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1.
Endocr Pract ; 27(6): 607-613, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34120701

RESUMO

OBJECTIVE: The American Joint Committee on Cancer tumor node metastasis (TNM) staging system eighth edition (TNM-8) for differentiated thyroid cancer (DTC) has been introduced as a replacement for tumor node metastasis staging system seventh edition (TNM-7). We present the first study from a Middle Eastern population comparing these 2 versions of the TNM staging system. METHODS: We compared TNM-8 with TNM-7 in 701 patients with DTC seen during a 3-year period with a median age of 37 years (6-83) and a female-to-male ratio of 558 (79.6%) to 143 (20.4%). RESULTS: The number (%) of patients within each stage in TNM-7 and TNM-8, respectively, are as follows: stage I = 503 (71.6%) and 583 (83.2%), stage II = 52 (7.4%) and 81 (11.4%), stage III = 53 (7.6%) and 6 (0.9%), and stage IV = 93 (13.2%) and 31 (4.6%). Overall, 172 patients (24.5%) were downstaged in TNM-8 compared to that in TNM-7, as follows: 26, 30, and 24 patients from stages II, III, and IV in TNM-7 to stage I in TNM-8; 23 and 32 patients from TNM-7 stages III and IV to TNM-8 stage II; 6 patients from stage IVa in TNM-7 to stage III in TNM-8; and 31 patients from stage IVc in TNM-7 to stage IVb in TNM-8. TNM-7 and TNM-8 predicted the long-term outcome well (median follow-up, 7.9 years), but Kaplan-Meier analysis showed better separation of cancer-specific survival in TNM-8 compared to TNM-7. CONCLUSIONS: Compared with TNM-7, TNM-8 approximately downstaged a quarter of DTC patients and was more robust in separating the outcome of different stages over time.


Assuntos
Neoplasias da Glândula Tireoide , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Hospitais , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
2.
Nat Commun ; 12(1): 3464, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103493

RESUMO

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/patologia , Diferenciação Celular , Sobrevivência Celular , Colo/patologia , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Feto/patologia , Inflamação/patologia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
3.
Sci Rep ; 11(1): 11334, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059708

RESUMO

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy. The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia. Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death). A total of 449 patients were included: 39% female, median age 63 (IQR, 50-77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95% CI 3.2-26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7-15.9) in those exposed to pLMWH; p-value = 0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95% CI 0.51-3.79) for patients with an admission PaO2/FiO2 ≤ 300 mmHg and 0.27 (0.03-2.18) for those with PaO2/FiO2 > 300 mmHg; p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Heparina de Baixo Peso Molecular/uso terapêutico , Intubação Intratraqueal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Idoso , COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Cidade de Roma , Índice de Gravidade de Doença
4.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070214

RESUMO

During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10-4) by Kaplan-Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10-4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10-4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.


Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Queratina-7/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Cistadenocarcinoma Seroso/mortalidade , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-19/metabolismo , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Neoplasias Gástricas/metabolismo , Vimentina/metabolismo
5.
Zhonghua Bing Li Xue Za Zhi ; 50(6): 645-649, 2021 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-34078054

RESUMO

Objective: To identify important prognostic molecular markers of triple negative breast cancer (TNBC) using high throughput sequencing technology and to explore the correlation of spindle checkpoint protein BUB1B and clinicopathological features with patients' prognosis. Methods: The clinicopathological data and prognostic information of TNBC diagnosed at the West China Hospital of Sichuan University from 2009 to 2017 were collected. Forty-seven fresh tumor samples and 139 formalin fixed paraffin-embedded samples were selected. The fresh tumor samples were subject to RNA sequencing (RNA-seq). The enrichment analysis and protein-protein interaction (PPI) analysis were performed after intersection of difference analysis between RNAseq and GEO (Gene Expression Omnibus) datasets GSE38959 and GSE65194. Kaplan-Meier plotter database was used to analyze the relationship between expression of BUB1B and prognosis. Immunohistochemical staining was used to verify its expression in TNBC and correlation with clinicopathological features and prognosis. Results: Using edgeR to perform differential expression analysis between 47 TNBC tumor tissues and 12 normal tissues, 1 559 up-regulated genes and 1 376 down-regulated genes were identified, while only 131 differentially expressed genes were overlapping with those in GSE38959 and GSE65194. Enrichment analysis was mainly enriched in cell cycle, JAK-STAT signaling pathway and p53 signaling pathway. The top 10 genes ranked by degree of association were TOP2A, BUB1B, MKI67, PLK1, RRM2, PCNA, KPNA2, SMC4, PBK and IGF1. Kaplan-Meier plotter database analysis showed that the expression of BUB1B was significantly correlated with the prognosis of TNBC [overall survival, hazard ratio (HR)=0.52, 95%CI (0.35-0.77), P=0.001; distant metastasis-free, HR=0.72, 95%CI (0.52-0.98), P=0.038]. The immunohistochemical analyses of 139 formalin fixed paraffin-embedded samples showed that the low expression of BUB1B was correlated with poor prognosis in TNBC [HR=0.41, 95%CI (0.18-0.95), P=0.024]. Conclusions: The low expression of BUB1B protein is associated with poor prognosis in TNBC patients, and the molecular mechanism related with prognosis and potential therapeutic targets need to be further studied.


Assuntos
Neoplasias de Mama Triplo Negativas , Proteínas de Ciclo Celular/genética , China , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Neoplasias de Mama Triplo Negativas/genética
6.
BMC Genomics ; 22(Suppl 1): 436, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112093

RESUMO

BACKGROUND: Gene interaction patterns, including modules and motifs, can be used to identify cancer specific biomarkers and to reveal the mechanism of tumorigenesis. Most of the existing module network inferencing methods focus on gene independent functional patterns, while the studies of overlapping characteristics between modules are lacking. The objective of this study was to reveal the functional overlapping patterns in gene modules, helping elucidate the regulatory relationship between overlapping genes and communities, as well as to explore cancer formation and progression. RESULTS: We analyzed six cancer datasets from The Cancer Genome Atlas and obtained three kinds of gene functional modules for each cancer, including Independent-Community, Dependent-Community and Merged-Community. In the six cancers, 59(3.5%) Independent-Communities were identified, while 1631(96.5%) Dependent-Communities were acquired. Compared with Lemon-Tree and K-Means, the gene communities identified by our method were enriched in more known GO categories with lower p-values. Meanwhile, those identified distinguishing communities can significantly distinguish the survival prognostic of patients by Kaplan-Meier analysis. Furthermore, identified driver genes in the gene communities can be considered as biomarkers which can accurately distinguish the tumour or normal samples for each cancer type. CONCLUSIONS: In all identified communities, Dependent-Communities are the majority. Our method is more effective than the other two methods which do not consider the overlapping characteristics of modules. This indicates that overlapping genes are located in different specific functional groups, and a communication bridge is established between the communities to construct a comprehensive carcinogenesis.


Assuntos
Redes Reguladoras de Genes , Neoplasias , Carcinogênese , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias/genética , Prognóstico
7.
Braz J Med Biol Res ; 54(7): e10612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34008756

RESUMO

Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors (PBT) that may lead to novel therapeutic strategies. Participants of the cohort Pediatric Brain Tumor Atlas: CBTTC (CBTTC cohort), were randomly divided into training and validation cohorts. In the training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied to preliminary screening of prognostic genes. The LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation and CBTTC cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. Also, gene set enrichment analysis (GSEA) and immune infiltrating analyses were conducted to understand function annotation and the role of the signature in the tumor microenvironment. An eight-gene signature was built, which was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen, either in the training or validation cohorts. The eight-gene signature was further proven to be independent of other clinic-pathologic parameters via the Cox regression analyses. Moreover, ROC analysis demonstrated that this signature owned a better predictive power of PBT prognosis. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and was closely related to CD8 T cells and monocytes in the tumor environment. Identifying the eight-gene signature (CBX7, JADE2, IGF2BP3, OR2W6P, PRAME, TICRR, KIF4A, and PIMREG) could accurately identify patients' prognosis and the signature had close interactions with the immunodominant tumor environment, which may provide insight into personalized prognosis prediction and new therapies for PBT patients.


Assuntos
Neoplasias Encefálicas , Perfilação da Expressão Gênica , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Criança , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Complexo Repressor Polycomb 1 , Prognóstico , Microambiente Tumoral
8.
Medicine (Baltimore) ; 100(21): e26015, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032720

RESUMO

ABSTRACT: The purpose of this study was to determine the glucose metabolism at delay phase measured by pretreatment dual-time-point 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/ computed tomography (CT) provides prognostic information independent of well-known prognostic factors in patients with intrahepatic or perihilar cholangiocarcinoma (ICC or PCC).From July 2012 to December 2017, 55 patients (men 27, women 28, mean age 68 ±â€Š11 years) with pathologically proven ICC or PCC were enrolled in this retrospective study. The dual-time-point 18F-FDG PET/CT as part of a staging workup was performed in all patients. The patient's data includes age, sex, serum CA19-9, presence of LN or distant metastasis, early SUVmax (early maximum standardized uptake value [eSUV]), delay SUVmax (delay maximum standardized uptake value [dSUV]), retention index of SUVmax (percent change of maximum standardized uptake values [ΔSUV]), neutrophil to lymphocyte ratio (NLR) and histopathology including pCEA, p53, Ki-67 index. The analysis of the relationship between metabolic parameters and survival was done using the Kaplan-Meier curve and Cox proportional hazards regression model.Median survival for all patients was 357 days. Median early and delay SUVmax was 5.2 (range: 2.0-21.4) and 6.5 (range 2.7-24.5), respectively. The overall survival was found to be significantly related to eSUV, dSUV, ΔSUV, age, serum CA19-9 and NLR in univariate analysis. In multivariate analysis, dSUV (P = .014, 95%CI; 1.30-10.7, HR 3.74) and ΔSUVmax (P = .037, 95%CI; 1.05-6.12, HR 2.5) were independent factors of overall survival. Kaplan-Meier curve analysis clearly showed the significant difference of overall survival between 2 groups (high eSUV, low eSUV + high ΔSUV vs low eSUV and ΔSUV, P < .001) among the comparisons of the SUV parameters on FDG PET. In the receiver operating characteristic analysis using combinations of the SUV parameters, the 2 groups [eSUV + ΔSUV (P = .0001, area under the curve [AUC] 0.68) and dSUV + ΔSUV (P = .0002, AUC 0.71)] showed significantly larger AUC than the other groups applying eSUV or dSUV alone (AUC 0.61 and AUC 0.68).dSUV and ΔSUV on pretreatment dual-time-point 18F-FDG PET/CT can be useful parameters in the prediction of survival in patients with ICC or PCC.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Tumor de Klatskin/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Tumor de Klatskin/diagnóstico , Tumor de Klatskin/patologia , Tumor de Klatskin/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos
9.
Anticancer Res ; 41(5): 2357-2362, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952460

RESUMO

BACKGROUND: Death associated proteins (DAPs) are involved in the apoptosis of various cell types in response to interferon gamma, including cancer cells. The present study assessed both DAP1 and DAP3 in human pancreatic cancer. MATERIALS AND METHODS: DAP1 and DAP3 transcripts were quantitatively analysed in pancreatic tumour tissues and paired adjacent normal tissues using real time PCR followed by statistical analyses for their clinical implications. RESULTS: Levels of DAP3 transcripts in pancreatic cancer were markedly higher than in normal tissues, whereas DAP1 had lower levels in cancer versus normal tissues. Adenocarcinomas showed higher levels of DAP3 than other histological types. Patients with high levels of DAP3 had a significantly shorter overall survival than those with low levels (p=0.012). The status of DAP3 and lymph node involvement identified patients with poor survival (p<0.00001). CONCLUSION: DAP3 was highly expressed in pancreatic tumour tissues and was significantly associated with shorter survival.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias Pancreáticas/genética , Proteínas de Ligação a RNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia
10.
Medicine (Baltimore) ; 100(18): e25880, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951002

RESUMO

ABSTRACT: Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I-II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan-Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18-35 and 36-40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846-0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859-0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36-40 years) group while there was no significant survival difference in the younger group (18-35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.


Assuntos
Neoplasias da Mama/cirurgia , Tomada de Decisão Clínica , Mastectomia Segmentar/estatística & dados numéricos , Mastectomia/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Contraindicações de Procedimentos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar/efeitos adversos , Estadiamento de Neoplasias , Prognóstico , Medição de Risco/estatística & dados numéricos , Programa de SEER/estatística & dados numéricos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
11.
Sci Rep ; 11(1): 9626, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953307

RESUMO

Early classification and risk assessment for COVID-19 patients are critical for improving their terminal prognosis, and preventing the patients deteriorate into severe or critical situation. We performed a retrospective study on 222 COVID-19 patients in Wuhan treated between January 23rd and February 28th, 2020. A decision tree algorithm has been established including multiple factor logistic for cluster analyses that were performed to assess the predictive value of presumptive clinical diagnosis and features including characteristic signs and symptoms of COVID-19 patients. Therapeutic efficacy was evaluated by adopting Kaplan-Meier survival curve analysis and cox risk regression. The 222 patients were then clustered into two groups: cluster I (common type) and cluster II (high-risk type). High-risk cases can be judged from their clinical characteristics, including: age > 50 years, chest CT images with multiple ground glass or wetting shadows, etc. Based on the classification analysis and risk factor analysis, a decision tree algorithm and management flow chart were established, which can help well recognize individuals who needs hospitalization and improve the clinical prognosis of the COVID-19 patients. Our risk factor analysis and management process suggestions are useful for improving the overall clinical prognosis and optimize the utilization of public health resources during treatment of COVID-19 patients.


Assuntos
/tratamento farmacológico , Idoso , Antivirais/uso terapêutico , /etiologia , China/epidemiologia , Análise por Conglomerados , Comorbidade , Sistemas de Apoio a Decisões Clínicas , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
12.
Medicine (Baltimore) ; 100(21): e26017, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032721

RESUMO

ABSTRACT: Skin melanoma remains a highly prevalent and yet deadly form of cancer, with the exact degree of melanoma-associated mortality being strongly dependent upon the local tumor microenvironment. The exact composition of stromal and immune cells within this microenvironmental region has the potential to profoundly impact melanoma progression and prognosis. As such, the present study was designed with the goal of clarifying the predictive relevance of stromal and immune cell-related genes in melanoma patients through comprehensive bioinformatics analyses. We therefore analyzed melanoma sample gene expression within The Cancer Genome Atlas database and employed the ESTIMATE algorithm as a means of calculating both stromal and immune scores that were in turn used for identifying differentially expressed genes (DEGs). Subsequently, univariate analyses were used to detect DEGs associated with melanoma patient survival, and through additional functional enrichment analyses, we determined that these survival-related DEGs are largely related to inflammatory and immune responses. A prognostic signature comprised of 10 genes (IL15, CCL8, CLIC2, SAMD9L, TLR2, HLA.DQB1, IGHV1-18, RARRES3, GBP4, APOBEC3G) was generated. This 10-gene signature effectively separated melanoma patients into low- and high-risk groups based upon their survival. These low- and high-risk groups also exhibited distinct immune statuses and differing degrees of immune cell infiltration. In conclusion, our results offer novel insights into a number of microenvironment-associated genes that impact survival outcomes in melanoma patients, potentially highlighting these genes as viable therapeutic targets.


Assuntos
Biomarcadores Tumorais/genética , Melanoma/mortalidade , Transcriptoma/genética , Microambiente Tumoral/genética , Adulto , Idoso , Algoritmos , Biomarcadores Tumorais/imunologia , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , Medição de Risco/métodos , Transcriptoma/imunologia , Microambiente Tumoral/imunologia
13.
Medicine (Baltimore) ; 100(21): e26170, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032778

RESUMO

ABSTRACT: To identify prognostic tumor-infiltrating immune cells of endometrial adenocarcinoma.The gene expression profiles of endometrial adenocarcinoma were downloaded from the Cancer Genome Atlas (TCGA). The abundance of tumor-infiltrating immune cells in endometrial adenocarcinoma samples was calculated by CIBERSORT algorithm. Kaplan-Meier analysis was used to identify prognostic tumor-infiltrating immune cells.This study identified 22 kinds of tumor-infiltrating immune cells. Macrophages M0 and CD8 T cells were prognostic factors of endometrial adenocarcinoma. The abundance of macrophages M0 (P = .038) was significantly correlated with better prognosis of endometrial adenocarcinoma. In contrast, the abundance of CD8 T cells (P = .049) was associated with poor prognosis of endometrial adenocarcinoma.Tumor-infiltrati macrophages M0 and CD8 T cells were prognostic factors of endometrial adenocarcinoma.


Assuntos
Adenocarcinoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Endométrio/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Algoritmos , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Microambiente Tumoral
14.
Nat Commun ; 12(1): 2482, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931647

RESUMO

While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.


Assuntos
Apoptose/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Haploinsuficiência , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , Dipeptídeos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Genes Supressores de Tumor , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Indóis/farmacologia , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Análise Serial de Proteínas , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
15.
Medicine (Baltimore) ; 100(18): e25811, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950985

RESUMO

ABSTRACT: This study aims to explore the prognostic variables for elderly papillary thyroid microcarcinoma (PTMC) patients as well as create a nomogram that could predict the occurrence of cervical lymph node metastasis (CLNM) on the basis of a large population database with high quality.A total of 5165 PTMC patients from Surveillance, Epidemiology, and End Results database database were enrolled in the study. In the meantime, we retrospectively collected 205 PTMC patients who underwent thyroidectomy in our medical center as an external control to test the accuracy of the model. The independent predictors of survival were identified by multivariate Cox regression analysis. Risk factors were selected as nomogram parameters to develop a model to predict CLNM. The C-index and calibration plots were used to evaluate CLNM model discrimination. The predictive nomogram was further validated in the external validation set.76.8% of the enrolled patients underwent thyroidectomy. Overall survival and cancer-specific survival were significantly better in patients who underwent surgery than in those who did not (P < .001). Sex, tumor size, and extent of tumor were included in a multivariable logistic regression model to predict lymph node metastasis. The nomogram had good discrimination with a C-index of 0.71. The calibration curves showed perfect agreement between nomogram predictions and actual observations.Elderly PTMC patients who received a surgical approach without radiotherapy showed survival advantage than those with other treatment strategies. Moreover, a nomogram model was established to predict the risk of CLNM, which will help clinicians in making treatment decisions.


Assuntos
Metástase Linfática/diagnóstico , Nomogramas , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/efeitos adversos , Estimativa de Kaplan-Meier , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pescoço , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Taxa de Sobrevida , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento
16.
Medicine (Baltimore) ; 100(18): e25834, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950994

RESUMO

ABSTRACT: Chromosomal aberrations are generally considered to have a remarkable impact on the outcome of multiple myeloma. Bortezomib helps to achieve complete responses and leads to longer life expectancy in many multiple myeloma patients. This study was designed to clarify whether bortezomib can improve the poor prognosis resulting from del(17q13), del(13q14), amp(1q21), t(4,14), t(14,16) in patients with multiple myeloma. A total of 255 MM patients treated with bortezomib-based regimens were included in this study. All chromosomal aberrations were detected by interphase fluorescence in situ hybridization. Kaplan-Meier survival and Multivariable Cox regression analysis were employed to assess the prognostic situation in progression-free survival and overall survival. The result showed that the progression-free survival and overall survival of patients with del(17q13) were shorter than those without del(17q13) in multivariate analysis and patients with del(13q14), amp(1q21), t(4,14), t(14,16) were similar to patients without these chromosomal aberrations in progression-free survival and overall survival after receiving bortezomib-based regimens.In conclusion Bortezomib-based regimens can overcome the poor prognosis derived from del(13q14), amp(1q21), t(4,14), t(14,16) but not del(17q13).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Aberrações Cromossômicas , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Tempo
17.
Anticancer Res ; 41(5): 2495-2499, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952477

RESUMO

BACKGROUND/AIM: Sino-nasal cancer is rare and often diagnosed at advanced stages. Some patients cannot receive curative treatment and are treated with palliative irradiation. We aimed to identify prognostic factors for survival to facilitate treatment personalization for this group. PATIENTS AND METHODS: Twelve patients treated with palliative radiotherapy for locally advanced sino-nasal cancer were retrospectively analyzed for survival. Ten characteristics were evaluated including age, gender, Karnofsky performance score (KPS), pre-radiotherapy hemoglobin, tumor site, lymph node involvement, histology, equivalent dose in 2 Gy-fractions, completion of radiotherapy and concurrent chemotherapy. RESULTS: On univariate analysis, KPS ≥70 (p<0.001) and completion of radiotherapy (p<0.001) were significantly associated with better survival. Chemotherapy showed a trend (p=0.097). In the multivariate analysis, KPS ≥70 was significant (p=0.025), and completion of radiotherapy showed a trend (p=0.080). CONCLUSION: KPS is an independent predictor of survival for palliative irradiation of sino-nasal cancer. Patients require close monitoring and care for side effects, since completion of radiotherapy is important for survival.


Assuntos
Neoplasias Nasais/radioterapia , Cuidados Paliativos/métodos , Radioterapia/métodos , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Nasais/patologia , Teste de Desfecho Sinonasal
18.
Anticancer Res ; 41(5): 2553-2561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952483

RESUMO

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
19.
N Engl J Med ; 384(19): 1789-1799, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33979487

RESUMO

BACKGROUND: Official recommendations differ regarding tympanostomy-tube placement for children with recurrent acute otitis media. METHODS: We randomly assigned children 6 to 35 months of age who had had at least three episodes of acute otitis media within 6 months, or at least four episodes within 12 months with at least one episode within the preceding 6 months, to either undergo tympanostomy-tube placement or receive medical management involving episodic antimicrobial treatment. The primary outcome was the mean number of episodes of acute otitis media per child-year (rate) during a 2-year period. RESULTS: In our main, intention-to-treat analysis, the rate (±SE) of episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P = 0.66). Because 10% of the children in the tympanostomy-tube group did not undergo tympanostomy-tube placement and 16% of the children in the medical-management group underwent tympanostomy-tube placement at parental request, we conducted a per-protocol analysis, which gave corresponding episode rates of 1.47±0.08 and 1.72±0.11, respectively. Among secondary outcomes in the main analysis, results were mixed. Favoring tympanostomy-tube placement were the time to a first episode of acute otitis media, various episode-related clinical findings, and the percentage of children meeting specified criteria for treatment failure. Favoring medical management was children's cumulative number of days with otorrhea. Outcomes that did not show substantial differences included the frequency distribution of episodes of acute otitis media, the percentage of episodes considered to be severe, and antimicrobial resistance among respiratory isolates. Trial-related adverse events were limited to those included among the secondary outcomes of the trial. CONCLUSIONS: Among children 6 to 35 months of age with recurrent acute otitis media, the rate of episodes of acute otitis media during a 2-year period was not significantly lower with tympanostomy-tube placement than with medical management. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02567825.).


Assuntos
Antibacterianos/uso terapêutico , Ventilação da Orelha Média , Otite Média/tratamento farmacológico , Otite Média/cirurgia , Doença Aguda , Antibacterianos/efeitos adversos , Pré-Escolar , Farmacorresistência Bacteriana , Feminino , Humanos , Lactente , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Otite Média com Derrame , Qualidade de Vida , Recidiva
20.
N Engl J Med ; 384(19): 1810-1823, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33979489

RESUMO

BACKGROUND: Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped. METHODS: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment. RESULTS: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents. CONCLUSIONS: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Rituximab/administração & dosagem , Vemurafenib/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Rituximab/efeitos adversos , Trombocitopenia/induzido quimicamente , Vemurafenib/efeitos adversos
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