Cancer risk assessment in modern radiotherapy workflow with medical big data.

Modern radiotherapy (RT) is being enriched by big digital data and intensive technology. Multimodality image registration, intelligence-guided planning, real-time tracking, image-guided RT (IGRT), and automatic follow-up surveys are the products of the digital era. Enormous digital data are created in the process of treatment, including benefits and risks. Generally, decision making in RT tries to balance these two aspects, which is based on the archival and retrieving of data from various platforms. However, modern risk-based analysis shows that many errors that occur in radiation oncology are due to failures in workflow. These errors can lead to imbalance between benefits and risks. In addition, the exact mechanism and dose-response relationship for radiation-induced malignancy are not well understood. The cancer risk in modern RT workflow continues to be a problem. Therefore, in this review, we develop risk assessments based on our current knowledge of IGRT and provide strategies for cancer risk reduction. Artificial intelligence (AI) such as machine learning is also discussed because big data are transforming RT via AI.

MiR-31 is a potential biomarker for diagnosis of head and neck squamous cell carcinoma.

MicroRNAs (miRNAs) play important roles in the development of head and neck squamous cell carcinoma (HNSCC). However, their potential clinical value as biomarkers remains poorly known. The aim of this study was to assess the association between tissue/serum miR-31 expression levels and prognosis of HNSCC. In this clinical study, tumor samples were obtained from 118 patients with HNSCC and 48 patients with oral epithelial dysplasia, and blood samples were collected from all the HNSCC cases and 60 normal controls. The expression levels of tissue/serum miR-31 were measured by real-time PCR. Chi-square test was used to evaluate the correlation between tissue/serum miR-31 and clinical parameters of HNSCC. Survival curves were constructed using the Kaplan-Meier method and log-rank test. Multivariate Cox regression analyses were used to estimate independent predictors of survival for HNSCC. Our findings showed that tissue miR-31 levels in HNSCC tumor specimens exhibited higher than that in oral epithelial dysplasia samples and normal tissues. Oral epithelial dysplasia with higher expression of miR-31 was more prone to progress into HNSCC. Likewise, serum miR-31 expression in HNSCC patients was markedly increased in compared to normal controls. Moreover, serum miR-31 performed well to distinguish HNSCC subjects from controls. In addition, increased tissue/serum miR-31 expression was positively correlated with poor clinical variables and dismal prognosis. Finally, tissue miR-31 was confirmed to be an independent prognostic factor for HNSCC. Taken together, miR-31 had strong potential as a promising biomarker in HNSCC detection.

A parameterized model for mean urinary inflow rate and its preliminary application in radiotherapy for cervical cancer.

Forty-nine patients with stage IIb cervical cancer were included to investigate the changes in bladder volume in response to different approaches to maintaining consistent bladder filling. The impacts of age (P age), water consumption (P wat ), and body mass index (BMI, P bmi ) on the mean urinary inflow rate (v tot ) were analysed. The bladder volume (BV) increased linearly over time. A large variation in v tot among individuals was observed, ranging from 0.19 to 5.13 ml/min. The v tot was correlated with P age (R = -0.53, p = 0.01) and P wat (R = 0.84, p = 0.00), and no correlation between v tot and P bmi was found (p > 0.05). Therefore, v tot could be parameterized using two methods: multivariable linear regression and iterative fitting. There was no statistically significant difference between the two methods. The model accuracy was successfully assessed with several validation tests for patients with good compliance (79.2% of all patients), and the proportion of radiotherapy (RT) fractions with zero wait time (one ultrasound (US) scan) increased from 6.5% to 41.2%. The optimal US scanning number and RT time could be provided using this model. This adaptive RT approach could reduce patient discomfort caused by holding onto urine and reduce technician labour as well as cost.

[Effect of different doses of radiation on human salivary gland adenoid cystic carcinoma cells].

PURPOSE: To explore the effect of different doses of radiation on human salivary gland adenoid cystic carcinoma cells (SACC-83, SACC-LM). METHODS: Different doses of radiation (0, 2, 4, 6, 8, 10 Gy) were applied to SACC-83, SACC-LM cells and the cells were continued to culture for 48 h. CCK-8 test, flow cytometry(FCM) and cell scratch experiment were used to observe cell proliferation, apoptosis and cell migration. SPSS19.0 software package was used for data analysis. RESULTS: The effect of radiation on SACC-LM cells survival rate, cell apoptosis, heteroploid and cell migration ability were significantly greater than that on SACC-83 cells (P<0.05). In SACC-83 cells, compared with other doses of radiation, 6 Gy of irradiation was the most sensitive on cell survival rate, cell apoptosis, heteroploid and cell migration ability. CONCLUSIONS: Radiation sensitivity of SACC-LM was greater than that of SACC-83 cells. With 6 Gy of radiation, changes of biology in SACC-83 cells most significant than other doses of radiation.

Correlation study of Bcl-2, B7-H1, EGFR, VEGF and colorectal cancer.

OBJECTIVE: To analyze the expressions of Bcl-2, B7-H1, EGFR and VEGF in colorectal cancer for the further investigation of their correlations with the clinical pathological features of colorectal cancer. METHOD: Fresh colorectal cancer tissues and the expressions of Bcl-2, B7-H1, VEGF and EGFR in paraneoplastic normal mucosal tissues of 57 cases were tested by immunohistochemisty method, and the results were analyzed by SPSS10.0. RESULTS: 1. Compared with paraneoplastic normal tissues, the expressions of Bcl-2 and B7-H1 in colorectal cancer tissues increased significantly with significant difference (P<0.05), while the expression of EGFR and VEGF in colorectal cancer tissues showed no significant difference with those in paraneoplastic normal tissue (P>0.05); 2. The correlation with clinical pathological features: there was significant difference of expression rates of EGFR between different genders (P<0.05); the expressions of BCL-2 and B7-H1 in colorectal cancer of the high- and medium- differentiated groups were significantly higher than those of the low-differentiated group, and the difference was significant (P<0.01); compared with the colorectal cancer patients without lymph node metastasis (Dukes stage A+B), the expression of B7-H1 in patients with lymph node metastasis (Dukes stage C+D) was significantly higher (P<0.05); 3. Within the high- and medium- differentiated colorectal cancer tissues, Bcl-2 expression rate in B7-H1 negative group was higher than the positive group with significant difference (P<0.01). CONCLUSIONS: In colorectal carcinoma, Bcl-2, B7-H1, EGFR and VEGF were all expressed, independent from age and depth of invasion. However, the expression level of Bcl-2 and B7-H1 correlated with tissue differentiation, and the latter also had correlation with tumor staging. Meanwhile, the short-term follow-up showed that high expression of Bcl-2/B7-H1 existed in death cases. Therefore, the expression detection of Bcl-2, B7-H1 might provide a clear understanding of the biological behavior of colorectal cancer, and was important for the diagnosis, treatment and prognosis judgment of colorectal cancer.

HMGA2 Expression in Renal Carcinoma and its Clinical Significance.

BACKGROUND: The objective of this study is to detect HMGA2 expression in renal carcinoma to explore its relationship with clinicopathology and its significance in prognosis. METHODS: Expressions of HMGA2 mRNA and protein were detected in 50 renal carcinoma specimens, 50 corresponding adjacent normal kidney tissue samples and 40 renal benign tumour specimens via reverse transcription polymerase chain reaction and immunohistochemical assay. Expression analysis was performed along with clinical data analysis. RESULTS: The relative expression levels of HMGA2 mRNA in renal carcinoma, renal benign tumour tissues and adjacent normal renal tissues were 0.84±0.23, 0.19±0.06 and 0.08±0.04, respectively. HMGA2 protein positive rates were 68.0%, 7.5% and 2.0%, with a significant difference (P<0.05). HMGA2 expression was not significantly correlated with gender, age, tumour size and histological type (P>0.05), but was significantly correlated with TNM stages and lymph node metastasis (P<0.05). CONCLUSIONS: The expressions of HMGA2 gene and protein in renal carcinoma were closely correlated with tumour formation, progression and metastasis. HMGA2 may become a powerful new pathological marker and prognostic factor for renal carcinoma.

Dosimetric evaluation of volumetric-modulated arc therapy (RapidArc) for primary leiomyosarcoma in the spine.

This study aims to investigate the suitability of volumetric-modulated arc therapy (VMAT) with RapidArc for primary leiomyosarcoma (LMS) in the spine, and present a new method to improve the target coverage and organs at risk (OAR) sparing. Five patients with LMS were retrospectively reviewed. The intensity-modulated radiotherapy (IMRT) with five coplanar beams (5b-IMRT) or seven coplanar beams (7b-IMRT), and VMAT using four quasi-quarter coplanar arcs (4q-VMAT) or two full coplanar arcs (2f-VMAT) were generated. Planning target volume (PTV) dose coverage, OAR dose sparing, conformity index (CI), and homogeneity index (HI) were evaluated. A hollow-cylinder model (HCM) was also used for feasible optimal beam arrangements. The mean doses to PTV were 95.2% ± 1.0%, 93.0% ± 1.0%, 97.9% ± 1.0% and 96.2% ± 1.5% for 4q-VMAT, 2f-VMAT, 5b-IMRT and 7b-IMRT respectively, while the mean maximum doses to spinal cord (SC) were 43.7 ± 0.9 Gy, 42.0 ± 0.8 Gy, 41.4 ± 1.2 Gy and 40.6 ± 1.4 Gy. Compared to 5b-IMRT, the mean doses delivered to kidneys decreased by about 35.1% (8.5 Gy), 2.5% (0.6 Gy) and 35.5% (8.6 Gy) for 4q-VMAT, 2f-VMAT, and 7b-IMRT, respectively. The CI proposed by Baltas et al. was twice as good with IMRT than with 4q-VMAT, and the numbers of monitor units were increased five- and threefold with 7b-IMRT and with 5b-IMRT compared to VMAT. The unexpected results we presented here show that VMAT technique can't achieve highly conformal treatment plans while maintaining SC sparing for LMS in the spine. An approach is proposed based on a hollow-cylinder model, but it is difficult to apply to clinical practice. In this case, VMAT is not superior to IMRT except for significant reduction in delivery time.

Prevalence of and risk factors for aspirin resistance in elderly patients with coronary artery disease.

OBJECTIVE: To assess the prevalence of and related risk factors for aspirin resistance in elderly patients with coronary artery disease (CAD). METHODS: Two hundred and forty-six elderly patients (75.9 ± 7.4 years) with CAD who received daily aspirin therapy (≥ 75 mg) over one month were recruited. The effect of aspirin was assessed using light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). Aspirin resistance was defined as ≥ 20% arachidonic acid (AA)-induced aggregation and ≥ 70% adenosine diphosphate (ADP)-induced aggregation in the LTA assay. An aspirin semi-responder was defined as meeting one (but not both) of the criteria described above. Based on the results of TEG, aspirin resistance was defined as ≥ 50% aggregation induced by AA. RESULTS: As determined by LTA, 23 (9.3%) of the elderly CAD patients were resistant to aspirin therapy; 91 (37.0%) were semi-responders. As determined by TEG, 61 patients (24.8%) were aspirin resistant. Of the 61 patients who were aspirin resistant by TEG, 19 were aspirin resistant according to LTA results. Twenty-four of 91 semi-responders by LTA were aspirin resistant by TEG. Multivariate logistic regression analysis revealed that elevated fasting serum glucose level (Odds ratio: 1.517; 95% CI: 1.176-1.957; P = 0.001) was a significant risk factor for aspirin resistance as determined by TEG. CONCLUSIONS: A significant number of elderly patients with CAD are resistant to aspirin therapy. Fasting blood glucose level is closely associated with aspirin resistance in elderly CAD patients.

The molecular mechanism of the anticancer effect of atorvastatin: DNA microarray and bioinformatic analyses.

The aim of this study was to identify the molecular mechanisms and biological pathways associated with the anticancer effects of atorvastatin. For this purpose, we conducted cell-based microarray and bioinformatic analyses to determine the effect of atorvastatin exposure on endothelial cell response. The results of bioinformatic analysis performed using the Connectivity Map (cMap) to examine the atorvastatin-induced changes in gene expression in the human umbilical vein endothelial cell line, EA.hy926, indicated that treatment with 10 µM of atorvastatin for 24 h upregulated the expression of 295 genes and downregulated the expression of 354 genes by 2-fold compared to the control treatment. The gene set enrichment analysis (GSEA), the Database for Annotation, Visualization and Integrated Discovery (DAVID) pathway analysis, and Gene Ontology (GO) analysis of differentially expressed genes revealed that Kruppel-like factors (KLFs) and cell cycle-related genes were the genes most significantly affected by atorvastatin treatment. The upregulation of KLFs and the downregulation of the cell cycle-related genes, including cyclin (CCN)A2, CCNE2, CCNB1 and CCNB2, were validated by real-time polymerase chain reaction (RT-PCR). A comparison of the gene expression profile of atorvastatin-treated cells with that of the control cells and with that of 6,100 compounds in the cMap database revealed that the profile of atorvastatin-treated cells was highly similar to that of histone deacetylase (HDAC) inhibitor-treated cells. Therefore, these results suggest that atorvastatin acts as an HDAC, a G1/S (start) and a G2/M (mitosis) cell cycle inhibitor. These findings provide evidence of the feasibility of the use of atorvastatin as an anticancer drug.

[Effect of irbesartan on the proliferation, apoptosis and VEGF mRNA expression of human umbilical vein cell line ea. hy926 in vitro].

OBJECTIVE: To evaluate the effect of irbesartan on the proliferation, apoptosis, and VEGF mRNA expression of human umbilical vein cell line EA.hy926 in vitro. METHODS: The human umbilical vein cell line EA.hyY926 were treated with various concentrations of irbesartan for 24 h. The cell proliferation after the treatment was detected by CCK8 assay, flow cytometry and FITC Annexin V/PI kit were used to detect changes in the cell apoptosis. RT-PCR was used to evaluate the expression of VEGF mRNA. RESULTS: There were no changes in cell shape with various concentration of irbesartan. CCK-8 assay showed a greater rate of the cell proliferation in irbesartan group than that in control group with a dose-independent manner after 24 h treatment. After incubation with irbesartan, cell proliferation rate was significant (P < 0.05). FCM analysis showed no significantly changes in the cell apoptosis. Irbesartan increased the proliferation of EA.hy926 cells. At concentration of 1 x 10(-4), 1 x 10(-5), 1 x 10(-6) mol/L, VEGF mRNA expression enhanced either (P < 0.05). CONCLUSION: Irbesartan could promote the proliferation and up-regulated VEGFmRNA expression in EA.hy926 cell line. This result suggested that in addition to antihypertensive effect, angiotensin receptor antagonist might be a novel therapeutic approach to chronic ischemic heart disease as heart failure.

[Irbesartan regulates inflammatory gene expressions related to atherosclerosis in EA.hy926 cells].

OBJECTIVE: To characterize if irbesartan regulates vascular inflammatory gene expression profiles related to atherosclerosis in EA.hy926 cells. METHODS: Human umbilical vein endothelial cell line EA.hy926 cultured in vitro was incubated with irbesartan (1×10(-6) mol/L) for 24 h. The total RNA was extracted from the cells for gene expression profiling. The DAVID Gene Functional Classification Tool was used to analyze the disease- and function-related genes in the cells. Real-time quantitative polymerase chain reaction (RT-PCR) was used to verify the genes showing differential expression after irbesartan treatment. The protein levels of angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) were tested by Western blotting. RESULTS: Compared with the control cells, 56 genes were found to show marked changes following irbesartan treatment, including 39 up-regulated and 17 down-regulated genes. Disease analysis suggested that these genes were related to such diseases as coronary atherosclerosis, myocardial infarction, and colorectal cancer. Eight genes, namely MMP2, PTGS2, PECAM1, SELP, SELL, CYP1A1, MMRN1, and HSPA1A, were involved in atherosclerosis and myocardial infarction. Verification by RT-PCR produced a result consistent with the gene array result. AT1R was down-regulated while AT2R up-regulated in irbesartan-treated cells. CONCLUSION: Irbesartan regulates the inflammatory gene expressions related to atherosclerosis in EA.hy926 cells. These inflammatory factors may promote destabilization of atherosclerotic plaque possibly in relation to AT2R overexpression.

[Establishment of animal model of breast cancer dormancy].

OBJECTIVE: Tumor dormancy has been defined clinically as a condition in which tumor cells are present but do not grow for a long period of time. Breast cancer is noted for its long periods of tumor dormancy and metastases can occur many years after treatment. METHOD: Simulating the characteristics of breast cancer patients after treatment, we established the animal model of breast cancer dormancy by inoculating 500 Ca761-03 cells into the limb muscle of 615 mice and then selecting animals with tumor dormancy 2 months post inoculation (corresponding to 5 years for humans). RESULTS: Two months after inoculation of Ca761-03 cells into the muscle of 615 mice, tumor occurred in 30% of the mice. The remaining 70% of mice did not show tumor growth. After repeated traumatic stimulation, 90% of the mice developed tumors after 5 months, therefore representing tumor dormancy. CONCLUSIONS: These results demonstrate that breast cancer cells can remain in a dormant state for long periods of time in vivo. Trauma can stimulate the dormant tumor cells to proliferate again, and causes tumor relapse. This murine model system promises a sound animal model for the study of solid tumor dormancy.

[Establishment and characterization of a rabbit tumor cell line VX2].

OBJECTIVE: To establish a rabbit tumor cell line and to characterize its biological parameters. METHODS: VX2 tumor tissue was used for the primary culture in vitro. After 40 passages, the cell morphology, CK expression (immunohistochemical staining), cell cycle, karyotype and tumorigenecity in rabbits and nude mice were investigated. RESULTS: The newly established cell line VX2 was maintained in continuous culture for over 70 passages in 10 months. Morphologically, VX2 cells were polygonal to short spindled. Tonal fibril and tight junction were found under the electron microscope. CK was positive. The cell cycle analysis showed 69.3% in G1 phase, 5.6% in G2 phase and 25.1% in S phase. The population doubling time was 34.5 hours. The chromosomal analysis showed a hypotriploidy with a median chromosome number of 58 approximately 62. The tumorigenecity in rabbits and nude mice were both 100%. CONCLUSION: The established VX2 cell line derived from rabbit squamous carcinoma could serve as a model system for experimental oncology in the rabbit.