Objective:To evaluate the safety and effectiveness of fuzuloparib for the treatment of ovarian epithelial cancer patients in the real world setting.Methods:A retrospective analysis was conducted on the baseline data of 4 620 ovarian cancer patients who had received fuzuloparib monotherapy or combination therapy. Another 224 ovarian cancer patients who were willing to receive fuzuloparib monotherapy or combination therapy were prospectively enrolled, and their baseline characteristics, drug effectiveness, and safety data were analyzed.Results:(1) Among the 4 620 patients in the retrospective cohort, the median age of patients was 60 years; tumor types: 89.8% (4 149/4 620) had ovarian cancer. Among patients with clearly documented information, the vast majority had a histological type of serous carcinoma (82.9%, 3 770/4 546) and International Federation of Gynecology and Obstetrics (FIGO) staging of Ⅲ-Ⅳ (90.9%, 1 537/1 691). (2) Among the 224 patients in the prospective cohort, the median age of patients was 57 years; tumor types: 83.9% (188/224) had ovarian cancer. Among patients with clearly documented records, the predominant pathologic type was serous carcinoma (91.9%, 193/210), and FIGO stage was Ⅲ-Ⅳ in 79.9% (139/174). (3) Among the 224 prospective patients: 84 patients received first-line fluzoparib maintenance therapy, 92 patients received fluzoparib maintenance therapy after platinum-sensitive recurrence, 23 patients received direct fluzoparib treatment after platinum-sensitive recurrence, 19 patients received direct fluzoparib treatment after platinum-resistant recurrence. The median follow-up durations were 8.5, 8.7, 7.9, and 6.7 months, respectively. The median durations of fluzoparib treatment were 6.7, 4.8, 3.1, and 1.9 months, respectively. The median progression-free survival (PFS) times were not reached during follow-up, 12.6 months, not reached during follow-up, and 4.8 months, respectively. The 1-year PFS rates were 84.1%, 55.0%, 69.8%, and 45.5%, respectively. The remaining 6 patients received other fluzoparib regimens. (4) Among the 224 patients in the prospective dataset, 205 had safety data recorded. Of these, 127 patients (62.0%, 127/205) experienced treatment-related adverse events, with common events including anemia (24.4%, 50/205), thrombocytopenia (21.0%, 43/205), and leukopenia (19.5%, 40/205). Among the 205 patients, 43 (21.0%, 43/205) experienced grade 3 or higher treatment-related adverse events, with common events including anemia (8.3%, 17/205) and thrombocytopenia (8.3%, 17/205).Conclusions:The effectiveness of fuzuloparib in clinical application is generally consistent with other drugs in the same class, with good safety. This study provids new clinical evidence for the treatment of ovarian cancer with fuzuloparib.

Objective:To evaluate the safety and effectiveness of fuzuloparib for the treatment of ovarian epithelial cancer patients in the real world setting.Methods:A retrospective analysis was conducted on the baseline data of 4 620 ovarian cancer patients who had received fuzuloparib monotherapy or combination therapy. Another 224 ovarian cancer patients who were willing to receive fuzuloparib monotherapy or combination therapy were prospectively enrolled, and their baseline characteristics, drug effectiveness, and safety data were analyzed.Results:(1) Among the 4 620 patients in the retrospective cohort, the median age of patients was 60 years; tumor types: 89.8% (4 149/4 620) had ovarian cancer. Among patients with clearly documented information, the vast majority had a histological type of serous carcinoma (82.9%, 3 770/4 546) and International Federation of Gynecology and Obstetrics (FIGO) staging of Ⅲ-Ⅳ (90.9%, 1 537/1 691). (2) Among the 224 patients in the prospective cohort, the median age of patients was 57 years; tumor types: 83.9% (188/224) had ovarian cancer. Among patients with clearly documented records, the predominant pathologic type was serous carcinoma (91.9%, 193/210), and FIGO stage was Ⅲ-Ⅳ in 79.9% (139/174). (3) Among the 224 prospective patients: 84 patients received first-line fluzoparib maintenance therapy, 92 patients received fluzoparib maintenance therapy after platinum-sensitive recurrence, 23 patients received direct fluzoparib treatment after platinum-sensitive recurrence, 19 patients received direct fluzoparib treatment after platinum-resistant recurrence. The median follow-up durations were 8.5, 8.7, 7.9, and 6.7 months, respectively. The median durations of fluzoparib treatment were 6.7, 4.8, 3.1, and 1.9 months, respectively. The median progression-free survival (PFS) times were not reached during follow-up, 12.6 months, not reached during follow-up, and 4.8 months, respectively. The 1-year PFS rates were 84.1%, 55.0%, 69.8%, and 45.5%, respectively. The remaining 6 patients received other fluzoparib regimens. (4) Among the 224 patients in the prospective dataset, 205 had safety data recorded. Of these, 127 patients (62.0%, 127/205) experienced treatment-related adverse events, with common events including anemia (24.4%, 50/205), thrombocytopenia (21.0%, 43/205), and leukopenia (19.5%, 40/205). Among the 205 patients, 43 (21.0%, 43/205) experienced grade 3 or higher treatment-related adverse events, with common events including anemia (8.3%, 17/205) and thrombocytopenia (8.3%, 17/205).Conclusions:The effectiveness of fuzuloparib in clinical application is generally consistent with other drugs in the same class, with good safety. This study provids new clinical evidence for the treatment of ovarian cancer with fuzuloparib.

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.
Female ; Humans ; Uterine Cervical Neoplasms/drug therapy* ; Prospective Studies ; Quality of Life ; Neoplasm Staging ; Chemoradiotherapy ; Chemotherapy, Adjuvant/adverse effects* ; Adjuvants, Immunologic ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Retrospective Studies

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.
Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Dactinomycin/adverse effects* ; Female ; Gestational Trophoblastic Disease/drug therapy* ; Humans ; Methotrexate/therapeutic use* ; Pregnancy ; Retrospective Studies

Objective: To investigate the clinicopathologic characteristics, immunophenotypes, molecular genetics, and diagnostic and differential diagnostic features of biphenotypic sinonasal sarcoma (BSNS). Methods: Three cases of BSNS were retrieved, the histomorphology, immunophenotype and molecular genetics were analyzed with review of literature. Results: There were 2 male and 1 female patient aged 45, 29 and 40 years, respectively.Computed tomography and magnetic resonance imaging examinations showed a large polypoid mass occupying the sinonasal cavity in all 3 patients. Microscopically, these tumors were un-circumscribed and composed of cellular spindle-shaped cells arranged in long and interlaced fascicles. A hemangiopericytoma-like growth pattern was frequently identified. The overlying hyperplastic respiratory epithelium invaginated down into the tumor forming a cystic (2 cases), glandular (1 case) structures and inverted in a papilloma-like (1 case)pattern, and foci of eosinophilic metaplasia were also noted in 2 of the three cases. The tumor nuclei were bland-appearing, mitoses were scarce and necrosis was absent. Immunohistochemically, the tumor cells showed co-expression of neural and myogenic markers in all the 3 cases, including that 3/3 showed diffuse and strong positivity of S-100 protein, 3/3 positivity of smooth muscle actin (1 diffuse and 2 focal), 1/2 diffuse positivity of calponin, 1/3 focal positivity of desmin, and 1/1 focal positivity of MyoD1.In addition, 1 detected for β-catenin showed focal nuclear positivity. None of the 3 showed positivity to cytokeratin, CD34 or SOX10 in the tumor cells.Ki-67 showed an index <5%, 10% and <2%, respectively. Fluorescence in situ hybridization analysis showed rearrangements of PAX3 gene in all 3 cases. In case 3, reverse transcription polymerase chain reaction, followed by Sanger sequencing, demonstrated an in-frame fusion between PAX3 and FOXO1.Follow-up information (range 3-15 months)showed no evidence of local recurrence or distant metastasis in three cases. Conclusions BSNS is a newly described entity which can be readily confused with a variety of benign and malignant spindle cell tumors encountered in the sinonasal cavity; immunohistochemistry co-expression of neural and myogenic markers and PAX3 gene rearrangement can help distinguish this tumor from its many mimickers.

MicroRNAs (miRNAs) play critical roles in the development and progression in various cancers.Dysfunctional miR-9 expression remains ambiguous,and no consensus on the metastatic progression of ovarian cancer has been reached.In this study,results from the bioinformatics analysis show that the 3'-UTR of the E-cadherin mRNA was directly regulated by miR-9.Luciferase reporter assay results confirmed that miR-9 could directly target this 3'-UTR.miR-9 and E-cadherin expression in ovarian cancer tissue was quantified by qRTPCR.Migration and invasion were detected by wound healing and Transwell system assay in SKOV3 and A2780.qRT-PCR and Western blot were performed to detect the epithelial-mesenchymal transition-associated mRNA and proteins.Immunofluorescence technique was used to analyze the expression and subcellular localization of Ecadherin,N-cadherin,and vimentin.The results showed that miR-9 was frequently upregulated in metastatic serous ovarian cancer tissue compared with paired primary ones.Upregulation of miR-9 could downregulate the expression of E-cadherin but upregulate the expression of mesenchymal markers (N-cadherin and vimentin).Overexpression of miR-9 could promote the cell migration and invasion in ovarian cancer,and these processes could be effectively inhibited via miR-9 inhibitor.Thus,our study demonstrates that miR-9 may promote ovarian cancer metastasis via targeting E-cadherin and a novel potential therapeutic approach to control metastasis of ovarian cancer.

OBJECTIVETo explore the effect of ataxia telangiectasia mutated and RAD3 related protein (ATR) expression and ATR kinase activity on the sensitivity to cisplatin in ovarian cancer SKOV3 cells.

METHODSSiRNA targeting ATR was transfected into SKOV3 cells for 48 h to reduce the ATR protein level, and ATR kinase inhibitor VE-821 was used for 12 h to inhibit the ATR pathway activity. The alteration of cell viability was examined by CCk-8 assay. Expression levels of ATR, p-ATR and γ-H2AX proteins were detected by Western blot. The DNA double strand breaks (DSB) marker γ-H2AX and homologous recombination repair key protein RAD51 and their co-localization in the cells were examined under the confocal microscope. The status of DNA double strand breaks (DSB) in single cells was visualized by alkaline comet assay. Finally, the cell cycle distribution was assessed using flow cytometry.

RESULTSDDP caused evident DNA double strands breaks and activated ATR kinase pathway. ATR-siRNA notably reduced ATR protein level, the 48 h IC(50) value of DDP was 72.12 µmol/L and 41.25 µmol/L, respectively, in the NC-siRNA and ATR-siRNA groups (P < 0.05). Confocal microscopic assay presented decreased recruitment of RAD51 at the DSB loci and comet assay showed enhanced DSB in the cells after ATR knocking down. After the inhibition of ATR kinase by VE-821, the 48 h IC(50) value of DDP was 75.32 µmol/L and 45.64 µmol/L, respectively, in the DMSO and VE-821 groups (P < 0.05 for both), confocal microscopic assay demonstrated reduced RAD51 recruitment, and comet assay showed increased DSB in cells after ATR kinase inhibition. Flow cytometry showed that percentage of cells distributed in G(0)/G(1), S and G(2)/M phases was 71.2%, 13.4% and 15.4%, repectively, after 40 µmol/L DDP treatment for 24 h. Compared with that of control group (G(0)/G(1): 54.2%, S: 21.3% and G(2)/M: 24.4%), DDP induced G(0)/G(1) phase arrest. DDP intervention resulted in the cell cycle status (G(0)/G(1): 43.2%, S: 20.4%, G(2)/M: 36.4%) in the ATR-siRNA group and (G(0)/G(1): 40.2%, S: 22.5%, G(2)/M: 37.3%) in the VE-821 group, indicating that the inhibition of ATR or ATR kinase could abrogate the effect of G(0)/G(1) phase arrest induced by DDP.

CONCLUSIONSSuppression of ATR can affect the homologous recombination repair in ovarian cancer cells, leading to accumulation of DNA double strand breaks in the cell nuclei as well as reduction of DDP-caused G(0)/G(1) phase arrest, finally enhances the sensitivity to cisplatin in the ovarian cancer SKOV3 cells.

Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cisplatin ; pharmacology ; DNA Repair ; Female ; Humans ; Ovarian Neoplasms ; Pyrazines ; RNA, Small Interfering ; Sulfones ; Transfection

Objective To explore the influence of MYC expression level on ovarian cancer cells adhesion and invasion ability,and the involvement of the integrinβ1 in the adhesion and invasion control. Methods Comparative study was done to analyze the relationship between the mRNA level of MYC and ITGB1 among sixty cell lines from the NCI-60 cells bank; Western blot was performed to demonstrate the correlation of MYC and ITGB1 protein level in ovarian cancer cell lines;Immunohistochemistry was adopted to compare the expression level of MYC and ITGB1 in paired primary and metastatic ovarian cancer tissue. Furthermore ,we employed in vitro adhesion test to detect the alteration of ovarian cancer cell adhesion ability to ECM molecular like fibronectin ,collagen I and laminin after fluctuation of MYC and ITGB1 expression; Transwell assay was applied to check the invasion ability variation with the disturbance of MYC and ITGB1 level. Results The mRNA levels of MYC and ITGB1 were dramatically inverse-correlated in NCI-60 cells bank(P<0.01);The protein levels of MYC and ITGB1 in ovarian cancer cell lines were also negative correlated; The primary ovarian cancer tissue showed lower expression of ITGB1 and higher expression of MYC,while the matched metastasis displayed the opposite outcome;Ovarian cancer cells reduced adhesive and invasive capacity in case of ITGB1 being down-regulated ,however, the adhesive and metastatic ability improved tremendously with elevation of ITGB1;Promoted adhesion and invasion ability and rise of ITGB1 expression were observed after downregulation of MYC,meanwhile,and inhibition of ITGB1 reversed the increasement of adhesion and invasion ability. Conclusions MYC,inversely-correlated with ITGB1 in ovarian cancer cells,inhibited ovarian cancer cells adhesion and invasion. Inhibition of MYC could lead to enhanced adhesion and invasion ability of ovarian cancer cells.

This study was aimed to explore the influence of breast cancer associated fibroblasts (CAFs) in migration and invasion of breast cancer cell line MCF-7, and investigate whether hepatocyte growth factor (HGF) is involved in this process. Primary breast CAFs and their corresponding normal breast fibroblasts (NFs) were obtained by collagenase digestion. On the basis of the co-culture, the migration and invasion capacity of MCF-7 cells was compared between CAFs and NFs by Transwell. The difference in the HGF expression between them was detected by ELISA. The secretion of HGF was knocked down by using RNA interference technology in CAFs. Then the changes of migration and invasion capacity of MCF-7 cells were investigated by Transwell. Eventually, we isolated high-purity CAFs and NFs, and the CAFs had a stronger ability in promoting MCF-7 migration and invasion than the NFs. ELISA results demonstrated that CAFs secreted higher HGF, and the capacity of MCF-7 migration and invasion was declined after knocking down the secretion of HGF in CAFs by RNA interference. It is suggested that CAFs can promote MCF-7 migration and invasion through HGF in vitro.

This study was aimed to explore the influence of breast cancer associated fibroblasts (CAFs) in migration and invasion of breast cancer cell line MCF-7,and investigate whether hepatocyte growth factor (HGF) is involved in this process.Primary breast CAFs and their corresponding normal breast fibroblasts (NFs) were obtained by collagenase digestion.On the basis of the co-culture,the migration and invasion capacity of MCF-7 cells was compared between CAFs and NFs by Transwell.The difference in the HGF expression between them was detected by ELISA.The secretion of HGF was knocked down by using RNA interference technology in CAFs.Then the changes of migration and invasion capacity of MCF-7 cells were investigated by Transwell.Eventually,we isolated high-purity CAFs and NFs,and the CAFs had a stronger ability in promoting MCF-7 migration and invasion than the NFs.ELISA results demonstrated that CAFs secreted higher HGF,and the capacity of MCF-7 migration and invasion was declined after knocking down the secretion of HGF in CAFs by RNA interference.It is suggested that CAFs can promote MCF-7 migration and invasion through HGF in vitro.