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1.
PLoS One ; 15(10): e0239806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002027

RESUMO

INTRODUCTION: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. MATERIALS AND METHODS: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. RESULTS: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis. CONCLUSIONS: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.


Assuntos
Mutação de Sentido Incorreto , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/genética , Idoso , Feminino , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/patologia
2.
Anticancer Res ; 40(11): 6305-6317, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109568

RESUMO

BACKGROUND/AIM: Neoadjuvant concurrent chemoradiotherapy (CCRT) is the standard therapeutic strategy for rectal cancer. However, 15-20% of patients undergoing neoadjuvant CCRT progress to recurrence or distant metastases. Therefore, identifying a predictive biomarker is necessary for treating CCRT. MATERIALS AND METHODS: We investigated the relationship between the levels of histone ubiquitination enzyme and clinicopathological outcomes in patients with rectal cancer who were administered CCRT and confirm the role of histone ubiquitination enzyme in regulating the cell response to ionizing radiation (IR). RESULTS: Clinical data indicated that UBE2B expression was significantly correlated with tumor regression grade. Inhibition of UBE2B elevated the genotoxicity of IR to radioresistant cell lines. In contrast, UBE2B over-expression reduced cell sensitivity to IR. Importantly, the recruitment of 53BP1 and Rad51 was remarkably prolonged in cells after pre-treatment with UBE2B inhibitor, TZ9, suggesting a defective DNA repair pathway in UBE2B-deficient cells. CONCLUSION: These results indicate that over-expression of UBE2B correlates with poor response and low survival rate in patients who are administered preoperative CCRT.


Assuntos
Quimiorradioterapia , Regulação Neoplásica da Expressão Gênica , Neoplasias Retais/genética , Neoplasias Retais/terapia , Enzimas de Conjugação de Ubiquitina/genética , Idoso , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Reparo do DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Tolerância a Radiação/efeitos da radiação , Radiação Ionizante , Neoplasias Retais/patologia , Enzimas de Conjugação de Ubiquitina/metabolismo
3.
Anticancer Res ; 40(5): 2947-2953, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366447

RESUMO

BACKGROUND/AIM: miRNA expression patterns vary within primary rectal cancers and play a pivotal role in carcinogenesis. It is unknown, however, if these regulatory changes also play a role in local recurrent rectal cancers. In this study, the expression of various angiogenetic small non-coding ribonucleic acids, namely miRNA-21, miRNA-215, miRNA-221, and miRNA-222 were analysed in cancerous and healthy rectal tissues. PATIENTS AND METHODS: miRNA expression was analyzed via quantitative polymerase chain reaction (qPCR). Samples were obtained from 20 patients who were treated for local recurrent rectal cancer at the Department for general and visceral surgery, Klinikum Oldenburg, Germany. RESULTS: No significant differences in the expression of miRNA-221, miRNA-222 and miRNA-215 were observed between cancerous and healthy rectal tissues. However, a significant differential expression was detected for miRNA-21. CONCLUSION: miRNA-21 is differentially expressed in recurrent rectal cancer tissue and healthy tissues. However, miRNA-215, miRNA-221 and miRNA-222 are not significantly differentially expressed.


Assuntos
MicroRNAs/metabolismo , Neoplasias Retais/genética , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias Retais/patologia
4.
Cancer Genomics Proteomics ; 17(3): 249-257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345666

RESUMO

BACKGROUND/AIM: Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients. PATIENTS AND METHODS: In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates. RESULTS: In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer). CONCLUSION: By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.


Assuntos
Adenocarcinoma/terapia , MicroRNAs/genética , Pequeno RNA não Traduzido/genética , Neoplasias Retais/terapia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Quimiorradioterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Prospectivos , Curva ROC , Neoplasias Retais/genética , Neoplasias Retais/patologia , Análise de Sequência de RNA/métodos , Resultado do Tratamento
5.
Cancer Genomics Proteomics ; 17(3): 291-299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345670

RESUMO

BACKGROUND: The progression of colorectal cancer (CRC) mainly stems from the occurrence of somatic mutation. However, there is little information that can be used to comprehensively analyse the importance of germline variants in CRC patients. PATIENTS AND METHODS: The candidate germline variants between tumor relapse and cured rectal adenocarcinoma (READ) were firstly filtered by whole-exome sequencing (n=4), and validated by targeted sequencing and associated with clinical outcome in READ (n=48). RESULTS: We identified 9 pathogenic germline variants that were clinically associated with survival outcome in READ, including TIPIN, TLR1, TLR10, OR4D6, IGSF3, UBBP4, OR6J1, FAM208A and DISC1. Patients carrying these germline susceptibility variants had an increased risk of poor survival outcome compared to those without these variants. CONCLUSION: Not only the tumor genome, but also the germline sequence must be analysed to depict the overall genetic profile, providing potential therapeutic strategies for personalized medicine.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/genética , Adenocarcinoma/patologia , Idoso , Exoma , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Medicina de Precisão , Prognóstico , Neoplasias Retais/patologia , Taxa de Sobrevida
6.
Technol Cancer Res Treat ; 19: 1533033820917978, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32266860

RESUMO

MicroRNAs are reported as a vital important factor in cancer cell initiation and progression processes. MicroRNA-19-3p has drawn the attention of many researchers in recent years because of its wide expression and its key role in serious kinds of tumor cells. However, the detailed mechanism of microRNA-19a-3p in these tumors is still poorly understood. So, in the present study, we aimed to explore the biological function and potential molecular mechanism of microRNA-19a-3p in different cancer cells. We first detect the relative level of miR-19a-3p in cancer cell lines and tumor tissues compared to normal cells and tissues. Results indicated the messenger RNA expression of microRNA-19a-3p existing in an aberrant low level in cancer cells and tissues. The overexpression of microRNA-19a-3p significantly reduced the cell proliferation, migration, and invasion ability in HCT116 cells. In addition to this, increased microRNA-19a-3p could induce cell apoptosis via promoting reactive oxygen species (ROS) accumulation, whereas inhibition of microRNA-19a-3p exhibited an opposite effect. Moreover, we predicated the target genes and the binding sites of microRNA-19a-3p and confirmed FAS as the targeting of microRNA-19a-3p through luciferase activity assay. Taken together, these results indicated that microRNA-19a-3p overexpression inhibited HCT116 cell proliferation, migration and invasion, induced cell apoptosis, and ROS accumulation via FAS targeting effect. It was conceivable that microRNA-19a-3p might serve as a potential molecular target for breast and liver cancer treatment.


Assuntos
MicroRNAs/metabolismo , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Receptor fas/metabolismo , Apoptose/fisiologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , MicroRNAs/genética , Neoplasias Retais/genética , Receptor fas/genética
7.
J Cancer Res Clin Oncol ; 146(5): 1321-1334, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32144533

RESUMO

PURPOSE: Uncertainty exists regarding comparative effectiveness of cetuximab versus bevacizumab in metastatic colorectal cancer (mCRC). We conducted a retrospective head-to-head multi-cohort study comparing clinical outcomes from both antibodies METHODS: Cohorts were defined by treatment line and subgroups by (K)RAS status and tumour sidedness. Among other outcomes, we estimated and compared response rates, progression-free (PFS) and overall survival (OS). RESULTS: Between January 2010 and April 2018, 311 patients were included. Except for (K)RAS mutation status, baseline characteristics were balanced across treatment groups. In the full analysis of first and second-line cohorts, PFS (first-line: HR = 0.85; 95% CI 0.64 to 1.13; P = 0.26; second-line: HR = 1.16; 95% CI 0.74 to 1.83; P = 0.51) and OS (first-line: HR = 0.83; 95% CI 0.61 to 1.15; P = 0.26; second-line: HR = 0.88; 95% CI 0.56 to 1.38; P = 0.58) were similar between bevacizumab and cetuximab arms. In subgroup analyses of first-line therapy, we found a survival difference favouring bevacizumab in right-sided tumours (PFS: HR = 0.52; 95% CI 0.29 to 0.93; P = 0.025; OS: HR = 0.60; 95% CI 0.32 to 1.12; P = 0.11), but not in left-sided (HR = 1.04; 95% CI 0.75 to 1.46; P = 0.81; OS: HR = 0.94; 95% CI 0.65 to 1.36; P = 0.74), or (K)RAS wild-type tumours (PFS: HR = 0.91; 95% CI 0.60 to 1.40; P = 0.67; OS: HR = 0.79; 95% CI 0.50 to 1.25; P = 0.31). Response rates were similar across treatment groups, except for the subgroup of patients bearing right-sided primaries, where bevacizumab performed substantially better. CONCLUSION: This study provides evidence suggesting bevacizumab and cetuximab lead to similar effectiveness outcomes in mCRC, except for right-sided tumours, where cetuximab seemed to show considerably poorer outcomes. Further research is needed to confirm these results.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Estudos de Coortes , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/genética , Neoplasias Retais/patologia , Estudos Retrospectivos
8.
PLoS One ; 15(2): e0226595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023246

RESUMO

Standard treatment for locally advanced rectal adenocarcinoma (LARC) includes a combination of chemotherapy with pyrimidine analogues, such as capecitabine, and radiation therapy, followed by surgery. Currently no clinically useful genomic predictors of benefit from neoadjuvant chemoradiotherapy (nCRT) exist for LARC. In this study we assessed the expression of 8,127 long noncoding RNAs (lncRNAs), poorly studied in LARC, to infer their ability in classifying patients' pathological complete response (pCR). We collected and analyzed, using lncRNA-specific Agilent microarrays a consecutive series of 61 LARC cases undergoing nCRT. Potential lncRNA predictors in responders and non-responders to nCRT were identified with LASSO regression, and a model was optimized using k-fold cross-validation after selection of the three most informative lncRNA. 11 lncRNAs were differentially expressed with false discovery rate < 0.01 between responders and non-responders to NACT. We identified lnc-KLF7-1, lnc-MAB21L2-1, and LINC00324 as the most promising variable subset for classification building. Overall sensitivity and specificity were 0.91 and 0.94 respectively, with an AUC of our ROC curve = 0.93. Our study shows for the first time that lncRNAs can accurately predict response in LARC undergoing nCRT. Our three-lncRNA based signature must be independently validated and further analyses must be conducted to fully understand the biological role of the identified signature, but our results suggest lncRNAs may be an ideal biomarker for response prediction in the studied setting.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/terapia , Quimiorradioterapia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/genética , RNA Longo não Codificante/genética , Neoplasias Retais/genética , Neoplasias Retais/terapia , Adenocarcinoma/patologia , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Análise de Componente Principal , RNA Longo não Codificante/metabolismo , Neoplasias Retais/patologia , Máquina de Vetores de Suporte
9.
Eur Radiol ; 30(4): 1948-1958, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31942672

RESUMO

OBJECTIVE: To develop a T2-weighted (T2W) image-based radiomics signature for the individual prediction of KRAS mutation status in patients with rectal cancer. METHODS: Three hundred four consecutive patients from center I with pathologically diagnosed rectal adenocarcinoma (training dataset, n = 213; internal validation dataset, n = 91) were enrolled in our retrospective study. The patients from center II (n = 86) were selected as an external validation dataset. A total of 960 imaging features were extracted from high-resolution T2W images for each patient. Five steps, mainly univariate statistical tests, were applied for feature selection. Subsequently, three classification methods, i.e., logistic regression (LR), decision tree (DT), and support vector machine (SVM) algorithm, were applied to develop the radiomics signature for KRAS prediction in the training dataset. The predictive performance was evaluated by receiver operating characteristics curve (ROC) analysis, calibration curve, and decision curve analysis (DCA). RESULTS: Seven radiomics features were screened as a KRAS-associated radiomics signature of rectal cancer. Our best prediction model was obtained with SVM classifiers with AUC of 0.722 (95%CI, 0.654-0.790) in the training dataset. This was validated in the internal and external validation datasets with good calibration, and the corresponding AUCs were 0.682 (95% CI, 0.569-0.794) and 0.714 (95% CI, 0.602-0.827), respectively. DCA confirmed its clinical usefulness. CONCLUSIONS: The proposed T2WI-based radiomics signature has a moderate performance to predict KRAS status, and may be useful for supplementing genomic analysis to determine KRAS expression in rectal cancer patients. KEY POINTS: • T2WI-based radiomics showed a moderate diagnostic significance for KRAS status. • The best prediction model was obtained with SVM classifier. • The baseline clinical and histopathological characteristics were not associated with KRAS mutation.


Assuntos
Algoritmos , DNA de Neoplasias/genética , Imagem por Ressonância Magnética/métodos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/diagnóstico , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Curva ROC , Neoplasias Retais/genética , Neoplasias Retais/metabolismo , Estudos Retrospectivos , Máquina de Vetores de Suporte
10.
Dis Markers ; 2020: 8459303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998419

RESUMO

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p = 0.016, r = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.


Assuntos
Carcinoma/genética , Terapia Neoadjuvante , Neoplasias Retais/genética , Adulto , Idoso , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/terapia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Cancer Sci ; 111(4): 1291-1302, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31997546

RESUMO

Postoperative distant metastasis dramatically affects rectal cancer patients who have undergone neoadjuvant chemoradiotherapy (NACRT). Here, we clarified the association between NACRT-mediated mammalian target of rapamycin (mTOR) signaling pathway activation and rectal cancer metastatic potential. We performed immunohistochemistry for phosphorylated mTOR (p-mTOR) and phosphorylated S6 (p-S6) on surgical specimen blocks from 98 rectal cancer patients after NACRT (cohort 1) and 80 colorectal cancer patients without NACRT (cohort 2). In addition, we investigated the association between mTOR pathway activity, affected by irradiation, and the migration ability of colorectal cancer cells in vitro. Based on the results of the clinical study, p-mTOR was significantly overexpressed in cohort 1 (with NACRT) as compared to levels in cohort 2 (without NACRT) (P < .001). High p-mTOR and p-S6 levels correlated with the development of distant metastasis only in cohort 1. Specifically, high p-S6 expression (HR 4.51, P = .002) and high pathological T-stage (HR 3.73, P = .020) after NACRT were independent predictors of the development of distant metastasis. In vitro, p-S6 levels and migration ability increased after irradiation in SW480 cells (TP53 mutation-type) but decreased in LoVo cells (TP53 wild-type), suggesting that irradiation modulates mTOR signaling and migration through cell type-dependent mechanisms. We next assessed the expression level of p53 by immunostaining in cohort 1 and demonstrated that p-S6 was overexpressed in samples with high p53 expression as compared to levels in samples with low p53 expression (P = .008). In conclusion, p-S6 levels after NACRT correlate with postoperative distant metastasis in rectal cancer patients, suggesting that chemoradiotherapy might modulate the mTOR signaling pathway, promoting metastasis.


Assuntos
Neoplasias Retais/tratamento farmacológico , Proteína S6 Ribossômica/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia Adjuvante/efeitos adversos , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Retais/genética , Neoplasias Retais/patologia , Neoplasias Retais/radioterapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
12.
Biomed Pharmacother ; 124: 109740, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972361

RESUMO

On account of the acquired drug resistance, the potency of cisplatin-based chemotherapy is far from satisfactory in rectal cancer. Increasing evidence has highlighted the crucial function of aberrantly expressed lncRNAs on the cisplatin resistance in multiple cancers. This research was the first attempt to decipher the underlying function and mechanism of long intergenic non-protein coding RNA 461 (LINC00461) in rectal cancer and also its relation to cisplatin resistance of rectal cancer. Data from this study revealed that LINC00461 expression was upregulated in rectal cancer cells. LINC00461 depletion restrained rectal cancer progression and sensitized rectal cancer cells to cisplatin. Molecular mechanism assays testified that LINC00461 bound with miR-593-5p. Besides, miR-593-5p upregulation improved the sensitivity of rectal cancer cells to cisplatin. Additionally, cyclin D1 (CCND1) was manifested to be a downstream target of miR-593-5p. Furthermore, CCND1 upregulation could reverse the effect of LINC00461 downregulation on rectal cancer progression and cisplatin resistance of rectal cancer. To sum up, LINC00461 mediates cisplatin resistance of rectal cancer by targeting miR-593-5p/CCND1 axis, shedding new light on the treatment of rectal cancer.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , RNA Longo não Codificante/genética , Neoplasias Retais/tratamento farmacológico , Linhagem Celular Tumoral , Ciclina D1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Retais/genética , Regulação para Cima
13.
Cancer Res Treat ; 52(1): 51-59, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31096736

RESUMO

PURPOSE: Mutation of the Kirsten Ras (KRAS) oncogene is present in 30%-40% of colorectal cancers and has prognostic significance in rectal cancer. In this study, we examined the ability of radiomics features extracted from T2-weighted magnetic resonance (MR) images to differentiate between tumors with mutant KRAS and wild-type KRAS. Materials and Methods: Sixty patients with primary rectal cancer (25 with mutant KRAS, 35 with wild-type KRAS) were retrospectively enrolled. Texture analysis was performed in all regions of interest on MR images, which were manually segmented by two independent radiologists. We identified potentially useful imaging features using the two-tailed t test and used them to build a discriminant model with a decision tree to estimate whether KRAS mutation had occurred. RESULTS: Three radiomic features were significantly associated with KRASmutational status (p < 0.05). The mean (and standard deviation) skewness with gradient filter value was significantly higher in the mutant KRAS group than in the wild-type group (2.04±0.94 vs. 1.59±0.69). Higher standard deviations for medium texture (SSF3 and SSF4) were able to differentiate mutant KRAS (139.81±44.19 and 267.12±89.75, respectively) and wild-type KRAS (114.55±29.30 and 224.78±62.20). The final decision tree comprised three decision nodes and four terminal nodes, two of which designated KRAS mutation. The sensitivity, specificity, and accuracy of the decision tree was 84%, 80%, and 81.7%, respectively. CONCLUSION: Using MR-based texture analysis, we identified three imaging features that could differentiate mutant from wild-type KRAS. T2-weighted images could be used to predict KRAS mutation status preoperatively in patients with rectal cancer.


Assuntos
Imagem por Ressonância Magnética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/diagnóstico , Neoplasias Retais/genética , Idoso , Tomada de Decisão Clínica , Árvores de Decisões , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC
14.
Int J Cancer ; 146(1): 94-102, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199501

RESUMO

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , GTP Fosfo-Hidrolases/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/genética , Proteína Supressora de Tumor p53/genética , Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
15.
Ann Surg ; 271(4): 716-723, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30216221

RESUMO

OBJECTIVE: The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. BACKGROUND: We utilized the National Cancer Database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. METHODS: We analyzed 5086 patients between 2010 and 2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4450 MSI-negative(-) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional-hazard ratios were used for survival. RESULTS: All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher-grade tumors (P < 0.05).The overall pCR rate was 8.6%, including 8.9% for MSI(-) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (odds ratio 0.65, 95% confidence interval 0.43-0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared with 73% without it (<0.001). CONCLUSION: Microsatellite instability was independently associated with a reduction in pCR for locally advanced rectal cancer after neoadjuvant chemoradiation in this NCDB-based analysis.


Assuntos
Instabilidade de Microssatélites , Neoplasias Retais/genética , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante
16.
J Cancer Res Clin Oncol ; 146(1): 105-115, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31781865

RESUMO

PURPOSE: We aimed to identify biomarkers of response to preoperative CRT in patients with LARC using comprehensive miRNA analysis. METHODS: This study included 65 rectal cancer specimens and 89 serum samples from patients diagnosed with LARC and treated with preoperative. All specimens were collected before CRT for evaluation of biologic differences between the good and poor CRT response groups (ypStage 0/I versus II/III/IV). For specific miRNA discovery, 800 miRNAs in 20 rectal cancer specimens were analyzed with a NanoString assay. For validation, a total of 65 tissue and 89 serum samples were tested with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the discovery set, 16 target miRNAs were detected. In the validation set, higher expression of three miRNAs (miR-199a/b-3p, miR-199a-5p, and miR-199b-5p) was significantly associated with better response to CRT. In the univariate survival analysis, upregulation of these three miRNAs was associated with superior relapse-free survival (RFS) and overall survival (OS). Meanwhile, only a higher level of tissue miR-199a-5p was associated with superior RFS [hazard ratio (HR), 0.0.91; 95% confidence interval (CI) 0.035-0.580; p = 0.002] and OS (HR, 0.272; 95% CI 0.023-0.658; p < 0.001) in the multivariate survival analysis. Also, a higher level of exosomal miR-199b-5p correlated with better response to CRT (p = 0.0397). CONCLUSION: High expression of tissue miR-199a/b-3p, miR-199a-5p, and miR-199b-5p was significantly associated with response to CRT, and a high level of tissue miR-199a-5p was associated with superior survival outcomes. Also, upregulated exosomal miR-199b-5p correlated with CRT response, reflecting its promise as a circulating biomarker of CRT response in patients with LARC.


Assuntos
MicroRNAs/biossíntese , Neoplasias Retais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/metabolismo , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Taxa de Sobrevida
17.
Clin Cancer Res ; 26(1): 183-192, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31852830

RESUMO

PURPOSE: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer. EXPERIMENTAL DESIGN: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan-Meier method and Cox regression. RESULTS: ctDNA detection rates were: 74% (n = 35/47) pretreatment, 21% (n = 10/47) mid CRT, 21% (n = 10/47) after completing CRT, and 13% (n = 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P = 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4-21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2-11.7; P = 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3-40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of ≥0.07% mid CRT or ≥0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P = 0.001). CONCLUSIONS: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.


Assuntos
Biomarcadores Tumorais/genética , Quimiorradioterapia/métodos , DNA Tumoral Circulante/sangue , Imagem por Ressonância Magnética/métodos , Mutação , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/patologia , Adulto , Idoso , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Medicina de Precisão , Estudos Prospectivos , Neoplasias Retais/sangue , Neoplasias Retais/genética , Neoplasias Retais/terapia , Fatores de Risco , Resultado do Tratamento
18.
Updates Surg ; 72(1): 73-82, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31863279

RESUMO

Recently, individualized approaches for the treatment of locally advanced rectal cancers (RC) have been introduced to determine the most beneficial one for boosting the tumor response and assessing the response more accurately. However, despite each patient and tumor have different molecular features, the studies at the molecular level are very limited. In this study, examining the clinical factors which are predictive of pathologic complete response (pCR), helping to determine a treatment program for the management of patients with locally advanced RC, and evaluating the relation between regression grade and MMR-MSI were aimed. 341 RC cases who had undergone surgery were included and divided into three groups according to their response to neoadjuvant treatment. The following parameters were analyzed for all patients: age at diagnosis, sex, tumor location, tumor differentiation, TNM stage, histological subtype, CEA (mean: < 5 ng/ml) level, lymphovascular-neural invasion, presence of mucinous subtype, grade, MMR, and MSI statuses. 147 patients (43.2%) had no response (group 1), 141 patients (41.3%) had an intermediate response (group 2), and 53 patients (15.5%) had a complete response (group 3). Neoadjuvant chemoradiotherapy was used in all of the patients with the same protocol. Multivariate analysis revealed that clinical T stage (p: 0.099) and MMR (p: 0.048) were the parameters which were significantly associated with pCR. Since MMR and MSI statuses were found to affect pCR, more careful patient selection for "watch and wait" protocol and further studies on molecular structures of the tumors for individualized therapies are required.


Assuntos
Quimiorradioterapia Adjuvante , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Humanos , Seleção de Pacientes , Neoplasias Retais/patologia
19.
Dis Colon Rectum ; 63(3): 300-309, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31842156

RESUMO

BACKGROUND: Patients with rectal cancer may undergo neoadjuvant chemoradiation even in early stages in an attempt to achieve complete clinical response and undergo organ preservation. However, prediction of tumor response is unavailable. In this setting, accurate identification of poor responders could spare patients with early stage disease from potentially unnecessary chemoradiation. OBJECTIVE: This study focused on development/test of a score based on DNA repair gene expression to predict response to neoadjuvant chemoradiation in patients with rectal cancer. DESIGN: Pretreatment biopsy samples from patients with rectal cancer undergoing neoadjuvant chemoradiation were collected and underwent gene expression analysis using RNA-Seq (test cohort). A score was constructed using 8 differentially expressed DNA repair genes between good (complete clinical) and poor responders (incomplete clinical) to treatment. The score was validated in 2 independent cohorts of patients undergoing similar treatment strategies and using quantitative polymerase chain reaction and microarray gene expression data. SETTINGS: This was a retrospective analysis of gene expression data from 3 independent institutions. PATIENTS: Patients with rectal cancer undergoing neoadjuvant chemoradiation (50.4-54.0 Gy and 5-fluorouracil-based chemotherapy) were eligible. Patients with complete clinical response, complete pathological response, or ≤10% residual cancer cells were considered good responders. Patients with >10% residual cancer cells were considered poor responders. The test cohort included 25 patients (16 poor responders). Validation cohort 1 included 28 patients (18 poor responders), and validation cohort 2 included 46 patients (22 poor responders). MAIN OUTCOMES MEASURES: Response was correlated with the DNA repair score calculated using the expression levels of 8 DNA repair genes. DNA repair score sensitivity, specificity, and positive and negative predictive values were determined in test and validation cohorts. RESULTS: Poor responders had significantly lower DNA repair scores when compared with good responders across all 3 cohorts, regardless of the gene expression platform used. A low score correctly predicted poor response in 93%, 90%, and 71% in test, validation 1, and validation 2 cohorts. LIMITATIONS: This study was limited by its small sample size, different gene expression platforms, and treatment regimens across different cohorts used. CONCLUSIONS: A DNA repair gene score may predict patients likely to have poor response to chemoradiation. This score may be a relevant tool to be investigated in future studies focused on chemoradiation used in the context of organ preservation. See Video Abstract at http://links.lww.com/DCR/B104. PREDICCIÓN DE RESPUESTA DEFICIENTE A LA RADIO-QUIMIOTERAPIA NEOADYUVANTE EN PACIENTES CON CÁNCER RECTAL UTILIZANDO UNA PUNTUACIÓN DE DESREGULACIÓN DE REPARACIÓN DE ADN: ESCOGER LOS PERDEDORES EN LUGAR DE LOS GANADORES: Los pacientes con cáncer rectal pueden someterse a radio-quimioterapia neoadyuvante incluso en estadios tempranos en el intento por lograr una respuesta clínica completa y permitir una preservación de órgano. Sin embargo, aun no existen herramientas disponible para la prediccion de la respuesta tumoral al tratamiento. En este contexto, la identificación precisa de los tumores con mala respuesta al tratamiento podría evitar que los pacientes con enfermedad en estadio temprano sean sometidos a radio-quimioterapia potencialmente innecesaria.Desarrollo / testeo de una puntuación basada en la expresión genes reparadores del ADN para predecir la respuesta a la nCRT en pacientes con cáncer rectal.Se recogieron muestras de biopsia de pre-tratamiento de pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante y se les realizó un análisis de expresión génica utilizando RNAseq (cohorte de prueba). Se construyó una puntuación utilizando 8 genes de reparación de ADN expresados diferencialmente entre buenos (respuesta clinica completa) y pobres respondedores (respuesta clinica incompleta) al tratamiento. La puntuación se validó en 2 cohortes independientes de pacientes sometidos a estrategias de tratamiento similares y utilizando qPCR y datos de expresión de genes en chips ADN (biotecnología -microarrays).Análisis retrospectivo de los datos de expresión génica de 3 instituciones independientes.Fueron incluidos aquellos pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante (50,4-54 Gy y quimioterapia basada en 5FU). Los pacientes con respuesta clínica completa, respuesta patológica completa o ≤10% de células cancerosas residuales se consideraron buenos respondedores. Los pacientes con> 10% de células cancerosas residuales se consideraron de respuesta deficiente. La cohorte de prueba incluyó a 25 pacientes (16 respondedores pobres). La cohorte de validación n. ° 1 incluyó a 28 pacientes (18 respondedores pobres) y la cohorte de validación n. ° 2 incluyó a 46 pacientes (22 respondedores pobres).La respuesta se correlacionó con la puntuación de reparación de ADN calculada utilizando los niveles de expresión de 8 genes de reparación de ADN. La sensibilidad del puntaje de reparación del ADN, la especificidad, los valores predictivos positivos y negativos se determinaron en las cohortes de prueba y validación.Los malos respondedores tuvieron puntuaciones de reparación de ADN significativamente más bajas en comparación con los buenos respondedores en las 3 cohortes, independientemente de la plataforma de expresión génica utilizada. Una puntuación baja predijo correctamente una respuesta pobre en el 93%, 90% y 71% en las cohortes de prueba, validación n. ° 1 y validación n. ° 2, respectivamente.Pequeño tamaño de la muestra, diferentes plataformas de expresión génica y regímenes de tratamiento en diferentes cohortes utilizadas.La puntuacion basada en genes de reparación del ADN puede predecir los pacientes con respuesta pobre a la radio-quimioterapia. Esta puntuación puede ser una herramienta relevante para investigar en futuros estudios centrados en la radio-quimioterapia utilizada en el contexto de la preservación de órganos. Consulte Video Resumen en http://links.lww.com/DCR/B104. (Traducción-Dr. Xavier Delgadillo and Dr. Laura Melina Fernandez).


Assuntos
Quimiorradioterapia , Reparo do DNA/genética , Perfilação da Expressão Gênica , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Biópsia , Colectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Strahlenther Onkol ; 196(5): 465-473, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31828392

RESUMO

PURPOSE: Considering the effects of P53 binding protein 1 (53BP1) expression and T lymphocyte infiltration density on tumor radiosensitivity, we investigated the relation of 53BP1 expression and immunoscore based on T lymphocyte infiltration density with the efficacy of neoadjuvant chemoradiotherapy (CRT) for rectal cancer. METHODS: Fifty-five patients with rectal cancer receiving neoadjuvant CRT followed by surgery were enrolled. The 53BP1 expression level and the density of CD3+, CD8+, and CD45RO+ T lymphocytes in the tumor tissues were examined by immunohistochemistry, and the relation of these findings to the rates of tumor regression, disease-free survival (DFS), and overall survival (OS) was analyzed. RESULTS: The levels of 53BP1 and the CD3/CD8 immunoscore were closely correlated with the response to CRT (p < 0.05), with an area under the receiver operating characteristic curve for CRT efficacy prediction of 0.626 and 0.717, respectively. Further survival analysis revealed that high 53BP1 expression effectively prolonged 2­year DFS compared with low 53BP1 expression (87.5% [95%CI 77.3-97.7] vs. 53.3% [95%CI 28.1-78.6]; p < 0.05), while the effect of immunoscore on survival was restricted by the expression status of 53BP1. Cox multivariate analysis confirmed 53BP1 as an independent prognostic factor in DFS. CONCLUSION: The pretreatment levels of 53BP1 and the immunoscore based on CD3+/CD8+ T cell infiltration density in tumor tissues are effective predictors for the CRT response, and 53BP1 has a more pronounced impact on prognosis.


Assuntos
Quimiorradioterapia Adjuvante , Regulação Neoplásica da Expressão Gênica/genética , Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imuno-Histoquímica , Contagem de Leucócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/patologia , Linfócitos do Interstício Tumoral/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Protectomia , Tolerância a Radiação , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Linfócitos T/efeitos da radiação , Resultado do Tratamento , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/análise , Adulto Jovem
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