Individualized Treatment of Patients With Early-Stage Epithelial Ovarian Cancer After Incomplete Initial Surgery.

OBJECTIVES: Incomplete initial surgery complicates subsequent management of early-stage epithelial ovarian carcinoma (ESEOC). This study aimed to determine the most appropriate strategies for individualized treatment of these patients. METHODS: Medical records of ESEOC patients treated at our hospital between 2000 and 2011 were reviewed, and 246 patients initially treated by incomplete surgery were included. A scoring system was established to assess the quality of initial surgery (QOIS). RESULTS: Of 246 patients, 130 underwent restaging surgery and 116 received chemotherapy only. Follow-up duration ranged from 4 to 148 months (median, 72 months). The 5-year overall survival (OS) rates were 87.5% and 74.7% in the restaging and chemotherapy groups, respectively. Survival analysis showed significantly better recurrence-free survival (RFS) and OS in the restaging group (P = 0.043 and P = 0.029, respectively). Multivariate analysis showed that histologic grade was an independent predictor for RFS and OS in the restaging group (P = 0.035 and P = 0.038, respectively), and histologic grade (P = 0.005 and P = 0.015, respectively) and QOIS (P = 0.044 and P = 0.024, respectively) were independent predictors for RFS and OS in the chemotherapy group. Subgroup analysis showed that restaging surgery produced better RFS and OS than chemotherapy in patients with low QOIS and unfavorable histology (5-year RFS, 58.5% vs 33.4%, P = 0.007; 5-year OS, 82.2% vs 54.4%, P = 0.011), whereas the outcomes between the treatment options were comparable in patients with high QOIS or favorable histology. CONCLUSIONS: Our results support individualized treatment of ESEOC patients initially treated by incomplete surgery. Restaging surgery is recommended only for patients with low QOIS and unfavorable histology.

Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome.

BACKGROUND: The aim of this study was to elucidate the value of putative cancer stem cell markers Musashi-1, ALDH1, Sox2, and CD49f in predicting the prognosis in cervical squamous cell carcinoma (CSCC). METHODS: Real-time PCR and immunohistochemistry staining was performed to examine Musashi-1, ALDH1, Sox2, and CD49f expression in archived specimens of CSCC patients with postoperative chemotherapy. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of CSC markers for overall survival (OS) and recurrent-free survival (RFS). RESULTS: The Real-time PCR data showed that the expression of all markers were increased in CSCC tissues compared with in paired normal cervical tissues (P < 0.05). The IHC result showed that high expression of Msi1, ALDH1, Sox2, and CD49f was found in 25.7%, 43.0%, 62.0% and 29.0% CSCC samples, respectively. Moreover, high expression of Msi1 (P = 0.033 and P = 0.003, respectively), ALDH1 (P = 0.015 and P = 0.002, respectively), and Sox2 (P = 0.005 and P = 0.003, respectively), and low expression of CD49f (P = 0.027 and P = 0.025, respectively) were correlated with poor OS and PFS in CSCC patients. Interestingly, tumors with Msi1(high)/CD49f(low) expression had the poorest prognosis according to Msi1/CD49f stratification. In multivariate Cox regression analysis, Sox2 expression (P = 0.047 and P = 0.018, respectively), ALDH1 expression (P = 0.013 and P = 0.003, respectively), and CD49f expression (P = 0.008 and P = 0.003, respectively) were independent prognostic markers for both OS and RFS. CONCLUSIONS: Our results suggest that cancer stem cell markers are linked with poor prognosis of CSCC patients.

Establishment of the retroperitoneal lymph node metastasis model of endometrial VX2 carcinoma in rabbits and observation of its metastatic features.

BACKGROUND: The objective of this study is to establish the retroperitoneal lymph node metastasis model of endometrial VX2 carcinoma in rabbits and observe of its metastatic features. METHODS: The VX2 cells were transplanted into the uterine muscularis mucosae of 48 rabbits by injecting carcinoma mass suspension. According to time, the rabbits were killed after the transplantation of VX2 cells, and they were divided into six groups, 15-, 18-, 21-, 24-, 27-, and 30-day group, and six rabbits in each group. Control groups consisted of those receiving no treatment or an injection of saline. The specimens of transplanted endometrial carcinoma and retroperitoneal lymph node in the rabbits were examined histopathologically after they were killed. RESULTS: All rabbits developed VX2 endometrial carcinoma which was confirmed with pathological examination. Significantly increased tumor volume was observed at day 24, 27, and 30 post-injection of VX2 cells (P < 0.05). The retroperitoneal lymph nodes were not enlarged completely in each rabbit in the 15-day group, partly enlarged in the 18- and 21-day group, and all enlarged in the 24-, 27-, and 30-day group. The histopathological examination revealed no complete retroperitoneal lymph node metastasis in the 15- and 18-day group, partial metastasis in the 21-day group, and complete metastasis in the 24-, 27-, and 30-day group. CONCLUSIONS: The model was established successfully by injecting carcinoma mass suspension, and various retroperitoneal lymph node metastasis model of endometrial VX2 carcinoma can be established rapidly in a month after the transplantation.

Primary vaginal sarcoma: Experience of a regional cancer center in China.

AIM: To evaluate the clinical characteristics of primary vaginal sarcoma, which is a rare malignancy METHODS: We retrospectively reviewed the clinical records of eight patients with primary vaginal sarcoma treated at Sun Yat-Sen University Cancer Centre from 1997 to 2012. RESULTS: Eight patients aged ≥ 17 years were identified (four had leiomyosarcoma, two had endometrial stromal sarcoma, one had undifferentiated sarcoma, and one had adenosarcoma). Four patients had stage I disease, one had stage II, and three had stage IV. Five patients with stage I or II tumor received surgery of mainly local wide excision. One of the five patients received postoperative radiation plus chemotherapy and two had postoperative chemotherapy only. Three of the four stage I patients who had low-grade tumors and received wide local excision were alive without disease at 21, 53, and 81 months, respectively. One stage I patient with a high-grade tumor received simple tumor excision only and died of the disease at 20 months. The patient with stage II disease was lost to follow up. The three stage IV patients received radiotherapy and/or chemotherapy and all died within 2 years. CONCLUSIONS: Surgery is the main treatment for primary vaginal sarcoma. Prognosis may be associated with tumor grade and stage.

The outcome and efficacy of adjuvant chemotherapy alone in patients with stage IIIA endometrial carcinoma with solitary adnexal involvement: a retrospective single-institution study.

OBJECTIVES: The appropriate adjuvant therapy for patients with endometrial carcinoma with solitary adnexal involvement is unclear. We conducted a retrospective single-institution study to evaluate the outcome and efficacy of adjuvant chemotherapy alone in this population. METHODS: All patients with endometrial carcinoma who received primary surgical treatment between January 1999 and May 2010 were reviewed. The patients who were diagnosed with stage IIIA disease based only on isolated adnexal involvement and treated with surgical procedures followed by adjuvant chemotherapy alone were included. Demographic, clinicopathologic, treatment and outcome data were collected. Recurrence and survival were analyzed. RESULTS: Among 1453 reviewed patients, 67 patients were identified. The median age was 48 years. All patients were treated with platinum-based adjuvant chemotherapy, with the majority (36/67, 53.7%) receiving paclitaxel plus carboplatin. The total number of cycles of chemotherapy administered was 305 (median four cycles/person). Most of the chemotherapy related toxicities were mild or moderate. The median follow-up time was 76 months. Eight patients experienced recurrence. The majority of initial relapses were distant (7/8, 87.5%), characterized by liver metastases (3/8, 37.5%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 89.6% and 91.9%, respectively. Multivariate analysis confirmed that grade 3 tumor was an independent predictor of worse DFS and OS (HR=5.19, P=0.048; HR=6.55, P=0.037, respectively). CONCLUSION: Patients with stage IIIA endometrial carcinoma with solitary adnexal involvement have favorable outcomes. Adjuvant chemotherapy alone may be effective and feasible for these patients.

Prognostic and Immunological Role of Cuproptosis-Related Gene MTF1 in Pan-Cancer.

Metal regulatory transcription factor 1 (MTF1) has been reported to induce the expression of metallothionein and other genes involved in metal homeostasis. However, the role of MTF1 in pan-cancer and tumor immunity remains unclear. In this study, we conducted a series of bioinformatics analyses to investigate the clinical significance and potential functions of MTF1 across various types of cancer. By employing bioinformatics algorithms and immunofluorescence assays, we analyzed the associations between MTF1 and immune infiltration in the tumor microenvironment as well as the expression levels of immune-related molecules. Our findings revealed dysregulation of MTF1 in pan-cancer along with its correlation with certain clinicopathological features, suggesting its diagnostic and prognostic value for multiple cancer types. Furthermore, our immune-associated analyses and assays demonstrated strong correlations between MTF1 expression and plasmacytoid dendritic cells (pDC), central memory T cells (Tcm), as well as several immune biomarkers. Subsequent in vitro assays indicated that MTF1 reduced the sensitivity of cancer cells to cuproptosis. Overall, our study highlights that MTF1 may serve as a promising biomarker for prognosis assessment and a potential therapeutic target for more effective treatment strategies against various cancers.

VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis.

BACKGROUND: Retroperitoneal lymph node (RLN) metastasis is an important indicator of endometrial cancer (EC) prognosis. Because vascular endothelial growth factor c (VEGF-c) is known to influence lymphangiogenesis and thereby lymph node metastasis, this study assessed the relationship of VEGF-c mRNA expression with RLN metastasis in EC. METHODS: The uterine muscularis mucosae of New Zealand white rabbits were inoculated with a VX2 tumor cell suspension after which they were sacrificed at 15, 18, 21, 24, 27 and 30 days. Control groups consisted of those receiving no treatment or an injection of saline. EC and metastatic RLN tissues along with peripheral blood samples were collected, and VEGF-c mRNA expression was evaluated using fluorescence real-time quantitative PCR. RESULTS: The establishment of an in vivo model of EC with complete RLN metastasis was pathologically confirmed at day 21 post-injection with VX2 cells. As compared to the control groups, VEGF-c mRNA expression increased significantly over time in the tumor site, RLN, and peripheral white blood cells of EC rabbits. Significantly higher VEGF-c mRNA expression was observed in metastatic RLNs as compared to those without metastasis (P < 0.001). In addition, increased VEGF-c mRNA expression was observed in peripheral white blood cells of rabbits with RLN metastasis (P < 0.002). CONCLUSION: Injection of a VX2 cell suspension is a simple method of establishing an in vivo EC model. VEGF-c may play an important role in the development of EC and its metastasis to RLN and may be useful marker to predict RLN metastasis.

Atypical chemokine receptors predict lymph node metastasis and prognosis in patients with cervical squamous cell cancer.

OBJECTIVE: Atypical chemokine receptors (ACRs), including CCX-CKR, DARC, and D6, have been reported to be involved in cancer invasion and metastasis. The objective of this study was to investigate the prognostic importance of ACRs in patients with cervical squamous cell carcinoma (CSCC). METHODS: The expression of three ACRs was investigated by immunohistochemical (IHC) examination in a total of 317 cervical specimens including 40 normal cervical tissues, 50 cases of carcinoma in situ of cervix (CIS), and 227 cases of CSCC by immunohistochemistry. RESULTS: The expression rate of DARC and CCX-CKR in CSCC, CIS, and normal cervix increased gradually (p<0.01). D6 expression is decreased in CSCC compared to either in CIS or in normal cervix (p<0.05). In addition, the expression of CCL2 and CCL19 was inversely associated with ACR expression (p<0.05), while that of LCA was positively correlated with ACR expression (p<0.05). Moreover, DARC expression, CCX-CKR expression, and ACR coexpression were negatively correlated with lymph node metastasis (P<0.01). D6 expression and ACR coexpression were negatively related to tumor size (p=0.018) and recurrence (p=0.028). In multivariate Cox regression analysis, CCX-CKR expression was a positive indicator for overall survival (p=0.008), and D6 expression was an independent predictor of both overall and recurrence-free survival (p=0.041) in CSCC. CONCLUSIONS: Our results suggest that the loss of ACRs may play important roles in the tumorigenesis and migration of cervical cancer. ACR expression may be considered as prognostic markers in patients with CSCC.

Expression of c-Src and phospho-Src in epithelial ovarian carcinoma.

Abnormal c-Src expression and activation has been observed in a number of tumors. To determine the therapeutic potential of Src inhibitors for ovarian cancer patients, this study aimed to explore the expression patterns of c-Src and phospho-Src in epithelial ovarian cancer. A total of 82 patients with epithelial ovarian cancer treated at Sun Yat-sen University Cancer Center from January 1999 to December 2005 were enrolled along with 25 patients with benign ovarian lesions; 20 normal ovarian tissues served as controls. Expression of c-Src and phospho-Src (Tyr416) was examined using immunohistochemistry. Survival analyses were performed using Kaplan-Meier curves. As compared to the control group, a significantly greater proportion of ovarian cancer tissues were positive for c-Src and phospho-Src expression (P < 0.001). c-Src expression was associated with age, while phospho-Src expression was significantly associated with age, FIGO stage, histology grade, and residual tumor size after surgery (all P < 0.05). The mean survival time was associated with phospho-Src expression, but not with c-Src expression. The mean survival times of patients with phospho-Src-positive tumors were significantly greater than those with phospho-Src-negative tumors (87.4 months, 95 % CI = 74.3-100.5 months and 91.5 months, 95 % CI = 84.7-98.2 months, respectively; P = 0.013). The increased c-Src expression and activation in epithelial ovarian cancer suggests that ovarian cancer patients may benefit from tyrosine kinase inhibitors such as Dasatinib. Activation of c-Src through phosphorylation at Tyr416 may play a role in the early stages of ovarian cancer development, and evaluation of its expression may be a useful prognostic marker of epithelial ovarian cancer.

Efficacy of poly (ADP-ribose) polymerase inhibitors monotherapy and the impact to subsequent platinum-based chemotherapy in breast cancer susceptibility genes1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse.

BACKGROUND: The therapeutic effect of poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy compared with platinum-based chemotherapy, and the impact to subsequent platinum-based chemotherapy after PARPi resistance were inconclusive in breast cancer susceptibility genes (BRCA)1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse. METHODS: BRCA1/2-mutated patients with secondary platinum-sensitive relapse included in this study did not receive any maintenance regimen after first- and second-line platinum-based chemotherapy, and the secondary platinum-free interval (PFI) was more than 6 months. Patients in study group were treated with PARPi monotherapy until disease progression, and patients in control group were treated with platinum-based chemotherapy without restriction. Progression-free survival (PFS) was defined as the time from third-line therapy to disease progression or death, PFS2 was defined as the time from platinum-based chemotherapy after PARPi resistance to next subsequent therapy or death. Post-recurrence survival (PRS) refers to the survival time after secondary platinum-sensitive relapse. RESULTS: A total of 119 patients were retrospectively analyzed, including 71 (59.7%) in study group and 48 (40.3%) in control group. The objective response rate (ORR: 77.5% vs. 80.0%, p=0.766) and PFS (median: 11.2 vs. 11.0 months, p=0.962) were comparable. The benefit of subsequent platinum-based chemotherapy after PARPi resistance was more pronounced in patients with PARPi treatment for more than 12 months (median PFS2: 8.6 vs. 4.3 months, p=0.040). PARPi monotherapy had no adverse effect on PRS compared with platinum-based chemotherapy (median PRS:41.2 vs. 42.8 months, p=0.323). Compared to patients in control group who had never received PARPi, PARPi monotherapy (median PRS: 41.2 vs. 33.7 months, p=0.019) and post-line treatment with PARPi in the control group (median PRS: 48.1 vs. 33.7 months, p=0.002) could prolong PRS for patients with secondary platinum-sensitive relapse. CONCLUSIONS: PARPi monotherapy was similar to platinum-based chemotherapy for BRCA1/2-mutated ovarian cancer patients with secondary platinum-sensitive recurrence, and could improve prognosis.

Differential routes of carboplatin administration influence lymphocyte apoptosis in retroperitoneal lymph nodes.

We aimed to investigate carboplatin distribution in retroperitoneal lymph nodes and its effect on lymphocyte apoptosis following intravenous (IV), intra-arterial (IA), and retroperitoneal (RP) administration. Sixty-three healthy female canines were randomly assigned as IV, IA, or RP administration of carboplatin. At 0.5, 1, 2, 4, 8, 24, and 72 h after carboplatin treatment, retroperitoneal lymph nodes (n = 6 at each time point) were collected and high-performance liquid chromatography was employed to measure the carboplatin content. The differences in carboplatin pharmacokinetics of the three administration routes were compared. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) was carried out to measure the lymphocyte apoptosis of the retroperitoneal lymphocytes. The peak concentration of carboplatin in plasma following IV administration was the highest among all approaches; as to the peak time, RP administration was longer than the other two administrations. Concentration for carboplatin in the retroperitoneal lymph node was highest following IA administration at early time points, but at higher time points, concentration was significantly higher following RP administration. Penetration of carboplatin into the retroperitoneal space was higher following RP administration. Following RP administration, the level of apoptotic lymphocytes in the retroperitoneal lymph nodes was significantly greater than either IV or IA. Following RP administration of carboplatin, the concentration, area under the curve of carboplatin and the number of apoptotic lymphocytes were significantly higher than those following IV and IA administration. This suggests that RP administration of carboplatin is beneficial for the treatment of retroperitoneal lymph node metastasis.

Summer dormancy of Myricaria laxiflora to escape flooding stress: Changes in phytohormones and enzymes induced by environmental factors.

Dormancy is an adaptation mechanism of plants to environmental stress. Myricaria laxiflora undergoes a long period of flooding stress every year. In order to determine whether this species escapes flooding stress through dormancy, young branches and leaves were collected at different time points before the onset of flooding, and changes in the content/activity of hormones/enzymes that are closely involved in plant growth were monitored. The inducing environmental factors of summer dormancy were identified. The branches and leaves of M. laxiflora showed the following trends as summer flooding approached: (1) gradual increase in the abscisic acid content; (2) gradual decrease in the gibberellin and cytokinin contents; and (3) a continuous decrease in the activities of malate dehydrogenase (MDH), ribulose diphosphate carboxylase (RuBisCo), and glycolate oxidase (GLO). Pearson correlation analysis revealed (1) daylight duration was highly correlated with the hormone content and enzyme activity; (2) the daily mean air temperature (DMAT) was significantly correlated with the cytokinin content. These findings suggest that daylight duration was the main environmental factor leading to changes in the phytohormone content and enzyme activity as well as leading to summer dormancy. M. laxiflora undergoes dormancy before the onset of summer flooding to escape summer flooding stress. Our data indicate that summer flooding does not impede the survival and growth of M. laxiflora.

Phase II trial of efficacy, safety and biomarker analysis of sintilimab plus anlotinib for patients with recurrent or advanced endometrial cancer.

BACKGROUND: Although co-inhibition of the angiogenesis and programmed death 1 (PD-1) pathways is proposed as an effective anticancer strategy, studies in Chinese patients with endometrial cancer are sufficient. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor affecting tumor angiogenesis and proliferation; sintilimab is an anti-PD-1 monoclonal antibody. METHODS: This was a phase II trial using Simon's two-stage design. This study enrolled patients with endometrial cancer who had progressed after platinum-based chemotherapy. Sintilimab 200 mg was administered intravenously on day 1 every 3 weeks, and anlotinib 12 mg was administered on days 1-14 in a 21-day cycle. The primary endpoint was the objective response rate (ORR) using the immune-related Response Evaluation Criteria in Solid Tumors criteria. Immunohistochemistry and whole-exome sequencing were used as correlative investigations. RESULTS: Between November 2019 and September 2020, 23 eligible patients were enrolled. The ORR and disease control rates were 73.9% (95% CI, 51.6 to 89.8) and 91.3% (95% CI, 72.0 to 98.9), respectively, with 4 complete and 12 partial responses. With a median follow-up of 15.4 months (95% CI, 12.6 to 18.3), the median progression-free survival was not reached, and the probability of PFS >12 months was 57.1% (95% CI, 33.6 to 75.0). Exploratory analysis revealed that mutations in the homologous repair pathway showed a trend for higher ORR (100% vs 0%, p=0.07). Treatment-related grade 3/4 adverse events were observed in 50.0% of the patients. CONCLUSIONS: Sintilimab plus anlotinib demonstrated robust therapeutic benefits with tolerable toxicity in endometrial cancer. TRIAL REGISTRATION NUMBER: NCT04157491.

A novel combination of niraparib and anlotinib in platinum-resistant ovarian cancer: Efficacy and safety results from the phase II, multi-center ANNIE study.

Background: Patients with platinum-resistant recurrent ovarian cancer (PROC) face poor prognosis and limited treatment options. Single-agent antiangiogenics and poly (ADP-ribose) polymerase (PARP) inhibitors both show some activities in platinum-resistant diseases. The ANNIE study aimed to evaluate the efficacy and safety of the novel combination of the PARP inhibitor niraparib and the antiangiogenic anlotinib in patients with PROC. Methods: ANNIE is a multicentre, single-arm, phase 2 study (ClinicalTrials.gov identifier NCT04376073) conducted at three hospitals in China. Eligible patients had histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months of last platinum-based chemotherapy. Patients with prior PARP inhibitor exposure were excluded. The enrolled patients received oral niraparib 200 mg or 300 mg (baseline body weight-directed) once daily continuously and anlotinib 10 mg (12 mg before protocol amendment) once daily on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Findings: Between May 22, 2020, and April 22, 2021, 40 patients were enrolled and treated. Thirty-six patients underwent post-baseline tumour assessments. By data cut-off (January 31, 2022), median follow-up was 15.4 months (95% CI 12.6-17.7). Intention-to-treat ORR was 50.0% (95% CI 33.8-66.2), including one complete response and 19 partial responses. Median (95% CI) progression-free survival and overall survival were 9.2 months (7.4-11.9) and 15.3 months (13.9-not evaluable), respectively. Drug-related, grade ≥3 TEAEs were reported in 26 (68%) patients. There were no treatment-related deaths. Interpretation: Niraparib plus anlotinib showed promising antitumour activity in patients with PROC. This oral combination warrants further investigation as a potential novel, convenient treatment option for patients with PROC. Funding: Zai Lab (Shanghai) Co., Ltd; Jiangsu Chia Tai-Tianqing Pharmaceutical Co., Ltd; the National Natural Science Foundation of China (No. 82102783).

Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer: The STARS Phase 3 Randomized Clinical Trial.

IMPORTANCE: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. OBJECTIVE: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. DESIGN, SETTING, AND PARTICIPANTS: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. INTERVENTIONS: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of disease-free survival (DFS) at 3 years. RESULTS: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00806117.

The effect of Elymus nutans sowing density on soil reinforcement and slope stabilization properties of vegetation-concrete structures.

Elymus nutans is an herbaceous plant that can be used to restore degraded alpine and subalpine ecosystems. Here, we evaluated how sowing density affects soil reinforcement and slope stabilization properties of vegetation-concrete structures. To investigate the optimal sowing density of E. nutans in vegetation-concrete applications for slope protection, six experimental treatments were established with different plant densities: control, I (1100 seeds/m2), II (2200 seeds/m2), III (3300 seeds/m2), IV (4400 seeds/m2), and V (5500 seeds/m2). Several parameters of plant growth in addition to soil reinforcement and slope stabilization properties were measured in each treatment, as well as the associations among parameters. As density increased, aboveground biomass continually increased, and plant heights, root surface areas, root lengths, and underground biomass all first increased and then decreased. In contrast, tiller numbers and the average root diameter gradually decreased with increasing density. Increased density also resulted in increased maximum water interception levels by aboveground stems and leaves. The maximum water interception by the aboveground stems and leaves was 41.75% greater in the highest density treatment (V) compared to the lowest density treatment (I). However, the enhancement of erosion resistance and soil shear strength first increased and then decreased as density increased, with maximal values observed in the medium-high density treatment (IV). Sowing density was highly correlated with aboveground biomass, plant heights, tiller numbers, and the maximum level of water interception by stems and leaves. Thus, sowing density directly influenced soil reinforcement and slope stabilization properties of aboveground plant components. However, density was not significantly correlated with belowground biomass, root lengths, root surface areas, the enhancement of erosion resistance, and soil shear strengths. Therefore, sowing density indirectly influenced soil reinforcement and slope stabilization of belowground plant components. Following from these results, we suggest that the optimal sowing density of E. nutans is approximately 4400 plants/m2 in their application within vegetation-concrete structures used for slope protection.

Spatiotemporal photosynthetic physiology responses of remnant Myricaria laxiflora populations to regulated water level fluctuations.

The construction of the Three Gorges-Gezhouba Dam cascade hydropower station has changed the water level fluctuation pattern of the habitats for remnant rare and endangered Myricaria laxiflora populations downstream of the dam. The present study utilized biochemical markers of photosynthetic physiology to evaluate the spatiotemporal responses of remnant populations to human-regulated water level fluctuations. The results showed that the photosynthetic physiological activities of remnant M. laxiflora populations underwent a period of rapid growth, followed by a gradual decline in the growth recovery phase after flooding. During the entire experimental period, photosynthetic physiological activities of remnant M. laxiflora populations changed with prolongation of emergence time: specifically, net photosynthetic rate and stomatal conductance initially decreased and then subsequently increased, intercellular carbon dioxide concentrations peaked at mid-phase and transpiration rate continuously increased. The maximum net photosynthetic rate, apparent photosynthetic quantum efficiency and dark respiration rate in the light-response curves of the plants continuously increased during growth. The water level gradient also significantly affected the photosynthetic physiological activities in the remnant populations, i.e. the photosynthetic physiological activities of high-altitude plants were significantly higher than the middle- and low-altitude plants. The changes in photosynthetic pigment content of plants in remnant populations during the growth recovery phase and the entire growth period were similar to those occurring in photosynthetic activities in plants. Further, canonical correspondence analysis showed that photosynthetic physiological activities in the plants were significantly correlated with changes in water levels, emergence time, elevation gradient, soil water and soil nitrogen contents. Therefore, the artificial regulation of water level fluctuations by large hydropower stations will inevitably affect the photosynthetic activities and growth of remnant M. laxiflora populations.

Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta-analysis.

OBJECTIVE: A meta-analysis was performed to determine if BRCA1/2 mutations are associated with improved overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer. RESEARCH DESIGN AND METHODS: Studies of patients with primary or recurrent ovarian cancer that examined the relationship between BRCA1/2 mutation status and outcomes were included. MAIN OUTCOME MEASURES: The primary outcomes were OS and PFS of patients with and without BRCA1 and BRCA2 mutations. The secondary outcome was treatment response: complete response, partial response, and overall response. RESULTS: Overall analysis revealed BRCA1/2 mutations were associated with improved OS [hazard ratio (HR) = 0.75; 95% confidence interval (CI): 0.64, 0.88; P < .001] and PFS (HR = 0.80; 95% CI: 0.64, 0.99; P = .039). BRCA1 mutations were significantly associated with improved OS (HR = 0.75) but not PFS, and BRCA2 mutations alone were not associated with either improved OS or PFS. The presence of BCRA1/2 mutations was associated with a better overall response rate, higher complete response rate, and lower partial response rate; however, BRCA1 or BRCA2 alone was not associated with overall response rate. CONCLUSIONS: BRCA1 mutations appear to be associated with improved OS in patients with ovarian cancer. However, the effect of BRCA1 mutations on PFS and BRCA2 mutations alone on OS and PFS is less clear.

Expression of COL6A1 predicts prognosis in cervical cancer patients.

COL6A1 has been shown to play an important role in tumor initiation and progression. The present study is to investigate the clinical significance of COL6A1 in cervical cancer. In this study, the COL6A1 expression levels in 10 paired cervical cancer tissues and the adjacent non-tumor tissues were examined by real-time PCR. The expression of COL6A1 protein was examined in 162 cervical cancer samples by immunohistochemistry, and the correlation of COL6A1 expression with clinicopathologic factors was analyzed. The overall and recurrent-free survival rates were estimated using Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with multivariate Cox regressions model. The result showed that COL6A1 expression was up-regulated in cervical cancer tissues in compared with that in non-tumor tissues. High expression of COL6A1 was significantly correlated with FIGO stage (P<0.001), tumor size (P=0.025) and lymph node metastasis (P=0.028) of the disease. Moreover, survival analysis showed that high expression of COL6A1 was significantly associated with poorer overall (OS) and recurrent free (RFS) survival (p=0.004 and =0.001, respectively) of cervical cancer patients. Multivariate analysis suggested that COL6A1 expression was an independent prognostic marker of cervical cancer (P=0.029). Thus, COL6A1 may serve as an oncogene in the initiation and progression of cervical cancer, and as a predictor of poor prognosis in cervical cancer patients.

WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition.

BACKGROUND: Previously, we found an 11-gene signature could predict pelvic lymph node metastasis (PLNM), and WNT2 is one of the key genes in the signature. This study explored the expression and underlying mechanism of WNT2 in PLNM of cervical cancer. METHODS: WNT2 expression level in cervical cancer was detected using western blotting, quantitative PCR, and immunohistochemistry. Two WNT2-specific small interfering RNAs (siRNAs) were used to explore the effects of WNT2 on invasive and metastatic ability of cancer cells, and to reveal the possible mechanism of WNT2 affecting epithelial-mesenchymal transition (EMT). The correlation between WNT2 expression and PLNM was further investigated in clinical cervical specimens. RESULTS: Both WNT2 mRNA and protein expression was upregulated in cervical cancer. High WNT2 expression was significantly associated with tumor size, lymphovascular space involvement, positive parametrium, and most importantly, PLNM. PLNM and WNT2 expression were independent prognostic factors for overall survival and disease-free survival. WNT2 knockdown inhibited SiHa cell motility and invasion and reversed EMT by inhibiting the WNT2/ß-catenin pathway. WNT2 overexpression in cervical cancer was associated with ß-catenin activation and induction of EMT, which further contributed to metastasis in cervical cancer. CONCLUSION: WNT2 might be a novel predictor of PLNM and a promising prognostic indicator in cervical cancer.