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Objective:To evaluate the dosimetric effects of different aperture shape controller (ASC) parameters based on the Halcyon 3.0 accelerator in the hippocampal avoidance-whole brain radiotherapy (HA-WBRT) plans.Methods:This study enrolled 13 patients treated with WBRT using a Halcyon 3.0 accelerator at the Department of Radiotherapy of the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. According to different aperture shape controller (ASC) parameters, the HA-WBRT plans were divided into six groups, namely non, very low, low, moderate, high, and very high ASC settings, marked by AO, AVL, AL, AM, AH, and AVH, respectively. This study presented a statistical evaluation of the effects of different ASC parameters on conformity index (CI), homogeneity index (HI), radiation doses to the hippocampus and other organs at risk, and the plans’ execution efficiency. Furthermore, using two dose verification tools, namely ArcCHECK and Portal Dosimetry, this study delivered a comprehensive analysis of the differences in beam delivery precision of the plans with different ASC parameters.Results:The six groups all met the requirements for clinical treatment. They had similar CI and HI values, with no statistically significant differences ( P > 0.05). The AVH group showed better protection effects on organs at risk. Compared to the control group, the AVL group showed lower Dmax of brainstems but higher Dmax of chiasma opticum ( F = 6.26, 8.04, P < 0.05). Compared to the control group, the AH group showed lower Dmax of eyeballs but higher Dmax of optic nerves ( F = 2.04, 1.37, P < 0.05). In contrast, the AVH group exhibited lower Dmax of brainstems, eyeballs, and lens than the control group ( F = 6.26, 2.04, 2.02, P < 0.05). No statistically significant differences were observed in dosimetric indices of other organs at risk ( P > 0.05). As verified using ArcCHECK and Portal Dosimetry, the γ passing rates of the six groups were over 98% at 2%/2 mm and 100% at 3%/3 mm. The overall γ passing rates verified using ArcCHECK were lower than those verified using Portal Dosimetry. The maximum difference in the monitor unit among the six groups was less than 15, and these groups did not show significant differences in terms of execution efficiency. Conclusions:The HA-WBRT plans based on the Halcyon 3.0 accelerator can meet the requirements for clinical treatment. Different ASC parameters can significantly optimize the dosimetric parameters. Among them, the AVH parameters can highly reduce the radiation dose to organs at risk. Furthermore, different ASC parameters show insignificant effects on beam delivery precision and plan execution efficiency, meeting the verification standards for clinical therapeutic doses.
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Objective:To study the effects of poly adenosine diphosphate ribose polymerase (PARP) inhibitors niraparib and pamiparib on the radiosensitivity of breast cancer cell lines MCF-7 and MDA-MB-436, and to explore its mechanism.Methods:MCF-7 and MDA-MB-436 cells were divided into control group, niraparib group, pamiparib group, radiation group, combination group treated with niraparib and radiation, and combination group treated with pamiparib and radiation, respectively. The effects of drugs on cell proliferation and radiosensitivity were measured by CCK-8 assay and colony formation assay, respectively. The effect of drugs combined with radiation on cell cycle and apoptosis were detected by flow cytometry. Immunofluorescence method was used to detect the changes of γ-H2AX focal number of cells. The expressions of FANCG, Bax and Bcl-2 mRNA and protein were detected by qPCR and Western blot, respectively.Results:Both niraparib and pamiparib inhibited the proliferation of breast cancer cells MCF-7 and MDA-MB-436 in a time-dose dependent manner. With the increase of irradiation dose, D0, Dq, SF2 value of MCF-7 and MDA-MB-436 cells decreased, and SER D0 and SER Dq value increased. Compared with control group, the percentages of cells in G 2/M phase were increased ( tMCF-7=41.66, 44.08, P<0.05; t436=24.69, 18.91, P<0.05), the percentage of cells in G 0/G 1 phase were decreased ( tMCF-7=8.67, 29.61, P<0.05; t436=26.39, 29.12, P<0.05), and the cell apoptosis rate was significantly increased ( tMCF-7=11.17, 11.71, P<0.05; t436=42.68, 15.89, P<0.05) in the combination group. Compared with control group, the number of γ-H2AX foci of MCF-7 cells in the radiation group and combination group treated with niraparib and radiation increased significantly at 2 h after irradiation ( t=8.89, 21.72, P<0.05). At 24 h after irradiation, the number of γ-H2AX foci basically returned to normal level in the radiation group but remained at a higher level in the combination group ( t=8.82, P<0.05). Compared with control group, the expressions of FANCG and Bcl-2 mRNA decreased ( tFANCG=14.07, P<0.05; tBcl-2=29.21, P<0.05), the expression of Bax mRNA increased ( t=8.90, P<0.05), and the expression of FANCG and Bcl-2 proteins decreased ( tFANCG=7.09, P<0.05; tBcl-2=10.24, P<0.05), while the expression of Bax protein increased ( t=2.90, P<0.05) in the combination group. Conclusions:PARP inhibitors niraparib and pamiparib can increase the radiosensitivity of breast cancer MCF-7 and MDA-MB-436 cells probably through down-regulating the expression of FANCG in FA-BRCA pathway, up-regulating apoptosis-related genes and inhibiting DNA damage repair.
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Objective:To evaluate the effectiveness and safety of concurrent chemoradiotherapy combined with nimotuzumab in the treatment of patients with inoperable esophageal squamous cell carcinoma (ESCC).Methods:A retrospective analysis was conducted on the clinical data of 503 patients with inoperable ESCC who underwent concurrent chemoradiotherapy in the Department of Radiation Oncology, Changzhou No. 2 People′s Hospital Affiliated to Nanjing Medical University and Department of Radiation Oncology, Affiliated Hospital of Jiangnan University from 2014 to 2020. Among these patients, 69 received concurrent chemoradiotherapy combined with nimotuzumab (the combined therapy group) and 434 received concurrent chemoradiotherapy alone (the concurrent chemoradiotherapy group). Patients of both groups were matched at a ratio of 1∶2 using the propensity score matching (PSM) method. As a result, 168 patients were determined for clinical analysis, including 61 in the combined therapy group and 107 in the concurrent chemoradiotherapy group. The short-term efficacy and adverse reactions of both groups were compared. The overall survival (OS) curves and progression-free survival (PFS) curves were plotted using the Kaplan-Meier method for the Log-rank test.Results:The two groups showed no statistical difference ( P > 0.05) in clinical baseline characteristics after the PSM. The objective response rate (ORR) of the combined therapy group was significantly higher than that of the concurrent chemoradiotherapy group with statistically significant differences (85.2% vs. 71.0%, χ2 = 4.33, P = 0.037). There was no statistical difference (98.4% vs. 91.6%, P > 0.05) in the disease control rate (DCR) between the two groups. The combined therapy group had median PFS of 28.07 months and 1-, 3-, and 5-year PFS ratios of 78.2%, 37.5% and 29.1%, respectively. The concurrent chemoradiotherapy group had mPFS of 19.54 months and 1-, 3-, and 5-year PFS ratios of 72.9%, 28.3% and 21.3%, respectively. Both groups showed statistically significant differences in PFS ( χ2 = 4.49, P = 0.034). The combined group had median OS of 34.93 months and 1-, 3-, and 5-year OS ratios of 88.5%, 46.8% and 37.4%, respectively. The concurrent chemoradiotherapy group had mOS of 24.30 months and 1-, 3-, and 5-year OS ratios of 81.3%, 35.2% and 28.0%, respectively. Both groups showed statistically significant differences in OS (χ 2= 5.11, P = 0.024), but did not show statistical differences ( P > 0.05) in the severity degree of each adverse effect during the treatment. Conclusions:Concurrent chemoradiotherapy combined with nimotuzumab can improve the ORR and prolong the PFS and OS of patients with inoperable ESCC compared with concurrent chemoradiotherapy alone. Furthermore, combining with nimotuzumab does not increase adverse effects and can be tolerated by patients with high safety.
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Cervical cancer is one of the most common malignant tumors in women worldwide. Locally advanced cervical cancer is mainly treated with radiotherapy and chemotherapy, but there are problems such as high recurrence rate and low survival rate. Bevacizumab, an angiogenic inhibitor that acts on vascular endothelial growth factor (VEGF), has been recommended by the National Comprehensive Cancer Network (NCCN) guidelines for the first-line treatment of recurrent / metastatic advanced cervical cancer in 2013. In recent years, the development of new targeted drugs for angiogenesis inhibitors, such as endostatin, has further optimized the new targeted therapy strategy for patients with locally advanced and advanced cervical cancer. Recombinant human endostatin (endostar) is a novel anti-angiogenesis drug independently developed by Chinese scientists. Although it has been applied in the treatment of cervical cancer, it needs to be further confirmed by high level evidence based medical evidence whether it can become a new option for targeted treatment of cervical cancer. In this article, clinical research progress on the treatment of cervical cancer by endostar combined with radiotherapy and / or chemotherapy was reviewed, aiming to provide reference for the optimization of cervical cancer treatment strategy.
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Objective:To evaluate the effect of niraparib, the poly (ADP-ribose) polymerase (PARP) inhibitor, on the radiosensitivity of esophageal squamous cell carcinoma (ESCC) and to preliminarily investigate its mechanism.Methods:Human esophageal squamous cell carcinoma cells ECA-109 and KYSE-150 were divided into the control, niraparib, single irradiation, combined (niraparib+irradiation) groups. Cell proliferation was measured by CCK-8 assay. The changes of cell survival rate were detected by colony formation assay. The changes of cell cycle and apoptosis were analyzed by flow cytometry. The number of γH2AX foci was detected by immunofluorescence, and the expression levels of PARP-1, cleaved-PARP, RAD51, mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase 1 and 2 (ERK1/2) ] and p-MAPK (ERK1/2) proteins were determined by Western blot. All data were expressed as Mean±SD. Data between two groups conforming to normal distribution through the normality test were subject to independent sample t-test and multiple groups were analyzed using one-way ANOVA. Results:In human ESCC cells ECA-109 and KYSE-150, the proliferation of ESCC cells was significantly inhibited by niraparib combined with irradiation, and the values of average lethal dose (D 0), quasi-threshould dose(D q), survival fraction after 2 Gy irradiation (SF 2) in the combined group were decreased compared with those in the single irradiation group. The effect of irradiation alone on apoptosis of ECA-109 and KYSE-150 cells was limited. Compared to single irradiation group, irradiation combined with niraparib further increased the apoptosis rate in ESCC cells ( P=0.015, P=0.006). In ECA-109 cells, G 2/M phase arrest was significantly increased in combined group compared with irradiation alone group ( P<0.001). In ECA-109 cells, the number of γH2AX foci in combined group was higher than that in the single irradiation group after 2 h, and showed a significantly slower decay of γH2AX foci ( P<0.001). Moreover, niraparib combined with irradiation enhanced the radiation-induced cleavage of PARP-1 and down-regulated the expression of Rad51 and p-MAPK(ERK1/2). Conclusion:Niraparib can increase the radiosensitivity of esophageal cancer cells by inhibiting cell proliferation, promoting cell apoptosis, inhibiting the repair of DNA damage and regulating the MARK-ERK signaling pathway.
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Esophageal squamous cell carcinoma (ESCC) is the most predominant pathological type of esophageal cancer in China. In recent years, with the development of molecular targeted drugs, targeted therapy has become a hot research topic in the field of ESCC treatment. Nimotuzumab is the first humanized monoclonal antibody targeting epidermal growth factor receptor (EGFR) in China, which has been approved for the treatment of early or locally advanced nasopharyngeal carcinoma. Several phase Ⅱ-Ⅲ clinical trials have explored the use of nimotuzumab in the treatment of ESCC, confirming its significant efficacy and survival benefit in the treatment of advanced ESCC, as well as its favorable safety profile.
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Most early-stage cervical cancer patients achieve good recovery through surgical treatment and concurrent chemoradiotherapy. However, for patients with recurrent, metastatic cervical cancer, the available effective treatment is rare and the prognosis is poor. In recent years, with the development of immunotherapy, especially immune checkpoint inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) , such as pembrolizumab, nivolumab, ipilimumab, has made breakthrough progress in the treatment of recurrent or metastatic cervical cancer.
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The poly ADP-ribose polymerase (PARP) is a class of nuclear enzymes highly expressed in eukaryotic cells and plays a key role in DNA damage repair. In recent years, PARP inhibitors have shown great potential in tumor therapy, and several PARP inhibitors have been approved by the FDA for maintenance therapy of a variety of cancers. PARP inhibitors mainly inhibit PARP enzymes and PARP trapping, resulting in the persistence of DNA single strand breaks, which are converted to double strand breaks during DNA replication. Studies have shown that PARP inhibitors not only have a significant anti-tumor effect, but also have a synergistic effect with radiotherapy. This paper reviewed the potential theoretical basis of PARP inhibitor combined with radiotherapy, summarized the recent progress of preclinical and clinical research on PARP inhibitors in tumor radiotherapy, sorted out the urgent problems in this field, and looked into the application prospect of PARP inhibitors in anti-tumor therapy.
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Objective:To validate the effect of TUT4 on the radiosensitivity of esophageal epithelial cells (HEEC) by regulating the uridylation of miR132/212 clusters.Methods:The expression of TUT4 in HEEC at 0, 6, 18, 24 and 48 h after 0, 2, 4, 6 and 8 Gy X-ray irradiation was detected by PCR. The HEEC cells were divided into four groups: NC group, shTUT4 group, 6 Gy group, and 6 Gy+ shTUT4 group. The effects of TUT4 on cell radiosensitivity, cell proliferation, cell cycle, mitochondrial damage, and oxygen free radical production were detected respectively. The effect of down-regulated TUT4 expression on miR132/212 uridylation was detected by RT-PCR, and the radiosensitivity of HEEC with overexpression of miR132/212 or miR132/212+ UUU was detected by clone formation and proliferation assay, respectively. Proliferation assay was performed to detect the proliferation of HEEC when TUT4 expression was down-regulated and miR132/212 or miR132/212+ UUU was overexpressed.Results:TUT4 expression increased after different doses of X-ray irradiation ( t=12.84, 62.06, 27.86, 32.43, P<0.05). Downregulation of TUT4 expression increased the radiosensitivity of HEEC ( t=13.2, 5.85, 7.31, P<0.05) with a SER D0of 1.41 and D0=0.79, Dq=1.61, SF2=0.47. Compared with 6 Gy group, cell proliferation in 6 Gy+ shTUT4 group was decreased ( t=7.12, 13.63, P<0.05), cells in S phase were increased ( t=11.98, P<0.05), mitochondrial damage was increased ( t=11.98, P<0.05), and ROS level was increased ( t=15.65, P<0.05). Down-regulation of TUT4 expression increased miR132/212 expression and decreased miR132/212+ UUU expression ( t=27.90, 60.99, P<0.05). Overexpression of miR132/212 increased the radiosensitivity of HEEC, and overexpression of miR132/212+ UUU decreased the radiosensitivity of HEEC, with SER D0 of 1.20 and 0.71, respectively. Cell proliferation of shTUT4 + miR132/212 group waslower than that of shTUT4 group( t=4.76, 7.65, P<0.05), and cell proliferation of shTUT4 + miR132/212+ UUU group was higher than that of shTUT4 ( t=7.22, P<0.05). Conclusions:X-ray irradiation increased the expression of TUT4 in HEEC, and the down-regulation of TUT4 reduced HEEC radiosensitivity and radiation damage, where the uridylation of miR132/212 was involved in.
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Objective:To analyze the prognostic factors of patients with Ⅰ B1-Ⅱ A cervical cancers after surgery and to assess the effects and adverse reactions of intensity-modulated radiotherapy(IMRT)combined with concurrent chemotherapy(CCRT). Methods:A retrospective analysis was performed based on the clinical and follow-up data of 362 patients with Ⅰ B1-Ⅱ A cervical cancers who were treated in Changzhou Second People′s Hospital from January 2009 to December 2019. Meanwhile, these patients suffered large primary tumors(LPT; tumors size: ≥4 cm), lymphatic vascular space invasion (LVSI), and deep stromal invasion(DSI; stromal infiltration depth: ≥1/2) after surgery and showed at least one intermediate-risk factor. Among these cases, 161 cases were treated with CCRT, 131 cases under-went single radiotherapy (RT), and 70 cases received unadjuvanted radiotherapy. The Kaplan-Meier method and the logrank test were adopted for univariate survival analysis, the binary logistic regression was used to analyze the recurrence risk, and Cox regression model was used for multivariate survival analysis. Results:The 3 and 5-year overall survival (OS) rates were 94.20% and 88.39%, respectively. The retrospective analysis showed that the risk factors of recurrence included tumor size ≥ 4 cm and poorly differentiated cancers( OR=3.287, 2.870, 95% CI: 1.366-7.905, 1.105-7.457, P<0.05). Compared with the treatment without adjuvant radiotherapy and RT, CCRT reduced the recurrence rate of tumors with tumor size of ≥ 4 cm, adenocarcinomas or adenosquamous carcinomas (pathological types), and poorly differentiated carcinomas( χ2=6.725-7.518, P<0.05). A multivariate analysis showed that the CCRT improved the recurrence-free survival ( HR=0.290, 95% CI: 0.128-0.659, P=0.003) and OS ( HR=0.370, 95% CI: 0.156-0.895, P=0.024). A subgroup analysis indicated that CCRT prolonged the OS of patients with tumor size ≥ 4 cm or poorly differentiated cancers compared to the patients receiving no radiotherapy or those treated with RT (χ 2=7.614, 5.964, P<0.05). Compared with the cases receiving single radiotherapy, those receiving CCRT did not suffer an increase in the incidence of hematology, radiation enteritis, and cystitis above grade 3 according to observation ( P>0.05). Conclusions:Among the intermediate-risk factors leading to the recurrence of postoperative cervical cancers, the factors of large primary tumors or poorly differentiated cancers affect the prognosis of patients.Compared with RT and the treatment without adjuvant radiotherapy, IMRT combined with concurrent chemotherapy can prolong the recurrence-free survival and overall survival of patients with large tumors or poorly differentiated cancers and adverse reactions induced are tolerable.
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Objective:To observe the effect and underlying mechanism of down-regulation of VEGFA on the radiosensitivity of esophageal cancer ECA-109 cells.Methods:Esophageal cancer cells were divided into four groups: sh-VEGFA group, vector control group, X-ray plussh-VEGFA group and X-ray plus vector group. The expressions of VEGFA gene and protein were detected by qPCR and Western blot, respectively. Cell proliferation and survival was measured by CCK8 assay and cloning formation, respectively. Cell apoptosis was detected by flow cytometry, and γ-H2AX foci were detected by immune-fluorescence assay.Results:Compared with the vector group, the expression of VEGFA gene was decreased in sh-VEGFA group ( t=11.98, P<0.05), and the expression of VEGFA protein was also reduced( t=12.38, P<0.05). After VEGFA being down-regulated, the cell proliferation( A450)was obviously inhibited( t=2.78, 7.25, 21.93, 13.21, P<0.05), and the cell clone formation of the sh-VEGFA group was significantly decreased so that D0, Dqand SF2 of sh-VEGFA group were decreased( t=5.83, 8.56, 7.68, P<0.05), and SERD0and SERDqwere increased. Compared with the vector group, the apoptosis rate in the sh-VEGFA group and the X-ray group was significantly increased and further increased in the sh-VEGFA plus X-ray group( t=17.63, 22.48, 33.87, P<0.05), and the number of γ-H2AX foci in both sh-VEGFA and vector groups were significantly increased within 2 h after X-ray irradiation. At 24 h after irradiation, the number of γ-H2AX foci returned to normal level in the vector group but remained at a higher level in the sh-VEGFA group ( t=7.00, P<0.05). Conclusions:Down-regulation of VEGFA inhibits the proliferation and colony formation, promotes apoptosis and hence increases the radiosensitivity of esophageal carcinoma cells via a pathway related to DNA damage repair.
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Objective To investigate the adverse effects and clinical efficacy of the intensive modulated radiotherapy (IMRT)and intravaginal brachytherapy combined with versus without chemotherapy in elderly patients with cervical cancer,and to analyze its prognostic factors.Methods Clinical data and follow-up results of 214 patients with cervical cancer aged ≥60 years undergoing IMRT and intravaginal brachytherapy combined with or without chemotherapy were retrospectively analyzed.The overall survival(OS) rate was calculated by using the Kaplan-Meier method.Prognostic factors were analyzed by Log-rank single factor test and Cox multivariate analysis.Results The rates of myelosuppression(≥grade 3)was higher in the concurrent chemo-radiotherapy group than in simple radiotherapy group(48.6％％ vs.15.8 ％,x2 =27.372,P ＜ 0.05).The complete response (CR)rate was higher in the concurrent chemo-radiotherapy group than in the simple radiotherapy group (83.0％ vs.68.3％,x 2=5.993,P=0.014).The 1-,3-and 5-year OS rate were 92.2 ％,79.3 ％ and 65.6 ％,respectively in all patients.Univariate analysis showed that the staging,lymph node metastasis status,pathological type and short-term efficacy of cervical cancer (based on FIGO guideline)were influencing factors for the prognosis (x2 =4.321-30.316,all P ＜ 0.05).Multivariate analysis showed that the FIGO staging,lymph node metastasis status and short-term efficacy were independent influencing factors for the prognosis(x2 =5.284-14.261,all P＜0.05).Conclusions The intensive modulated radiotherapy and intravaginal brachytherapy combined with chemotherapy have a good efficacy and favorable long-term survival rate for the treatment of cervical cancer in elderly patients,and its major adverse effects can be tolerated.The FIGO staging,lymph node metastasis status and short-term efficacy are independent influencing factors for the prognosis in elderly patients with cervical cancer.
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Objective@#To investigate the adverse effects and clinical efficacy of the intensive modulated radiotherapy(IMRT)and intravaginal brachytherapy combined with versus without chemotherapy in elderly patients with cervical cancer, and to analyze its prognostic factors.@*Methods@#Clinical data and follow-up results of 214 patients with cervical cancer aged ≥60 years undergoing IMRT and intravaginal brachytherapy combined with or without chemotherapy were retrospectively analyzed.The overall survival(OS)rate was calculated by using the Kaplan-Meier method.Prognostic factors were analyzed by Log-rank single factor test and Cox multivariate analysis.@*Results@#The rates of myelosuppression(≥grade 3)was higher in the concurrent chemo-radiotherapy group than in simple radiotherapy group(48.6% vs.15.8%, χ2=27.372, P<0.05). The complete response(CR)rate was higher in the concurrent chemo-radiotherapy group than in the simple radiotherapy group(83.0% vs.68.3%, χ2=5.993, P=0.014). The 1-, 3- and 5-year OS rate were 92.2%, 79.3% and 65.6%, respectively in all patients.Univariate analysis showed that the staging, lymph node metastasis status, pathological type and short-term efficacy of cervical cancer(based on FIGO guideline)were influencing factors for the prognosis(χ2=4.321-30.316, all P<0.05). Multivariate analysis showed that the FIGO staging, lymph node metastasis status and short-term efficacy were independent influencing factors for the prognosis(χ2=5.284-14.261, all P<0.05).@*Conclusions@#The intensive modulated radiotherapy and intravaginal brachytherapy combined with chemotherapy have a good efficacy and favorable long-term survival rate for the treatment of cervical cancer in elderly patients, and its major adverse effects can be tolerated.The FIGO staging, lymph node metastasis status and short-term efficacy are independent influencing factors for the prognosis in elderly patients with cervical cancer.
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Objective@#To investigate the adverse events and efficacy in cervical cancer patients receiving intensity modulated radiationtherapy (IMRT) plusbrachytherapy with or without chemotherapy, and to indentify the factors that may affect the prognosis.@*Methods@#In this retrospective analysis, we analyzed the clinical and follow-up data of the 422 cervical cancer patients, who received IMRT plus brachytherapy with or without chemotherapy.Among these patients, 353 cases received concurrent chemoradiotherapy and the other 69 cases received radiotherapy alone. Kaplan-Meier method was utilized to calculate the overall survival (OS) rates. Log-rank-test and Cox regression were performed to executing the univariate and multivariate analysis of the OS, respectively.@*Results@#The rate of complete response (CR) in the patients receiving concurrent chemoradiotherapy was significantly higher than that of the patients who received single radiotherapy (77.6% vs. 65.2%, χ2=4.812, P<0.05). The 1-, 3-, and 5-year OS rates were 93.4%, 79.4%, and 65.0%, respectively. Univariate analysis showed that age, Federation International of Gynecology and Obstetr(FIGO)2009 staging, lymph node metastasis, pathological type, chemotherapy experiences concurrent with radiotherapy, short-term efficiency, and sequential chemotherapy could affect the OS (χ2=6.375-613.123, P<0.05). Multivariate analysis showed that FIGO staging, lymph node metastasis, pathological type, chemotherapy experiences concurrent with radiotherapy, and the short-term efficacy were the independent determinants for the prognosis (χ2=3.930-42.994, P<0.05). For patients with positive pelvic lymph node, there were no statistical differences in the para-aortic lymph node (PALN) metastasis whether undergoing prophylactic extended field irradiation of the PALN or not(PALN metastasis rates: 6.1% vs. 16.8%, P>0.05). The OS for the patients receiving prophylactic extended field irradiation of the PALN was higher than that of patients without prophylactic radiation (χ2=3.953, P<0.05).@*Conclusions@#Cervical cancer patients receiving IMRT plus brachytherapy with or without chemotherapy had achieved promising prognosis. Prophylactic extended field irradiation of the PALN contributed to the improved OS in the patients with pelvic lymph node metastasis. FIGO staging, pathology type, lymph node metastasis, radiotherapy concurrent with chemotherapy or not, and short-term efficiency were independent factors for the prognosis.
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Objective@#To investigate the in vitro and in vivo effects of apatinib in esophageal squamous cell carcinoma and the underlying mechanisms.@*Methods@#The esophageal cancer cells, KYSE-150 and ECA-109, were divided into control group and apatinib treatment group at the concentrations of 2.5, 5, 10, 20 and 40 μmol/L respectively. All of experiments were performed in triplicate. MTT and colony formation assays were used to measure cell proliferation. Transwell assay was used to determine the migration capacity. The effect of apatinib on cell cycle and apoptosis was analyzed by flow cytometry. The expression of VEGF and VEGFR-2 was measured by real-time quantitative PCR (qRT-PCR). The concentration of VEGF in the cell supernatant was assessed by enzyme-linked immunosorbent assay (ELISA). The expression levels of MEK, ERK, p-MEK, p-ERK, JAK2, STAT3 and p-STAT3 after VEGF stimulation were detected by Western blot. Furthermore, the nude mice xenograft model was established. The tumor-bearing mice were randomly divided into control group, apatinib low dose treatment group (250 mg) and apatinib high dose treatment group (500 mg), respectively. Tumor inhibition rates of different groups were calculated. And then the expressions of VEGF and VEGFR2 were detected in xenograft tissues by immunohistochemical staining.@*Results@#In the presence of 20 μmol/L and 40 μmol/L of apatinib for 24 hours, the migration cell numbers of KYSE-150 and ECA-109 were 428.67±4.16 and 286.67±1.53 as well as 1 123.67±70.00 and 477.33±26.84, respectively, that were significantly lower than control group (P<0.05 for all). In addition, after treatment with 10 μmol/L, 20 μmol/L and 40 μmol/L of apatinib for 7 days on KYSE-150 and ECA-109, the colony formation rates were (65.12±25.48)%, (58.19±24.73)% and (29.10±22.40)% as well as (70.61±15.14)%, (61.12±17.21)% and (43.09±11.13)%, respectively. The colony formation rates of 20 μmol/L and 40 μmol/L of apatinib treatment groups were significantly lower than control group (100.00±0.00, P<0.05). The cell cycle ratio of G2/M phase and apoptosis rate of control group and 20 μmol/L apatinib group in KYSE-150 cells were (12.14±2.13)% and (3.49±0.74)% as well as (26.27±3.30)% and (15.65±1.54)%, respectively. The corresponding ratios in ECA-109 cells were (3.44±0.57)% and (6.31±1.43)% as well as (22.64±2.36)% and (49.26±1.62)%, respectively. The results show that apatinib suppressed cell cycle progression at G2/M phase and induced cell apoptosis in both KYSE-150 and ECA-109 cells (P<0.05 for all). In the presence of 20 μmol/L and 40 μmol/L of apatinib in KYSE-150 cells, the relative levels of VEGF mRNA were (42.57±10.43)% and (25.69±1.24)%, and those of VEGF-2 mRNA were (36.09±10.82)% and (13.99±6.54)%, which were all significantly decreased compared to control group (100.00±0.00, P<0.05 for all). For ECA-109 cells, the relative expression of VEGF and VEGFR2 showed similar tendency (P<0.05 for all). Moreover, after treatment with 20 μmol/L and 40 μmol/L of apatinib in KYSE-150 cells, the VEGF concentrations were (766.48±114.27) pg/ml and (497.40±102.18)pg/ml, which were significantly decreased compared to control group [(967.41±57.75) pg/ml, P<0.05)]. The results in ECA-109 were consistent (P<0.05). Furthermore, after treatment with 40 μmol/L of apatinib in KYSE-150 and ECA-109, the relative expression of p-MEK and p-ERK were 0.49±0.05 and 0.28±0.03 as well as 0.63±0.03 and 1.22±0.15, which were significantly lower than control group (1.23±0.19 and 0.66±0.07 as well as 1.03±0.20 and 1.76±0.20; P<0.05). The relative expression of STAT3, p-STAT3 in control group and experimental group were 0.96±0.15 and 0.85±0.16 as well as 0.62±0.09 and 0.36±0.13, respectively. The results showed that the protein levels of STAT3 and p-STAT3 were significantly lower than the control group (P<0.05 for all). The inhibition rates of apatinib in xenograft nude mice were 29.25% and 19.96% for 250 mg and 500 mg treatment groups. The concentration of VEGF were (25.11±4.12) pg/ml, (16.40±2.81) pg/ml and (15.04±4.88)pg/ml for control, 250 mg and 500 mg treatment groups, respectively.@*Conclusions@#Apatinib can inhibit cell proliferation, induce apoptosis and suppress migration of esophageal cancer cells in vitro and in vivo. This effect was mainly mediated via the alterations of Ras/Raf/MEK/ERK pathway and JAK2/STAT3 pathway.
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Objective: To study the mechanism of action of Danggui Shaoyao San (DSS) in the treatment of Alzheimer'sdisease (AD) from a systematic network level using network pharmacology. Methods: The active ingredients of DSS intreating AD was screened from the Traditional Chinese Medicine System Pharmacology Database (TCSMP), and thedrugs-targets-disease network was built. Target organ localization network, GO analysis and Pathway enrichmentanalysis were used for bioinformatics analysis. Results: 51 kinds of DSS active ingredients were screened by networkpharmacology, showing 377 predicted targets of active compounds. Among them, 197 targets were associated with AD, and the pharmacodynamic targets of DSS active compounds were highly enriched with AD-related signals. The pathwaywas closely related to the reduction of Aβ aggregation and inhibition of tau hyperphosphorylation and biological processessuch as anti-inflammatory and anti-apoptosis, and the mRNA expression of the targeted gene was mainly enriched in theliver, heart, and brain. Conclusion: DSS active compounds interact with multiple targets in multiple ways in a synergisticmanner, mainly to produce important therapeutic effects on AD with anti-inflammatory, anti-apoptotic, enhancingmetabolism and immune system.
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Objective@#To observe the pathological response in tumor tissues and the vascular endothelial growth factor (VEGF) changes in serum of patients with esophageal carcinoma receiving radiotherapy or concurrent chemoradiotherapy, and to investigate the relationship between these two factors and the prognosis of these patients.@*Methods@#A total of eighty-nine patients with esophageal carcinoma treating with radiotherapy or concurrent chemo-radiotherapy were prospective included. Gastroscopy and biopsy were performed at 4 week of radiotherapy to assess pathologicalresponse. VEGF serum levels were measured by double antibody sandwich avidin-biotin ELISA prior to, at 4 week of, and 1 week after radiotherapy. The relationship between pathological response in tumor tissues and VEGF serum changes and the prognosis of the patients were analyzed. The survival curve and survival rate were respectively drawn and calculated by the Kaplan-Meier method, and the Log-rank test was used for survival analysis. Multivariate Cox proportional hazard model was used to analyze the prognostic factors.@*Results@#Pathological responses were classified into two degrees: Non-CR responses (22 cases), and CR responses (67 cases). The 1-, 3- and 5-year OS rates in CR group and non-CR group were 77.6%, 46.3%, 35.2% (median OS: 30.0 months, 95%CI 14.3-45.6 months) and 50.0%, 0.0%, 0.0% (median OS: 11.4 months, 95%CI 4.2-18.6 months), respectively, showing that the OS in CR group were significantly higher than that in non-CR group (P<0.001). Meanwhile, the 1-, 3- and 5-year PFS rates in CR group and non-group were 69.7%, 40.9%, 34.3% (median PFS: 21.7 months, 95%CI 13.1-30.3 months) and 36.4%, 0.0%, 0.0% (median PFS: 7.4 months, 95%CI 2.1-12.4 months), respectively, showing that the PFS in CR group was significantly higher than that in non-CR group (P<0.001). VEGF serum changes were classified into three degrees: increased group (16 cases), stable group (43 cases) and decreased group (30 cases). The 1-, 3- and 5-year OS rates in VEGF increased group were 50.0%, 18.8%, 12.5% (median OS: 9.2 months, 95%CI 2.2-17.9 months), respectively, while the 1-, 3- and 5-year OS rates in VEGF stable group were 67.4%, 30.2%, 19.9% (median OS: 19.9 months, 95%CI 14.9-24.9 months), respectively, and the 1-, 3- and 5-year OS rates in VEGF-decreased group were 86.7%, 50.0%, 42.9% (median OS: 28.7 months, 95%CI 5.4-51.2 months), respectively, showing that the OS in VEGF-decreased group was significantly the highest among the three groups (P<0.05). The 1-, 3- and 5-year PFS rates in VEGF-increased group were 43.8%, 12.5%, 0 (median PFS: 8.0 months, 95%CI 2.5-15.9 months), respectively, while the 1-, 3- and 5-year PFS rates in VEGF stable group were 57.1%, 26.2%, 20.8% (median PFS: 15.5 months, 95%CI 10.7-20.4 months), respectively, and the 1-, 3- and 5-year PFS rates in VEGF decreased group were 76.7%, 46.7%, 39.7% (median PFS: 20.1 months, 95%CI 2.4-40.1 months), respectively, showing that the PFS in VEGF decreased group was significantly the highest among the three groups (P=0.013).@*Conclusions@#Pathological response and VEGF changing trend during radiotherapy were both closely related to prognosis of patients with esophageal carcinoma.@*Trial registration@#This clinical trial was registered in the United States Trial, ID: NCT01551641
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Objective@#To investigate the efficiency and safety of hypofractionated radiotherapy (HFR) combined with chemotherapy using paclitaxel for the treatment of esophageal cancer (EC) patients with post-operative tracheoesophageal groove lymph node (TGLN) metastasis.@*Methods@#A total of fifty-three post-operative EC patients with TGLN metastasis were randomly divided into HFR group (n=25), receiving a radiation of 60 Gy/20 fractions, and conventional fractionated radiotherapy (CFR) group (n=28), receiving a radiation of 60 Gy/30 fractions combined with chemotherapy using paclitaxel with a dosage of 50 mg once per week through tossing a coin. the adverse events and the prognosis between two groups were compared.@*Results@#The incidence of radiation esophagitis and pneumonitis (grade 3-4) between the HFR group and CFR group showed no statistically significant difference (44.0%, 25.0%, P>0.05; 16.0%, 7.1%, P>0.05). No statistical difference was noticed in the efficiency between the HFR group and the CFR group (P>0.05). The efficiency in patients with lymph node metastasis at diameters ≤2 cm was significantly higher than that with lymph node metastasis at diameters >2 cm (P<0.05). The median overall survival (OS) of the HFR group showed a significant increase compared with that of the CRF group [24.2 months (95%CI 16.2-32.1 months) vs. 11.8 months (95%CI 9.2-14.4 months)] (χ2=5.063, P<0.05). Both univariate and multivariate analysis indicated that TGLN diameter (P<0.05) and fractioned types (P<0.05) were factors that affected the prognosis.@*Conclusions@#The combination of HFR and chemotherapy contributed to the improvement of prognosis in EC patients with TGLN metastasis and there was no obvious increase in the adverse events.@*Trial registration@#Chinese clinical trial registry, ChiCTR1800016848
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Objective To evaluate the radiosensitivity effects of apatinib on the esophageal cancer cell line ECA-109 and its cancer stem-like cells,and to investigate the underlying mechanism.Methods A serum-free medium (SFM) was used to culture esophageal cancer stem cell line ECA-109 and enrich the esophageal stem-like spheres.ECA-109 and its stem-like cells were divided into control group,drug treatment group,radiation group and drug plus radiation group.Cell proliferations of ECA-109 and its stem-like cells were detected with CCK-8 method.The concentration of vascular endothelial growth factor (VEGF) in the cell culture medium was determined by enzyme linked immunosorbent assay(ELISA).Cell cycle and apoptosis were detected by flow cytometry method.The expressions of CHK2 and P-STAT3 proteins were detected by Western blot assay.Results With the administration with apatinib for 24,48 and 72 h,the half of the inhibitory concentration (IC50) of ECA-109 stem-like cells was significantly higher than that of the parent cells (t =8.17,9.29,18.85,P ＜ 0.05) in a time dependent manner (parental cells:r2 =0.94-0.97,P ＜0.05;stem-like cells:r2 =0.94-0.98,P ＜0.05).After administration with different concentrations of apatinib (parental cells:10 and 20 μmol/L;stem-like cells:30 and 40 μmol/L) combined with different dose of X-rays (6 and 8 Gy),the proliferations of ECA-109 and its stem-like cells were significantly (t =5.20-39.68,P ＜ 0.05) inhibited compared with radiation alone group.VEGF secretion from both ECA-109 cells and its stem like cells were significantly decreased in different manner (t =7.45,P ＜ 0.05).Compared with control group,the cell apoptosis rate and the percentages of cells in G2/M phase were significantly increased in drug plus radiation group (t =8.83,11.59,P ＜ 0.05),and the expressions of CHK2 and P-STAT3 were decreased in drug group (t =3.36,4.10,P ＜ 0.05).Compared with radiation group,the expressions of CHK2 and P-STAT3 were decreased in drug plus radiation group (t =9.05,2.36,P ＜ 0.05).Conclusions Apatinib enhanced the radiosensitivity of ECA-109 cells and its stem-like cells,which was much more effective on ECA-109 cells and may be related to the radiation-induced inhibition of VEGF signal pathway that can further inhibit cell proliferation,promote cell apoptosis and induce cell cycle redistribution.The higher intrinsic level of VEGF protein may contribute to radioresistance of ECA-109 stem-like cells.
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Objective To predict the tolerance range of set-up errors in clinical practice by predicting the virtual set-up errors of postoperative radiotherapy patients for breast cancer. Methods A retrospective analysis was made of the patients who underwent radiotherapy after breast cancer surgery in recent 3 years. According to different treatment method, 10 cases of breast cancer after modified radical mastectomy and 10 cases after breast conserving radical mastectomy were selected. The target area was delineated, the volume modulated radiation therapy plan was made, the virtual moving error of the center point of the plan was moved, and the maximum moving error was 5 mm by 1 mm step. After recalculating the dose, the corresponding data including the clinical target areas ( CT ) , CTV ( V50 ) , average heart volume, V20 of the affected lung and CTV volume were recorded. SPSS 19. 0 software was used for statistical analysis, and repeated measurement of variance analysis was used to analyze the changes of the actual dose in the target area after moving the center point. Linear regression analysis method was used to analyze the correlation between the CTV volume and the dose change after the CTV moving midline. Results The virtual set-up error had little influence on the axis direction of the approximate mammary tangent direction, while the vertical direction of the approximate mammary tangent direction had greater influence. After moving more than 3 mm on the vertical axis, the CTV ( V50 ) decreased to below 90％, which was lower than the general requirement for the target area of CTV. Statistical analysis of set-up errors in all directions showed that there was significant difference in dosimetric changes ( F=34. 182, 12. 877, 16. 443, 9. 846, 46. 829, 10. 122, 57. 931, P <0. 05) in all directions except the B direction of left breast set-up errors (P>0. 05). Between breast conserving surgery and modified radical mastectomy, there was little effect on target movement. Through correlation analysis, it was found that the volume of CTV in the target area of breast cancer patients was linearly related to the errors caused by the movement of B, C and B directions of left breast and right breast(F=5. 733, 18. 496, 6. 630, P<0. 05). Conclusions In postoperative radiotherapy for breast cancer, the errors perpendicular to the section of breast should be paid special attention to whether left or right breast. When the error of this direction exceeds 3 mm, CTV is obviously less than V50 below 83. 85％. The effect of set-up error on the dose of CTV was not related to the operation mode of breast cancer and there was no obvious correlation with the volume of the target area.