Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial.

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.

Chemotherapy initiation with single-course methotrexate alone or combined with dactinomycin versus multi-course methotrexate for low-risk gestational trophoblastic neoplasia: a multi-centric randomized clinical trial.

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.

Crosstalk between the Notch signaling pathway and non-coding RNAs in gastrointestinal cancers.

The Notch signaling pathway is one of the main signaling pathways that mediates direct contact between cells, and is essential for normal development. It regulates various cellular processes, including cell proliferation, apoptosis, migration, invasion, angiogenesis and metastasis. It additionally serves an important function in tumor progression. Non-coding RNAs mainly include small microRNAs, long non-coding RNAs and circular RNAs. At present, a large body of literature supports the biological significance of non-coding RNAs in tumor progression. It is also becoming increasingly evident that cross-talk exists between Notch signaling and non-coding RNAs. The present review summarizes the current knowledge of Notch-mediated gastrointestinal cancer cell processes, and the effect of the crosstalk between the three major types of non-coding RNAs and the Notch signaling pathway on the fate of gastrointestinal cancer cells.

Methylation-associated Has-miR-9 deregulation in paclitaxel- resistant epithelial ovarian carcinoma.

BACKGROUND: Drug resistance is still one of the key causes of death in epithelial ovarian carcinoma (EOC) patients, however there are very few strategies to reverse chemoresistance. Here we try to clarify whether and how miR-9 takes part in the regulation of paclitaxel sensitivity. METHODS: miR-9 expressions in EOC cells and tissues were detected by Realtime PCR. The target of miR-9 was validated through dual luciferase reporter assay and Western Blot. Methylation study, RNAi technique and cytotoxicity assay were used to determine the intrinsic mechanism of miR-9 in paclitaxel sensitivity regulation. RESULTS: miR-9 is down-regulated in paclitaxel resistant EOC. The patients with lower miR-9, Grade 3, Stage III -IV and suboptimal surgery present shorter survival time. miR-9 and suboptimal surgery are independent prognostic factors of EOC. Modulating miR-9 expression could change paclitaxel sensitivity of EOC cells. CCNG1, validated as a direct target of miR-9, mediates paclitaxel resistance. miR-9-1 and 3 gene hypermethylation would decrease miR-9 expression, while demethylation of miR-9 gene could restore miR-9 expression and improve paclitaxel sensitivity in chemoresistance EOC cells. Furthermore, methylation-associated miR-9 deregulation in EOC cells could be induced by paclitaxel exposure. CONCLUSIONS: Methylation-associated miR-9 down-regulation is probably one of the key mechanisms for paclitaxel resistance in EOC cells, via targeting CCNG1. Our findings may also provide a new potential therapeutic target to reverse paclitaxel resistance in EOC patients.

[Progress on strategies to promote vascularization in bone tissue engineering].

With the continuous development of bone tissue engineering, a variety of emerging bone graft materials provided various methods for repairing bone defects. Early and rapid accomplishment of revascularization of materials interior after implantation of bone transplantation materials is a difficulty faced to bone tissue engineering. Blood vessels ingrowth provides the requisite netritional support for the regeneration reconstruction of bone tissue, for this reason, vascularization plays a significant role in bone tissue engineering. However,there is not a golden standard strategy of vascularization at present. Scaffold materials, cells and growth factors still are three indispensable elements in tissue engineering, and are cardinal points of the promoting vascularization strategies. Multiple growth factors or multiple cells combined with scaffolds, which are hot spots, have obtained excellent vascularization. This review focused on the comprehensive strategies for promoting the successful vascularization of tissue engineered scaffolds.

Highly elevated serum CA-125 levels in patients with non-malignant gynecological diseases.

PURPOSES: To identify patients with highly elevated serum CA-125 levels and analyze their clinical characteristics. METHODS: Patients with non-malignant gynecologic disease (NMGDs, n = 41), in whom serum CA-125 levels were over 1,000 IU/ml were retrospectively enrolled in the study. Seventy-one patients with epithelial ovarian cancer (EOC), in whom, serum CA-125 levels were over 1,000 IU/ml were included as the comparison group. Clinical parameters were compared between the two groups. RESULTS: In NMGDs group, 43.90% of the patients had endometriosis. The median of serum CA-125 level in NMGDs was much lower than that of EOC subjects (P < 0.001). Compared to EOC group, the patients in NMGDs group were much younger (P < 0.001) and had fewer histories of pelvic masses (P < 0.001) but had more clinical complaints such as acute abdominal symptoms (P < 0.001) and/or abnormal vaginal bleeding (P = 0.022). Clinical progresses of these two groups were correlated with changes of serum CA-125 levels by follow-up for up to 386 days. CONCLUSIONS: High levels of serum CA-125 were found not only in the EOC, but also in some NMGDs, especially in the reproductive patients with complaints of acute abdomen symptoms or abnormal vaginal bleeding.

Outcomes of conservative therapy for young women with early endometrial adenocarcinoma.

Four of six patients with endometrial cancer had initial response to progesterone therapy and obtained complete response; three among them had successful pregnancies with three live births. The results suggest that progesterone therapy, combined with assisted reproductive technology, provides more chance of carrying a full-term pregnancy for patients with endometrial adenocarcinoma.

Low molecular weight fraction secreted by SKOV3 cells expands peripheral CD4+CD25+ regulatory T cells and enhances their suppressive capacity.

The increase of CD4+CD25+ regulatory T cells in patients with ovarian carcinoma has been verified. Here we investigated the effects of supernatant derived from ovarian carcinoma cell SKOV3 on peripheral regulatory T cells. Supernatant from SKOV3 was collected and fractionated into three different molecular weight fractions (MWFs). The proliferation of the CD4+CD25+ regulatory T cells cultured in complete RPMI 1640 medium with the different stimulators was detected. The phenotype (GITR and CTLA-4) of natural and expanded CD4+CD25+ T cells was detected by flow cytometry. Foxp3 mRNA expression of low MWF-expanded CD4+CD25+ T cells was detected by RT-PCR. Those expanded CD4+CD25+ regulatory T cells showed enhanced capacity to suppress CD4+CD25- T proliferation and increased expression of GITR and CTLA-4. In brief, low molecular weight fraction of supernatant secreted by SKOV3 could expand peripheral CD4+CD25+ regulatory T cells and enhance their suppressive function.

Evaluation of the accuracy of intra-operative gross examination for the surgical management of endometrial cancer.

OBJECTIVE: The aim of this study was to explore the clinical value of intra-operative gross examination for the surgical management of endometrial carcinoma. STUDY DESIGN: A retrospective study was conducted in 424 women who underwent surgical treatment for endometrial carcinoma between January 2002 and December 2006. The results of myometrial invasion and cervical infiltration as assessed by intra-operative gross examination were compared with the final microscopic histopathological results in 401 patients. The accuracy, sensitivity, and specificity were calculated. Chi-squared or Fisher's exact tests were used for the comparison of categorical variables. RESULTS: Intra-operative gross examination correctly identified the depth of microscopic myometrial invasion in 90.3% of patients. The sensitivity in detecting myometrial invasion was 80.6% and the specificity was 92.4%. With regard to cervical involvement, gross examination had an overall accuracy of 84.3%. The sensitivity in detecting cervical involvement was 32.6% and the specificity was 99.0%. Usually, cervical involvement cannot be correctly identified by intra-operative gross examination in patients with diffuse foci. CONCLUSION: The data suggest that intra-operative gross examination is a simple and good method of predicting myometrial invasion, but it may not be the ideal way to assess cervical involvement in endometrial carcinoma.

Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen.

OBJECTIVE: To evaluate the effectiveness of the etoposide and cisplatin/etoposide, methotrexate and actinomycin D (EP-EMA) regimen in patients with gestational trophoblastic neoplasia who had been successfully treated with the etoposide, methotrexate, and actinomycin D/cyclophosphamide and vincristine (EMA-CO) regimen but experienced a relapse, or who became refractory to EMA-CO treatment. METHODS: From January 1999 to December 2005, 18 patients with gestational trophoblastic neoplasia who had been successfully treated with the EMA-CO regimen but sustained a relapse (n=7) or who became refractory to it (n=11) were treated with the EP-EMA regimen. The effectiveness, adverse effects, and tolerated dose intensity of the EP-EMA regimen were retrospectively analyzed. RESULTS: The 18 patients received a total of 74 cycles of the EP-EMA regimen and 12 (66.7%) achieved complete remission. Nine of the 11 patients (81.8%) apparently resistant to the EMA-CO regimen achieved complete remission. However, only 3 of the 7 patients (42.9%) who experienced a relapse after treatment with the EMA-CO regimen achieved complete remission. The main adverse effects of the EP-EMA regimen were myelosuppression and gastrointestinal problems. Because of myelosuppression and hepatotoxicity, only 56.8% of the patients could be treated with the planned dose intensity. CONCLUSION: EP-EMA may be an effective option for the treatment of gestational trophoblastic neoplasia in patients resistant to treatment with the EMA-CO regimen. However, it does not seem to benefit all the patients who experienced a relapse after treatment with the EMA-CO regimen.

[Sensitivity of PTEN gene-transfected endometrial carcinoma cell line to doxorubicin-induced apoptosis].

OBJECTIVE: To investigate whether PTEN can increase sensitivity of Ishikawa cells, an endometrial carcinoma cell line, to doxorubicin. METHODS: Ishikawa cells transfected by PTEN gene or not were separately treated with serial concentrations of doxorubicin. The sensitivity of cells to doxorubicin was determined by MTT assay. The cells were stained with Hoechst 33258 and examined under fluorescence microscope to determine cell apoptosis. Immunoprecipitation and Western blotting analysis were performed to evaluate the effects of doxorubicin on phosphorylation of Bad and Akt/PKB. RESULTS: Doxorubicin induced cell death of the PTEN-transfected and non-transfected Ishikawa cells in a dose-dependent manner, but the cell death was more significant in PTEN-expressing clones than in parental Ishikawa cells. A low concentration of doxorubicin (0.1 micromol/L) did not affect cell apoptosis in PTEN-null Ishikawa cells, but it induced cell apoptosis in PTEN-expressing clones. A high concentration of doxorubicin (1 micromol/L) induced cell apoptosis in both cell lines. However, the percentage of apoptotic cells was higher in PTEN-expressing clones than that in parental Ishikawa cells. In the PTEN-expressing clones, expression of phospho-Akt/PKB and phospho-Bad (Ser-136) was down regulated. Doxorubicin reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in both cell lines, but the most significant reduction occurred in the PTEN-expressing clones. CONCLUSION: PTEN significantly enhances chemosensitivity of Ishikawa cells to doxorubicin. With PTEN expression, doxorubicin may exert apoptosis-induction activity by downregulation of the PI3k/Akt/PKB signaling pathway in Ishikawa cells.

[Tumor-infiltrating dendritic cells in epithelial ovarian carcinoma and correlation with the expression of vascular endothelial growth factor].

OBJECTIVE: To investigate the density and activation status of tumor infiltrating dendritic cells (TIDC) in epithelial ovarian carcinoma (EOC) and correlation with the expression of vascular endothelial growth factor (VEGF). METHODS: Streptavidin-peroxidase (SP) and Picture two-step immunohistochemistry methods were used to detect S-100(+), CD(83)(+) TIDC and the expression of VEGF in 57 primary EOCs, 32 benign ovarian tumors (benign control) and 16 normal ovarian tissues (normal control). RESULTS: (1) Two types of heterogeneous distribution pattern of TIDC in EOC were observed under the microscope. The number of S-100(+) TIDC in EOC [median 4.3 cells/high power field (HPF)], was significantly higher than that in benign controls (median 1.8 cells/HPF) and normal controls (median 2.0 cells/HPF, P = 0.000 and 0.015). The number of S-100(+)DC in early stage was significantly higher than that in advanced stage (median 6.0 and 3.8 cells/HPF, P = 0.026). Few CD(83)(+) TIDCs infiltrated tumor stromal tissue in EOC (median 0). (2) The expression of VEGF was significantly higher in EOC than in controls (P = 0.000). (3) The number of S-100(+) DC in EOC was negatively correlated to the expression of VEGF in tumor cells (P = 0.001). CONCLUSIONS: (1) The number of S-100(+) TIDC increases significantly in EOC. Ovarian carcinoma cells may stimulate recruitment of TIDC in EOC, but TIDC can be suppressed by VEGF. (2) Maturation of TIDC in EOC is severely inhibited.

[Efficacy and side effects of methotrexate in the treatment of ectopic pregnancy].

OBJECTIVE: To study the efficacy and side effects of methotrexate with different protocols in the treatment of ectopic pregnancy (EP). METHODS: Total of 648 patients who had EP and were treated only with MTX were analysed. Patients were divided into six groups according to protocol: Group 1, 100 mg intravenously (IV); Group 2, 100 mg, IV, followed by citrovorum factor; Group 3, 20 mg, IV every day for five days; Group 4, 20 mg intramusculary (IM) every day for five days; Group 5, 75 mg, IV; Group 6, 75 mg, IM. RESULTS: The rates of repeated MTX injection in group 1 - 6 because of inadequate decrease of hCG were 23.3%, 25.0%, 21.4%, 20.6%, 24.4% and 22.4% respectively. Success rates were 87.4%, 85.4%, 90.5%, 92.6%, 86.3% and 91.4% respectively. Rates of liver dysfunction were 10.3%, 8.3%, 64.3%, 69.1%, 8.7% and 31.0%. CONCLUSION: Single-dose of 75 mg MTX IV injection may be the best regimen in the treatment of EP because of the same efficacy but the least side effects.