Yanling Feng

Screening and identification of biomarkers in ascites related to intrinsic chemoresistance of serous epithelial ovarian cancers.

Objective The ability to predict responses to chemotherapy for serous epithelial ovarian cancer (EOC) would be valuable since intrinsically chemoresistant EOC patients (persistent or recurrent disease within 6 months) gain little benefit from standard chemotherapy. The aim of this study was to screen and identify distinctive biomarkers in ascites of serous EOC associated with intrinsic chemoresistance. Methods Protein samples from ascites of 12 chemosensitive and 7 intrinsically chemoresistant serous EOC patients were analyzed using two-dimensional fluorescence difference in gel electrophoresis (2-D DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Furthermore, the identified proteins were validated by ELISA in ascites samples from 19 chemosensitive and 9 intrinsically chemoresistant EOC patients. Results The number of spots detected in all 2-D DIGE gels ranged from 1523–1711 using DeCyder software analysis. Thirty-four spots were differentially expressed based on the criteria of an average ratio of more than 1.5 and a student t-test P value <0.05. After MALDI-TOF/TOF MS analysis, 11 differentially expressed proteins, including 3 up-regulated and 8 down-regulated proteins, in ascites of chemoresistant tumors were successfully identified. Of the four selected proteins (ceruloplasmin, apoliprotein A-IV, transthyretin and haptoglobin) in ascites tested by ELISA, only ceruloplasmin was present at significantly different levels between the chemoresistant and chemosensitive ascites samples with average concentrations of 192.2 µg/ml and 157.5 µg/ml, respectively (P = 0.001). Conclusion The significantly up-regulated level of ceruloplasmin in the ascites fluid of intrinsic chemoresistant serous EOC patients suggests its potential as a prognostic biomarker for responses to chemotherapy. This finding prompts further investigation with a larger study in order to validate the clinical utility of ceruloplasmin.

Metastasis to deep obturator and para-aortic lymph nodes in 649 patients with cervical carcinoma.

OBJECTIVE The extent of retroperitoneal lymph node dissection for early stage cervical cancer remains debatable. Our study aimed to investigate the incidence of metastases in deep obturator lymph nodes (DOLNs) and para-aortic lymph nodes (PALNs) and its association with clinicopathological factors in cervical carcinoma. METHOD Six hundred and forty-nine patients with stage IB to IIB cervical cancer underwent radical hysterectomy, pelvic lymphadenectomy and/or para-aortic lymphadenectomy. The incidence and distribution of metastases in retroperitoneal lymph nodes and the associated factors were analyzed. RESULTS Metastases in pelvic lymph nodes (PLNs) were found in 175 patients. Of the 175 cases with positive PLNs, 15 had DOLN metastases. Only two cases without PLN metastases had positive DOLNs. There was no significant correlation between DOLN metastasis and tumor histology, differentiation or capillary lymphatic space involvement. PALN metastasis occurred in 19 of 137 patients with cervical lesions larger than 2 cm in diameter. Eighteen of the 19 patients also had PLN involvement. Logistic regression analysis showed that PLN metastasis and larger tumors were independent risk factors for metastasis to PALNs. CONCLUSION DOLN metastasis is not common and may be secondary to metastasis to other PLNs. Routine removal of DOLNs might be unnecessary when PLNs are negative. Para-aortic sampling or lymphadenectomy should be considered when the PLNs are positive or/and the cervical lesion is larger than 2 cm.

High Expression of KIF20A Is Associated with Poor Overall Survival and Tumor Progression in Early-Stage Cervical Squamous Cell Carcinoma

Background The kinesin family member 20a (KIF20A) protein has been implicated in the development and progression of many human cancers; however, its precise function and role in cervical cancer remain largely unclear. This study aimed to investigate the expression profile and prognostic value of KIF20A in patients with early-stage cervical squamous cell carcinoma. Methods We examined the mRNA and protein levels of KIF20A in eight cervical cancer cell lines and eight paired cervical cancer samples, compared with normal cervical epithelial cells and adjacent normal cervical tissues, respectively. Immunohistochemistry was performed to detect the expression of KIF20A in paraffin-embedded specimens from 169 early-stage cervical squamous cell carcinoma patients. Statistical analyses were applied to analyze the association between KIF20A expression and clinical variables, as well with patient survival. Results The mRNA and protein expression levels of KIF20A were significantly elevated in cervical cancer cell lines and lesions compared with normal cells and corresponding normal tissues (P < 0.05). Immunohistochemistry analysis in 169 cervical cancer cases revealed that increased KIF20A expression was strongly associated with human papillomavirus (HPV) infection (P = 0.008), clinical stage (P = 0.001), tumor recurrence (P = 0.016), vital status (P < 0.001), the property of the surgical margin (P = 0.032), the lymphovascular space involvement (P = 0.014), and pelvic lymph node metastasis (P = 0.001). The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression. KIF20A was an independent survival prognostic factor, as evidenced by univariate and multivariate analysis. Conclusions Our results illustrate that elevated KIF20A expression correlates with HPV infection, clinical stage, tumor recurrence, lymphovascular space involvement, pelvic lymph node metastasis, and poor outcome in early-stage cervical squamous cell carcinoma patients. KIF20A aberrant expression is a novel independent unfavorable prognostic factor and may present a potential therapeutic target for cervical cancer.

Clinical significance of ascites in epithelial ovarian cancer.

The prognostic significance of ascites in the dissemination of metastases in epithelial ovarian cancer (EOC) is unclear. Our study aimed to investigate the association between clinicopathological factors and the development of ascites, as well as its prognostic significance. Three hundred and thirty three patients with primary EOC were suitable for inclusion. We analyzed the correlation between clinicopathological factors, including the extent of metastases, and ascitic volume. The prognostic significance of ascites was assessed using the Kaplan-Meier method and multivariate Coxs regression analysis. The average ascitic volume was 1,800 ml. Significantly, more patients with advanced FIGO stage disease presented with ascites. The volume of ascites increased significantly when metastatic disease was present in more than three regions (p<0.05), and this was the sole factor identified as associated with ascitic volume by multiple linear regression analysis. Median survival was significantly different between those with an ascitic volume less than 1,800 ml (median survival = 58 months), and those with a volume greater than 1,800 ml (median survival = 28.6 months) (p<0.05). Subgroup analysis of stage III and IV patients also revealed a poor prognosis in the presence of massive ascites (p = 0.03). Multivariate analyses found that massive ascites and poor differentiation were independent poor prognostic factors for stage III and IV EOC patients by Cox regression, using a backward elimination procedure. The volume of ascites increased significantly with the extent of metastastic disease. Massive ascites and poor tumor differentiation were associated with a worse prognosis in patients with advanced stage ovarian cancer.

Adjuvant docetaxel and carboplatin chemotherapy administered alone or with radiotherapy in a “sandwich” protocol in patients with advanced endometrial cancer: a single-institution experience

Objective: To evaluate the outcomes of adjuvant chemotherapy administered alone or with radiotherapy in a “sandwich” protocol in patients with advanced endometrial cancer. Methods: The authors retrospectively reviewed the clinical records of patients with staged III – IV disease who received adjuvant chemotherapy (docetaxel plus carboplatin) administered alone or interposed with radiotherapy between January 2004 and August 2010. Results: Of the 35 study patients, 10 (28.6%) had stage IIIA disease, 15 (42.9%) had IIIC1 disease, 7 (20.0%) had IIIC2 disease and 3 (8.6%) had IVB disease. Nine (90.0%) of the 10 patients with stage IIIA disease received four to six cycles of adjuvant docetaxel and carboplatin chemotherapy alone. All 25 patients with stage IIIC – IVB disease and 1 patient with stage IIIA disease received radiotherapy sandwiched between chemotherapy cycles (total, three to six cycles). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.0 and 87.0%, respectively, for all patients. For patients with stage IIIC – IVB disease, the 3-year PFS and OS rates were 62.4 and 81.8%, respectively. Conclusion: Combination chemotherapy with docetaxel and carboplatin interposed with radiotherapy is efficacious and well tolerated for stage IIIC – IVB endometrial cancer. Adjuvant chemotherapy alone with docetaxel and carboplatin might be sufficient for stage IIIA disease.

Low initial human papillomavirus viral load may indicate worse prognosis in patients with cervical carcinoma treated with surgery

Objective To evaluate the prognostic implication of human papillomavirus (HPV) viral load in cervical cancer patients who underwent radical hysterectomy. Methods We conducted a retrospective review of patients with stage IA2 through stage IIIA cervical carcinoma who underwent radical hysterectomy at Sun Yat-sen University Cancer Center between January 2005 and December 2009. Patients who had undergone preoperative hybrid capture 2 testing to detect HPV DNA were included. A total of 346 patients positive for HPV DNA were enrolled and stratified into two groups according to the median HPV viral load. Results HPV viral load was significantly correlated with lymphovascular space invasion (p=0.026) and deep stromal invasion (p=0.024). However, other factors, such as age, stage, histologic grade, histologic type, lymph node metastasis, and tumor size, were not significantly associated with viral load. Low HPV viral load was correlated with poor disease-free survival in univariate analysis (p=0.037) and multivariate analysis (p=0.027). There was no significant difference in overall survival with regard to initial HPV viral load. Conclusion Low initial HPV viral load may be a poor prognostic factor for cervical cancer patients who have undergone radical hysterectomy.

Prognostic and Safety Roles in Laparoscopic Versus Abdominal Radical Hysterectomy in Cervical Cancer: A Meta-analysis

Abstract Objective: Studies comparing the prognostic results between laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) in cervical cancer reported contradictory results. We aimed to evaluate the prognostic and safety roles of LRH by pooling studies in a meta-analysis. Materials and Methods: Original articles were searched in PubMed, EMBASE, and the Cochrane Library. The survival results (5-year disease-free survival [DFS], 5-year overall survival [OS], and recurrence rate [RR]), safety parameters (intra-, peri-, and postoperative complication rates and postoperative bowel or bladder recovery days), efficiency parameters (pelvic/para-aortic lymph nodes removed), and other parameters (operative time, estimated blood loss, and hospital of stay) between the two approaches were reviewed. Results: For the 2922 cases identified, DFS, OS, and RR did not differ in balanced prognostic factors, including lymph node metastasis, Stage IIB or above, non–squamous cancer histology, grade G3, lymphovascular space invasion, tumor size ≥4 cm, and positive parametrial and vaginal margin rates. Meanwhile, LRH was associated with higher complication rates and a shorter time to the recovery of bowel or bladder function than for ARH. The number of removed pelvic or para-aortic lymph nodes did not significantly differ. Other parameters showed LRH was associated with a longer operative time, less blood loss, and a shorter length of hospital stay. The survival and prognostic results did not differ in balanced prognostic factors. Conclusions: LRH is safe and has lower operative complication rates than ARH.

GOLPH3L is a Novel Prognostic Biomarker for Epithelial Ovarian Cancer.

Objective: Golgi phosphoprotein 3 (GOLPH3) is a highly conserved membrane protein that is involved in a variety of cancers such as colorectal cancer, gastric cancer, ovarian cancer, and breast cancer. GOLPH3L is a paralog of GOLPH3. Although these proteins share a similar amino acid sequence, much less is known regarding the subcellular functions or effects of GOLPH3L on cancer compared with GOLPH3. The role of GOLPH3L in epithelial ovarian cancer (EOC) has not yet been investigated. Methods: Using western blot, PCR and immunohistochemical analyses, we studied the clinical significance of GOLPH3L expression in EOC. The correlations between GOLPH3L expression and the clinicopathological variables of patients with EOC were assessed using Pearsons χ2 test. Kaplan-Meier analysis was used to compare the postoperative survival between groups of patients with EOC with varying levels of GOLPH3L expression. Results: High expression of GOLPH3L was more frequently observed in EOC tissues than in corresponding adjacent non-tumor tissues. The expression of GOLPH3L correlated closely with pre-operative CA125 level (P=0.031). Univariate analysis showed that age, FIGO stage, pre-operative cancer antigen (CA) 125, pre-operative albumin concentration (AC), optimal cytoreductive surgery (CRS) and GOLPH3L expression correlate significantly with overall survival (OS). Multivariate analysis revealed that GOLPH3L expression was an independent prognostic factor for OS of patients with EOC (102 months versus 72 months; P=0.013). Whats more, knocked down of GOLPH3L with small interfering RNA (siRNA) technology of OVCAR3 and SKOV3 cell lines reduced cell viability obviously, compared to the negative control and blank control groups. Conclusions: Our data show that increased expression of GOLPH3L is associated with poor prognosis of patients with EOC and may act as a novel, useful and independent prognostic indicator. Therefore, further studies are warranted.

The outcome and efficacy of adjuvant chemotherapy alone in patients with stage IIIA endometrial carcinoma with solitary adnexal involvement: A retrospective single-institution study

OBJECTIVES The appropriate adjuvant therapy for patients with endometrial carcinoma with solitary adnexal involvement is unclear. We conducted a retrospective single-institution study to evaluate the outcome and efficacy of adjuvant chemotherapy alone in this population. METHODS All patients with endometrial carcinoma who received primary surgical treatment between January 1999 and May 2010 were reviewed. The patients who were diagnosed with stage IIIA disease based only on isolated adnexal involvement and treated with surgical procedures followed by adjuvant chemotherapy alone were included. Demographic, clinicopathologic, treatment and outcome data were collected. Recurrence and survival were analyzed. RESULTS Among 1453 reviewed patients, 67 patients were identified. The median age was 48 years. All patients were treated with platinum-based adjuvant chemotherapy, with the majority (36/67, 53.7%) receiving paclitaxel plus carboplatin. The total number of cycles of chemotherapy administered was 305 (median four cycles/person). Most of the chemotherapy related toxicities were mild or moderate. The median follow-up time was 76 months. Eight patients experienced recurrence. The majority of initial relapses were distant (7/8, 87.5%), characterized by liver metastases (3/8, 37.5%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 89.6% and 91.9%, respectively. Multivariate analysis confirmed that grade 3 tumor was an independent predictor of worse DFS and OS (HR=5.19, P=0.048; HR=6.55, P=0.037, respectively). CONCLUSION Patients with stage IIIA endometrial carcinoma with solitary adnexal involvement have favorable outcomes. Adjuvant chemotherapy alone may be effective and feasible for these patients.

Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study

BACKGROUND Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simons two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. FINDINGS Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. INTERPRETATION The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. FUNDING None.