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1.
Artigo em Inglês | MEDLINE | ID: mdl-34360285

RESUMO

The association of short-term particulate matter concentration with cardiovascular disease (CVD) among cancer survivors is yet unclear. Using the National Health Insurance Service database from South Korea, the study population consisted of 22,864 5-year cancer survivors with CVD events during the period 2015-2018. Using a time-stratified case-crossover design, each case date (date of incident CVD) was matched with three or four referent dates, resulting in a total of 101,576 case and referent dates. The daily average particulate matter 10 (PM10), 2.5 (PM2.5), and 2.5-10 (PM2.5-10) on the day of case or referent date (lag0), 1-3 days before the case or referent date (lag1, lag2, and lag3), and the mean value 0-3 days before the case or referent date (lag0-3) were determined. Conditional logistic regression was conducted to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for CVD according to quartiles of PM10, PM2.5, and PM2.5-10. Compared to the 1st (lowest) quartile of lag0-3 PM10, the 4th (highest) quartile of lag0-3 PM10 was associated with higher odds for CVD (aOR 1.13, 95% CI 1.06-1.21). The 4th quartiles of lag1 (aOR 1.12, 95% CI 1.06-1.19), lag2 (aOR 1.09, 95% CI 1.03-1.16), lag3 (aOR 1.06, 95% CI 1.00-1.12), and lag0-3 (aOR 1.11, 95% CI 1.05-1.18) PM2.5 were associated with higher odds for CVD compared to the respective 1st quartiles. Similarly, the 4th quartile of lag0-3 PM2.5-10 was associated with higher CVD events (aOR 1.11, 95% CI 1.03-1.19) compared to the 1st quartile. Short-term exposure to high levels of PM may be associated with increased CVD risk among cancer survivors.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Sobreviventes de Câncer , Doenças Cardiovasculares , Neoplasias , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Doenças Cardiovasculares/epidemiologia , Estudos Cross-Over , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Humanos , Neoplasias/epidemiologia , Material Particulado/efeitos adversos , Material Particulado/análise
2.
Cancer Res ; 81(18): 4778-4793, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34301762

RESUMO

N6-methyladenosine (m6A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m6A modification in the 3'UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. In vitro and in vivo, tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1-regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies. SIGNIFICANCE: This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.

3.
BMC Cancer ; 21(1): 710, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134651

RESUMO

BACKGROUND: There is no evidence whether it is best to stop drinking alcohol at all or whether it is okay to drink a little in that light-to-moderate alcohol use was associated with low cardiovascular disease (CVD) compared to non-drinker among colorectal cancer (CRC) survivors, who are regarded as vulnerable to CVD. Therefore, we evaluated the association between alcohol consumption and incident CVD among long-term survivors of CRC. METHODS: This population-based, retrospective cohort study utilized data from the Korean National Insurance Service of 20,653 long-term survivors of CRC diagnosed between 2006 and 2012. Participants were followed up to the date of CVD, death, or December 31, 2018. All patients were categorized according to their daily alcohol consumption (g/day). The outcomes were incident CVD, including ischemic heart disease (IHD) and ischemic and hemorrhagic stroke, analyzed using the Cox proportional hazards regression after adjusting for cardiovascular risk factors and history of chemotherapy and radiotherapy. RESULTS: There was no association between alcohol consumption and incident CVD among long-term survivors of CRC. Additionally, hazardous alcohol consumption (≥ 40 g/day in male patients and ≥ 20 g/day in female patients) was associated with increased CVD, ischemic stroke, and hemorrhagic stroke (adjusted hazard ratio [95% confidence interval]: 1.51 [1.15-1.97], 1.60 [1.03-2.48], and 2.65 [1.25-5.62], respectively) compared with non-drinkers. CONCLUSION: No discernable protective association was found between alcohol consumption and incident CVD for even light-to-moderate drinking among long-term survivors of CRC. Alcohol consumption ≥40 g/day in male patients and ≥ 20 g/day in female patients was associated with an increased risk of stroke compared with non-drinkers. These novel results provide useful evidence when advising survivors of CRC regarding alcohol use.

4.
J Cancer Surviv ; 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34138453

RESUMO

PURPOSE: Cancer survivors are currently considered high-risk populations for cardiovascular disease. However, no studies have directly evaluated risks and benefits of physical activity for stroke among long-term colorectal cancer survivors. METHODS: This large-scale observational cohort study used data from the Korean National Health Insurance Service database. Newly diagnosed colorectal cancer patients diagnosed between 2006 and 2013 who survived at least 5 years were studied. The primary outcome was stroke, including ischemic stroke and hemorrhage stroke. All patients were followed up to the date of stroke, death, or December 2018, whichever occurred earliest. RESULTS: Of 20,674 colorectal cancer survivors with a median age of 64 years, stroke occurred in 601 patients (2.9%). Moderate-to-vigorous physical activity lowered stroke risk in 5-9 time/week group (adjusted hazard ratio [aHR], 0.72; 95% confidence interval [CI], 0.57-0.93; P=0.010), but not in ≥10 time/week group (aHR, 0.85; 95% CI, 0.62-1.17; P=0.327). Walking also lowered stroke risk in 4-5 time/week group (aHR, 0.75; 95% CI, 0.58-0.97; P=0.028), but not in ≥6 time/week group (aHR, 0.96; 95% CI, 0.78-1.18; P=0.707). In addition, benefits of physical activity were maximized when carried out both moderate-to-vigorous physical activity and walking with moderate frequency (aHR, 0.77; 95% CI, 0.60-0.97; P=0.027). CONCLUSIONS: Moderate frequency of moderate-to-vigorous physical activity (5-9 time/week) and walking (4-5 time/week) significantly lowers the risk of stroke, whereas high-frequency physical activity reduces the benefits of physical activity. IMPLICATIONS FOR CANCER SURVIVORS: Physical activity with moderate frequency is important in the prevention of stroke for long-term colorectal cancer survivors.

5.
Semin Arthritis Rheum ; 51(4): 685-691, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34139521

RESUMO

OBJECTIVES: To determine the association of first, second, and third-line biologic disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib with drug survival among seropositive rheumatoid arthritis (RA) patients. METHODS: The study population was composed of 8,018 seropositive RA patients who were prescribed bDMARDs or tofacitinib between January 2014 and January 2019 from the Korean Health Insurance Review and Assessment Service database. First, second, and third-line choice of tumor necrosis factor inhibitors (TNFi) including etanercept, infliximab, adalimumab, and golimumab, as well as non-TNFi including tocilizumab, rituximab, tofacitinib, and abatacept were assessed. Multivariate Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for drug failure according to bDMARD or tofacitinib choice starting from the initial prescription date. RESULTS: Compared to first etanercept users, patients with first tocilizumab (aHR 0.56, 95% CI 0.46-0.68), tofacitinib (aHR 0.27, 95% CI 0.18-0.42), or abatacept (aHR 0.83, 95% CI 0.69-0.99) had lower risk of drug failure. Second choice of tocilizumab (aHR 0.38, 95% CI 0.25-0.55), tofacitinib (aHR 0.23, 95% CI 0.15-0.37), or abatacept (aHR 0.54, 95% CI 0.35-0.84) was associated with lower drug failure risk compared to second etanercept users. Finally, third choice of tocilizumab (aHR 0.32, 95% CI 0.16-0.62) or tofacitinib (aHR 0.35, 95% CI 0.19-0.63) was associated with lower drug failure risk compared to third TNFi users. CONCLUSION: First and second-line tocilizumab, tofacitinib, or abatacept may lead to improved drug survival. Third-line use of tocilizumab or tofacitinib may be beneficiary in reducing drug failure risk among seropositive RA patients.

6.
Sci Rep ; 11(1): 10152, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980955

RESUMO

The association of fluctuations in body mass index with cardiovascular risk in long-term is not well understood. This study aimed to investigate cardiovascular outcomes of weight fluctuation. Total of 67,101 obese adults from the Korean National Health Insurance Service who received health examinations in three separate biennial periods were included. Participants were followed up from January 1, 2008 to the date of cardiovascular disease, death, or December 31, 2015, and categorized into 9 distinctive groups according to the BMI. Continuous weight gain showed an increased risk of overall cardiovascular disease (hazard ratio [HR], 2.36; P = 0.007), whereas weight loss after weight maintenance (HR, 0.91; P = 0.016) and weight maintenance after weight loss (HR, 0.91; P = 0.004) were ameliorative compared to the no weight change group. As for coronary heart disease, weight maintenance after weight gain was unfavorable (HR, 1.25; P = 0.004) while weight loss after weight maintenance (HR, 0.82; P < 0.001), weight cycling (HR, 0.83; P = 0.043), and weight maintenance after weight loss (HR, 0.88; P = 0.012) were beneficial. Weight maintenance after weight loss is beneficial for obese adults in terms of cardiovascular risks. In addition, weight loss is in part related to reduced risk of coronary heart disease despite weight cycling.

7.
J Clin Gastroenterol ; 55(9): e77-e86, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33883516

RESUMO

GOALS: This meta-analysis evaluated the comparative effectiveness of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC). BACKGROUND: It is unclear whether TDF or ETV is more effective in reducing the risk of HCC in chronic hepatitis B (CHB) patients with or without underlying cirrhosis. METHODS: We searched the MEDLINE database through April 13, 2020, for studies involving CHB treated with TDF and/or ETV. Primary and secondary outcomes were the incidence of HCC and overall survival, respectively, calculated as risk ratios (RRs). Adjusted results were further evaluated by pooling propensity score matched cohorts. RESULTS: Of the 229 records identified, 17 studies were included in the quantitative analysis. TDF treatment was associated with a significantly lower risk of HCC development [RR, 0.63; 95% confidence interval (CI), 0.43-0.93; P=0.024] and mortality (RR, 0.69; 95% CI, 0.57-0.84; P=0.003) than ETV treatment. Moreover, TDF significantly lowered HCC risk in patients with cirrhosis (RR, 0.69; 95% CI, 0.56-0.84) and antiviral treatment-naive patients (RR, 0.59; 95% CI, 0.35-0.98) compared with ETV. Among treatment-naive patients, TDF significantly prolonged survival compared with ETV (RR, 0.69; 95% CI, 0.52-0.91). CONCLUSIONS: TDF likely confers a lower risk of HCC development and longer survival in patients with CHB, especially among treatment-naive patients and those with underlying cirrhosis, than ETV.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33916625

RESUMO

(1) Background: There is limited information regarding association between long-term exposure to air pollutants and risk of chronic kidney disease (CKD) (2). Methods: This study acquired data of 164,093 adults aged at least 40 years who were residing in 7 metropolitan cities between 2002 and 2005 from the Korean National Health Insurance Service National Sample Cohort database. CKD risk was evaluated using the multivariate Cox hazards proportional regression. All participants were followed up with until CKD, death, or 31 December 2013, whichever occurred earliest. (3) Results: Among 1,259,461 person-years of follow-up investigation, CKD cases occurred in 1494 participants. Air pollutant exposures including PM10, SO2, NO2, CO, and O3 showed no significant association with incident CKD after adjustments for age, sex, household income, area of residence, and the Charlson comorbidity index. The results were consistent in the sensitivity analyses including first and last year annual exposure analyses as well as latent periods-washed-out analyses. (4) Conclusions: Long-term exposure to air pollution is not likely to increase the risk of CKD.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Ozônio , Insuficiência Renal Crônica , Adulto , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Cidades , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Humanos , Dióxido de Nitrogênio/análise , Ozônio/análise , Material Particulado/análise , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/epidemiologia , República da Coreia/epidemiologia
9.
Adv Sci (Weinh) ; 7(13): 2000224, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32670760

RESUMO

The spatial heterogeneity of immune microenvironment in hepatocellular carcinoma (HCC) remains elusive. Here, a single-cell study involving 17 432 600 immune cells of 39 matched HCC (T), nontumor (N), and leading-edge (L) specimens by mass cytometry is conducted. The tumor-associated CD4/CD8 double-positive T (DPT) cells are found enriched in L regions with synergetic expression of PD-1/HLA-DR/ICOS/CD45RO and exhibit a higher level of IFN-γ, TNF-α, and PD-1 upon stimulation. The enrichment of DPT and PD-1+DPT in L regions indicates favorable prognosis. These tumor-associated DPT cells with similar phenotype are also verified in other tumors and HCC animal models. Single-cell RNA-seq further characterizes the molecular features of DPT cells and uncovers 11 clusters with different cytotoxicity, exhaustion, and activation scores. TCR-based trajectory analysis reveals that tumor-associated DPT clusters share separated ancestries with local CD4+ or CD8+SPT cells rather than CD3+PBMC cells. TCR clones with frequency above 10 are mainly found coexisting in DPT and CD8+SPT cells. Specifically, PD-1highDPT cluster (TDPT_10) shares the same ancestry with exhausted CD8+SPT cluster (TCD8T_2) and shows higher expression similarity and closer pathological location to PD-1+CD8+ than PD-1+CD4+T cells. Together, this study systematically characterizes the unique distribution of PD-1+DPTs in HCC and puts forward new insights for the function and origin of tumor-associated DPT cells.

10.
Theranostics ; 10(12): 5384-5397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32373219

RESUMO

Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4 mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4 wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.

11.
Hepatobiliary Pancreat Dis Int ; 19(2): 138-146, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32139295

RESUMO

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection. METHODS: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values. RESULTS: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively. CONCLUSIONS: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Quimioembolização Terapêutica , Colangiocarcinoma/terapia , Micro-Ondas/uso terapêutico , Recidiva Local de Neoplasia/terapia , Nomogramas , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Coagulação Sanguínea , Colangiocarcinoma/secundário , Colangiocarcinoma/cirurgia , Colelitíase/complicações , Cães , Feminino , Hepatite Infecciosa Canina/complicações , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Carga Tumoral , Adulto Jovem
12.
Front Oncol ; 10: 143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32140448

RESUMO

Background: Artificial Intelligence (AI) frameworks have emerged as a novel approach in medicine. However, information regarding its applicability and effectiveness in a clinical prognostic factor setting remains unclear. Methods: The AI framework was derived from a pooled dataset of intrahepatic cholangiocarcinoma (ICC) patients from three clinical centers (n = 1,421) by applying the TensorFlow deep learning algorithm to Cox-indicated pathologic (four), serologic (six), and etiologic (two) factors; this algorithm was validated using a dataset of ICC patients from an independent clinical center (n = 234). The model was compared to the commonly used staging system (American Joint Committee on Cancer; AJCC) and methodology (Cox regression) by evaluating the brier score (BS), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under curve (AUC) values. Results: The framework (BS, 0.17; AUC, 0.78) was found to be more accurate than the AJCC stage (BS, 0.48; AUC, 0.60; IDI, 0.29; NRI, 11.85; P < 0.001) and the Cox model (BS, 0.49; AUC, 0.70; IDI, 0.46; NRI, 46.11; P < 0.001). Furthermore, hazard ratios greater than three were identified in both overall survival (HR; 3.190; 95% confidence interval [CI], 2.150-4.733; P < 0.001) and disease-free survival (HR, 3.559; 95% CI, 2.500-5.067; P < 0.001) between latent risk and stable groups in validation. In addition, the latent risk subgroup was found to be significantly benefited from adjuvant treatment (HR, 0.459; 95% CI, 0.360-0.586; P < 0.001). Conclusions: The AI framework seems promising in the prognostic estimation and stratification of susceptible individuals for adjuvant treatment in patients with ICC after resection. Future prospective validations are needed for the framework to be applied in clinical practice.

14.
Hepatobiliary Pancreat Dis Int ; 19(1): 3-11, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31932195

RESUMO

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a lethal complication after pediatric liver transplantation, but information regarding risk factors for the development of PTLD remains unclear. This study was to identify characteristics and risk factors of PTLD. METHODS: A total of 705 pediatric patients who underwent liver transplantation between January 2017 and October 2018 were studied. Impact of clinical characteristics and Epstein-Barr virus (EBV) infection on the development of PTLD was evaluated. In addition, ImmuKnow assay was adopted in partial patients to analyze the immune status. RESULTS: Twenty-five (3.5%) patients suffered from PLTD with a median time of 6 months (3-14 months) after transplantation. Extremely high tacrolimus (TAC) level was found in 2 fatal cases at PTLD onset. EBV infection was found in 468 (66.4%) patients. A higher peak EBV DNA loads (>9590 copies/mL) within 3 months was a significant indicator for the onset of PTLD. In addition, the ImmuKnow assay demonstrated that overall immune response was significantly lower in patients with EBV infection and PTLD (P<0.0001). The cumulative incidence of PTLD was also higher in patients with lower ATP value (≤187 ng/mL, P<0.05). CONCLUSIONS: A careful monitoring of EBV DNA loads and tacrolimus concentration might be supportive in prevention of PTLD in pediatric patients after liver transplantation. In addition, application of the ImmuKnow assay may provide guidance in reducing immunosuppressive agents in treatment of PTLD.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Trifosfato de Adenosina/análise , Adolescente , Criança , Pré-Escolar , DNA Viral/análise , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Humanos , Lactente , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/imunologia , Masculino , Modelos de Riscos Proporcionais , Carga Viral
17.
Hepatobiliary Pancreat Dis Int ; 18(3): 242-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30956053

RESUMO

BACKGROUND: There is no data regarding prognostic impact of interleukin (IL)-26 on outcomes of patients with hepatocellular carcinoma (HCC). The present study aimed to evaluate the prognostic impact of IL-26 on HCC patients undergoing liver resection. METHODS: From 2003 to 2008, 122 patients with HCC who received surgical curative resection were enrolled. Patients were stratified into IL-26-upper and -lower groups according to the median expression level from immunohistochemical staining of resected specimens. Prognostic impact of IL-26 was estimated using Kaplan-Meier curves. Univariate and multivariate analyses were performed to evaluate time-dependent prognostic impact and independency of IL-26. Demographic and clinical factors that were associated with IL-26 were comprehensively identified. RESULTS: Prognosis of the patients with high level of IL-26 revealed to be significantly unfavorable in both cumulative recurrence-free survival (P < 0.001) and overall survival (P = 0.002). Upper expression of IL-26 (HR: 1.643; 95% CI: 1.021 to 2.644; P = 0.041) and microvascular invasion (HR: 3.303; 95% CI: 1.255 to 8.696; P = 0.016) were identified as significant independent prognostic factors for overall survival in the multivariable analysis. CONCLUSIONS: IL-26 is a novel prognostic factor for HCC after resection. Evaluation of IL-26 expression may be potentially valuable in clinical therapy when planning individualized follow-up schedule and evaluating candidates for prophylactic adjuvant treatment to prevent recurrence.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Interleucinas/análise , Neoplasias Hepáticas/cirurgia , Adulto , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Medição de Risco , Fatores de Risco , Fatores de Tempo , Carga Tumoral
18.
BMC Cancer ; 19(1): 208, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849953

RESUMO

BACKGROUND: Tumor-associated lymphangiogenesis is considered significant in number of solid malignancies. However, its impact on prognosis of intrahepatic cholangiocarcinoma (ICC) after resection remains further confirmation. Herein, we conducted this study to evaluate prognostic impact of tumor-associated lymphangiogenesis in patients with ICC. METHODS: Extent of tumor-associated lymphangiogenesis of ICC was evaluated by quantifying microlymphatic vessel density (MLVD) from immunohistochemical staining of a lymphatic endothelial-specific antibody (podoplanin). Clinicopathological characteristics were comprehensively analyzed to identify MLVD-associated factors. The patients were stratified into high and low MLVD groups according to the distinctive correlation between the MLVD and overall survival using the Spearman's correlation test. Kaplan-Meier estimation was performed to confirm prognostic impact of MLVD in patients with ICC. Univariate and multivariate analyses were performed using the Cox proportional hazard model. RESULTS: The MLVD between 4 to 12 counts showed inverse proportion to the overall survival (Spearman's r = - 0.66; 95% confidence interval [CI], - 0.82 to - 0.39; p <  0.0001), which was set as a cut-off for the high MLVD group, whereas the MLVD between 13 to 25 showed no correlation to the overall survival (r = - 0.11; 95% CI, - 0.38 to 0.19; p = 0.4791). The high MLVD group showed more frequent lymph node metastasis (p <  0.001) and were more likely to suffer from recurrence of the tumor compared to the low MLVD group (p <  0.001). The high MLVD was found to be independently associated with reduced overall and recurrence-free survival. The 5-year overall survival of the patients with high MLVD was significantly lower compared to those with low MLVD (0% vs 48%). CONCLUSIONS: Our study reveals that tumor-associated lymphangiogenesis is significantly associated with increased lymphatic metastasis, recurrence of the tumor, and reduced overall survival in patients with ICC, thus providing guidance when estimating postresection prognosis.


Assuntos
Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Vasos Linfáticos/patologia , Neovascularização Patológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Biomarcadores Tumorais , Colangiocarcinoma/metabolismo , Colangiocarcinoma/terapia , Comorbidade , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Carga Tumoral
19.
Ann Transl Med ; 7(23): 744, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32042760

RESUMO

Background: Anatomical location is considered in diagnostic and therapeutic approaches of cholangiocarcinoma (CCA). However, disparities and its extents in proportion of surgical candidates, prognostic factors, prognostic genetic networks, susceptibility for lymph node dissection, and disease stage at diagnosis remain to be confirmed. Methods: A total of 11,710 patients with cholangiocarcinoma from Surveillance, Epidemiology, and End Results Cancer Registries (SEER) and 45 CCA patients with paired tumor and normal specimens from The Cancer Genome Atlas were studied. Kaplan-Meier estimation, Cox proportional hazards regression, Pearson's correlation, comparison between anatomical location (distal, intrahepatic, and perihilar)-dependent CCAs, differential expressive gene stratification, potential interactive gene identification, and confirmation on pathways of the prognostic networks were carried out. Results: Survival outcomes were most favorable in the distal type, followed by perihilar and intrahepatic types, but postsurgical prognosis was slightly higher in intrahepatic type compared to perihilar type. Distant historic stage at diagnosis was noticed in intrahepatic type. Significant prognostic factors and their hazards ratios were dependent to the anatomical location. In addition, lymph node dissection provided significant survival benefits in perihilar type only. Furthermore, prognosis-predictive genes, as well as potential processes and pathways, were significantly among the anatomical location-dependent types that the genes barely overlapped. Conclusions: There are disparities in almost all aspects among distal, intrahepatic, and perihilar CCAs. Anatomical location needs to be considered in treatment, prognostic estimation, identifying targets, and developing therapeutic approaches for CCA.

20.
Int J Biol Sci ; 14(10): 1333-1342, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123080

RESUMO

Background & aims: VEGFR-3 has been shown of great significance in lymph node metastasis and some malignancies, however, its expression in tumors and impact on outcome of intrahepatic cholangiocarcinoma (iCCA) remains unknown. The aim of this study was to assess the role of VEGFR-3 positive tumors for prognosis of iCCA and tumor-associated lymphangiogenesis. Methods: Clinicopathological features, prognostic factors and survival rate were analyzed to evaluate the influence of VEGFR-3 positive expression on prognosis of iCCA. In addition, tumor-associated lymphangiogenesis quantified as micro-lymphatic vessel density (MLVD) was assessed to explore the correlation between VEGFR-3 expression and lymph node metastasis for iCCA. Results: Patients with VEGFR-3 positive tumors had increased lymph node metastasis (p=0.025) and were more likely to suffer from tumor recurrence compared with VEGFR-3 negative tumors (p<0.001). VEGFR-3 expression in tumors was identified as an independent prognostic factor for both overall and recurrence-free survival in surgical resected patients with iCCA. In addition, higher MLVD was significantly associated with VEGFR-3 positive expression in tumors (p<0.001), which facilitate lymph node metastasis and significantly worse survival rates. Conclusions: Our study reveals that VEGFR-3 positive expression in tumors represents an independent prognostic factor for both overall and recurrence-free survival in hepatic resected patients with iCCA. VEGFR-3 positive tumors favor lymph node metastasis, tumor recurrence and worse outcomes through tumor-associated lymphangiogenesis.


Assuntos
Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Colangiocarcinoma/genética , Feminino , Humanos , Imuno-Histoquímica , Linfangiogênese/fisiologia , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
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