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1.
Ann Surg Oncol ; 26(11): 3682-3692, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264117

RESUMO

BACKGROUND: Systemic inflammation response is involved in the development and progression of cancers. This study aimed to evaluate the prognostic value of a preoperative Fibrinogen-Albumin Ratio Index (FARI) in patients undergoing hepatectomy for colorectal liver metastases (CRLM) and compare it with established systemic inflammation markers, including the neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, and systemic immune-inflammation index. METHODS: Patients who underwent hepatectomy for CRLM between November 2002 and December 2016 were considered for inclusion. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of markers in predicting survival. Multivariable Cox regression analysis was used to identify independent predictors for overall survival (OS) or disease-free survival (DFS). RESULTS: A total of 452 consecutive patients were enrolled. The areas under the ROC curve of the FARI in predicting OS and DFS were superior to other inflammatory markers and carcinoembryonic antigen (CEA). The optimal cut-off value of the FARI was 7.6%. Patients with a high FARI (> 7.6%) showed significantly decreased OS and DFS (all p < 0.001). In multivariable analysis, the FARI was the only inflammatory marker that independently predicted OS and DFS. Additionally, regardless of patients having a high or low CEA, the FARI further stratified these patients into subgroups with significantly distinct OS and DFS (all p < 0.05). The FARI also showed good clinical utility in patients with different clinical characteristics. CONCLUSIONS: A preoperative FARI is an independent predictor of OS and DFS for patients undergoing hepatectomy for CRLM, superior to the established systemic inflammation markers and CEA.

2.
Eur J Surg Oncol ; 45(11): 2070-2077, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31279595

RESUMO

BACKGROUND: Hepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection. METHODS: The nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured. RESULTS: Based on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection. CONCLUSIONS: The proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.

3.
Eur J Surg Oncol ; 45(8): 1349-1356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054852

RESUMO

OBJECTIVE: Location of the primary tumor side has become an increasingly prognostic factor for colorectal liver metastasis. The present study was to perform a meta-analysis to investigate if primary right-sided tumor impacted on long-term survival outcome of colorectal liver metastases following local treatment. METHOD: Eligible trials were identified from the Embase, PubMed, Web of Science and the Cochrane database that were published before October in 2018. English language trials that compared long-term survival outcome of primary left-sided tumor with right-sided tumor colorectal liver metastases following local treatment were included. Hepatic resection for colorectal liver metastases was investigated. The main study outcomes included overall survival and disease free survival of primary right-sided colorectal liver metastases following local treatment. The risk factors of largest tumor size, primary node metastases, multiple tumor and RAS mutation were also analyzed. A systematic review and meta-analysis was done using a fixed-effects model. Hazard ratio with a 95% confidence interval was used to measure the pooled effect. RESULTS: A total of twelve studies with 6387 patients were included. For primary right-sided colorectal liver metastases patients following hepatic resection, the overall pooled HR for 5-year overall survival rate was 1.354 (95% CI: 1.238-1.482; p = 0.000; I2 = 33.7%, p = 0.138). The pooled HR for 5-year disease free survival rate of primary right-sided CRLM in the included studies calculated using the fix-effects model was 1.104 (95% CI: 0.987-1.235; p = 0.084; I2 = 0%, p = 0.477). CONCLUSION: It demonstrated that primary right-sided for colorectal liver metastases location was a significantly worse prognostic factor in terms of overall survival.

4.
Eur J Surg Oncol ; 45(9): 1551-1558, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30879931

RESUMO

BACKGROUND: The definition of R1 resection in colorectal cancer liver metastases (CRLM) remains debatable. This retrospective study was conducted to clarify the impact of R1 margin on patient survival after liver resection for CRLM, taking into consideration tumor biology, including RAS status and chemotherapy response. METHODS: We retrospectively analysed the clinical and survival data of 214 CRLM patients with initially resectable liver metastases who underwent liver resection after receiving neoadjuvant chemotherapy between January 2006 and December 2016. RESULTS: R1 resection significantly impacted patients' overall survival (OS) and disease-free survival (DFS) in the overall patient cohort (5-year OS: 53.2% for R0 vs 38.2% for R1, P = 0.001; 5-year DFS: 26.5% for R0 vs 10.5% for R1, P = 0.002). In the RAS wild-type subgroup and respond to chemotherapy (RC) subgroup, R1 reached a similar OS to those who underwent R0 resection (RAS wild-type, P = 0.223; RC, P = 0.088). For the RAS mutated subgroup and no response to chemotherapy (NRC) subgroup, OS was significantly worse underwent R1 resection (RAS mutant, P = 0.002; NRC, P = 0.022). When considering tumor biology combining RAS and chemotherapy response status, R1 resection was only acceptable in patients with both RAS wild-type and RC (5-year OS: 66.4% for R0 vs 65.2% for R1, p = 0.884), but was significantly worse in those with either RAS mutation or NRC. CONCLUSIONS: Tumor biology plays an important role in deciding the appropriate resection margin in patients with CRLM undergoing radical surgery. R1 resection margin is only acceptable in RAS wild-type patients who respond to chemotherapy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30506713

RESUMO

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used staging system for hepatocellular carcinoma (HCC). However, the classifications of early (BCLC-A) and intermediate (BCLC-B) stage HCC remain controversial. AIM: To refine the staging of BCLC-A and -B. METHODS: A total of 986 patients with HCC undergoing liver resection from two institutions formed the training cohort, and 694 from another institution were the validation cohort. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of tumour size in predicting overall survival (OS), and determined the optimised cut-off. Discriminatory performance was evaluated using Harrell's concordance index (C-index). RESULTS: Patients with multiple tumours exceeding Milan criteria but within up-to-seven criteria had similar OS and disease-free survival (DFS) to those with multiple tumours meeting Milan criteria, and were assigned to the modified BCLC-A stage. The area under the ROC curve of tumour size for predicting OS was 0.778, and the diameter of 7 cm was the optimal cut-off to identify patients with single tumours who had higher OS than BCLC-B stage patients. Due to the similar OS, patients with single HCCs >7 cm were assigned to the modified BCLC-B stage. The C-indexes of the modified BCLC classification for OS and DFS were higher compared to the original version. The findings were supported by the validation cohort. CONCLUSIONS: The modified staging of BCLC-A and -B, based on single tumour >7 cm and multiple tumours beyond up-to-seven criteria, could be more accurate to predict the prognosis of HCC patients. Liver resection could benefit patients with resectable multifocal HCCs beyond the Milan criteria.

7.
Liver Cancer ; 7(3): 235-260, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30319983

RESUMO

Background: Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. Summary: This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. Key Messages: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.

8.
World J Surg Oncol ; 16(1): 207, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322402

RESUMO

BACKGROUND: Liver resection is the first-line treatment for patients with resectable colorectal liver metastasis (CRLM), while radiofrequency ablation (RFA) can be used for small unresectable CRLM because of disease extent, poor anatomical location, or comorbidities. However, the long-term outcomes are unclear for RFA treatment in resectable CRLM. This study aimed to compare the recurrence rates and prognosis between resectable CRLM patients receiving either liver resection or RFA. METHODS: Consecutive patients who underwent RFA or hepatic resection from November 2010 to December 2015 were assigned in this retrospective study. Propensity score analysis was used to eliminate baseline differences between groups. Survival and recurrence rates were compared between patients receiving liver resection and RFA. RESULTS: With 1:2 ratio of propensity scoring, 46 patients in the RFA group and 92 in the resection group were successfully matched. Overall survival was similar between the two groups, but the resection group had a higher disease-free survival (median, 22 months vs. 14 months). Whereas among patients with a tumor size of ≤ 3 cm, disease-free survival was similar in the two groups (median, 24 months vs. 21 months). Compared to the resection group, the RFA group had a higher rate of intrahepatic recurrence (34.8% vs. 12.0%) and a shorter recurrence free period. The local and systemic recurrence rate and recurrence-free period for the same were insignificant in the two groups. Poor disease-free survival was associated with RFA, T4, tumor diameter > 3 cm, and lymph node positivity. CONCLUSION: Among patients with technically resectable CRLM, resection provided greater disease-free survival, although both treatment modalities provided similar overall survival.

9.
HPB (Oxford) ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30249510

RESUMO

BACKGROUND: Microvascular invasion (MVI) is a powerful predictor of recurrence in patients who undergo liver resection for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in HCC patients with MVI, and further select potential patients benefitting from PA-TACE. METHODS: Patients who had HCC with MVI and underwent liver resection between September 2004 and December 2015 were identified for further analysis. Overall survival (OS) and disease-free survival (DFS) were compared between patients treated with and without PA-TACE. Propensity score matching analysis was used to minimize inter-group differences. RESULTS: A total of 176 patients with HCC and MVI were included. In both the entire and propensity-matched cohorts, OS and DFS were higher in PA-TACE group than non-TACE group (all P < 0.05). In subgroup analyses, PA-TACE showed efficacy in improving OS and DFS in HCC patients at early stage beyond Milan criteria and intermediate stage, but not in patients within Milan criteria. Multivariable analysis identified PA-TACE as a significantly favorable factor of OS and DFS for patients beyond Milan criteria, but not for those within Milan criteria. CONCLUSION: PA-TACE could be beneficial for patients who have HCC with MVI beyond Milan criteria, but not for those within Milan criteria.

10.
Gut ; 67(11): 2006-2016, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29802174

RESUMO

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Misturas Complexas/uso terapêutico , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Quimioterapia Adjuvante , Misturas Complexas/efeitos adversos , Feminino , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Análise de Sobrevida , Resultado do Tratamento
11.
Eur J Surg Oncol ; 44(6): 771-777, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29580735

RESUMO

BACKGROUND: Primary tumour location has long been debated as a prognostic factor in colorectal cancer patients with liver metastases (CRLM) undergoing liver resection. This retrospective study was conducted to clarify the prognostic value of tumour location after radical hepatectomy for CRLM and its underlying causes. METHODS: We retrospectively analysed clinical data from 420 patients with CRLM whom underwent liver resection between January 2002 and December 2015. Right-sided (RS) tumours include tumours located in the cecum, ascending colon, and transverse colon, and left-sided (LS) tumours include those located in the splenic flexure, descending colon, sigmoid colon, and rectum. RESULTS: Both overall survival (OS) and disease-free survival (DFS) were similar between patients with RS and LS primary tumours (5-year OS: 46.5% vs 38.3%, P = 0.699; 5-year DFS: 29.1% vs 22.4%, P = 0.536). Specifically, RAS mutation rate was significantly higher in patients with RS tumours (P = 0.007). Subgroup analysis showed that the RAS mutation on the LS and RS tumours have different prognostic impact for CRLM patients on long-term survival after hepatic resection (RS, OS: P = 0.437, DFS: P = 0.471; LS, OS: P < 0.001, DFS: P = 0.002). The multivariable analysis showed that RAS mutant is an independent factor influencing OS in patients with LS primary tumour only. CONCLUSIONS: The site of the primary tumour has no significant impact on the long-term survival in patients with CRLM undergoing radical surgery. However, prognostic value of RAS status differs depending on the site of the primary tumour.


Assuntos
Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Idoso , China/epidemiologia , Neoplasias Colorretais/mortalidade , Imagem de Difusão por Ressonância Magnética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Taxa de Sobrevida/tendências
12.
Oncotarget ; 8(45): 79927-79934, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-29108374

RESUMO

Numerous factors affect the prognosis of colorectal liver metastasis (CRLM) patients after hepatic resection. We investigated several factors related to overall survival in patients with CRLM to identify those most likely to benefit from hepatic resection, and produced a rational tumor biology score system. Three hundred CRLM patients treated with preoperative chemotherapy followed by hepatic resection between 2006 and 2016 were enrolled in our study. Clinicopathologic and long-term survival data were collected and assessed. Patient 1-, 3-, and 5-year overall survival rates were 92.7%, 58.3%, and 45.8%, respectively, while 1-, 3-, and 5-year disease-free survival rates were 44.7%, 28.6%, and 24.2%, respectively. Multivariate Cox regression analysis revealed poor preoperative chemotherapy response, Fong clinical risk score > 2, and KRAS mutation to be independent prognostic indicators in CRLM patients. As part of a preoperative staging system in which one point was assigned for each factor, a total score (out of 3) was predictive of long-term survival following surgery. These factors facilitate personalized prognostic assessments in CRLM patients planning for resection.

13.
Chin Med J (Engl) ; 130(4): 470-476, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28218222

RESUMO

BACKGROUND: Human U three protein 14a (hUTP14a) promotes p53 degradation. Moreover, hUTP14a expression is upregulated in several types of tumors. However, the expression pattern of hUTP14a in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to investigate hUTP14a expression and its prognostic value in HCC. METHODS: The hUTP14a expression was evaluated using immunohistochemistry (IHC) in HCC tissue specimens. The correlations between hUTP14a expression and clinicopathological variables were analyzed. The Kaplan-Meier method was used to analyze the association between hUTP14a expression and survival. Independent prognostic factors associated with overall survival (OS) and disease-free survival (DFS) were analyzed using the Cox proportional-hazards regression model. RESULTS: The IHC data revealed that the hUTP14a positivity rate in HCC tissue specimens was significantly higher than that in nontumorous tissue specimens (89.9% vs. 72.7%, P < 0.05). The hUTP14a expression was detected in both the nucleolus and the cytoplasm. The positivity rate of nucleolar hUTP14a expression in HCC tissue specimens was higher than that in the nontumorous tissue specimens (29.3% vs. 10.1%, P < 0.05). No significant difference was found between HCC and nontumorous tissue specimens of cytoplasmic hUTP14a expression (60.6% vs. 62.6%, P > 0.05). In addition, no significant correlation was found between nucleolar hUTP14a expression and other clinicopathological variables. The 5-year OS and DFS rates in patients with positive nucleolar hUTP14a expression were significantly lower than those in patients with negative hUTP14a expression (P = 0.004 for OS, P = 0.003 for DFS). Multivariate analysis showed that nucleolar hUTP14a expression was an independent prognostic factor for OS (P = 0.004) and DFS (P < 0.001). CONCLUSIONS: The positivity rate of hUTP14a expression was significantly higher in HCC specimens. Positive expression of nucleolar hUTP14a might act as a novel prognostic predictor for patients with HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Ribonucleoproteínas Nucleolares Pequenas/genética
14.
Oncol Lett ; 14(6): 8051-8059, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29344248

RESUMO

Clinical risk scores and response to pre-operative chemotherapy are prognostic factors of colorectal liver metastases. The aim of the present study was to evaluate the effectiveness of combining these factors to predict patient survival and to select patients for curative therapy. The study included 189 patients who underwent hepatectomy following neo-adjuvant chemotherapy, for initially resectable colorectal liver metastases, between January 2005 and December 2015. Patients were stratified into four sub-groups: A1-2, low clinical risk scores with/without a response to pre-operative chemotherapy; and B1-2, high clinical risk scores with or without a response to pre-operative chemotherapy. Treatment and survival data were analysed. Survival was significantly longer in patients with low clinical risk scores and a response to pre-operative chemotherapy; these factors were confirmed as independent prognostic factors by multivariate analysis. Combining clinical risk score and chemotherapy response classification, patient survival was significantly longer for groups A1-2/B1 compared with for group B2, in which only 10.2% of patients were alive after 5 years. Of those with no response to first-line chemotherapy, survival was significantly longer in patients who responded to second-line chemotherapy. A combined clinical risk score and chemotherapy response classification may aid in identifying suitable candidates for potentially curative therapy.

15.
Mol Med Rep ; 14(2): 1617-23, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27315121

RESUMO

Methyl-CpG binding domain 2 (MBD2) leads to the silencing of methylated genes in cancer cells and was implicated in the activation of prometastatic genes in hepatocellular carcinoma (HCC). The present study aimed to investigate the expression status of MBD2 in HCC and the correlation with surgical outcomes. The correlation between clinical prognostic factors and MBD2 were also evaluated. MBD2 expression was analyzed by western blotting in 20 paired HCC and paratumor liver (PTL) tissues. In addition, immunohistochemistry was performed on the 159 HCC samples following hepatic resection performed between January 2003 and October 2008. The correlation between clinicopathological factors and MBD2 expression was also evaluated by statistical analysis to determine the prognostic value of MBD2 expression in HCC. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. Compared with PTL tissues, MBD2 expression was shown to be upregulated in 10 of the 20 HCC tissues (50%) by western blotting. The immunohistochemistry data indicated significant increase of the MBD2 expression level in 81 cases (50.94%) compared with the PTL tissues (0/159, 0%, P<0.001). The upregulated MBD2 expression in HCC tissues was correlated with BCLC stage B, tumor size >5 cm and microscopic vascular invasion. Multivariate analysis revealed that MBD2 was an independent prognostic factor for overall survival [HR, 2.089; P=0.001] and disease-free survival (HR, 1.601; P=0.022). In conclusion, MBD2 expression was elevated in HCC tissue, which suggesting MBD2 as a candidate prognostic marker of HCC.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Adulto , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Feminino , Seguimentos , Hepatectomia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Carga Tumoral
16.
Cancer Discov ; 6(9): 1022-35, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27297552

RESUMO

UNLABELLED: In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. SIGNIFICANCE: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti-PD-1 to enhance anti-PD-1 efficacy; a targeted IL10 delivery to CD8(+) TILs using anti-PD-1-IL10 or anti-CTLA4-IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022-35. ©2016 AACR.See related commentary by Peng et al., p. 953This article is highlighted in the In This Issue feature, p. 932.


Assuntos
Comunicação Autócrina , Proteínas do Sistema Complemento/imunologia , Interleucina-10/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Análise por Conglomerados , Complemento C3/imunologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imunomodulação , Interleucina-10/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 7(24): 37277-37287, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27074564

RESUMO

Neoadjuvant chemotherapy is being increasingly accepted as an effective treatment of resectable colorectal liver metastases (CRLM), but it may also damage the hepatic parenchyma. We performed a meta-analysis to compare the outcomes of patients who received neoadjuvant chemotherapy (NEO) prior to hepatic resection with hepatic resection without neoadjuvant chemotherapy (SG). Eligible trials were identified from Embase, PubMed, the Web of Science and the Cochrane library. Hazard ratios (HRs) with a 95% confidence intervals (CIs) were used to measure the pooled effect using a random-effects model. Statistical heterogeneity was detected by I2 test. Sensitivity analyses and publication bias were also assessed. The study outcomes included 3-year, 5-year disease-free and overall survival rate, respectively. Eighteen studies involving 6,254 patients were included. The pooled HRs for 5-year DFS and 5-year OS for NEO in the included studies calculated using the random-effects model were 1.38 (95 % CI; 1.26-1.51, p=0.00; I2=9.6%, p=0.36) and 1.19 (95% CI: 1.02-1.38; p=0.03; I2=49.2%, p=0.03), respectively. For CRLM patients with factors indicating a high risk of recurrence, the pooled HR for 5-year OS of NEO in the included studies calculated using the random-effects model was 0.69 (95% CI: 0.55-0.87; p=0.00; I2=0.0%, p=0.48). These results suggest neoadjuvant chemotherapy improved survival of patients with initially resectable CRLM and a high risk of disease recurrence.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/mortalidade , Taxa de Sobrevida , Resultado do Tratamento
18.
World J Surg Oncol ; 14: 62, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26936459

RESUMO

BACKGROUND: Hepatic resection has the highest local controllability that results in long-term survival for hepatocellular carcinoma (HCC). This study aimed to investigate the role of hepatic resection in selected patients of intermediate and advanced stage. METHODS: Clinical, pathological, and outcome data of 542 consecutive patients were retrospectively analyzed from a single center. The Kaplan-Meier method was used to estimate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. RESULTS: The 1-, 3-, and 5-year overall survival rates were 89.0, 64.3, and 53.0%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 72.2, 44.5, and 34.2%, respectively. Preoperative α-fetoprotein level >400 ng/mL, macroscopic vascular invasion, microscopic portal vein thrombosis, multiple tumor nodules, and the largest tumor size >5 cm were significantly correlated with overall survival. When these clinical risk factors were used in a postoperative staging system, assigning one point for each factor, the total score was precisely predictive of long-term survival. For patients with surgery plus adjuvant TACE (transarterial chemoembolization), the median overall survival was 56 months (range 1-110 months) and the 5-year OS rate was 48.5%. CONCLUSIONS: Hepatic resection is efficient and safe for HCC patients of intermediate and advanced stage. The adjuvant TACE should be recommended for HCC patients with poor risk factors.


Assuntos
Carcinoma Hepatocelular/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
19.
World J Gastroenterol ; 22(6): 2126-32, 2016 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-26877617

RESUMO

AIM: To evaluate the feasibility and survival outcomes of a liver-first approach. METHODS: Between January 2009 and April 2013, 18 synchronous colorectal liver metastases (sCRLMs) patients with a planned liver-first approach in the Hepatopancreatobiliary Surgery Department I of the Beijing Cancer Hospital were enrolled in this study. Clinical data, surgical outcomes, morbidity and mortality rates were collected. The feasibility and long-term outcomes of the approach were retrospectively analyzed. RESULTS: Sixteen patients (88.9%) completed the treatment protocol for primary and liver tumors. The main reason for treatment failure was liver disease recurrence. The 1 and 3 year overall survival rates were 94.4% and 44.8%, respectively. The median survival time was 30 mo. The postoperative morbidity and mortality were 22.2% and 0%, respectively, following a hepatic resection, and were 18.8% and 0%, respectively, after a colorectal surgery. CONCLUSION: The liver-first approach appeared to be feasible and safe. It can be performed with a comparable mortality and morbidity to the traditional treatment paradigm. This approach might offer a curative opportunity for sCRLM patients with a high liver disease burden.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metastasectomia/métodos , Adulto , Idoso , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Estudos de Viabilidade , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Metastasectomia/efeitos adversos , Metastasectomia/mortalidade , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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