Development and verification of a hypoxia- and immune-associated prognosis signature for esophageal squamous cell carcinoma.

Background: Esophageal cancer is one of the most common gastrointestinal malignancies worldwide, with high morbidity and mortality in China. The clinical importance of the interaction between hypoxia and immune status in the tumor microenvironment has been established in esophageal squamous cell carcinoma (ESCC). This study aims to develop a new hypoxia- and immune-based gene signature to predict the survival of ESCC patients. Methods: The RNA-sequencing and clinical data of 173 cases of ESCC and 271 normal tissues were obtained from The Cancer Genome Atlas (TCGA) data portal and the Genotype-Tissue Expression (GTEx) database. Hypoxia-related genes (HRGs) and immune-related genes (IRGs) were retrieved from publicly shared data. Differentially expressed gene (DEG) analyses were carried out by the DESeq2 method using the edgeR package in R. Based on the intersection of the DEGs and HRGs/IRGs, differentially expressed HRGs (DEHRGs) and differentially expressed IRGs (DEIRGs) were obtained. DEHRGs and DEIRGs associated with prognosis were evaluated using univariate Cox proportional hazards analysis. A prognostic risk score model was constructed according to the genes acquired through Cox regression. Univariate analysis and Cox proportional hazards analysis were used to determine the independent prognostic factors related to prognosis. A nomogram was developed to predict the 1-, 2-, and 3-year overall survival (OS) probability. Results: A total of 73 intersecting genes were obtained as DEHRGs and a total of 548 intersecting genes were obtained as DEIRGs. The risk score was established using 8 genes (FABP7, TLR1, SYTL1, APLN, OSM, EGFR, IL17RD, MYH9) acquired from univariate Cox analysis. Based on this 8-gene-based risk score, a risk prognosis classifier was constructed to classify the samples into high- and low-risk groups according to the median risk score. The nomogram model was constructed to predict the OS of ESCC patients. Conclusions: The hypoxia- and immune-based gene signature might serve as a prognostic classifier for clinical decision-making regarding individualized management, follow-up plans, and treatment strategies for ESCC patients.

Pattern of distant metastases and predictive nomograms in colorectal mucinous adenocarcinoma: a SEER analysis.

BACKGROUND: We evaluated the metastatic patterns and explored the prognostic value of distant metastasis pattern in patients with metastatic colorectal mucinous adenocarcinoma (MC) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Between 2010 and 2015, newly diagnosed colorectal MC patients were selected using the SEER database. Patient prognosis was compared based on the clinicopathological parameters, treatment method, and the site and number of metastatic organs. Cox analyses were used to identify factors associated with overall survival (OS). A nomogram was built to predict the patient's survival. Harrell's concordance index (c-index) and calibration curves were used to analyze the discriminative ability of the prognostic factors. RESULTS: Of 3,088 patients diagnosed with colorectal MC, the liver was the only metastatic organ in 78.4% (997/1,271) of all liver metastasis cases, the lung was the only metastatic organ in 41.0% (164/400) of all lung metastasis cases, bone was the only metastatic organ in 26.6% (29/109) of all bone metastasis cases, and the brain was the only metastatic organ in 23.5% (4/17) of all brain metastasis cases. Compared with the untreated cases, those treated with chemotherapy, surgery, and radiotherapy had better OS (P<0.001). There were marked OS differences (P<0.001) between patients with and without liver and bone metastases. Patients with bone metastasis had the best survival, while those with brain metastasis had the worst survival (P<0.001). Patients with one metastatic site had better prognosis compared to those with two or three (P<0.001). Patients with liver metastasis had the best survival, while those with bone and brain metastasis had the worst survival (P<0.001). Multivariate analysis showed that age <65 years, non-black race, grade I, N0 stage, chemotherapy, radiation, surgery, liver metastasis, and bone metastasis were independent prognostic factors. A nomogram was constructed to predict survival probability. The c-index value was up to 0.745. The calibration plot showed that the nomogram was clinically useful. CONCLUSIONS: Metastatic MC (mMC) patients had a characteristic distant metastasis pattern. This study constructed a new and sufficiently accurate prognostic model of mMC based on population-based data. These findings can be utilized to predict prognosis and guide mMC patient management.

Fractionated Stereotactic Radiation Therapy Using Volumetric Modulated Arc Therapy in Patients with Solitary Brain Metastases.

PURPOSE: To analyze retrospectively the clinical efficacy and safety for patients treated with fractionated stereotactic radiation therapy (FSRT) using volumetric modulated arc therapy. METHODS: Between 2016 and 2017, 46 patients with solitary brain metastasis who underwent FSRT consisting of 25-40 Gy/5 fractions were recruited in this study. All targets within the same course received different prescriptions according to size. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up was 11 months (3-53 months). The 6-month and 12-month local control rate calculated by Kaplan-Meier estimate was, respectively, 95% and 86%. Tumor diameter < 2.5 cm obtained 100% improved 12-month local control rate compared with 66% in those with ≥2.5 cm (P < 0.001). The 12-month local control calculated by Kaplan-Meier estimate was 95% in tumors with >30 Gy treatment and only 60% in tumors with ≤30 Gy treatment (P = 0.001). Multivariate analysis revealed that the prescription dose ≤ 30 Gy resulted in increased local failure (hazard ratio (HR), 0.14 (range, 0.019-0.95; P = .046)). Grade 3 or worse toxic effects were found in 5 (11%) patients, and no patient experienced surgical resection for symptomatic radioactive necrosis. CONCLUSIONS: FSRT for solid brain metastasis appears to have the advantages of a high rate of local control with a minimal risk of severe toxicity and deserves application in the clinical practice.

Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer.

PURPOSE: This study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. MATERIALS AND METHODS: Lewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed. RESULTS: For the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen-specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved. CONCLUSION: Our results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials.

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.

miR­497 suppresses malignant phenotype in non­small cell lung cancer via targeting KDR.

The aim of the present study was to evaluate the expression of microRNA­497 (miR­497) in non­small cell lung cancer (NSCLC) tissues and cell lines, and to investigate possible mechanisms associated with its regulatory role on cell behaviors. The expression level of miR­497 was evaluated in 15 cases of NSCLC tissues and 8 adjacent normal tissues, and in 8 NSCLC cell lines, including H1975, A549, H358, H1650, H460, Calu­1, H1299 and H292, by reverse transcription­quantitative polymerase chain reaction. Effects of miR­497 overexpression on cell proliferation, invasion, apoptosis and radiosensitivity were examined with a Cell Counting Kit­8 assay, Matrigel assay, flow cytometry and a clone formation assay in vitro, respectively, and in an in vivo ectopic tumor nude mice model. A dual luciferase reporter assay was employed for interaction between miR­497 and its target gene kinase insert domain receptor (KDR). A significantly decreased level of miR­497 was determined in NSCLC tissues, compared with adjacent normal tissues, and Calu­1 and H1975 exhibited the lowest miR­497 expression among the 8 NSCLC cell lines. miR­497 overexpression could inhibit cell proliferation and invasion, promote cancer cell apoptosis and decrease cell clone formation following radiation treatment in vitro, and decrease tumor growth in vivo. Furthermore, a dual luciferase reporter assay revealed that KDR as the target gene for miR­497. It was demonstrated that miR­497 was downregulated in NSCLC specimens. Additionally, miR­497 directly targeted and downregulated KDR expression, and inhibited malignant behaviors of NSCLC cells. These data indicated that miR­497 could serve as a tumor suppressor gene involved in NSCLC pathogenesis.

Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells.

BACKGROUND: The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive. METHODS: Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA. RESULTS: Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect. CONCLUSION: Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

Apatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer: a case report.

The first-line treatment for metastatic esophageal squamous cell cancer (ESCC) is a platinum- or fluorouracil-based agent, followed by later treatment with taxanes or irinotecan. However, there is still no standard third-line treatment for patients with metastatic ESCC. We present a 62-year-old man initially diagnosed with locally advanced ESCC. After esophagectomy, the patient was administrated with six cycles of docetaxel and cisplatin combined with radiotherapy. After 8.0 months, computed tomography showed the left cervical lymph node metastasis. However, the metastatic lymph node was not significantly shrunk after locally palliative radiotherapy and the patient was intolerant of irinotecan as second-line systemic therapy. Then, the patient was rechallenged with six cycles of docetaxel combined with apatinib (an oral tyrosine kinase inhibitor to vascular endothelial growth factor receptor 2 [VEGFR2]), followed by single dose of apatinib as maintenance therapy. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard, partial response was achieved in this case after treating with docetaxel combined with apatinib. Now, the progression-free survival of this patient has been 7.5 months. After administrating with apatinib for 2 weeks, hypertension (grade III) was observed. Thus, the dose of apatinib was decreased from 850 to 500 mg and then the adverse effects were controllable and tolerable. In conclusion, apatinib with concurrent docetaxel provided potential efficacy as a salvage treatment for patients with metastatic ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.

Role of the NRP-1-mediated VEGFR2-independent pathway on radiation sensitivity of non-small cell lung cancer cells.

PURPOSE: To determine if inhibiting neuropilin-1 (NRP-1) affects the radiosensitivity of NSCLC cells through a vascular endothelial growth factor receptor 2 (VEGFR2)-independent pathway, and to assess the underlying mechanisms. METHODS: The expression of VEGFR2, NRP-1, related signaling molecules, abelson murine leukemia viral oncogene homolog 1 (ABL-1), and RAD51 were determined by RT-PCR and Western blotting, respectively. Radiosensitivity was assessed using the colony-forming assay, and the cell apoptosis were analyzed by flow cytometry. RESULTS: We selected two cell lines with high expression levels of VEGFR2, including Calu-1 cells that have high NRP-1 expression, and H358 cells that have low NRP-1 expression. Upon inhibition of p-VEGFR2 by apatinib in Calu-1 cells, the expression of NRP-1 protein and other related proteins in the pathway was still high. Upon NRP-1 siRNA treatment, the expression of both NRP-1 and RAD51 decreased (p < 0.01; p < 0.05). Upon ABL-1 siRNA treatment, the expression of NRP-1 was increased and the expression of RAD51 was unchanged. Calu-1 cells treated with NRP-1 siRNA exhibited significantly higher apoptosis and radiation sensitivity in radiation therapy compared to Calu-1 cells treated with apatinib alone (p < 0.01; p < 0.01). The apoptosis and radiation sensitivity in H358 cells with NRP-1 overexpression was similar to the control group regardless of VEGFR2 inhibition. CONCLUSIONS: We demonstrated that when VEGFR2 was inhibited, NRP-1 appeared to regulate RAD51 expression through the VEGFR2-independent ABL-1 pathway, consequently regulating radiation sensitivity. In addition, the combined inhibition of VEGFR2 and NRP-1 appears to sensitize cancer cells to radiation.

A Pilot Study of Apatinib as Third-Line Treatment in Patients With Heavily Treated Metastatic Colorectal Cancer.

BACKGROUND: Antiangiogenic therapy has shown improved clinical outcome in metastatic colorectal cancer (mCRC). After the failure of standard treatments, regorafenib and TAS-102 would be recommended for patients with mCRC, however, they have not been approved in China during this study period. PATIENTS AND METHODS: This pilot study aimed to assess the efficacy and safety of apatinib, a novel oral inhibitor targeting vascular endothelial growth factor receptor 2, as third-line treatment for patients with mCRC refractory to standard therapies. In this retrospective study, all patients received apatinib treatment until progressive disease (PD), death, unacceptable toxicity, and curative surgery. The dose or treatment schedule was modified according to the physician's discretion according to the toxicity profiles. RESULTS: Between March 2015 and June 2017, 36 patients were enrolled and eligible for evaluation of the safety and efficacy. One patient (2.8%) achieved complete response, 3 (8.3%) achieved partial response, 24 (66.7%) achieved stable disease, and 8 (22.2%) PD. The objective response rate and the disease control rate were 11.1% (4 of 36), and 77.8% (28 of 36), respectively. Moreover, the median overall survival (OS) since the initiation of first-line treatment was 33.2 months. The median progression-free survival (PFS) and median OS from apatinib treatment were 4.8 and 10.1 months, respectively. Intergroup analysis showed that there was no significant difference in median PFS and median OS between patients who were previously treated with and without bevacizumab. The most common Grade 3 to 4 adverse reactions were hand-foot syndrome, hypertension, and proteinuria. CONCLUSION: Our results suggested that apatinib was active as a third-line treatment of refractory mCRC with a manageable tolerability profile. In addition, preliminary data suggested that the efficacy of apatinib would not be affected by previous bevacizumab treatment. Further prospective randomized controlled clinical trials are urgently needed.

Raf1 is a prognostic factor for progression in patients with non­small cell lung cancer after radiotherapy.

Raf-1 proto-oncogene, serine/threonine kinase (Raf1) acts as a part of the RAS/RAF/MEK/ERK signaling pathway and regulates cell migration, apoptosis and differentiation. However, few studies are available on the expression and clinical significance of Raf1 in non­small cell lung cancer (NSCLC). This study investigated the clinical value and prognostic significance of Raf1 in NSCLC patients, following radiotherapy. We evaluated the Raf1 expression using immunohistochemical analyses of samples from 110 NSCLC patients who received radiotherapy. The association between Raf1 expression and clinicopathological variables was also analyzed. The multivariate Cox proportional hazard model was used to determine the prognostic value of Raf1 in regards to progression and 3­year survival. Significant associations between Raf1 expression and invasion and metastasis capability in lung cancer A549 and H1299 cell lines were identified. Results showed that 44.5% (49/110) of the NSCLC patient specimens demonstrated Raf1 expression, which was found to be positively correlated with lymph node metastasis (P=0.014), T stage (P=0.038) and poor histological differentiation (P=0.029). Later progression was observed in patients with negative or low Raf1 expression than in patients with high Raf1 expression (P=0.002). The multivariate analysis indicated that Raf1 is an independent prognostic factor for time to progression (TTP) (HR, 1.94; 95% CI, 1.16­3.25; P=0.01). A high Raf1 expression was found to result in a poor 3­year overall survival (OS)(HR, 1.64; 95% CI, 0.98­2.75; P=0.06). Raf1 overexpression was correlated with early progression in NSCLC. Raf1 may serve as a novel prognostic factor and potential target for improving the long­term outcome of NSCLC patients.

A pilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical Trial/Experimental Study.

BACKGROUND: Malignant glioma is the most common primary malignant brain tumor that displays high vascularity, making vascular endothelial growth factor receptors become promising targets. This study was conducted to evaluate the efficacy and safety of apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeted vascular endothelial growth factor receptor 2, combined with irinotecan, in patients with recurrent malignant glioma. METHODS: Ten patients with recurrent malignant glioma who were experiencing relapse after treatment of temozolomide were enrolled in this study. They received oral apatinib (500 mg qd) in conjunction with irinotecan (340 mg/m or 125 mg/m depending on use of enzyme-inducing antiepileptic drugs) for 6 cycles. After that the patients continued to take apatinib as maintenance. Dosage adjustment occurred in only 3 (30.0%) patients. RESULTS: Among the 10 patients, 9 were available for the efficacy evaluation. There were 5 with partial response, 2 with stable disease and 2 with progressive disease. The objective response rate and the disease control rate (DCR) were 55% (5/9) and 78% (7/9), respectively. The median progress free survival time was 8.3 months. As for safety analysis, the most 3 common adverse events were gastrointestinal reaction (31.8%), hypertension (22.7%), and myelosuppression (18.0%). CONCLUSION: Apatinib combined with irinotecan seems to be a promising therapeutic option for recurrent malignant glioma patients. Perspective clinical studies with adequate sample size are required to validate our results. TRIAL REGISTRATION: NCT02848794 /Ahead-BG306.

Protein salvador homolog 1 acts as a tumor suppressor and is modulated by hypermethylation in pancreatic ductal adenocarcinoma.

Salvador (SAV) is a gene product that contains two protein-protein interaction modules known as WW domains and is believed to act as a scaffolding protein for Hippo and Warts. SAV1 is the human homolog of Salvador, which is the most well characterized upstream signaling component of Hippo pathway. Although its role in some tumors is known, SAV1 function in other types of tumors, including pancreatic tumor, is still obscure. Here, we determined the role of SAV1 in pancreatic ductal adenocarcinoma (PDAC) development and progression. Our results revealed that SAV1 suppressed expression promoted PDAC invasion and migration, and repressed pancreatic cancer cells apoptosis. Moreover, SAV1 was silenced by hypermethylation. Thus, SAV1 worked as a cancer suppressor and it might be considered as a target for pancreatic cancer therapy.

CD44+CD24+ subset of PANC-1 cells exhibits radiation resistance via decreased levels of reactive oxygen species.

Emerging evidence has suggested that pancreatic adenocarcinoma is sustained by pancreatic cancer stem cells. The present study aimed to investigate the expression patterns of the pancreatic cancer stem cell surface markers cluster of differentiation CD44 and CD24 in a pancreatic adenocarcinoma cell line, and to investigate the possible mechanisms for their radiation resistance. Flow cytometry was used to analyze the expression patterns of CD44 and CD24 in the pancreatic adenocarcinoma PANC-1 cell line. In addition, a multi-target click model was used to fit cell survival curves and determine the sensitizer enhancement ratio. The apoptosis and cycle distribution of the four cell subsets was determined using flow cytometry, and the level of reactive oxygen species (ROS) was determined using the 2',7'-dichlorofluorescin diacetate probe. The present results identified that the ratios of CD44+ and CD24+ in the sorted PANC-1 cell line were 92.0 and 4.7%, respectively. Prior to radiation, no statistically significant differences were observed among the four groups. Following treatment with 6 MV of X-rays, the rate of apoptosis was decreased in the CD44+CD24+ group compared with other subsets. The percentage of G0/G1 cells was highest in the CD44+CD24+ group compared with the three other groups, which exhibited increased radiosensitivity. In addition, the level of ROS in the CD44+CD24+ group was reduced compared with the other groups. In summary, the results of the present study indicated that CD44+CD24+ exhibited stem cell properties. The lower level of ROS and apoptosis in CD44+CD24+ cells may contribute to their resistance to radiation in pancreatic adenocarcinoma.

Apatinib concurrent gemcitabine for controlling malignant ascites in advanced pancreatic cancer patient: A case report.

RATIONALE: Malignant ascites (MA) is one of the poor prognostic factors for advanced pancreatic cancer and can bring about serious symptoms. The improvement of quality of life for patients is priority. However, there is no standard method for the treatment for pancreatic cancer-mediated MA. Apatinib is a novel and highly selective tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. There are no reports of concurrent apatinib with gemcitabine in patients with pancreatic cancer-mediated MA. PATIENT CONCERNS: Herein, we presented a 64-year-old man patient who visited hospital due to abdominal pain for 1 month. DIAGNOSES: He was initially diagnosed with pancreatic cancer and his first symptom was MA. INTERVENTIONS: After failing in tube drainage and gemcitabine therapy, the patient received gemcitabine combined apatinib orally and after administrated 1 month, the MA was evaluated as nearly clear response according to the RECIST 1.1 standard, and without further need of paracentesis. The CEA and CA199 reached the lowest level after administrating for 2.5 months during the treatment process. OUTCOMES: 10.5 months following apatinib administration, the patient achieved a progression-free survival for more than 11 months. Hypertension (grade IV), hand-foot syndrome (grade I) and proteinuria (grade II) were observed. LESSONS: It indicated that apatinib concurrent gemcitabine may be a superior choice for pancreatic cancer-mediated MA. Further clinical trials required to confirm its efficacy and safety.

Mean platelet volume provides beneficial diagnostic and prognostic information for patients with resectable gastric cancer.

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related mortalities worldwide. Platelets play an important and multifaceted role in cancer progression. Elevated mean platelet volume (MPV) detected in peripheral blood has been identified in various types of cancer. In the present study, we investigated the application value of MPV in early diagnostic and prognostic prediction in patients with resectable gastric cancer. In total, 168 patients with resectable gastric cancer were included and separated into the gastric cancer and healthy control groups according to median pre-operatic MPV value (MPV low, <10.51 or MPV high, ≥10.51). The results showed that the pre-operatic MPV level was significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operatic MPV level correlated with improved clinicopathological features, including decreased depth of invasion, less lymphonodus metastasis and early tumor stage. The Kaplan-Meier plots showed that the patients with higher pre-operatic MPV had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant decrease in the MPV level. The patients whose MPV level decreased following surgery had an improved OS. Multivariate Cox regression analysis revealed that the depth of invasion, lymphonodus metastasis, American Joint Committee on Cancer (AJCC) stage, and changes in MPV following surgery were prognostic factors affecting OS, and the AJCC stage and pre-operatic MPV were prognostic factors affecting DFS. In conclusion, MPV measurement can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer.

BACKGROUND: Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related deaths worldwide. China has a high incidence of gastric cancer. Inflammation is a critical component of tumor progression. It has been widely accepted that gastric cancer is an inflammation-driven cancer. In this study, we investigated the application value of systemic inflammatory response (SIR) markers, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR), in early diagnosis and prognostic prediction in patients with resectable gastric cancer. MATERIALS AND METHODS: One hundred and sixty-two patients with resectable gastric cancer were included and separated into groups according to median pre-operative PLR or NLR values (PLR low: < 208 or PLR high: ≥ 208, and NLR low: < 4.02 or NLR high: ≥ 4.02, respectively). To evaluate the changes in PLR or NLR values after operation, we introduced the concept of postpre-operative PLR or NLR ratios (< 1 indicated PLR or NLR values were decreased after operation, while ≥ 1 suggested not decreased PLR or NLR values). RESULTS: Pre-operative PLR and NLR levels were significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operative PLR and NLR levels correlated with better clinicopathological features, including decreased depth of invasion, less lymph node metastasis and early tumor stage. Kaplan-Meier plots illustrated that higher pre-operative NLR and PLR had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant CONCLUSIONS: PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

MiR-145, a microRNA targeting ADAM17, inhibits the invasion and migration of nasopharyngeal carcinoma cells.

MiR-145 is downregulated and functions as a tumor suppressor in many malignancies. In this study, the biological function, molecular mechanism, and direct target genes of miR-145 in nasopharyngeal carcinoma (NPC) cells were investigated. Cell survival was detected by cell viability assay, and cell cycle was determined through flow cytometry. Invasion and migration of NPC cells were examined using cell invasion and wound healing assays, respectively. A disintegrin and metalloproteinase 17 (ADAM17) was verified as the target of miR-145 through luciferase reporter assay, qRT-PCR, and Western blot analysis. In NPC cell lines, miR-145 expression was significantly downregulated and ADAM17 protein expression was upregulated. ADAM17 was downregulated at the post-transcriptional level by miR-145 via the binding site of ADAM17-3'UTR. Transfection with miR-145 mimic suppressed cell growth and induced cell cycle arrest in the G0/G1 phase by upregulating key G0/G1 phase regulators, namely, p53 and p21. MiR-145 also inhibited cellular migration and invasion through targeting ADAM17 involving the regulation of EGFR and E-cadherin. Knockdown of ADAM17 elicited similar effects to that of miR-145 on NPC cells. This study reveals that miR-145 suppressed the invasion and migration of NPC cells by targeting ADAM17. Thus, miR-145 could be a therapeutic target for NPC.

Downregulating HMGA2 attenuates epithelial-mesenchymal transition-induced invasion and migration in nasopharyngeal cancer cells.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is associated with invasion and metastasis of cancer cells. High-mobility group AT-hook 2 (HMGA2) has been found to play a critical role in EMT in a number of malignant tumors. However, whether HMGA2 regulates the EMT in human nasopharyngeal carcinoma (NPC) is unclear. OBJECTIVE: The aim of this study was to investigate the effect and mechanism of HMGA2 in inducing invasion and migration in NPC. METHODS: In NPC tissues samples, the association of HMGA2 mRNA expression with clinicopathological characteristics were estimated by real-time quantitative RT-PCR(qRT-PCR). In vitro, following the silencing of HMGA2 in CNE-1 and CNE-2 cell lines, the viability and metastatic ability were analyzed using Cell Counting Kit-8 (CCK8), colony formation assay, and transwell assay. EMT and transforming growth factor-beta (TGFß)/Smad3 signaling pathway-related protein expression changes were evaluated using western blot. RESULTS: HMGA2 was upregulated in NPC cell lines and clinical specimens (P < 0.01), and HMGA2 expression correlated significantly with metastasis (P = 0.02) and disease-free survival of NPC (hazard ratio: 3.52; 95% confidence interval: 1.34-7.79; P = 0.01). In addition, following in vitro knockdown of HMGA2, the aggressiveness of cells was markedly inhibited, Vimentin and Snail level was downregulated and E-cadherin expression was upregulated. Moreover, the expression of key proteins TGFßRII and p-Smad3 of the TGFß/Smad3 signaling pathway was inhibited by the downregulation of HMGA2. CONCLUSION: HMGA2 might maintain EMT-induced invasion and migration through the TGFß/Smad3 signaling pathway in NPC cell lines.

HMGA2 is associated with epithelial-mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma.

OBJECTIVE: High-mobility group protein 2 (HMGA2) and epithelial-mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis. However, the clinical significance of HMGA2 and its relationship with EMT markers in nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the clinicopathological significance and prognostic value of HMGA2, E-cadherin, and vimentin in NPC. METHODS: Using immunohistochemistry, HMGA2, E-cadherin, and vimentin expression levels were evaluated in NPC (n=124) and non-tumoral inflammatory nasopharynx (n=20) tissues. The association of HMGA2 and EMT markers with clinicopathological characteristics and relationships between the protein levels and overall survival were analyzed. RESULTS: Compared with non-tumorous tissues, HMGA2 and vimentin levels were markedly increased in NPC tissues, whereas decreased E-cadherin levels were observed (P<0.001). Moreover, HMGA2 expression was positively correlated with vimentin levels (r=0.431, P<0.001) and negatively correlated with E-cadherin amounts (r=-0.413, P<0.001) in NPC tissues. The expression of all three proteins correlated significantly with tumor N stage, TNM stage, and 2-year metastasis. Furthermore, significant correlations were found for T stage, N stage, TNM stage, HMGA2, E-cadherin, and vimentin (all P<0.013) with poor prognosis (univariate analysis). However, multivariate analyses showed that only HMGA2 (hazard ratio [HR]: 2.683, 95% confidence interval [CI]: 1.185-6.077, P=0.018) and N stage (HR: 7.892, 95% CI: 2.731-22.807, P<0.001) were independent predictors of poor prognosis. CONCLUSION: These results demonstrated that HMGA2, an independent prognostic factor, may promote NPC progression and metastasis, and is significantly associated with EMT proteins. Therefore, HMGA2 may be considered a potential therapeutic target in NPC.