Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib.

BACKGROUND: With the development of radiological technologies, radiotherapy has been gradually widely used in the clinic to intracranial tumours and become standardised. However, the related central nervous system disorders are still the most obvious complications after radiotherapy. This study aims to quantify the effectiveness of anlotinib, a small molecule inhibitor of multiple receptor tyrosine kinases, in mitigating acute phase of radiation-induced brain injury (RBI) in a mouse model. METHODS: The onset and progression of RBI were investigated in vivo. All mice, (except for the sham group) were irradiated at a single-fraction of 20 Gy and treated with different doses of anlotinib (0, 0.2 and 0.8 mg/kg, respectively). The expression levels of glial fibrillary acidic protein (GFAP), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) were assessed by western blot. Histological changes were identified by luxol fast blue (LFB) staining. RESULTS: The expression levels of GFAP, HIF-1α, and VEGF were downregulated following treatment with anlotinib. However, anlotinib failed to inhibit the development of demyelination. Cerebral edema [as measured by brain water content (BWC)] was also mitigated following treatment with anlotinib. CONCLUSIONS: In summary, treatment with anlotinib significantly mitigated the adverse effects of acute RBI in a dose-dependent manner by downregulating the activation of astrocytes, improving brain hypoxia, and alleviating cerebral edema.

Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer.

The brain expressed x­linked gene 1 (BEX1) is a member of the BEX family and is aberrantly expressed in many cancers. However, the clinical significance of BEX1 expression level and its role in the pathology of esophageal squamous cell cancer (ESCC) remain unknown. In the present study, we determined BEX1 expression in the tumor and adjacent normal tissues from 118 ESCC patients by immunohistochemistry and determined the proliferation and growth of ESCC cells following ectopic overexpression of BEX1 in cultured cells and in mouse­ESCC xenografts. We observed that BEX1 was downregulated in ESCC tissues compared to adjacent normal tissues, and low BEX1 expression was significantly associated with larger ESCC tumor volume (P<0.001), advanced T stage (P=0.011) and advanced clinical stage (P=0.039). Additionally, survival analysis revealed that low expression of BEX1 significantly predicted poor prognosis in patients with ESCC (P<0.001). Multivariate analysis revealed that low BEX1 expression was an independent prognostic factor of poor survival (P=0.039). In vitro analysis revealed that overexpression of BEX1 inhibited ESCC cell proliferation and colony formation. Furthermore, in vivo tumorigenesis assays revealed that ectopic overexpression of BEX1 suppressed ESCC tumor growth in mice. Further immunoblotting analysis demonstrated that BEX1 upregulation led to reduced expression and phosphorylation of NF­κB p65, indicating inhibition of the NF­κB signaling pathway by BEX1. Our findings indicated that low BEX1 expression may be an independent prognostic marker for poor survival and may serve as a potential target for ESCC therapy.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

[Treating Radiation Peumonitis by Zlyin Huoxue Granule Combined Glucocorticoids and Antibiotics: a Clinical Observation].

OBJECTIVE: To observe the clinical effect of Ziyin Huoxue Granule (ZHG) combined glucocorticoids and antibiotics in treatment of radiation pneumonitis. METHODS: Totally 70 radiation pneumonitis patients were assigned to the treatment group and the control group according to random digit table, 35 in each group. All patients received glucocorticoids and antibiotics. Patients in the treatment group additionally took ZHG, one dose per day for 4 successive weeks. Watters clinical-radiologic-physiologic (CRP) score, Karnofsky Performance Status Scale (KPS) , and acute radiation injury classification [set by Radiation Therapy Oncology Group (RTOG)] were observed in the two groups before and after treatment. The application time for antibiotics and glucocorticoids was compared between the two groups. RESULTS: All patients completed this trial, and nobody dropped out or died. There was no statistical difference in Watters-CRP scores, KPS, or RTOG between the two groups before treatment (P > 0.05). Compared with before treatment in the same group, RTOG classification was obviously improved in the two groups (P < 0.05). Compared with the control group, Watters-CRP scores decreased, KPS increased, the application time for antibiotics and glucocorticoids was reduced (P < 0.05). The efficacy of RTOG classification was better in the treatment group than in the control group, but with no statistical difference between the two groups (P > 0.05). CONCLUSION: ZHG combined glucocorticoids and antibiotics was superior in treating radiation pneumonitis to using glucocorticoids or antibiotics alone in elevating Watters-CRP scores, shortening the application time for glucocorticoids and antibiotics, and improving patients' physical conditions.

Radiation dose is associated with prognosis of small cell lung cancer with superior vena cava syndrome.

Approximately 10% of small cell lung cancer (SCLC) cases develop superior vena cava syndrome (SVCS). Many SCLC patients with SVCS have relatively limited disease, requiring curative rather than palliative treatment. Besides chemotherapy, radiotherapy is important for treating SCLC with SVCS. We retrospectively evaluated the influence of radiotherapy dose on the prognosis of 57 patients with SCLC with SVCS treated with concurrent chemoradiotherapy. The mean biological equivalent radiation dose was 71.5 Gy. We administered etoposide/cisplatin as sequential and concurrent chemotherapy. All patients received at least one cycle of concurrent chemotherapy. All patients had partial or complete response; SVCS-associated symptoms were reduced in 87.7% (50/57) of patients within 3-10 days after treatment. Radiation dose did not affect 2-year local control (74.2% vs. 80.8%). Patients who received high-dose radiation had a lower 2-year overall survival rate than those who received low-dose radiation (11.6 vs. 33%; P = 0.024). The high dose group median survival was 15.0 months (95% confidence interval [CI]: 11.2-19.0) compared with 18.7 months (95% CI: 13.9-23.6) in the low dose group. Grade 3/4 neutropenia occurred in 22/26 high dose patients (84.6%) and 21/31 low dose patients (67.7%). In the high dose group, 30.8% of patients had grade 3/4 esophagitis compared with 19.4% of low dose patients. Only 29.0% of low dose patients received < 4 cycles of chemotherapy in the first 12 weeks after treatment began compared with 46.2% of high dose patients. Concurrent chemoradiotherapy is a tolerable modality for treating stage IIIA/IIIB SCLC with SVCS. Moderate-dose radiotherapy is preferable.

A phase II trial of post-operative chemoradiotherapy for completely resected gastric cancer with D2 lymphadenectomy.

The optimal post-operative adjuvant treatment for completely resected gastric cancer with D2 lymphadenectomy remains controversial. The present study was a phase II trial on post-operative chemoradiotherapy in 30 patients with gastric cancer. Patients with stage II to IV (M0) gastric cancer received two cycles of chemotherapy prior to and following chemoradiotherapy. The chemotherapy consisted of a 2-h infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2), which was followed by a 46-h continuous infusion of 5-fluorouracil (5-FU; 2,400 mg/m2) through a portable pump, repeated every 3 weeks. The chemoradiotherapy consisted of 45 Gy of radiotherapy for 5 weeks and 5-FU continuous infusion (350 mg/m2/day). In total, 30 patients were enrolled in this study. All patients underwent the chemoradiotherapy treatment as planned. A total of 10 (33.3%) patients relapsed; two (6.7%) locoregional relapses and mediastinum metastases, four (13.3%) peritoneal relapses, and four (13.3%) distant metastases. The three-year overall survival and disease-free survival rates were 72.7 and 65%, respectively. The toxicities of chemotherapy and radiotherapy, consisting of neutropenia, nausea and hand-foot syndrome, were observed. In conclusion, post-operative chemoradiotherapy following complete resection of gastric cancer with D2 lymphadenectomy is feasible in a significant subset of patients.

MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4.

BACKGROUND: Overexpression of microRNA-182 (miR-182) is found in various human cancers, including non-small cell lung cancer (NSCLC). Our aim is to investigate the association of miR-182 expression with the sensitivity of NSCLC to cisplatin. METHODS: TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-182 and programmed cell death 4 (PDCD4) protein. miR-182 and (or) PDCD4 depleted cell lines were generated using miR-182 inhibitor and (or) siRNA. The viabilities of treated cells were analyzed using MTT assay. RESULTS: The expression level of miR-182 in A549 cell line was significantly higher than that in NHBE cell line (p < 0.01). Transfection of miR-182 inhibitor induced sensitivity of A549 cells to cisplatin. A549 cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-182 inhibitor using Western blot analysis. In addition, the enhanced growth-inhibitory effect by miR-182 inhibitor was weakened after the addition of PDCD4 siRNA. CONCLUSIONS: The results of the present study demonstrated that overexpression of miR-182 may involve in chemoresistance of NSCLC cells to cisplatin by down-regulating PDCD4. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793467320130186.

A phase II study of preoperative chemotherapy with modified FOLFOX6 followed by surgery and postoperative chemoradiation in patients with localized gastric adenocarcinoma.

The optimal neoadjuvant and adjuvant treatment for gastric cancer remains controversial. We conducted a phase II study using preoperative chemotherapy with modified FOLFOX6 followed by surgical resection and postoperative chemoradiation in patients with gastric carcinoma. Preoperative chemotherapy (two or three cycles) consisted of a 2-h infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46-h continuous infusion of 5-fluorouracil (5-FU; 2,400 mg/m2). Surgical resection was planned 4 weeks after the last chemotherapy cycle. Patients underwent postsurgical chemoradiation, receiving a total dose of 45 Gy and 5-FU continuous infusion (350 mg/m2/day). The primary end points were feasibility, overall response rate, and R0 resectability rate after preoperative chemotherapy. The secondary end points were tolerability, treatment-associated complications, disease-free survival, and overall survival. Nineteen patients were enrolled in this study. After neoadjuvant treatment, four patients (21.1%) experienced progressive disease, six patients (31.6%) showed partial remission, and nine patients (47.3%) showed stable disease. In 15 patients (78.9%) R0 resectability could be achieved. Eleven of these patients (73.3%) were able to undergo postoperative chemoradiation. Notably, eight (72.7%) of these patients were disease free and alive at median follow-up of 60 months. Chemotherapy associated neutropenia, neutropenic fever, and anastomotic dehiscence were observed. The combination of preoperative chemotherapy and postoperative chemoradiation is feasible in a significant subset of gastric cancer patients.

High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma.

p53 and microtubule-associated protein 1 light chain 3A (LC3A) are regulators of apoptosis and autophagy and are expressed at high levels in a number of human tumors. The purpose of the current study was to evaluate the clinicopathological and prognostic significance of p53 and LC3A expression levels in esophageal squamous cell carcinomas (ESCCs). p53 and LC3A expression levels were measured by immunohistochemistry in 114 patients with stage II/III (Tany N+M0 or T3,4 Nany M0) ESCCs treated with surgery followed by adjuvant concurrent chemoradiotherapy. The overexpression of p53 and LC3A was observed in 57 and 54% of ESCC samples, respectively. p53 staining was nuclear and LC3A was localized to the cytoplasm of tumor cells. p53 overexpression was more frequently observed in ESCCs with positive lymph nodes (P=0.017). Patients with ESCCs overexpressing p53 and LC3A were associated with a lower 5­year overall survival rate than those with low p53 and LC3A expression (18.0 vs. 54.4%; P=0.001). Univariate and multivariate analyses revealed that the overexpression of p53 or LC3A was not associated with poor patient outcome (P>0.05). However, patients with high levels of p53 and LC3A co-expression had poor clinical prognoses (P=0.027). Thus, p53 and LC3A co-expression is an independent prognostic marker for patients with ESCC.