Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial.

This is a phase Ib study of anlotinib plus a programmed death-ligand 1 (PD-L1) inhibitor TQB2450 for platinum-resistant or -refractory ovarian cancer. Thirty-four patients are enrolled and receive treatment. The objective response rate (ORR) is 47.1%, and the disease control rate is 97.1%. The median duration of response (DOR) has not been reached, and 61.3% of patients have a DOR of at least 8 months. The median progression-free survival (PFS) is 7.8 months, and the median overall survival (OS) has not been reached. The PD-L1-positive group has an ORR of 25.0%, whereas the PD-L1-negative group has an ORR of 92.9%. Treatment-related grade 3 or 4 adverse events (AEs) occur in 70.6% of patients, with the most common being hypertension (29.4%) and palmar-plantar erythrodysesthesia syndrome (29.4%). Anlotinib plus TQB2450 show promising antitumor activity and manageable toxicities in patients with platinum-resistant or -refractory ovarian cancer. A phase 3 randomized controlled trial to further validate our findings is ongoing.

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 Simon's 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.

iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling.

BACKGROUND: Epithelial-mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC. METHODS: By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved. RESULTS: Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients. CONCLUSIONS: iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.

Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits.

OBJECTIVE: To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status. METHODS: Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining. RESULTS: Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant. CONCLUSION: Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.

Large animal model for retroperitoneal lymphatic and lung metastasis.

Retroperitoneal lymph node and lung metastasis are important prognostic factors for gynecologic cancer. The present study aimed to develop a new animal model for retroperitoneal lymph node and lung metastasis. VX2 squamous cell carcinoma tumor tissues were injected into the left gastrocnemius muscle of 38 healthy female New Zealand white rabbits. Animals were randomized into three groups according to day of sacrifice: 1, day 19; 2, day 22; and 3, day 25. Implanted primary tumor (IPTu), left and right retroperitoneal lymph node volumes and lung wet weights were measured on the day of sacrifice. The IPTu and left and right retroperitoneal lymph node volumes increased in a time­dependent manner. In addition, the proportion of animals with metastasis to the left peritoneal lymph nodes and the number of nodes involved increased over time. For days 19, 22 and 25, the proportion of animals with nodal metastasis was 58.3, 84.6 and 100%, respectively, and the number of affected nodes (range) was 3 (2­3), 3 (3­5) and 4 (4­5), respectively. No metastasis was detected in the right peritoneal lymph nodes. Metastasis to the lungs also increased with time, but was not statistically significant at days 19, 22 and 25 with metastasis present in 33.3, 38.5 and 76.9% of animals, respectively. Rates of metastases to the left retroperitoneal lymph nodes and lungs were found to positively correlate with the volumes (r=0.416 and 0.449, respectively). The current study assessed the characterization of a rabbit VX2 carcinoma model. This animal model is likely to be useful for evaluating retroperitoneal lymph node and lung metastasis.

Biological characteristics of dendritic cells derived from peripheral blood of patients with epithelial ovarian cancer.

BACKGROUND AND OBJECTIVE: Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells (APC) and play a vital role in stimulating human immune response against cancer. At present, most data concerning the immuno-biological function of DCs are obtained from healthy donors. The information about the biological characteristics of DCs from patients is limited. In this study, the biological characteristics of monocyte-derived dendritic cells (MoDCs) from patients with ovarian cancer were investigated. METHODS: Monocytes were isolated from peripheral blood mononuclear cells (PBMC) of eight epithelial ovarian cancer patients and 13 healthy women volunteers, cultured with interleukin 4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF), and stimulated with tumor necrosis factor-alpha (TNF-alpha). At seven days after induction, the morphologic characteristics of MoDCs were observed. The features of phenotype were analyzed using flow cytometry. The ability of MoDCs to stimulate proliferation of lymphocytes was tested by allogeneic mixed leukocytes reaction (MLR). RESULTS: Mature MoDCs with typical morphology were obtained after seven days of culture. MoDCs from both patients and healthy women expressed high levels of HLA-ABC (MHC-I), HLA-DR (MHC-II) and large amounts of CD86 and CD80. There was no significant differences between MoDCs from ovarian cancer women and healthy women in the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD86 and CD80 (p > 0.05). The MLR was significantly weaker in ovarian cancer patients than in healthy women (p < 0.05). CONCLUSION: MoDCs from ovarian cancer patients may present lower capacity of stimulating proliferation of lymphocytes, indicating that the patients' MoDCs may have immunological function defect at certain extent.

[Prognostic value of serum CA(125) level change during chemotherapy post-surgery in patients with advanced epithelial ovarian carcinoma].

OBJECTIVE: To investigate the prognostic value of the changes in serum CA(125) level during chemotherapy post-surgery in patients with advanced epithelial ovarian carcinoma. METHODS: A retrospective analysis was conducted on 142 patients with stage III - IV epithelial ovarian carcinoma who had primary treatment in the Cancer Center of the Sun Yat-sen University during January 1998 to December 2003. The changes in CA(125) levels during chemotherapy post-surgery in patients were analyzed. The survival outcomes of patients with various levels of CA(125) were studied using Kaplan-Meier method. Multivariate Cox regression model was used to assess the correlations between survival and the change in CA(125) level during chemotherapy and other prognostic factors. RESULTS: The 3-year overall survival (OS) was 64%, 71%, and 64% respectively in patients with different pretreatment CA(125) levels (< or = 500, > 500 - 1500 and > 1500 kU/L; P > 0.05). The CA(125) level was normalized (0 - 35 kU/L) in 77 (54.2%) patients after three cycles of postoperative chemotherapy. It revealed significant differences in 3-year OS (84% vs. 42%) and 5-year OS (56% vs. 15%) between the patients with normalized and elevated CA(125) levels (n = 48) after three cycles of chemotherapy (P < 0.01). Multivariate analysis showed that residual tumor size > 1 cm (P < 0.01) and elevated CA(125) after three-cycle postoperative chemotherapies (P < 0.01) were two independent factors related to survival. In the subgroup of optimal cytoreduction (residual tumor size < or = 1 cm), the 3-year and 5-year OS rate were 88% and 64% for patients with normalized CA(125) level after three cycles of chemotherapy respectively, while only 52% and 18% for patients with elevated CA(125) level (P < 0.01). Similarly, even in the suboptimal cytoreduction group, the 3-year and 5-year OS were also significantly increased for patients with normalized CA(125) level after three cycles of chemotherapy post-surgery, as compared with patients with elevated CA(125) level (74% vs. 33% in 3-year OS, 32% vs. 13% in 5-year OS; P < 0.01). CONCLUSIONS: CA(125) level after three cycles of chemotherapy post-surgery is an independent predictor of survival for advanced ovarian carcinoma. Whatever the patients undergo, optimal or suboptimal cytoreduction, if the CA(125) becomes normalized after three cycles of chemotherapy, they would have more favorable prognosis than those with elevated CA(125) after three cycles of chemotherapy.