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Purpose: This study aims to develop and validate a model predictive for the incidence of grade 4 radiation-induced lymphopenia (G4RIL), based on dosiomics features and radiomics features from the planning CT of nasopharyngeal carcinoma (NPC) treated by radiation therapy. Methods: The dataset of 125 NPC patients treated with radiotherapy from August 2018 to March 2019 was randomly divided into two sets-an 85-sample training set and a 40-sample test set. Dosiomics features and radiomics features of the CT image within the skull bone and cervical vertebrae were extracted. A feature selection process of multiple steps was employed to identify the features that most accurately forecast the data and eliminate superfluous or insignificant ones. A support vector machine learning classifier with correction for imbalanced data was trained on the patient dataset for prediction of RIL (positive classifier for G4RIL, negative otherwise). The model's predictive capability was gauged by gauging its sensitivity (the likelihood of a positive test being administered to patients with G4RIL) and specificity in the test set. The area beneath the ROC curve (AUC) was utilized to explore the association of characteristics with the occurrence of G4RIL. Results: Three clinical features, three dosiomics features, and three radiomics features exhibited significant correlations with G4RIL. Those features were then used for model construction. The combination model, based on nine robust features, yielded the most impressive results with an ACC value of 0.88 in the test set, while the dosiomics model, with three dosiomics features, had an ACC value of 0.82, the radiomics model, with three radiomics features, had an ACC value of 0.82, and the clinical model, with its initial features, had an ACC value of 0.6 for prediction performance. Conclusion: The findings show that radiomics and dosiomics features are correlated with the G4RIL of NPC patients. The model incorporating radiomics features and dosiomics features from planning CT can predict the incidence of G4RIL in NPC patients.
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BACKGROUND: Peripheral neutrophil-lymphocyte ratio (NLR), reflecting immune-inflammation status, shows great potential for tumor progression and outcome. Pre-treatment NLR does not fully reflect the immune-inflammatory response to treatment. This study aimed to introduce the NLR trend as a new indicator and to investigate its prognostic value in patients with nasopharyngeal carcinoma receiving radiotherapy. METHODS: This retrospective study evaluated patients with nasopharyngeal carcinoma treated with radiotherapy. The NLR trend value was calculated from the fitted line gradient via the NLRs before, during (at least once), and after each patient's first radiotherapy. The Kaplan-Meier curve and log-rank test were used to calculate and compare survival outcomes of different pretreatment NLRs and NLR trends for progression-free survival, locoregional recurrence-free survival (LRFS), and overall survival at 3 and 5 years. Multivariate Cox regression analyses were performed to assess the association between the NLR trend plus 3- and 5-year overall survival. RESULTS: The study included 528 patients. A lower NLR trend predicted worse progression-free survival, LRFS, plus 3- and 5-year overall survival. Multivariate Cox regression analysis showed that the NLR trend independently predicted 3- and 5-year overall survival. Sub-group analysis showed that the prognosis of patients with a low pretreatment NLR and a high NLR trend were superior to those of other groups. CONCLUSION: The NLR trend independently predicted the prognosis of patients with nasopharyngeal carcinoma receiving radiotherapy. The NLR trend and the pretreatment NLR combination is more precise than pretreatment NLR in predicting prognosis. A high NLR trend may be evidence of a positive immune response to radiotherapy in patients with nasopharyngeal carcinoma.
Subject(s)
Nasopharyngeal Neoplasms , Neutrophils , Disease-Free Survival , Humans , Lymphocytes/pathology , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/radiotherapy , Nasopharyngeal Neoplasms/pathology , Neutrophils/pathology , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND & PURPOSE: We investigated clinical and genetic factors associated with severe radiation-induced lymphopenia (RIL) in a randomized clinical trial of photon vs. proton radiation, with chemotherapy, for non-small cell lung cancer. METHODS: XRCC1 rs25487 was genotyped in lymphocytes from serial peripheral blood samples. Severe RIL was defined as absolute lymphocyte count (ALC) < 0.3 × 109 cells/L. Univariate and multivariate analyses were used to identify independent risk factors, which were then used to group patients for risk of severe RIL. RESULTS: Univariate analysis of the 178 patients in this analysis showed that older age, larger tumors, higher lung V5 and mean lung dose, and higher heart V5 and mean heart dose were associated with severe RIL during treatment (P < 0.05). The XRCC1 rs25487 AA genotype was also associated with increased risk of severe RIL during treatment (AA vs. others: hazard ratio [HR] = 1.665, 95% confidence interval [CI] 1.089-2.500, P = 0.018). Multivariate analyses showed that older age (HR = 1.031, 95% CI 1.009-1.054, P = 0.005), lung V5 (HR = 1.039, 95% CI 1.023-1.055, P < 0.0001), and AA genotype (AA vs. others, HR = 1.768, 95% CI 1.165-2.684, P = 0.007) were independently associated with higher incidence of severe RIL. These three risk factors (age ≥ 56 years, lung V5 ≥ 51% and XRCC1 rs25487 AA) distinguished patients at different risk of developing severe RIL (P < 0.0001). CONCLUSIONS: Age, lung V5 and XRCC1 rs25487 AA were all linked with risk of severe RIL. Our predictive risk model may be helpful for identifying patients at high risk of severe RIL so that treatment can be modified.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Lymphopenia , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Genotype , Humans , Lung , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Lymphocytes , Middle Aged , X-ray Repair Cross Complementing Protein 1/geneticsABSTRACT
OBJECTIVES: To evaluate the application value of CT-based radiomics features for the ascending and descending types of nasopharyngeal carcinoma (NPC). METHODS: A total of 217 NPC patients (48 ascending type and 169 descending type), who obtained CT images before radiotherapy in Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University from February 2015 to October 2017, were analyzed retrospectively. All patients were randomly divided into a training set (n=153) and a test set (n=64). Gross tumor volume in the nasopharynx (GTVnx) was selected as regions of interest (ROI) and was analyzed by radiomics. A total of 1 300 radiomics features were extracted via IBEX. The least absolute shrinkage and selection operator (LASSO) logistic regression was performed to choose the significant features. Support vector machine (SVM) and random forest (RF) classifiers were built and verified. RESULTS: Six features were selected by the LASSO from 1 300 radiomics features. Compared with SVM classifier, RF classifier showed better classification performance. The area under curve (AUC) of the receiver operating characteristic (ROC) curve, accuracy, sensitivity, and specificity were 0.989, 0.941, 1.000, and 0.924, respectively for the training set; 0.994, 0.937, 1.000, and 0.924, respectively for the validation set. CONCLUSIONS: CT-based radiomics features possess great potential in differentiating ascending and descending NPC. It provides a certain basis for accurate medical treatment of NPC, and may affect the treatment strategy of NPC in the future.
Subject(s)
Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , ROC Curve , Retrospective Studies , Sensitivity and SpecificityABSTRACT
In our study, 1,105 cases of nasopharyngeal carcinoma (NPC) and 1,430 normal controls recruited from Hunan province, southern China were typed for human leukocyte antigen (HLA)-B locus by Sanger sequencing exons 2-4. Besides confirming the NPC association with HLA-B*46:01 allele, HLA-A*02:07-B*46:01 and HLA-A*33:03-B*58:01 haplotypes (all positive), and HLA-B*13 lineage (negative), all of which were relatively common, strong negative associations were observed for five low-frequency and rare alleles or lineages, including HLA-B*07, -B*27:04, -B*39, -B*51:02 and -B*55:02, with odds ratio (OR) ranging from 0.16 to 0.3 (all pcorrected < 0.05). These strong protective associations were independent of linkage disequilibrium (LD) between HLA-A and HLA-B loci. Further analysis indicated a single amino acid change from histidine to tyrosine at residue 171 is probably crucial for the mutant allele, HLA-B*51:02, to mediate resistance to NPC. A subset of NPC cases (n = 821) and normal controls (n = 1,035) were tested for antivirus capsid antigen immunoglobulin A (anti-VCA IgA), which differed drastically between the two groups [67.7% vs. 5.5%, OR (95% confidence interval) = 36 (26.55-48.81), p < 0.0001]. HLA-B allelic variation did not associate with seropositivity for anti-VCA IgA in either group. Results from our study show, more clearly than previously, the existence of a cluster of low-frequency and rare HLA-B variants conferring low, or very low risk to NPC, a phenomenon not observed in other ethnic groups. Our data shed new insights into genetic susceptibility to NPC in southern Chinese populations. Future independent studies are warranted to replicate the findings reported in our study.
Subject(s)
Genetic Predisposition to Disease/genetics , HLA-B Antigens/genetics , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Neoplasms/genetics , Adult , Alleles , China/epidemiology , Female , Gene Frequency , HLA-A Antigens/genetics , Haplotypes , Humans , Male , Middle Aged , Mutation , Nasopharyngeal Carcinoma/epidemiology , Nasopharyngeal Neoplasms/epidemiology , Odds RatioABSTRACT
BACKGROUND AND PURPOSE: We evaluated the relationship between patient-, tumor-, and treatment-related features and radiation-induced lymphopenia (RIL) and evaluated the correlation between RIL and survival outcome in NPC patients to help improve the treatment strategy. METHODS: This retrospective study included 374 patients with stage II-IVa NPC who had been treated with definitive RT and were enrolled from 2004 to 2015; The associations between the G3-4 RIL (absolute lymphocyte count, ALC < 0.5 × 109 cells/L) during RT and patient-, tumor-, and treatment-related factors were assessed using Cox regression analyses. The correlation between ALC nadir and survival was examined using a Kaplan-Meier analysis, compared with the log-rank test, and confirmed by a Cox proportional hazards analysis. RESULTS: In the multivariate analysis, lower baseline ALC and intensity modulated radiation therapy (IMRT) (vs. 2 dimensional-conformal radiation therapy,2D-CRT) were identified as 2 independent factors that were associated with G3-4 RIL. In the multivariate survival analysis, patients with G3-4 ALC nadir had longer local recurrence-free survival durations (LRFS) (vs. G0-2 nadir, HR = 0.548, P = 0.005) and longer progression-free survival durations (PFS) (vs. G0-2 nadir, HR = 0.676, P = 0.022), while patients with G4 ALC nadir had a shorter distant-metastasis-free survival duration (DMFS) (vs. G0-2 nadir, hazard ratio [HR] = 2.567, P = 0.037). CONCLUSIONS: In the study, lymphopenia during RT were affected by baseline ALC and RT modality independently. Moreover, G3-4 ALC nadir was independently linked with longer PFS and LRFS durations, while G4 ALC nadir was independently linked with a shorter DMFS duration.
Subject(s)
Chemoradiotherapy/adverse effects , Lymphopenia/mortality , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Neoplasms/mortality , Radiotherapy, Intensity-Modulated/adverse effects , Adolescent , Adult , Aged , Female , Humans , Lymphocyte Count , Lymphopenia/etiology , Lymphopenia/pathology , Male , Middle Aged , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/radiotherapy , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/radiotherapy , Nasopharyngeal Neoplasms/therapy , Prognosis , Retrospective Studies , Survival Rate , Young AdultABSTRACT
PURPOSE: We compared differences in patterns of locoregional failure, and the influence of adaptive planning on those patterns, in patients who received passive scattering proton therapy (PSPT) versus intensity modulated photon therapy (IMRT) for non-small cell lung cancer. METHODS AND MATERIALS: Treatment simulation computed tomography scans and dose distributions were registered with images depicting the recurrence. Local failure (LF) was defined as failure within the internal target volume (ITV); marginal failure (MF) as failure between the ITV and planning target volume (PTV) plus a 10-mm margin (PTV+10mm); and regional failure (RF) as outside the PTV+10mm. Weekly during-treatment 4-dimensional computed tomography simulation and verification plans were obtained for all patients. Adaptive plans were developed if the verification plan showed deviations in protocol-specified dose distribution, and failure locations were recorded for those patients as well. RESULTS: Of the 212 patients analyzed, most (152 [72%]) had no failure; of the 60 patients with failure, 27 (45%) had LF (within the ITV), 23 (38%) had MF (between the ITV and PTV+10mm), and 10 (17%) had RF (>10 mm outside the PTV). MF rates were no different for IMRT patients (16 of 136 [12%]) or PSPT patients (7 of 76 [9%], log-rank P = .558). The only independent predictor of MF on Cox proportional hazards analysis was T3-4 status. Large tumors and use of PSPT independently predicted the need for adaptive planning. Although 5-year overall survival rates were poorer for patients with large tumors versus small tumors (P < .001), the rates were similar for patients with large tumors who received adaptive planning versus small tumors. CONCLUSIONS: No differences in LF, MF, or RF patterns were found for IMRT versus PSPT. Proton therapy more often required adaptive planning, and the techniques used for adaptive planning did not compromise tumor control. Response to chemoradiation by larger tumors predicted favorable survival.
Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Chemoradiotherapy/methods , Lung Neoplasms/therapy , Proton Therapy/methods , Radiotherapy, Intensity-Modulated/methods , Adult , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Proportional Hazards Models , Radiotherapy Planning, Computer-Assisted , Treatment Failure , Tumor BurdenABSTRACT
P73 antisense RNA 1T (non-protein coding), also known as TP73-AS1 or PDAM, is a long non-coding RNA which may regulate apoptosis via regulation of p53-dependent anti-apoptotic genes. An abnormal change of TP73-AS1 expression was noticed in cancers. The effects of TP73-AS1 in brain glioma growth and the underlying mechanism remain unclear so far. In the present study, TP73-AS1 was specifically upregulated in brain glioma tissues and cell lines, and was associated with poorer prognosis in patients with glioma. TP73-AS1 knocking down suppressed human brain glioma cell proliferation and invasion in vitro, as well as HMGB1 protein. MiR-142 has been reported to play a pivotal role in cancers; here we observed that TP73-AS1 and miR-142 could negatively regulate each other. Results from luciferase assays suggested that TP73-AS1 might compete with HMGB1 for miR-142 binding. Further, HMGB1/RAGE was involved in TP73-AS1/miR-142 regulation of glioma cell proliferation and invasion. In glioma tissues, TP73-AS1 and HMGB1 expression was up-regulated, whereas miR-142 expression was down-regulated. Data from the present study revealed that TP73-AS1 promoted the brain glioma growth and invasion through acting as a competing endogenous RNA (ceRNA) to promote HMGB1 expression by sponging miR-142. In conclusion, we regarded TP73-AS1 as an oncogenic lncRNA promoting brain glioma proliferation and invasion, and a potential target for human brain glioma treatment. J. Cell. Biochem. 119: 3007-3016, 2018. © 2017 Wiley Periodicals, Inc.
Subject(s)
Brain Neoplasms/genetics , Glioma/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Signal Transduction , Antigens, Neoplasm/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , HMGB1 Protein/genetics , Humans , Male , Mitogen-Activated Protein Kinases/genetics , Prognosis , Survival Analysis , Up-RegulationABSTRACT
BACKGROUND: It is known that hypertension is associated with high levels of vascular endothelial growth factor (VEGF) expression which is, in turn, highly connected to the prognosis of a wide array of cancers. The purpose of this study was to evaluate the relationship between hypertension and prognosis of nasopharyngeal carcinoma (NPC) with definitive radiotherapy in a Chinese population. PATIENTS AND METHODS: We retrospectively reviewed 4493 patients with NPC who received definitive radiotherapy from 1995 to 2006, with a minimum follow-up of 5 years. Kaplan-Meier survival analysis and Cox proportional hazard model were utilized to determine the association between hypertension and overall survival (OS). RESULTS: A total of 802 patients with NPC suffered from hypertension as compared to 3691 patients with no associated hypertension. Kaplan-Meier analysis revealed median overall survival of 101.1 and 110.0 months, respectively (p<0.05). In univariate survival analysis, patients with hypertension had worse OS (p<0.05) than non-hypertension patients. Patients with higher grade hypertension also had worse OS (p<0.05) compare to patients with grade 1 hypertension. In multivariate survival analysis, patients with hypertension had significantly worse OS (p<0.05) than non-hypertension patients, as well as M stage (p<0.001), after adjustment for related clinical confounding factors. CONCLUSION: Our findings provide evidence that hypertension is an independent factor and result in poorer survival outcomes in patients with NPC, the mechanism is still unclear, and it worth further research.
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It is known that hypertension could increase the plasma levels of VEGF and that ß-blockers propranolol could counteract the effect. Our aim was to explore the possibility of improving survival outcomes for patients with and patients without hypertension. In addition, we also compared the efficacy of the usage of ß-blockers in inoperable non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed 1753 NSCLC patients who underwent concurrence/sequential chemoradiotherapy in our hospital from 1994 to 2005. A total of 606 inoperable patients with stage III were enrolled in this study. Fifty-five patients survived until the follow-up date of May 2011. From the 606 patients, 123 of them had hypertension. We identified 11 of them who took ß-blockers orally. Kaplan-Meier methods and Cox proportional hazard model were utilized to analyze the overall survival (OS) outcome among patients with hypertension and patients without hypertension. After that, we compared the patients who took ß-blockers with patients who did not take ß-blockers in the whole stage III cohort using the same approaches. The Kaplan-Meier analysis revealed that there were no significant survival outcomes between hypertension and non-hypertention groups (P>0.05). No significant difference was found between using ß-blockers and not using them in the hypertention group (P>0.05). We also found no statistical significance between using ß-blockers and not using them in the whole cohort of 606 NSCLC patients (P>0.05). The results from both univariate or multivariate analysis using the Cox proportional hazards regression model indicated that there was no statistical difference between hypertension and non-hypertension group. There was also no difference between using ß-blockers and not using them in the whole stage III cohort (P>0.05). For the patients with hypertension, the usage of ß-blockers did not influence the overall survival in stage III inoperable NSCLC. Further randomized clinical trials will be warranted to validate this finding.
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Deletion of major histocompatibility complex class I chain-related genes A (MICA*Del) was investigated in 3,411 DNA samples from two southern Chinese Han populations (Hunan Han, HNH; Guangdong Han, GDH), two northern Chinese populations (Inner Mongolia Han, IMH; Inner Mongolia Mongol, IMM) and one southeastern Chinese Han population (Fujian Han, FJH) using an in-house polymerase chain reaction-sequence specific priming (PCR-SSP) assay, which enables direct discrimination between heterozygote and homozygote for MICA*Del. MICA*Del showed a frequency ranging from 0.8% in FJH to 5.7% in IMM (Pcorrected < 0.05), indicating northward increase in frequency of MICA*Del in Chinese populations. In contrast to the association reported recently in a Taiwan Chinese population and a Malaysian Chinese cohort, MICA*Del distribution did not differ between 1,120 patients with nasopharyngeal carcinoma (NPC) and 1,483 normal controls in the HNH population (1.03% in NPC cases vs 1.18% in the controls, OR (95% CI) = 0.87 (0.51-1.47), p = 0.69). Further gender-stratified analysis also failed to disclose any male-specific association reported in a Taiwan Chinese population. Multi-locus typing of the 94 samples carrying MICA*Del revealed two new haplotypes, HLA-A*11:01-B*13:01-MICA*Del-MICB*009N-DRB1*04:06 and HLA-B*35:01-MICA*Del-MICB*009N-DRB1*15:01, in addition to HLA-B*48-MICA*Del. Unexpectedly, two samples with MICA*Del in the HNH population were each consistently found to have two distinct MICA alleles, indicating the existence of two MICA gene copies on certain HLA haplotypes. Based on the results from a sizeable case-control study, our data suggest that there is no association between MICA*Del and NPC in the southern Chinese Han population.
Subject(s)
Carcinoma/genetics , Histocompatibility Antigens Class I/genetics , Nasopharyngeal Neoplasms/genetics , Adult , Asian People/genetics , Case-Control Studies , China , Female , Gene Deletion , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Sequence DeletionABSTRACT
In this study, copy number variation (CNV) of NKG2C gene was investigated in 1129 normal, unrelated individuals representing two southern Chinese Han populations (Hunan Han and Guangdong Han), two northern Chinese populations (Inner Mongolia Han and Inner Mongolia Mongol) and one southeastern Chinese Han population (Fujian Han) using polymerase chain reaction-sequence-specific priming (PCR-SSP) method. CNV of NKG2C gene did not vary significantly among the five Chinese populations, with NKG2C gene deletion showing a frequency ranging from 0.2031 to 0.2688. Compared with worldwide ethnic groups, very significant difference was observed between the five Chinese populations and the Mexican mestizos (all Pcorrected=0.0025), and between the Fujian Han population and the German population (Pcorrected=0.005). We further examined CNV of NKG2C and HLA-E allelic distribution in 653 patients afflicted with nasopharyngeal carcinoma (NPC) in Hunan province. Neither CNV of NKG2C nor HLA-E was associated with NPC. There was a trend of reduced NPC risk in individuals who were homozygous for both HLA-E(∗)01:03 and NKG2C deletion (0.46% vs. 2.51%, P=0.0076, Pcorrected=0.0684, OR (95% CI)=0.1794 (0.0473-0.6809)). Taken together, our results suggest that NKG2C deletion and HLA-E signalling pathway does not play a major role in determining genetic susceptibility to NPC.
Subject(s)
DNA Copy Number Variations , Ethnicity , Histocompatibility Antigens Class I/genetics , NK Cell Lectin-Like Receptor Subfamily C/genetics , Nasopharyngeal Neoplasms/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma , China , DNA Mutational Analysis , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Sequence Deletion/genetics , Young Adult , HLA-E AntigensABSTRACT
BACKGROUND: Single nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non-metastatic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: The study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. RESULTS: Multivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031-3.438; Pâ=â0.039] and heavy smokers (≥20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010-4.036; Pâ=â0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073-24.021; Pâ=â0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056-6.248; Pâ=â0.038). CONCLUSIONS: The ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival.
Subject(s)
DNA-Binding Proteins/genetics , Endonucleases/genetics , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/mortality , Polymorphism, Genetic , Adult , Aged , Alleles , Amino Acid Substitution , Carcinoma , DNA-Binding Proteins/metabolism , Endonucleases/metabolism , Female , Follow-Up Studies , Genotype , Humans , Immunohistochemistry , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/radiotherapy , Neoplasm Staging , Prognosis , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Retrospective Studies , Risk Factors , Sequence Analysis, DNA , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , X-ray Repair Cross Complementing Protein 1 , Young AdultABSTRACT
The aim of this study was to compare the dosimetric characteristics of left-sided whole breast irradiation among 3-dimensional conformal radiotherapy (3D-CRT), 4-field inverse-planned intensity-modulated radiotherapy (IP-IMRT) and hybrid IMRT technique (combining 3D-CRT beams and IP-IMRT beams) with respect to target coverage and irradiation of organs at risk. The 3 different planning techniques were analyzed for 8 patients with left-sided breast conserving surgery. Plans were compared on the basis of planning target volume (PTV) dose conformity, homogeneity and the volumes of normal tissues treated based on dose-volume histograms (DVHs). DVHs were calculated for the PTV, heart, and the bilateral lungs, contralateral breast, and soft tissue surrounding the breast PTV (VOB) volume. IP-IMRT and hybrid IMRT techniques comparably improved the PTV dose homogeneity and conformity (CI) significantly, compared to the conventional 3D-CRT technique (P<0.017); the IP-IMRT technique only could additionally benefit patients by decreasing the high-dose (40 Gy) volume for heart and ipsilateral lung compared with the hybrid IMRT technique (P<0.017); the hybrid IMRT plans achieved a further improvement by compromising the increase of low-dose volume (total lung V13, contralateral lung V5, heart V10 and soft tissue surrounding the breast V5) compared with IP-IMRT plans (P<0.017). Hybrid IMRT plans achieved equivalent PTV dose uniformity to IP-IMRT plans and compromised the low-dose volume and requirement of clinic resource between IP-IMRT and 3D-CRT plans, promoting it as a standard practice of left-sided breast irradiation for patients in good-ordered cardiopulmonary health.
Subject(s)
Breast Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted , Radiotherapy, Conformal/methods , Radiotherapy, Intensity-Modulated/methods , Breast/radiation effects , Breast Neoplasms/surgery , Female , Heart/radiation effects , Humans , Imaging, Three-Dimensional , Lung/radiation effects , Mastectomy, Segmental , Radiotherapy DosageABSTRACT
Single nucleotide polymorphisms (SNPs) in the p53, MDM2 and p21 genes of the p53 pathway have been extensively studied. The main aim of the current retrospective study was to evaluate the possible predictive value of SNPs in the p53 pathway in locoregionally advanced nasopharyngeal carcinoma (NPC) in response to radiotherapy. In total, 75 consecutive patients with locoregionally advanced NPC were enrolled. Three SNPs in the p53 pathway were identified using the Sanger sequencing method from retrospectively collected paraffin-embedded biopsy specimens. The effects of genetic polymorphisms on patient progressionfree survival (PFS) were analyzed using the Cox proportional hazards model, Kaplan-Meier method and log-rank test. All of the selected subjects completed questionnaires on smoking habits prior to treatment. Multivariate analysis showed that the p53 codon 72 Pro/Pro genotype [hazard ratio (HR), 0.300; 95% confidence interval (CI), 0.092-0.983; P=0.047] and heavy smoking (≥30 pack-years) (HR, 2.899; 95% CI, 1.349-6.229; P=0.006) are independent significant prognostic factors for PFS in patients with locoregionally advanced NPC. Moreover, mean times to disease progression for heavy smokers (≥20 pack-years) carrying p53 codon 72 Arg/Arg, p21 codon 31 Arg/Arg and MDM2 309 SNP G/G genotypes were only 14.78 ± 3.00, 11.00 ± 0.58 and 11.17 ± 1.85 months, respectively. These time scales were less than half of those recorded for patients containing other genotypes and moderate smokers (<20 pack-years). In conclusion, the p53 codon 72 polymorphism is an independent prognostic marker for locoregionally advanced NPC. Moreover, analysis of SNPs in the p53 pathway may facilitate the identification of patients at high risk of poor disease outcome in subgroups of heavy smokers.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/genetics , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/radiotherapy , Proto-Oncogene Proteins c-mdm2/genetics , Radiation Tolerance/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Carcinoma , Disease-Free Survival , Female , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Polymorphism, Single Nucleotide , Retrospective Studies , Smoking , Surveys and Questionnaires , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Codon 72 (Arg/Pro), the most frequently studied single nucleotide polymorphism (SNP) of p53 to date, is associated with the ability of the gene to induce cell apoptosis. The PI3K/Akt pathway plays an essential role in the transcriptional activation function of p53, and is an important factor in radiotherapy resistance. The present study was designed to evaluate the prediction of response to radiotherapy based on p53 codon 72 SNP and pAkt expression in biopsy specimens of locoregional nasopharyngeal carcinoma (NPC) before treatment. MATERIALS AND METHODS: In total, 75 consecutive patients with locoregional NPC were enrolled. The p53 codon 72 SNP was identified from retrospectively collected paraffin-embedded biopsy specimens using Sanger sequencing. Expression patterns of p53, p21, 14-3-3σ, and pAkt proteins were investigated using immunohistochemical analyses. The effects of genetic polymorphisms and protein expression on progression-free survival (PFS) were evaluated using the Cox proportional hazards model, Kaplan-Meier method, and log-rank test. RESULTS: The p53 codon 72 Pro/Pro carriers showed lower risk of disease progression (local recurrence and distant metastases) (HR: 0.300; 95% CI: 0.092-0.983; p=0.047). However, this association between the p53 codon 72 polymorphism and PFS was not significant in the pAkt-positive subgroup. No association was observed between protein expression of p53, p21 or 14-3-3σ and p53 codon72 polymorphisms. Notably, positive expression of p53 protein appeared to be correlated with poorer PFS among patients diagnosed as local regional lymph node metastasis (N+) before treatment (p=0.032). CONCLUSIONS: The p53 codon 72 Pro/Pro genotype may be an effective independent prognostic marker for better outcome in patients with locoregional NPC. Based on the current findings, we hypothesize that pAkt weakens the predictive value of p53 codon 72 SNP in NPC. A combination of positive p53 protein expression and local regional lymph node metastasis may additionally be predictive of high risk of disease progression.
Subject(s)
Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-akt/biosynthesis , Radiation Tolerance/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Carcinoma , Codon , Disease-Free Survival , Female , Genotype , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/mortality , Phosphorylation , Polymerase Chain Reaction , Proportional Hazards Models , Transcriptome , Young AdultABSTRACT
The degradation of basement membranes by tumor cells involves secretion and activation of proteinases, such as the matrix metalloproteinases (MMPs), and results from an imbalance between their inhibitors and activators that are controlled by various growth factors or cytokines, among which TGF-ß(1) may be the most intriguing. In order to study the therapeutic effect and molecular mechanism of hyperthermia on aggressive malignant melanoma, the expression levels of TGF-ß(1) and Smad4 in B16F10 cells were dynamically analyzed by RT-PCR and western blotting for 24 h after heat treatment, from which time-dependent changes were determined. As expected, the proliferation and invasive ability of B16F10 cells were suppressed strongly by heat treatment. Furthermore, we compared the expression of TGF-ß(1) in melanoma mouse models before and after magnetic fluid hyperthermia (MFH) in vivo. After hyperthermia, the tumor growth rate was reduced with a decline in TGF-ß(1) protein expression. We conclude that changes in the TGF-ß(1) pathway induced by hyperthermia may be an important part of the molecular mechanism involved.
Subject(s)
Hyperthermia, Induced , Melanoma, Experimental/metabolism , Melanoma, Experimental/therapy , Skin Neoplasms/metabolism , Skin Neoplasms/therapy , Transforming Growth Factor beta1/metabolism , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Collagen , Drug Combinations , Female , Laminin , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Proteoglycans , RNA, Messenger/metabolism , Signal Transduction , Skin Neoplasms/pathology , Smad4 Protein/metabolism , Survival AnalysisABSTRACT
Magnetic fluid hyperthermia (MFH) induced by a magnetic field has become a new heating technology for the treatment of malignant tumors due to its ability to heat the tumor tissue precisely and properly, and due to its significant therapeutic effects. In this study, MFH induced by radiofrequency capacitive field (RCF) for the treatment of transplanted subcutaneous tumors in rats, was investigated. A total of 50 rats bearing subcutaneous tumors were randomly divided into five groups, including i) a pseudo-treatment (PT) control group, ii) magnetic fluid (MF) group, iii) pure hyperthermia (PH) group, iv) magnetic fluid hyperthermia 1 (MFH1) group, and v) magnetic fluid hyperthermia 2 (MFH2) group. Tumors were irradiated for 30 min in the MFH1 group 24 h following injection of MF. Tumors were irradiated for 30 min in the MFH2 group 24 h following injection of MF, and irradiation was repeated for 30 min 72 h following injection of MF. Tumor volumes, tumor volume inhibition ratios and survival times in the rat model were examined. Temperatures of tumor cores and rims both rapidly reached the desired temperature (â¼50°C) for tumor treatment within 5 to 10 min in the MFH1 and MFH2 groups, and we maintained this temperature level by manually adjusting the output power (70-130 W). Tumor volumes of the MFH1 and MFH2 groups were reduced compared to those of the PT, MF and PH groups. The inhibitory effect on tumor growth in the MFH2 group (91.57%) was higher compared to that in the MFH1 group (85.21%) and the other groups. The survival time of the MFH2 group (51.62±2.28 days) and MFH1 group (43.10±1.57 days) was increased compared to that of the PH, MF and PT groups. The results obtained show that MFH induced by RCF may serve as a potential and promising method for the treatment of tumors.
ABSTRACT
Radiation-induced side effects on normal tissue are determined largely by the capacity of cells to repair radiation-induced DNA damage. X-ray repair cross-complementing group 1 (XRCC1) plays an important role in the repair of DNA single-strand breaks. Studies have shown conflicting results regarding the association between XRCC1 gene polymorphisms (Arg399Gln, Arg194Trp, -77T>C and Arg280His) and radiation-induced side effects in patients undergoing whole breast radiotherapy. Therefore, we conducted a meta-analysis to determine the predictive value of XRCC1 gene polymorphisms in this regard. Analysis of the 11 eligible studies comprising 2,199 cases showed that carriers of the XRCC1 399 Gln allele had a higher risk of radiation-induced toxicity than those with the 399 ArgArg genotype in studies based on high-quality genotyping methods [Gln vs. ArgArg: OR, 1.85; 95% CI, 1.20-2.86] or in studies with mixed treatment regimens of radiotherapy alone and in combination with chemotherapy [Gln vs. ArgArg: OR, 1.60; 95% CI, 1.09-2.23]. The XRCC1 Arg399Gln variant allele was associated with mixed acute and late adverse reactions when studies on late toxicity only were excluded [Gln allele vs. Arg allele: OR, 1.22; 95% CI, 1.00-1.49]. In contrast, the XRCC1 Arg280His variant allele was protective against radiation-induced toxicity in studies including patients treated by radiotherapy alone [His allele vs. Arg allele: OR, 0.58; 95% CI, 0.35-0.96]. Our results suggest that XRCC1 399Gln and XRCC1 280Arg may be independent predictors of radiation-induced toxicity in post-surgical breast cancer patients, and the selection of genotyping method is an important factor in determining risk factors. No evidence for any predictive value of XRCC1 Arg194Trp and XRCC1 -77T>C was found. So, larger and well-designed studies might be required to further evaluate the predictive value of XRCC1 gene variation on radiation-induced side effects in patients undergoing whole breast radiotherapy.
Subject(s)
Genetic Predisposition to Disease , Genotype , Alleles , Case-Control Studies , Humans , Polymorphism, Genetic , Risk FactorsABSTRACT
The present study aimed to investigate heating-induced alterations of breast cancer cell invasion abilities and the potential mechanisms associated with TGF-ß1 expression. MCF-7 cells were heated at 43, 45, 47 and 37 °C for 30 min. In vitro cell invasion ability was evaluated by matrigel invasion assay. The activity of matrix metalloproteinase (MMP)-2/9 was investigated by gelatin zymographic assays. Expression of vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) was investigated by immunocytochemistry and RT-PCR. Apoptosis was analysed by flow-cytometry. The invasive potential of MCF-7 cells was reduced by heating, and MMP-2/9 secretion and enzymatic activity were suppressed. Furthermore, VEGF and TGF-ß1 mRNA and proteins were suppressed by hyperthermia. These results suggest that down-regulation of the expression of TGF-ß1, EGF and MMPs by hyperthermia probably accounts for the inhibition of the invasive abilities of MCF-7 cells.