The Association between Epidermal Growth Factor Receptor Single Nucleotide Polymorphisms and Radiochemotherapy Response in Cervical Cancer.

Emerging data reveal that epidermal growth factor receptor (EGFR) single nucleotide polymorphisms (SNPs) can act as efficacy indicators for tumor treatment. Here, the association between EGFR R497K (rs11543848) and -216G/T (rs712829) SNPs and radiochemotherapy response in cervical cancer was investigated. EGFR R497K and -216G/T genotypes were analyzed by polymerase chain reaction-ligation detection reaction in 196 cervical cancer patients receiving radiotherapy alone, or in combination with chemotherapy. Compared with the 497G/G genotype, the A/A genotype significantly increased sensitivity to radiochemotherapy treatment (adjusted OR = 0.244, 95% CI = 0.087-0.680). Sensitivity to radiochemotherapy was not significantly different in carriers of the 'T' allele than that measured for the -216G/G genotype (adjusted OR = 2.412, 95% CI = 0.856-6.979). Additionally, the 497A/A genotype conferred a reduced risk of recurrence or metastasis than did the G/G genotype (adjusted OR = 0.248, 95% CI = 0.078-0.786, P < 0.05). Moreover, carriers of the 'T' allele did not have significantly modified risk of recurrence or metastasis compared with those with the -216G/G genotype (adjusted OR = 1.027, 95% CI = 0.324-3.253). Multivariate analysis revealed an association between clinical stage and treatment response (adjusted OR = 3.575, 95% CI = 1.662-7.692) and between age and the risk of recurrence or metastasis (adjusted OR = 0.319, 95% CI = 0.148-0.691). Our results show that, in patients with cervical cancer, the R497K polymorphism is correlated with treatment response and the risk of recurrence or metastasis. The R497K SNP might be a genetic marker for prediction of radiochemotherapy response and the risk of recurrence and/or metastasis in patients with cervical cancer.

Expression of PH Domain Leucine-rich Repeat Protein Phosphatase, Forkhead Homeobox Type O 3a and RAD51, and their Relationships with Clinicopathologic Features and Prognosis in Ovarian Serous Adenocarcinoma.

BACKGROUND: Ovarian serous adenocarcinoma can be divided into low- and high-grade tumors, which exhibit substantial differences in pathogenesis, clinicopathology, and prognosis. This study aimed to investigate the differences in the PH domain leucine-rich repeat protein phosphatase (PHLPP), forkhead homeobox type O 3a (FoxO3a), and RAD51 protein expressions, and their associations with prognosis in patients with low- and high-grade ovarian serous adenocarcinomas. METHODS: The PHLPP, FoxO3a, and RAD51 protein expressions were examined in 94 high- and 26 low-grade ovarian serous adenocarcinomas by immunohistochemistry. The differences in expression and their relationships with pathological features and prognosis were analyzed. RESULTS: In high-grade serous adenocarcinomas, the positive rates of PHLPP and FoxO3a were 24.5% and 26.6%, while in low-grade tumors, they were 23.1% and 26.9%, respectively (P < 0.05 vs. the control specimens; low- vs. high-grade: P > 0.05). The positive rates of RAD51 were 70.2% and 65.4% in high- and low-grade serous adenocarcinomas, respectively (P < 0.05 vs. the control specimens; low- vs. high-grade: P > 0.05). Meanwhile, in high-grade tumors, Stage III/IV tumors and lymph node and omental metastases were significantly associated with lower PHLPP and FoxO3a and higher RAD51 expression. The 5-year survival rates of patients with PHLPP- and FoxO3a-positive high-grade tumors (43.5% and 36.0%) were significantly higher than in patients with PHLPP-negative tumors (5.6% and 7.2%, respectively; P< 0.05). Similarly, the 5-year survival rate of RAD51-positive patients (3.0%) was significantly lower than in negative patients (42.9%; P< 0.05). In low-grade tumors, the PHLPP, FoxO3a, and RAD51 expressions were not significantly correlated with lymph node metastasis, omental metastasis, Federation of Gynecology and Obstetrics stage, or prognosis. CONCLUSIONS: Abnormal PHLPP, FoxO3a, and RAD51 protein expressions may be involved in the development of high- and low-grade ovarian serous adenocarcinomas, suggesting common molecular pathways. Decreased PHLPP and FoxO3a and increased RAD51 protein expression may be important molecular markers for poor prognosis, and RAD51 may be an independent prognosis factor, of high-grade, but not low-grade, ovarian serous adenocarcinomas.

Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases.

BACKGROUND: Due to satisfactory cytoreductive surgery combined with platinum-based chemotherapy in epithelial ovarian cancer has improved greatly, however, the relapse rate also high. In current study, we analyzed prognostic factors related to secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer. METHODS: Clinical and follow-up data from 103 patients with recurrent epithelial ovarian cancer who received secondary cytoreductive surgery and were admitted to our hospital between January 2000 and December 2008 were analyzed. RESULTS: Median survival after recurrence (RS) after the first relapse for the 103 patients was 36 months, and median overall survival (OS) was 60 months. Patients without visible residual tumors after secondary cytoreductive surgery had longer RS and OS compared to those with residual tumors ≥1 cm. The RS and OS of patients without visible residual tumors after secondary cytoreductive surgery were not significantly different compared to those with residual tumors between 0.1 and 1 cm. Patients with disease free interval (DFI) ≥ 12 months at secondary cytoreductive surgery had longer RS and OS compared to those with DFI < 12 months. Patients with one recurrent lesion had longer RS and OS compared to those with more than one lesion. CONCLUSIONS: Residual tumor at secondary cytoreductive surgery, DFI and number of lesions were independent prognostic factors for secondary cytoreductive surgery in patients with epithelial ovarian cancer. Patients with DFI ≥12 months and a single lesion had better prognosis for achieving satisfactory cytoreduction, especially the absence of visible residual tumors.

Implementation of Constant Dose Rate and Constant Angular Spacing Intensity-modulated Arc Therapy for Cervical Cancer by Using a Conventional Linear Accelerator.

BACKGROUND: Volumetric-modulated arc therapy (VMAT) can only be implemented on the new generation linacs such as the Varian Trilogy® and Elekta Synergy®. This prevents most existing linacs from delivering VMAT. The purpose of this study was to investigate the feasibility of using a conventional linear accelerator delivering constant dose rate and constant angular spacing intensity-modulated arc therapy (CDR-CAS-IMAT) for treating cervical cancer. METHODS: Twenty patients with cervical cancer previously treated with intensity-modulated radiation therapy (IMRT) using Varian Clinical 23EX were retreated using CDR-CAS-IMAT. The planning target volume (PTV) was set as 50.4 Gy in 28 fractions. Plans were evaluated based on the ability to meet the dose volume histogram. The homogeneity index (HI), target volume conformity index (CI), the dose to organs at risk, radiation delivery time, and monitor units (MUs) were also compared. The paired t-test was used to analyze the two data sets. All statistical analyses were performed using SPSS 19.0 software. RESULTS: Compared to the IMRT group, the CDR-CAS-IMAT group showed better PTV CI (0.85 ± 0.03 vs. 0.81 ± 0.03, P = 0.001), clinical target volume CI (0.46 ± 0.05 vs. 0.43 ± 0.05, P = 0.001), HI (0.09 ± 0.02 vs. 0.11 ± 0.02, P = 0.005) and D95 (5196.33 ± 28.24 cGy vs. 5162.63 ± 31.12 cGy, P = 0.000), and cord D2 (3743.8 ± 118.7 cGy vs. 3806.2 ± 98.7 cGy, P = 0.017) and rectum V40 (41.9 ± 6.1% vs. 44.2 ± 4.8%, P = 0.026). Treatment time (422.7 ± 46.7 s vs. 84.6 ± 7.8 s, P = 0.000) and the total plan Mus (927.4 ± 79.1 vs. 787.5 ± 78.5, P = 0.000) decreased by a factor of 0.8 and 0.15, respectively. The IMRT group plans were superior to the CDR-CAS-IMAT group plans considering decreasing bladder V50 (17.4 ± 4.5% vs. 16.6 ± 4.2%, P = 0.049), bowel V30 (39.6 ± 6.5% vs. 36.6 ± 7.5%, P = 0.008), and low-dose irradiation volume; there were no significant differences in other statistical indexes. CONCLUSIONS: Patients with cervical cancer treated with CDR-CAS-IMAT using Varian Clinical 23EX can get equivalent or superior dose distribution compared to those treated with IMRT. CDR-CAS-IMAT has a less treatment time and MU, which can reduce the uncertainty factor and patient discomfort in treatment.

Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway.

AIM: The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. METHODS: Male C57BL/6 mice were treated with SolB (200 mg · kg(-1) · d(-1), ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. RESULTS: SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5-20 µmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. CONCLUSION: SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.

[Relationship of XRCC1 polymorphism with the risks and clinicopathological factors of cervical cancer].

OBJECTIVE: To explore the correlation of XRCC1 Arg194Trp Arg399Gln SNPs with the risks and clinicopathological factors of cervical cancer. METHODS: Polymorphisms Arg194Trp, Arg399Gln of XRCC1 gene in 253 cervical cancer patients and 350 healthy controls were analyzed by mismatch amplification polymerase chain reaction (MAMA-PCR). RESULTS: Compared with the Arg/Arg genotypes, the Trp/Trp genotypes could increase the risk of cervical cancer (P = 0.000) . Arg/Arg was a protection factor with an odds ratio of 0.116 (95%CI = 0.043-0.316) . The frequency of Arg and Gln allele among cervical cancer and healthy controls were 56.81%, 43.19% and 64.86%, 35.14%. Compared with the Arg genotypes, the Gln genotypes could increase the risk of cervical cancer (P < 0.05) . Compared with the Arg/Arg genotypes, the Gln/Gln genotypes could increase the risk of cervical cancer (P < 0.01) . Arg/Arg was a protection factor with an odds ratio of 0.188 (95%CI = 0.089-0.398) . Using haplotypes 194Trp-399Gln as a reference, women carrying 194Arg-399Gln and 194Arg-399Arg halpotypes had a significantly decreased risk for cervical carcinoma. The adjusted OR and 95%CI were 0.613 [0.446, 0.842] and 0.635 [0.449, 0.899]. The frequencies of Arg/Arg, Arg/Gln, Gln/Gln genotype had significant relationship with clinical stage and histological grade. Tumor diameter, patient age and neoplastic form had no relationship. CONCLUSION: Compared with the Arg/Arg genotypes, the Trp/Trp and Gln/ Gln genotypes could increase the risk of cervical cancer. The Trp or Gln genotypes risk increases. Arg may be a protection factor. The frequencies of Arg399Gln SNP have a correlation with stage and histological grade.