Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study.

BACKGROUND: Maintenance therapy (MT) for recurrent or metastatic cervical cancer remains non-standardized. This study assessed MT effectiveness using a comprehensive approach and identifies prognosis factors inpatients with recurrent or metastatic cervical cancer. METHODS: From January 2019 and December 2021, over 6000 patients from six Chinese institutions were retrospectively examined. Patients had recurrent/metastatic cervical cancer and underwent first-line chemotherapy with or without MT. We calculated overall and progression-free survival using Kaplan-Meier analysis, comparing via log-rank test, and conducted Cox regression for prognostic factors. RESULTS: Overall, 274 patients were stratified into an MT group (n = 77) and a non-MT group (n = 197). The 3-year OS rates were 52.5 % and 28.0 % for the MT and non-MT groups, respectively. The MT group had significantly enhanced median OS (37 vs. 21 months; HR, 0.43; 95 % CI, 0.30-0.61; P < 0.001) and PFS (21 vs. 14 months; HR, 0.65; 95 % CI, 0.47-0.90; P = 0.014) compared with the non-MT group. No significant differences in efficacy were observed among the various MT regimens, whether PD-1 monoclonal antibody, targeted therapeutic agents, or a combination of both. Extended PFS and OS were observed in patients receiving > 8 MT cycles. Multivariate analyses revealed that oligometastasis, MT, exclusive prior surgery (as opposed to combined surgery and radiotherapy), and extended interval before recurrence were independent OS predictors (P = 0.045, P < 0.001, P = 0.010, and P = 0.005, respectively); oligometastasis, concurrent radiotherapy, MT, and extended interval before recurrence were independent PFS predictors (P = 0.004, P = 0.007, P = 0.009, and P = 0.003). CONCLUSIONS: The MT integration markedly extended PFS and OS in patients diagnosed with recurrent or metastatic cervical cancer.

Epithelioid trophoblastic tumor of the lower uterine segment and cervical canal: A case report.

BACKGROUND: Epithelioid trophoblastic tumor (ETT) is the rarest type of gestational trophoblastic tumor (GTT). It has been reported that more than 50% of ETTs arise in the uterine cervix or the lower uterine segment. Here, we report a case of ETT within the lower uterine segment and cervical canal and discuss its manifestations, possible causes, and related influencing factors. CASE SUMMARY: A 35-year-old woman (gravida 7, miscarriage 3, induction 2 with 1 being twins, para 2 of cesarean section, live 2), who had amenorrhea for 9 mo after breastfeeding for 22 mo after the last cesarean section, was diagnosed with ETT. The lesion was present in the lower uterine segment and endocervical canal with severe involvement of the anterior wall of the lower uterine segment and the front wall of the lower uterine segment where the cesarean incisions were made. Laboratory tests showed slight elevation of serum beta-human chorionic gonadotropin. Intraoperative exploration showed the presence of a normal-sized uterus body with an enlarged tumor in the lower uterine segment. The surface of the lower uterine segment was light blue, the entire lesion was approximately about 8 cm × 8 cm × 9 cm, with compression and displacement of the surrounding tissue. Histological examination diagnosed ETT. Immunohistochemical analysis showed positive expression of p63, with a Ki-67 proliferation index of 40%. CONCLUSION: A search of the PubMed database using the search terms "cesarean section" and "epithelioid trophoblastic tumor" retrieved nine articles, including 13 cases of ETT and ETT-related lesions, all 13 cases had a history of cesarean section, and the lesions were all located at the cesarean section incision on the anterior wall of the lower uterine segment. The present case is the 14th reported case of ETT after cesarean section. Therefore, we deduced that cesarean section trauma had an important effect on the occurrence of ETT at this site.

The Glutaminase Inhibitor Compound 968 Exhibits Potent In vitro and In vivo Anti-tumor Effects in Endometrial Cancer.

BACKGROUND: Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Hence, interfering with glutamine metabolism may impose anti-tumor effects. OBJECTIVE: In this study, we assessed the anti-tumorigenic effects of glutaminase-1 enzyme (GLS1) inhibition in endometrial cancer in vitro and in vivo. METHODS: The human endometrial cancer cell lines Ishikawa and HEC-1B were used. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, and AKT/mTOR pathway inhibition were assessed. The synergistic effects of compound 968 and paclitaxel were also analyzed. The in vivo effect of compound 968 was evaluated using tumor xenografts. RESULTS: We found that the GLS1-targeting compound 968 was able to reduce cancer cell proliferation in a dose- and time-dependent manner. Compound 968 combined with a low concentration of paclitaxel showed stronger inhibitory effects. Further analyses indicated that compound 968 induced cell cycle arrest at the G1 phase, as well as increased the production of cellular reactive oxygen species (ROS) and promoted cellular stress and cancer cell apoptosis. Additionally, the treatment of endometrial cancer with compound 968 downregulated the expression of GLS1 and cyclin D1 and upregulated the expression of P21 and E-cadherin. Moreover, the treatment of endometrial cancer cells with compound 968 significantly reduced the levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473), indicative of AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. In addition, western blotting analysis indicated that GLS1 expression was upregulated in human endometrial cancer tissues. CONCLUSION: Compound 968 may be a promising approach for the management of human endometrial cancer.

Tislelizumab Combined with Carboplatin-Paclitaxel for Treatment of Metastatic or Recurrent Endometrial Cancer: a Retrospective Clinical Study.

BACKGROUND: Metastatic or recurrent endometrial cancers with low survival rate had no standard or limited therapy choice. The aim of our study was to determine the efficiency and safety of tislelizumab combined with carboplatin-paclitaxel as a front-line therapy for patients with metastatic or recurrent endometrial cancer. METHODS: This clinical retrospective cohort study examined 24 Chinese patients with metastasis or recurrence but had not yet received treatment. The therapeutic regimen consisted of 6 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (target AUC: 5 mg/mL/min) with tislelizumab (200 mg) once every 3 weeks, and then intravenous tislelizumab (200 mg) once every 3 weeks until disease progression or unacceptable toxicity. RESULTS: At the 18-month follow-up, 8 patients were still receiving treatment, 13 were dead, and 3 withdrew. The objective response rate (ORR) was 62.5%, the disease control rate was 75.00%. The ORR was 77.78% for patients positive for PD-L1 and 69.23% for patients positive for MSI-H. The median overall survival time was 11.50 months, and the median progression-free survival time was 6.00 months. Half of the patients experienced 3 - 4 grade adverse events. There were no allergic reactions or treatment-related deaths. CONCLUSIONS: Tislelizumab combined with carboplatin-paclitaxel was used as a front-line therapy, had a beneficial effect and was safe for patients with metastatic or recurrent endometrial cancer.

LPCAT1 functions as an oncogene in cervical cancer through mediating JAK2/STAT3 signaling.

Cervical cancer is a major gynecological tumor worldwide. Unfortunately, the molecular mechanisms involved in cervical cancer tumorigenesis still requires more clarification. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), an enzyme involved in phosphatidylcholine metabolism, has been reported to regulate the proliferation, epithelial-mesenchymal transition (EMT) and recurrence of malignancies. Here in our study, we found that LPAT1 was over-expressed in clinical cervical cancer tissues, and its high expression was closely correlated with poor outcomes of patients. We further showed that LPCAT1 knockdown remarkably restrained the proliferation, migration and invasion of cervical cancer cells, while it significantly induced apoptosis. RNA-seq and bioinformatics assays initially showed that interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway was a key mechanism for LPCAT1 to regulate cervical cancer progression. LPCAT1 silence strongly decreased IL-6, p-Janus kinase 2 (JAK2) and p-STAT3 expression levels in cervical cancer cells. Similarly, the expression levels of IL-6/STAT3 target genes were also highly down-regulated in cervical cancer cells with LPCAT1 deletion. Importantly, we found that human recombinant IL-6 addition considerably abolished the function of LPCAT1-knockdown to suppress the proliferation and EMT process in cervical cancer cells, accompanied with mitigated apoptotic cell death. Furthermore, our animal experiment results validated that stable LPCAT1 deletion efficiently reduced the tumor growth rates of xenograft mouse models and lung metastasis in vivo. Collectively, all our findings revealed that LPCAT1 may be a promising alternative prognostic biomarker and therapeutic target for cervical cancer through regulating JAK2/STAT3 signaling pathway.

Camrelizumab (SHR-1210) with carboplatin and albumin-binding paclitaxel in patients with metastatic or recurrent cervical cancer: An open-label, phase 2 trial.

Aims: This study evaluates the safety and preliminary antitumor efficacy of camrelizumab with albumin-binding paclitaxel and cisplatin as first-line therapy for patients with recurrent or metastatic cervical carcinoma. Methods and Material: In this phase 2, open-label, prospective study, 35 patients with recurrent or metastatic cervical carcinoma with no previous systemic chemotherapy were included. The patients were treated with a maximum of six cycles of camrelizumab on day 1, albumin-binding paclitaxel, and carboplatin on day 2, every 3 weeks, followed by camrelizumab once every 3 weeks. The primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were duration of response (DoR) and safety. Furthermore, 27 patients were included in the per-protocol set for efficacy analysis, whereas for the safety analysis, all patients were included. Results: The median follow-up was 4.53 months, and the complete response, partial response, and stable disease were also achieved in 4 (14.81%), 6 (22.22%), and 13 (48.15%) patients. The ORR and DCR were 40.00% (95% confidence interval: 21.13-61.33%) and 92.00% (73.97-99.01%), respectively. The median DoR was 6.70 months. In addition, the most common adverse events (AEs) were reactive cutaneous capillary endothelial proliferation (RCCEP) (23, 65.71%), gastrointestinal reaction (8, 22.86%), and fever (8, 22.86%). Grade 3 AEs included 5 (14.29%) myelosuppression, and grade 4 AEs included 1 (2.86%) RCCEP and 1 (2.86%) bladder inflammation. Conclusions: Combination therapy of camrelizumab and albumin-bound paclitaxel and carboplatin shows promising efficacy and manageable toxicities in patients with recurrent or metastatic cervical cancer.

Predictive Value of let-7a for Cancer Cell Repopulation between Chemotherapy and Long-Term Survival: A Prospective Study.

OBJECTIVE: Repopulation during radiation is a classic theory in radiobiology. The long intervals between cycles of chemotherapy provide better micro-circumstance than radiation for the repopulation of cancer cells. METHODS: Patients with inoperable stage III and stage IV lung cancer were enrolled prospectively. Peripheral blood and tumor tissues were obtained before treatment and each cycle of chemotherapy to detect the serum let-7a expression and Ki-67 index. RESULTS: Fifty-two consecutive consenting patients were enrolled prospectively. The median follow-up was 13 months (range: 2-62 months). A strong correlation was found between the Ki-67 index and serum let-7a before treatment (r =-0.667, P<0.001). The serum let-7a expression levels were upregulated or downregulated significantly during chemotherapy. Patients with relatively low baseline let-7a expression levels had significantly worse overall survival (OS) and progression-free survival (PFS) than patients with relatively high baseline serum let-7a levels (P<0.001, P=0.005, respectively). CONCLUSION: This prospective study demonstrated that let-7a was correlated with tumor proliferation in lung cancer, with high prognostic value. Furthermore, it showed that repopulation, as correlated with let-7a, may exist during chemotherapy, which would give us a new perspective in overcoming the chemoresistance of lung cancer and would help in determining individual treatment strategies.

A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy.

BACKGROUND: Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. METHODS: Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0. RESULTS: A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. CONCLUSIONS: As an early index that can reflect the tissue's radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future's clinical work.

Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB-IIIB): a 3-year prospective study.

BACKGROUND: Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy. METHODS: A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB-IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8- interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-ß (TGF-ß), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). RESULTS: We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-ß levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-ß level significantly decreased compared with the levels before cCRT (P < 0.05). CONCLUSION: Circulating Th17 cells in the LACC patients (FIGO stage IIB-IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.

Wilms' Tumor 1-Associated Protein Contributes to Chemo-Resistance to Cisplatin Through the Wnt/ß-Catenin Pathway in Endometrial Cancer.

BACKGROUND: Cisplatin remains the mainstay of endometrial cancer (EC) chemotherapy. Wilms' tumor 1-associated protein (WTAP), playing a critical role in transcriptional and post-transcriptional regulation, has been reported as an oncogene, and its expression is elevated in multiple types of human tumors. Recent evidence has shown that the increased expression of WTAP is also closely related to chemo-resistance. However, its specific role in the susceptibility of human EC cells to cisplatin remains largely unexplored. METHODS: WTAP over-expression and WTAP depletion cell lines as well as their corresponding controls were constructed by transfection with lentivirus. Western blotting analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the expression of WTAP. Cell proliferation assay, colony formation assay, cell cycle assay, and apoptosis analysis were adopted to evaluate the effect of WTAP on the chemo-sensitivity of EC cells to cisplatin as well as its underlying mechanism. Immunofluorescence staining was used to assess the translocation of ß-catenin. Moreover, a subcutaneous xenograft tumor model was established to assess the effect of WTAP on tumor growth after cisplatin treatment. RESULTS: Depletion of WTAP in RL95-2 cells significantly enhanced the chemo-susceptibility of cells to cisplatin and increased the cell apoptosis, while WTAP over-expression in ARK-2 cells exhibited the opposite effects. Additionally, WTAP depletion significantly suppressed xenograft-tumor growth and enhanced sensitivity and apoptosis of tumor cells in vivo. Mechanistic analysis exhibited that WTAP over-expression facilitated the cytoplasm-to-nucleus translocation of ß-catenin and enhanced the GSK3ß phosphorylation at Ser9, while WTAP depletion revealed the opposite results, indicating that WTAP rendered chemo-resistance of EC cells to cisplatin by promoting the Wnt/ß-catenin pathway. CONCLUSIONS: WTAP might promote the chemo-resistance of EC cells to cisplatin through activating the Wnt/ß-catenin pathway. Collectively, our findings offered novel insights into EC treatment.

Apatinib combined with chemotherapy or concurrent chemo-brachytherapy in patients with recurrent or advanced cervical cancer: A phase 2, randomized controlled, prospective study.

OBJECTIVE: Apatinib mesylate is a novel vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, which has exhibited good safety and efficacy in several types of solid tumors. The present study aimed to assess the clinical efficacy and safety of apatinib combined with chemotherapy and concurrent chemo-brachytherapy (CCBT) in patients with recurrent and advanced cervical cancer. METHODS: A total of 52 patients with first diagnosed recurrent or untreated International Federation of Gynecology and Obstetrics stage IVB cervical cancer admitted at Shandong Cancer Hospital and Institute between July 2016 and May 2018 were analyzed in the current randomized controlled trial. The patients were randomly divided into 2 groups: the apatinib-treated group and the control group. Patients with recurrent cervical cancer in the apatinib-treated group were administered apatinib and carboplatin-paclitaxel as first-line chemotherapy. Patients with advanced cervical cancer were administered apatinib in combination with CCBT. In control group, patients with recurrent cervical cancer were treated with chemotherapy alone while patients with advanced cervical cancer received CCBT. RESULTS: The progression-free survival was significantly prolonged in apatinib group compared with control group (10.1 months; 95% confidence interval (CI), 8.42-11.79 vs 6.4 months; 95% CI, 3.88-8.92; P < .01; hazard ratio (HR), 0.44; 95% CI, 0.25-0.78; P < .01). The objective response rate in apatinib group was obviously higher than that in control group (64.3% vs 33.3%, P < .05). Proteinuria, hand-foot syndrome, mucositis, and hypertension in all Grades were statistically more common in apatinib group than in control group. Apatinib did not obviously aggravate other radiotherapy or chemotherapy side effects. CONCLUSION: Apatinib exhibited promising clinical efficacy in cervical cancer patients, resulting in an improved response rate and prolonged progression-free survival compared with the control group, and had manageable side effects. Our study revealed that apatinib combination therapy, adenocarcinoma, and bone metastasis.

Postoperative adjuvant chemotherapy combined with intracavitary brachytherapy achieved the equivalent survival compared with concurrent chemoradiotherapy in cervical cancer patients with intermediate-risk.

OBJECTIVES: The current study was aimed to evaluate the efficacy and toxicity of postoperative adjuvant chemotherapy (CT) combined with intracavitary brachytherapy (ICRT) in cervical cancer patients with intermediate-risk. METHODS: We analyzed the medical records of 558 patients who were submitted to radical surgery for Stage IB-IIA cervical cancer. A total of 172 of those 558 patients were considered intermediate-risk according to the GOG criteria. Among those 172 patients, 102 were subjected to CT combined with ICRT (CT+ICRT) and the remaining 70 patients were treated with concurrent chemoradiation (CCRT). The 3-year disease free survival (DFS), overall survival (OS), and complications of each group were evaluated and analyzed. RESULTS: No significant difference was observed in 3-year DFS or OS of the patients submitted to CT+ICRT and CCRT. Importantly, the frequencies of grade III to IV acute complications were significantly higher in patients submitted to CCRT than in those treated with CT+ICRT (Hematologic, P = 0.016; Gastrointestinal, P = 0.041; Genitourinary, P = 0.019). Moreover, the frequencies of grade III-IV late complications in patients treated with CCRT were significantly higher compared with CT+ICRT-treated patients (Gastrointestinal, P = 0.026; Genitourinary, P = 0.026; Lower extremity edema, P = 0.008). CONCLUSIONS: Postoperative adjuvant CT+ICRT treatment achieved equivalent 3-year DFS and OS but low complication rate compared to CCRT treatment in early stage cervical cancer patients with intermediate-risk.

Derlin1 functions as an oncogene in cervical cancer via AKT/mTOR signaling pathway.

BACKGROUND: Cervical cancer (CC) ranks third in the morbidity and mortality of female cancer around the world. Derlin1 has been found to be overexpressed in several human cancers. However, it is still unclear about its roles in CC. The research aims to explore the relationship between Derlin1 and CC. METHODS: We purchased a human CC tissues microarray, which contained CC tissues and corresponding para-cancerous tissues from 93 patients with primary cervical squamous cell carcinoma. Immunohistochemical staining was used to confirm the expression of Derlin1 in these tissues. And we detected the differential expression of Derlin1 in cervical cancer cell lines and normal cervical epithelial cells (H8). Further, the cervical cancer cell lines SiHa and C33A were used as an in vitro model, which was down-regulated the expression of Derlin1 using siRNA interference technology. The effects of Derlin1 down-regulating in CC cell lines on cell proliferation and migration were detected by CCK8 assay and transwell assay, respectively. The effect of Derlin1 down-regulating on apoptosis was analyzed by flow cytometry, and apoptosis-related proteins were detected using western blotting. In-depth mechanisms were studied using western blotting. In addition, the effects of Derlin1 up-regulating in normal cervical epithelial cells also were exposed. RESULTS: Derlin1 was significantly elevated in CC tissues (81.7%, 76/93), and the expression of Derlin1 was positively correlated with the tumor size, pathological grade, and lymph node metastasis in CC patients. And Derlin1 was high expressed in cervical cancer cell lines compared to H8 cells. Knockdown of Derlin1 in cervical cancer cell lines inhibited cell proliferation and migration. Moreover, knockdown of Derlin1 induced apoptosis and affected the expression of apoptosis-related proteins, including Bcl-2, Bax, Bim, caspase3 and caspase9. Further experiments showed that AKT/mTOR signal pathway might be involve in this processes that knockdown of Derlin1 inhibited the expression of p-AKT and p-mTOR. Over-expression of Derlin1 in H8 cells promoted cell proliferation and migration via up-regulated the expression of p-AKT and p-mTOR. CONCLUSION: Derlin1 is an oncogene in CC via AKT/mTOR pathway. It might be a potential therapeutic target for CC.

Derlin1 functions as an oncogene in cervical cancer via AKT/mTOR signaling pathway

BACKGROUND: Cervical cancer (CC) ranks third in the morbidity and mortality of female cancer around the world. Derlin1 has been found to be overexpressed in several human cancers. However, it is still unclear about its roles in CC. The research aims to explore the relationship between Derlin1 and CC. METHODS: We purchased a human CC tissues microarray, which contained CC tissues and corresponding para-cancerous tissues from 93 patients with primary cervical squamous cell carcinoma. Immunohistochemical staining was used to confirm the expression of Derlin1 in these tissues. And we detected the differential expression of Derlin1 in cervical cancer cell lines and normal cervical epithelial cells (H8). Further, the cervical cancer cell lines SiHa and C33A were used as an in vitro model, which was down-regulated the expression of Derlin1 using siRNA interference technology. The effects of Derlin1 down-regulating in CC cell lines on cell proliferation and migration were detected by CCK8 assay and transwell assay, respectively. The effect of Derlin1 down-regulating on apoptosis was analyzed by flow cytometry, and apoptosis-related proteins were detected using western blotting. In-depth mechanisms were studied using western blotting. In addition, the effects of Derlin1 up-regulating in normal cervical epithelial cells also were exposed. RESULTS: Derlin1 was significantly elevated in CC tissues (81.7%, 76/93), and the expression of Derlin 1 was positively correlated with the tumor size, pathological grade, and lymph node metastasis in CC patients. And Derlin 1 was high expressed in cervical cancer cell lines compared to H8 cells. Knockdown of Derlin 1 in cervical cancer cell lines inhibited cell proliferation and migration. Moreover, knockdown of Derlin 1 induced apoptosis and affected the expression of apoptosis-related proteins, including Bcl-2, Bax, Bim, caspase3 and caspase9. Further experiments showed that AKT/mTOR signal pathway might be involve in this processes that knockdown of Derlin 1 inhibited the expression of p-AKT and p-mTOR. Over-expression of Derlin 1 in H8 cells promoted cell proliferation and migration via up-regulated the expression of p-AKT and p-mTOR. CONCLUSION: Derlin 1 is an oncogene in CC via AKT/mTOR pathway. It might be a potential therapeutic target for CC.

Effect of Intravenous Dexmedetomidine During General Anesthesia on Acute Postoperative Pain in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Dexmedetomidine has been shown to have an analgesic effect. However, no consensus was reached in previous studies. METHODS: Electronic databases such as PubMed, Embase, and Cochrane Central were searched for relevant randomized controlled trials. The relative risk and weighted mean difference (WMD) were used to analyze the outcomes. Random-effects model was used for meta-analysis. RESULTS: Compared with the normal saline group, patients using DEX showed a significantly decreased pain intensity within 6 hours [WMD=-0.93; 95% confidence interval (CI), -1.34 to -0.53) and at 24 hours after surgery (WMD=-0.47; 95% CI, -0.83 to -0.11). DEX usage significantly reduced the cumulative opioids consumption at 24 hours after surgery (WMD=-6.76; 95% CI, -10.16 to -3.35), decreased the rescue opioids consumption in postanesthesia care unit (WMD=-3.11; 95% CI, -5.20 to -1.03), reduced the risk of rescue analgesics (relative risk=0.49; 95% CI, 0.33-0.71), and the interval to first rescue analgesia was prolonged (WMD=34.93; 95% CI, 20.27-49.59). CONCLUSIONS: Intravenous DEX effectively relieved the pain intensity, extended the pain-free period, and decreased the consumption of opioids during postoperative recovery of adults in general anesthesia.

RSF-1 overexpression determines cancer progression and drug resistance in cervical cancer.

BACKGROUND: Remodeling spacing factor 1 (RSF-1/HBXAP) has been linked to a variety of cancer types, however, its roles and the therapeutic potential are not clear in cervical cancer. METHODS: RSF-1 expression in cancer tissues was analyzed by immunohistochemical staining followed by statistical analysis with SPSS. Anti-RSF-1 studies were performed by treating cells with specific siRNA or a dominant mutant form (RSF-D4). RESULTS: RSF-1 expression correlates with cancer progression that strongly-positive staining can be found in 67.7% carcinomas and 66.7% CIN lesions, but none in normal tissues. Such overexpression also associated with increased tumor size, poor differentiation, higher nodal metastasis and advanced clinical stages. Kaplan- Meier analysis confirmed that cancer patients with high RSF-1 levels exhibited a significantly shorter survival time than those with low RSF-1 levels. Downregulation of RSF-1 by siRNA silencing or RSF-D4 reduced cell growth and increased drug sensitivity toward paclitaxel treatment in HeLa cells. CONCLUSIONS: RSF-1 participates in the tumor progression of cervical cancer and could be considered as an early prognostic marker for cancer development and clinical outcome. Therapies based on anti-RSF-1 activity may be beneficial for patients with RSF-1 overexpression in their tumors.

L1CAM promotes epithelial to mesenchymal transition and formation of cancer initiating cells in human endometrial cancer.

Identification of novel factors critical for epithelial to mesenchymal transition (EMT) and cancer initiating cell (CIC) formation may aid in the identification of novel therapeutics for the treatment of endometrial cancer. The present study demonstrated that L1 cell adhesion molecule (CAM) is critical for EMT and formation of CICs in endometrial cancer. Overexpression of L1CAM may promote EMT with increased formation of CICs in HEC-1A endometrial cancer cells. CICs and mesenchymal status resist chemotherapeutic drugs and may regenerate the various cell types in tumors, thereby resulting in relapse of the disease. The present study demonstrated that overexpressing L1CAM promoted paclitaxel resistance and regulated paclitaxel resistance-associated microRNA expression in HEC-1A cells. Furthermore, it was demonstrated that overexpressing L1CAM promoted anoikis resistance in HEC-1A cells. This link between L1CAM and EMT/CICs may provide a novel target for advancing anticancer therapy.

Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study.

We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 (n = 88) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy. Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer.

Suppression of SIK1 by miR-141 in human ovarian cancer cell lines and tissues.

Epithelial ovarian cancer (EOC), the sixth most common cancer in women worldwide, is the most commonly fatal gynecologic malignancy in developed countries. One of the main reasons for this is that relatively little was known about the molecular events responsible for the development of this highly aggressive disease. In the present study, we demonstrated that salt­inducible kinase 1 (SIK1; which is also known as MSK/SIK/SNF1LK) was downregulated in ovarian cancer tissue samples. Using HEY ovarian cancer cells, we noted that SIK1 overexpression inhibited proliferation as well as cancer stem cell-associated traits. Silencing SIK1 promoted the proliferation of the EG ovarian cancer cell line. We performed an analysis of potential microRNAs (miRNAs or miRs) target sites using three commonly used prediction algorithms: miRanda, TargetScan and PicTar. All three algorithms predicted that miR-141 targets the 3'UTR of SIK1. Subsequent experiments not only confirmed this prediction, but also showed that miR-141 was associated with the progression of this disease. Finally, we found that miR-141 promoted proliferation of EG cells, whereas silencing miR-141 restored SIK1 expression and inhibited the proliferation of the HEY cells. Elucidating the molecular mechanism of ovarian cancer not only enables us to further understand the pathogenesis and progression of the disease, but also provides new targets for effective therapies.

A 10-gene expression signature of Notch pathway predicts recurrence in ovarian carcinoma.

Patients with ovarian carcinoma are at high risk of tumor recurrence. In the present study, 81 Notch pathway genes were selected to find recurrence-related genes in The Cancer Genome Atlas dataset. A 10-gene signature (FZD4, HES1, PSEN2, JAG2, PPARG, FOS, HEY1, CDC16, MFNG, and EP300) was identified and validated that is associated with recurrence-free survival time, but not with overall survival time, in the TCGA dataset and in other two independent datasets, GSE9891 and GSE30161. This gene signature gave a significant performance in discriminating patients at high risk of recurrence from those at low risk, as measured by the area under the receiver operating characteristic curve. Cox proportional hazards regression analyses demonstrated that the prognostic value of this 10-gene set is independent of other clinical variables in all three datasets. The potential as a biomarker for predicting high- and low-risk subgroups for recurrence in ovarian cancer patients deserves further investigation in prospective patient cohorts in the future.