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1.
J Cell Mol Med ; 26(12): 3471-3482, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35579380

RESUMO

Colorectal cancer (CRC) is a worldwide disease with worse survival. Our objective is to identify previously unrecognized prognostic factors to better evaluate disease progression. Seven GEO datasets were collected and analysed using R software, followed by KEGG enrichment analysis and TFs network construction. LASSO-COX analysis was performed to select the most useful prognostic features. COX model was used to analyse prognostic factors associated with OS. The survival curve was constructed using Kaplan-Meier analysis. A Nomogram model was also constructed to predict prognosis. A total of 3559 differentially expressed genes (DEGs) and 66 differentially expressed transcription factors were identified. FOXD1 was identified as the most differentially expressed factor of TFs covering the most downstream DEGs and independent risk prognostic factor. Next, FOXD1 expression was detected using immunohistochemical staining in 131 CRC patients' tissue and the association between FOXD1 expression and clinicopathologic features was analysed. High expression of FOXD1 was correlated with TNM stage and pathological differentiation. Multivariate COX regression analyses confirmed that FOXD1 high-expression, TNM stage and tumour differentiation were independent prognostic risk factor of OS and DFS. Patients with high expression of FOXD1 were more likely to have poor overall survival and disease-free survival. The combination of FOXD1 and Plk2 which we have previously reported allowed us to predict the survival of post-surgical CRC patients more accurately, adding to the former prognostic model based on the TNM Stage. The results showed that patients with high expression of both FOXD1 and Plk2 have the worst survival. A combination of FOXD1 and Plk2 can better evaluate patients' survival.


Assuntos
Neoplasias Colorretais , Fatores de Transcrição Forkhead , Proteínas Serina-Treonina Quinases , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Estimativa de Kaplan-Meier , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
2.
JAMA ; 327(16): 1577-1584, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35471505

RESUMO

Importance: Cardiovascular disease (CVD) is the leading cause of mortality in the US, accounting for more than 1 in 4 deaths. Each year, an estimated 605 000 people in the US have a first myocardial infarction and an estimated 610 000 experience a first stroke. Objective: To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD. The systematic review also investigated the effect of aspirin use on colorectal cancer (CRC) incidence and mortality in primary CVD prevention populations, as well as the harms (particularly bleeding) associated with aspirin use. The USPSTF also commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level. Population: Adults 40 years or older without signs or symptoms of CVD or known CVD (including history of myocardial infarction or stroke) who are not at increased risk for bleeding (eg, no history of gastrointestinal ulcers, recent bleeding, other medical conditions, or use of medications that increase bleeding risk). Evidence Assessment: The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit. The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit. Recommendation: The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. (C recommendation) The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (D recommendation).


Assuntos
Aspirina , Doenças Cardiovasculares , Adulto , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/prevenção & controle , Simulação por Computador , Hemorragia/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Prevenção Primária , Medição de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle
3.
Ann Intern Med ; 175(3): JC32, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35226529

RESUMO

SOURCE CITATION: Senore C, Riggi E, Armaroli P, et al. Long-term follow-up of the Italian flexible sigmoidoscopy screening trial. Ann Intern Med. 2022;175:36-45. 34748376.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Humanos , Incidência , Programas de Rastreamento , Sigmoidoscopia
5.
J Immunother Cancer ; 10(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110358

RESUMO

BACKGROUND: Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs. METHODS: We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset. RESULTS: The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement. CONCLUSIONS: Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.


Assuntos
Ascite/etiologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Idoso , Ascite/patologia , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Instabilidade de Microssatélites , Metástase Neoplásica , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Análise de Sobrevida
6.
Future Oncol ; 18(9): 1067-1076, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35109668

RESUMO

Aim: To evaluate polypharmacy (PP) in patients with metastatic colorectal cancer receiving regorafenib. Methods: Patients with metastatic colorectal cancer receiving regorafenib were included and divided into two categories by their PP status: PP- (<5 regular drug use/day) and PP+ (≥5 regular drug use/day). Results: 80 patients were included. 31 (38.7%) patients had PP. The median number of drugs used was three and seven in PP- and PP+ patients, respectively. Antiemetics (26.5%) and antacids (48.4%) were the most common drugs used by PP- and PP+ patients, respectively. In multivariate analysis, the risk of death was higher in PP+ patients (hazard ratio: 2.1; 95% CI: 1.2-3.7; p = 0.005). Conclusion: PP was an independent prognostic factor for overall survival in patients with metastatic colorectal cancer receiving regorafenib.


Regorafenib is a targeted therapy option that is used in patients with chemotherapy-refractory metastatic colorectal cancer. Because of the chemotherapy-refractory stage of the disease, patients are prone to use more medications for symptom palliation. Polypharmacy (PP) refers to the drug burden in an individual, and the use of five or more drugs in a day is usually considered to represent PP. In this study, the authors assessed the impact of PP in patients with metastatic colorectal cancer treated with regorafenib. The authors' study found that PP had a negative impact on survival outcomes in these patients. This is why inappropriate drug use should be assessed at each visit and the medication discontinued if it is not an essential part of the treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Metástase Neoplásica , Compostos de Fenilureia/uso terapêutico , Polimedicação , Piridinas/uso terapêutico , Fatores Etários , Idoso , Estudos de Coortes , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Registros Médicos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Turquia
7.
PLoS One ; 17(2): e0263818, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35176030

RESUMO

BACKGROUND: Black patients and underinsured patients with colorectal cancer (CRC) present with more advanced disease and experience worse outcomes. The study aim was to evaluate the interaction of health insurance status and race with treatment and survival in metastatic CRC. MATERIALS AND METHODS: Patients diagnosed with metastatic CRC within NCDB from 2006-2016 were included. Primary outcomes included receipt of chemotherapy and 3-year all-cause mortality. Multivariable logistic regression and Cox-regression (MVR) including a two-way interaction term of race and insurance were performed to evaluate the differential association of race and insurance with receipt of chemotherapy and mortality, respectively. RESULTS: 128,031 patients were identified; 70.6% White, 14.4% Black, 5.7% Hispanic, and 9.3% Other race. Chemotherapy use was higher among White compared to Black patients. 3-year mortality rate was higher for Blacks and lower for Hispanics, in comparison with White patients. By MVR, Black patients were less likely to receive chemotherapy. When stratified by insurance status, Black patients with private and Medicare insurance were less likely to receive chemotherapy than White patients. All-cause mortality was higher in Black patients and lower in Hispanic patients, and these differences persisted after controlling for insurance and receipt of chemotherapy. CONCLUSION: Black patients and uninsured or under-insured patients with metastatic CRC are less likely to receive chemotherapy and have increased mortality. The effect of health insurance among Blacks and Whites differs, however, and improving insurance alone does not appear to fully mitigate racial disparities in treatment and outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Disparidades em Assistência à Saúde , Seguro Saúde/estatística & dados numéricos , /estatística & dados numéricos , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/economia , Neoplasias Colorretais/etnologia , Feminino , Seguimentos , Humanos , Cobertura do Seguro , Masculino , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
JAMA Netw Open ; 5(2): e2149040, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35179586

RESUMO

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias Colorretais , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
9.
BMC Cancer ; 22(1): 153, 2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35130849

RESUMO

PURPOSE: The purpose of the current study is to analyze the difference of short-term and oncologic outcomes between younger and older colorectal cancer (CRC) patients who underwent primary CRC surgery using a propensity score matching (PSM) analysis. METHODS: We retrospectively collected CRC patients who underwent primary surgery in a single clinical database from Jan 2011 to Jan 2020. The short-term and oncologic outcomes were compared between younger aged group and older aged group. RESULTS: A total of 4599 patients were included in this study, and there were 4196 patients in older aged group and 403 patients in younger aged group. After 1:1 ratio PSM, there were 401 patients in each group. No significant difference was found in terms of baseline information after PSM (p>0.05). Younger aged group had larger retrieved lymph nodes before (p<0.001) and after PSM (p=0.001) than older aged group. In multivariate analysis, younger age was an independent predictor of better overall survival (OS) (p<0.001, HR=2.303, 95% CI=1.658-3.199) and disease-free survival (DFS) (p=0.008, HR=1.425, 95% CI=1.098-1.850). In terms of different tumor stage after PSM, younger aged group had better OS than older group in stage II (p<0.001) and stage IV (p=0.028) CRC, and younger aged group had better DFS than older group in stage II (p=0.016) CRC. CONCLUSION: Younger CRC patients had larger retrieved lymph nodes and better prognosis than older CRC patients after primary CRC surgery.


Assuntos
Fatores Etários , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Excisão de Linfonodo/estatística & dados numéricos , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
10.
Sci Rep ; 12(1): 2767, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177765

RESUMO

In a quest for prognostic biomarkers in early-stage colorectal cancer, we investigated NNMT (nicotinamide N-methyltransferase) in large cohorts of patients. Immunohistochemical examination of 679 patients illustrates that NNMT protein is predominantly expressed in the cancer stroma at varying levels, and about 20% of cancer tissues overexpress NNMT when compared to levels observed in normal colorectal mucosa. Clinical correlation analyses of 572 patients with early-stage cancers reveal that NNMT protein overexpression is significantly associated with shorter overall and disease-free survival, but no such correlation is found in late-stage colorectal cancer. Analyses of TCGA and CPTAC colorectal cancer cohorts show that NNMT mRNA expression is positively correlated with protein levels, is significantly higher in CIMP-high or MSI subtypes than in CIMP-low or MSS subtypes, and is positively correlated with its paralog INMT but not with its interaction partners such as PNMT, ADK, APP, ATF6, BMF, BRD4, CDC37, or CRYZ. In early-stage cancers, NNMT expression is higher in BRAF-mutated than in BRAF wild type tumors but is not affected by KRAS or PIK3CA mutation status. As a cancer stromal protein with important roles in metabolism and cancer epigenetics, NNMT is emerging as a promising biomarker for risk stratification of early-stage cancers.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Colorretais , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Nicotinamida N-Metiltransferase/biossíntese , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
11.
Diabetes ; 71(3): 497-510, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35040477

RESUMO

Colorectal cancer (CRC) and diabetes are two of the most prevalent chronic diseases worldwide with dysregulated receptor tyrosine kinase signaling and strong co-occurrence correlation. Plasma autoantibodies represent a promising early diagnostic marker for both diseases before symptoms appear. In this study, we explore the value of autoantibodies against receptor-type tyrosine-protein phosphatase-like N (PTPRN; full-length or selected domains) as diagnostic markers using a cohort of individuals with type 2 diabetes (T2D), CRC, or both diseases or healthy individuals. We show that PTPRN autoantibody levels in plasma discriminated between patients with T2D with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of patients with CRC. Mechanistically, PTPRN depletion significantly reduced invasiveness of CRC cells in vitro and liver homing and metastasis in vivo by means of a dysregulation of the epithelial-mesenchymal transition and a decrease of the insulin receptor signaling pathway. Therefore, PTPRN autoantibodies may represent a particularly helpful marker for the stratification of patients with T2D at high risk of developing CRC. Consistent with the critical role played by tyrosine kinases in diabetes and tumor biology, we provide evidence that tyrosine phosphatases such as PTPRN may hold potential as therapeutic targets in patients with CRC.


Assuntos
Autoanticorpos/sangue , Neoplasias Colorretais/imunologia , Diabetes Mellitus Tipo 2/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/fisiologia , Adulto , Animais , Biomarcadores/sangue , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Fatores de Risco
12.
Biochim Biophys Acta Mol Basis Dis ; 1868(4): 166353, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35063646

RESUMO

The inactivation of tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) by epigenetic and post-transcriptional modification has been reported in multiple human malignancies. DNA methyltransferase 3A (DNMT3A) is involved in de novo establishment of DNA methylation and plays a vital role in tumorigenesis. However, whether DNMT3A can regulate colorectal cancer (CRC) progression via modulation of DAB2IP remains unclear. In this study, we revealed that DNMT3A was significantly increased in CRC, predicting a poor overall survival. Functionally, ectopic expression of DNMT3A in CRC cells enhanced cell proliferation, whereas DNMT3A knockdown had the opposite effect by inducing cell cycle arrest. Mechanistically, methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) proved that the expression of DAB2IP was epigenetically suppressed by DNMT3A-mediated promoter methylation in CRC cells. Using dual-luciferase reporter assay and ChIP-PCR assay, we further confirmed that DNMT3A restrained the transcriptional activity of DAB2IP promoter through directly binging to it. In addition, DNMT3A could activate the MEK/ERK signaling pathway via efficiently downregulating DAB2IP. Inhibition of the MEK/ERK cascade abrogated the oncogenic effects of DNMT3A on CRC cells. In conclusion, our study demonstrates that DNMT3A facilitates CRC progression by regulating DAB2IP mediated MEK/ERK activation, providing promising targets for CRC treatment.


Assuntos
Neoplasias Colorretais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Metilação de DNA , /genética , Humanos , Prognóstico , Piridonas/farmacologia , Pirimidinonas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Proteínas Ativadoras de ras GTPase/antagonistas & inibidores , Proteínas Ativadoras de ras GTPase/genética
13.
Biomed Pharmacother ; 147: 112630, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35051860

RESUMO

Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ABCC11/DPYD to improve systemic chemotherapy in CRC.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/uso terapêutico , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fluoruracila/química , Fluoruracila/uso terapêutico , França , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Cancer Discov ; 12(3): OF1, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34987029

RESUMO

The KRAS inhibitor sotorasib provides some clinical benefit in patients with advanced or metastatic KRASG12C-mutant colorectal cancer, according to results of a phase II clinical trial. The objective response rate was 9.7%, the disease control rate was 82.3%, and the progression-free survival was 4 months.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Humanos , Mutação , Piperazinas/uso terapêutico , Piridinas , Pirimidinas
15.
BMC Cancer ; 22(1): 44, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996408

RESUMO

BACKGROUND: Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells. A reduction in numbers and enzymatic activities of peroxisomes was found in colon adenocarcinomas. However, the role of peroxisomes or the peroxisome pathway in colorectal cancer (CRC) is not defined. METHODS: In the current study, a peroxisome score was calculated to indicate the activity of the peroxisome pathway using gene set variant analysis based on transcriptomic datasets. CIBERSORTx was chosen to infer enriched immune cells for tumors among subgroups. The SubMap algorithm was applied to predict its sensitivity to immunotherapy. RESULTS: The patients with a relatively low peroxisome score and high level of T-cell immunoglobulin and mucin domain 3 (TIM-3) presented the worse overall survival than others. Moreover, low peroxisome scores were associated with high infiltration of lymphocytes and poor prognosis in those CRC patients. Thus, a PERLowTIM3High CRC risk subpopulation was identified and characterized by high immune infiltration. The results also showed that CD8 T cells and macrophages highly infiltrated tumors of the PERLowTIM3High group, regardless of consortium molecular subtype and microsatellite instability status. This subgroup had the highest tumor mutational burden and overexpression of immune checkpoint genes. Further, the PERLowTIM3High group showed a higher probability of responding to programmed cell death protein-1-based immunotherapy. In addition, genes involved in peroxisomal metabolic processes in CRC were also investigated since peroxisome is a rather pleiotropic and highly metabolic organelle in cell. The results indicated that only those genes involved in fatty acid alpha oxidation could be used to stratify CRC patients as similar as peroxisome pathway genes. CONCLUSIONS: We revealed the favorable prognostic value of the peroxisome pathway in CRC and provided a new CRC stratification based on peroxisomes and TIM3, which might be helpful for CRC diagnostics and personalized treatment.


Assuntos
Neoplasias Colorretais , Receptor Celular 2 do Vírus da Hepatite A/genética , Peroxissomos/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Transcriptoma/genética
16.
Sci Rep ; 12(1): 127, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996992

RESUMO

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco , Adulto Jovem
17.
Nutrients ; 14(1)2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-35011082

RESUMO

BACKGROUND: Malnutrition increases worse outcomes during hospital admission for elective colorectal cancer (CRC) surgery in older adults. METHODS: This work was designed an observational, monocentric, case-control study nested in a cohort of patients undergoing elective surgery for CRC disease at the Hospital Universitario de la Ribera (HULR) (Alzira, Valencia, Spain) between 2011 and 2019. The study considered patients with a CONUT score in the range of moderate to severe malnutrition (>4 points), with control patients with normal nutritional situations or mild malnutrition. RESULTS: Moderate-to-severe malnutrition cases presented a greater length of stay (LOS), a higher incidence of adverse events (both medical and surgical complications), a higher incidence of surgical-wound infection, a greater need for blood transfusion, and a greater amount of transfused packed red blood cells. During hospitalization, the percentage of patients without nutritional risk decreased from 46 to 9%, and an increase in mild, moderate, and severe risk was observed. Patients with severe nutritional risk at hospital admission had significantly increased mortality at 365 days after discharge (HR: 2.96 (95% CI 1.14-7.70, p = 0.002)). After adjusting for sex, age, and Charlson index score, patients with severe nutritional risk at admission maintained a higher mortality risk (HR: 3.08 (95% CI 1.10-8.63, p = 0.032)). CONCLUSION: Malnutrition prevalence is high in older adults undergoing CRC elective surgery. Furthermore, this prevalence increases during hospital admission. Malnutrition is linked to worse outcomes, such as LOS, surgical and clinical complications, and mortality. For this reason, nutritional interventions are very important in the perioperative period.


Assuntos
Neoplasias Colorretais/cirurgia , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Desnutrição/complicações , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue/estatística & dados numéricos , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Tempo de Internação , Masculino , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Espanha/epidemiologia , Infecção da Ferida Cirúrgica/epidemiologia , Resultado do Tratamento
18.
Cancer Treat Rev ; 103: 102326, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35016085

RESUMO

BACKGROUND: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed. METHODS: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines. RESULTS: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively. CONCLUSIONS: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome.


Assuntos
Bevacizumab/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Hipertensão/induzido quimicamente , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
Nutrients ; 14(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35057525

RESUMO

Cancer survival continues to improve in high-income countries, partly explained by advances in screening and treatment. Previous studies have mainly examined the relationship between individual dietary components and cancer prognosis in tumours with good therapeutic response (breast, colon and prostate cancers). The aim of this review is to assess qualitatively (and quantitatively where appropriate) the associations of dietary patterns and cancer prognosis from published prospective cohort studies, as well as the effect of diet interventions by means of randomised controlled trials (RCT). A systematic search was conducted in PubMed, and a total of 35 prospective cohort studies and 14 RCT published between 2011 and 2021 were selected. Better overall diet quality was associated with improved survival among breast and colorectal cancer survivors; adherence to the Mediterranean diet was associated to lower risk of mortality in colorectal and prostate cancer survivors. A meta-analysis using a random-effects model showed that higher versus lower diet quality was associated with a 23% reduction in overall mortality in breast cancer survivors. There was evidence that dietary interventions, generally combined with physical activity, improved overall quality of life, though most studies were in breast cancer survivors. Further cohort and intervention studies in other cancers are needed to make more specific recommendations.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Dieta/mortalidade , Fidelidade a Diretrizes/estatística & dados numéricos , Neoplasias/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias Colorretais/mortalidade , Dieta Mediterrânea , Comportamento Alimentar , Feminino , Humanos , Masculino , Política Nutricional , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Int J Mol Sci ; 23(2)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35054980

RESUMO

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that are present at the initial diagnosis. Herein, we performed a systematic exploration and established a novel five-panel gene signature as a prognostic and early diagnosis biomarker after performing differential gene expression analyses in five independent in silico CRCs cohort and independently validating it in one clinical cohort, using immunohistochemistry. Four genes (BDNF, PTGS2, GSK3B, and CTNNB1) were significantly upregulated and one gene (HPGD) was significantly downregulated in primary tumor tissues compared with adjacent normal tissues throughout all the five in silico datasets. The univariate CoxPH analysis yielded a five-gene signature that accurately predicted overall survival (OS) and recurrence-free survival (RFS) in the in silico training (AUC = 0.73 and 0.69, respectively) and one independent in silico validation cohort (AUC = 0.69 and 0.74, respectively). This five-gene signature demonstrated significant associations with poor OS in independent clinical validation cohorts of colon cancer (CC) patients (AUC = 0.82). Intriguingly, a risk stratification model comprising of the five-gene signature together with TNM stage and gender status achieved an even superior AUC of 0.89 in the clinical cohorts. On the other hand, the circulating mRNA expression of the upregulated four-gene signature achieved a robust AUC = 0.83 with high sensitivity and specificity as a diagnosis marker in plasma from CRC patients. We have identified a novel, five-gene signature as an independent predictor of OS, which in combination with TNM stage and gender offers an easy-to-translate and facile assay for the personalized risk-assessment in CRC patients.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Regulação Neoplásica da Expressão Gênica , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Técnicas de Diagnóstico Molecular , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Transcriptoma
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