglobin, lymphedema, and vault dehiscence, were observed in 5 patients (8.5%). Median follow-up time was 3.1 (0.6-8.6) years and 3 patients experienced recurrence (1 local and 2 distant failures). Five-year disease-free survival was 94.9% (56/59) and the 5-year overall survival rate was 98.3% (58/59). Conclusions: SPA LRH is feasible and safe for patients with early-stage cervical cancer when performed by experienced surgeons without compromising the radicality and oncologic outcomes.restrictio