Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆.

BACKGROUND: This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/µl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. RESULTS: Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 [95% confidence interval (CI), 10.9-not evaluable] versus 5.4 (95% CI, 3.7-5.7) months [hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001], and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%). CONCLUSIONS: Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.

[Curative effects and influenced factors of primary chemotherapy with single-agent methotrexate on low-risk gestational trophoblastic neoplasia].

Objective: To evaluate the efficacy of primary chemotherapy with single-agent methotrexate (MTX) for low-risk gestational trophoblastic neoplasia and to analysis the influenced factors. Methods: We retrospectively reviewed 259 cases with low-risk gestational trophoblastic neoplasia whose primary chemotherapies were MTX 0.4 mg·kg(-1) (maximum 25 mg) daily for 5 days every other week. Patients' data between January 2001 and June 2015 was collected and the relationships of different factors to outcomes of chemotherapy were also evaluated. Results: 183 of the 259 patients (70.66%, 183/259) achieved complete primary remission and all patients achieved complete remission after salvage chemotherapy. Univariate analysis showed that FIGO score, serum level of HCG before treatment and interval months from previous pregnancy were significantly associated with outcome of chemotherapy (P=0.001, 0.018, 0.014 respectively). Logistic regression analysis showed that the FIGO score (OR=4.094) and antecedent pregnancy (OR=0.268) were two independent factors predictive for the outcome of chemotherapy. Conclusions: Primary chemotherapy with single-agent MTX may still be one of the options for patients with low risk GTN. The FIGO score and antecedent pregnancy are two independent risk factors of outcome of single-agent MTX chemotherapy.

Identification of cancer stem cell-like cells from human epithelial ovarian carcinoma cell line.

Cancer stem cells (CSCs) play an important role in the development, invasion, and drug resistance of carcinoma, but the exact phenotype and characteristics of ovarian CSCs are still disputable. In this study, we identified cancer stem cell-like cells (CSC-LCs) and investigated their characteristics from the ovarian adenocarcinoma cell line 3AO. Our results showed that CSC-LCs were enriched in sphere-forming test and highly expressed CD44(+)CD24⁻. The spheres and CD24⁻ cells possessed strong tumorigenic ability by transplantation into nonobese diabetic/severe combined immunodeficient mice. CD44(+)CD24⁻ cells expressed stem cell markers and differentiated to CD44(+)CD24(+) cells by immunofluorescence assay and fluorescence-activated cell-sorting analysis. In vitro experiments verified that CD44(+)CD24⁻ cells were markedly resistant to carboplatin and paclitaxol. In conclusion, our study identifies the CD44(+)CD24⁻ phenotype, self-renewal, high tumorigenicity, differentiation potential, and drug resistance of ovarian CSC-LCs. Our findings may provide the evidence needed to explore a new strategy in the treatment of ovarian cancer.

EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: a clinical analysis of 54 patients.

This study was designed to analyze the outcomes of chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) with EMA-CO regimen as primary and secondary protocol in China. Fifty-four patients with high-risk GTN received 292 EMA/CO treatment cycles between 1996 and 2005. Forty-five patients were primarily treated with EMA-CO, and nine were secondarily treated after failure to other combination chemotherapy. Adjuvant surgery and radiotherapy were used in the selected patients. Response, survival and related risk factors, as well as chemotherapy complications, were retrospectively analyzed. Thirty-five of forty-five patients (77.8%) receiving EMA-CO as first-line treatment achieved complete remission, and 77.8% (7/9) as secondary treatment. The overall survival rate was 87.0% in all high-risk GTN patients, with 93.3% (42/45) as primary therapy and 55.6% (5/9) as secondary therapy. The survival rates were significantly different between two groups (chi(2)= 6.434, P =0.011). Univariate analysis showed that the metastatic site and the number of metastatic organs were significant risk factors, but binomial distribution logistic regression analysis revealed that only the number of metastatic organs was an independent risk factor for the survival rate. No life-threatening toxicity and secondary malignancy were found. EMA-EP regimen was used for ten patients who were resistant to EMA-CO and three who relapsed after EMA-CO. Of those, 11 patients (84.6%) achieved complete remission. We conclude that EMA-CO regimen is an effective and safe primary therapy for high-risk GTN, but not an appropriate second-line protocol. The number of metastatic organs is an independent prognostic factor for the patient with high-risk GTN. EMA-EP regimen is a highly effective salvage therapy for those failing to EMA-CO.

Discovery of altered protein profiles in epithelial ovarian carcinogenesis by SELDI mass spectrometry.

OBJECTIVE: Identification of proteomic alterations in epithelial ovarian tumorigenesis may facilitate the understanding of progression of this disease. METHODS: Specific protein peak patterns were identified in 20 microdissected epithelial ovarian tumors (13 epithelial ovarian cancers (EOCs) and 7 low malignant potential (LMP) tumors), as well as in the matched normal cells. Protein profiles were generated by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) from all the different types of cells. RESULTS: Among seven protein peaks from EOC cells, six were significantly increased while one was decreased compared with normal cells, and three peaks from LMP cells were markedly increased while one was decreased compared with normal cells. CONCLUSIONS: The combination of SELDI and laser capture microdissection (LCM) is effective in finding the key molecules in ovarian tumorigenesis. Further identification of these protein peaks is important and these malignant protein signatures lend themselves to identification of populations at high-risk for EOC and for monitoring response to EOC chemopreventive agents.

Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells.

Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse.

[Study on targeting drug delivery system--the animal behavior in vivo after hepatic arterial embolization of methotrexate microsphere].

The cross-linked MTX-gelatin microsphere was chosen as an experimental model. Pharmacokinetics and biodegradable period of the microsphere were studied after hepatic arterial embolization in vivo in dogs. After hepatic arterial infusion, the concentration of MTX-ms in peripheral vein blood increased rapidly and declined slowly. In contrast, the peak time of the drug concentration of infused MTX solution appeared at once and decreased rapidly. The half-life of MTX-ms in vivo was 2.14 times as much as that of MTX solution. During the assay period of sixteen hours the drug concentration of MTX-ms in hepatic vein blood was constantly higher than that of MTX solution. The follow-up angiography revealed that microsphere is a kind of peripheral embolic agent and its degradable time in vivo is about one month. Both sustained release and embolization effectiveness of microsphere will be significant in treatment of hepatic cancer.

[Study on targeting drug delivery system--the characteristics of methotrexate microsphere and experimental treatment of hepatic tumor in rats by arterial embolization].

Preparation of methotrexate microsphere (MTX-ms) by emulsion-freezing technique was introduced and the experimental results proved that MTX entrapped in the microspheres exhibited good stabilities towards temperature, cobalt-60 radiation and light. The dissolution and inflation rate of the microspheres in pH 7.4 buffer solution at different times measured by Coulter counter was presented. Antitumor activity of MTX-ms after hepatic arterial embolization was examined in a model of liver tumor in Wistar rats. The group of rats treated with MTX-ms showed a rather significant reduction in tumor growth and more extended tumor necrosis as compared with the other groups, e.g. normal saline solution, MTX solution, placebo gelatin-ms and the results demonstrate that the effect of arterial chemoembolization used by MTX-ms is superior to that of the groups either using arterial chemotherapy or arterial embolization alone in treating rat liver cancer.

Study on CXCR4/SDF-1alpha axis in lymph node metastasis of cervical squamous cell carcinoma.

CXCR4/stromal-cell-derived factor-1alpha (SDF-1alpha) is involved in many cancer metastatic mechanisms. Cervical squamous cell cancer (SCC) tissues (n=35), normal cervical tissues (n=10), metastatic (n=10) and nonmetastatic lymph nodes (n=50), and Hela cells were stained immunohistochemically with CXCR4 monoclonal antibody (mAb). Meanwhile, lymph nodes were stained immunohistochemically with rabbit anti-SDF-1alpha. In vitro invasion of Hela cells was evaluated using Transwell Permeable Supports (Corning, NY), in which Hela cells with/without CXCR4 mAb preincubation were seeded in the upper chambers and medium containing 0-100 ng/mL SDF-1alpha was added to the lower compartments. For evaluating the effect of CXCR4/SDF-1alpha on proliferation of cervical cancer cells, Hela cells were cultured for 72 h exposed to SDF-1alpha with and without CXCR4 mAb. We found that CXCR4 was expressed on SCC cells in all cervical cancer, metastatic lymph node, and Hela cells but not in normal cervix. SDF-1alpha was expressed on lymph cells in all lymph nodes. SDF-1alpha induced the directed migration of Hela cells with a concentration-dependent model, which was inhibited by CXCR4 mAb (P<0.05). SDF-1alpha also stimulated the proliferation of Hela cells mediated by CXCR4 (P<0.05). CXCR4/SDF-1alpha axis probably participates in the metastasis toward lymph nodes in cervical cancer.

Multichannel ballistic transport in multiwall carbon nanotubes.

The electric transport properties of an individual vertical multiwall carbon nanotube (MWCNT) were studied in situ at room temperature in a scanning electron microscope chamber. It was found that the single MWCNT has a large current-carrying capacity, and the maximum current can reach 7.27 mA. At the same time, a very low resistance of about 34.4 ohms and a high conductance of about (460-490)G0 were obtained. The experimental observations imply a multichannel quasiballistic conducting behavior occurring in the MWCNTs with large diameter, which can be attributed to the participation of multiple walls in electrical transport and the large diameter of the MWCNTs.

Proliferation and differentiation in the human fetal endocrine pancreas.

The morphogenesis and growth of the endocrine pancreas has not been well investigated in man although it represents an important issue in diabetology. We examined human fetal pancreas from 12 to 41 weeks of gestation immunocytochemically to evaluate proliferative activity with the Ki-67 marker, and cytodifferentiation with cytokeratin 19 (ductal cells), synaptophysin (all endocrine cells), and insulin, glucagon, somatostatin and pancreatic polypeptide (islet cell types). Ki-67 labelling was found in all these cell types but was much higher in ductal cells than in islet cells. An intermediate population expressed synaptophysin but lacked islet hormones. With increasing gestational age the Ki-67 labelling index decreased from 17 to 4% in ductal cells, from 9 to 1% in synaptophysin-positive cells, and from 3 to 0.1% in insulin- or glucagon-positive cells. From 12 to 16 weeks, all epithelial cells including the endocrine islet cells expressed cytokeratin 19. Thereafter cytokeratin 19 expression decreased and eventually disappeared from most islet cells, whereas strong expression remained in the ductal cells. We show that differentiated human islet cells have only very limited proliferative capacity, and we demonstrate the existence of transitional differentiation stages between ductal and islet cells.