RESUMEN
Objective: To explore a method for culturing hepatocellular carcinoma and tumor-infiltrating lymphocytes (HCC-TIL) and investigate the mechanism of TIL in killing tumors. Methods: The distribution of regulatory T cells (Treg) in HCC was detected by immunohistochemistry. Conventional TIL and oligoclonal TIL were isolated by the traditional method of enzyme digestion combined with mechanical treatment for whole HCC and micro HCC tissue block culturing method. MTT was used to compare the killing activity of TIL. Flow cytometry was used to analyze the proportion of CD8+ T cells and Treg cells in TIL. Tumor-bearing mice were established, and TIL adoptive immunotherapy was performed. Results: Treg cells were mainly distributed in the stroma of HCC. In vitro experiments showed oligoclonal TIL had higher cytotoxicity to tumor cells which negatively correlated with the proportion of Treg cells. In vivo experiments showed oligoclonal TIL had a higher anti-tumor effect. IFN-γ in peripheral blood and the positive rate of intratumoral lymphocytic infiltration in oligoclonal TIL group were both higher. TGF-ß and IL-10 in peripheral blood and the positive rate of intratumoral FoxP3 and IL-17 were both lower than those in conventional TIL group. Conclusion: The oligoclonal TIL culture method could obtain TIL with higher purity, and cytotoxicity to tumor cells was associated with Treg cells. The oligoclonal TIL had cytotoxicity to autologous HCC cells and significant inhibitory effect on the growth of transplanted tumors. The mechanism might be associated with the inhibition of Treg cells proliferation, increase of IFN-γ secretion, and decrease of TGF-ß, IL-10, and IL-17 secretion.
Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Animales , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Evolución Clonal , Citocinas , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Humanos , Inmunidad , Inmunoterapia Adoptiva , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/patología , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Circulating tumor cells (CTCs) are cancer cells shed from either the primary tumor or its metastases that circulate in the peripheral blood. The CTCs are regarded as the source of tumor recurrence and metastasis and speculated as the indicators of residual tumors, thereby indicating a poor prognosis. Although CTCs play a vital role in tumor metastasis and recurrence, little is known about the underlying survival mechanisms in the blood circulation. The accumulating evidence has revealed that CTCs might survive in the peripheral blood by overcoming the mechanical damage due to shear stress, resistance to anoikis, evasion of immune destruction, and resistance to chemotherapy. The present review addresses the putative survival mechanisms underlying the formation and migration of CTCs according to their biological characteristics and blood microenvironment. In addition, the relationship between CTCs and microenvironment is illustrated, and the influencing factors related to the interactions of CTCs with various components in the peripheral blood are reviewed with respect to the platelets, immune cells, cytokines, and circulating tumor microemboli (CTM). Furthermore, the recent advances in the new treatment strategies targeting the survival mechanisms of CTCs are also discussed.
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Microambiente Celular/genética , Recurrencia Local de Neoplasia/sangre , Neoplasias/sangre , Células Neoplásicas Circulantes/patología , Anoicis/genética , Biomarcadores de Tumor/sangre , Citocinas/sangre , Humanos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Partial hepatectomy is a potentially curative therapy for intrahepatic cholangiocarcinoma (ICC). Unfortunately, the overall surgical prognosis remains dismal and the actual 10-year survival has not been reported. This study aimed to document 10-year actual survival rates, identify the prognostic factors associated with 10-year survival rate, and analyze the characteristics of patients who survived ≥ 10 years. Among 251 patients who underwent curative liver resection for ICC between 2003 and 2006 at the Eastern Hepatobiliary Surgery Hospital, 21 patients (8.4%) survived ≥ 10 years. The 5-, 7-, and 10-year overall survival rates were 32.3%, 22.3% and 8.4%, respectively. The 10-year cumulative incidence of ICC-related death and recurrence were 80.9% and 85.7%, respectively. Multivariate analysis based on competing risk survival analysis identified that tumor > 5 cm was independently associated with ICC-related death and recurrence (hazard ratios: 1.369 and 1.445, respectively), in addition to carcinoembryonic antigen (CEA) >10 U/mL, carbohydrate antigen 19-9 (CA19-9) >39 U/mL, multiple nodules, vascular invasion, nodal metastasis and local extrahepatic invasion. Patients who survived ≥ 10 years had a longer time to first recurrence, lower levels of CEA, CA19-9 and alkaline phosphatase, less perioperative blood loss, solitary tumor, smaller tumor size, and absence of nodal metastasis or local extrahepatic invasion. In conclusion, a 10-year survival after liver resection for ICC is possible and can be expected in approximately 8.4% of patients.
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Neoplasias de los Conductos Biliares/mortalidad , Colangiocarcinoma/mortalidad , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Causas de Muerte , Colangiocarcinoma/patología , Colangiocarcinoma/cirugía , Femenino , Hepatectomía , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Complicaciones Posoperatorias , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Carga TumoralRESUMEN
Midkine is overexpressed in hepatocellular carcinoma (HCC) and plays a role in tumor progression, but less is known about its role in resistance of circulating tumor cells (CTCs) to anoikis which leading to recurrence and metastasis. The aim of the present study was to analyze whether midkine was associated with HCC progression with anoikis resistance. We found that cultured HCC cells were more resistant to anoikis, which paralleled midkine expression, and midkine treatment significantly inhibited anoikis in a dose-dependent manner. Furthermore, in in vitro and in vivo assays, knockdown of midkine resulted in significant sensitivity to anoikis, decreased cell survival and significantly decreased tumor occurrence rate. Patients with midkine-elevated HCC had higher CTC counts and less apoptotic CTCs, as well as significantly higher recurrence rate and shorter recurrence-free interval. To understand the molecular mechanism underlying the midkine with HCC progression, we performed in vitro and in vivo studies. We found that midkine plays an important role in enhancement of HCC cell resistance to anoikis, thereby promoting subsequent metastasis. Activation of PI3K/Akt/NF-κB/TrkB signaling by midkine-activated anaplastic lymphomakinase (ALK) is responsible for anoikis resistance.
Asunto(s)
Anoicis/genética , Carcinoma Hepatocelular/genética , Citocinas/metabolismo , Neoplasias Hepáticas/genética , Animales , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Midkina , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/patologíaRESUMEN
BACKGROUND: Tumor recurrence after liver resection for intrahepatic cholangiocarcinoma is common. The effective treatment for recurrent intrahepatic cholangiocarcinoma remains to be established. This study evaluated the short- and long-term prognoses of patients after repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma. METHODS: Data for 72 patients who underwent R0 repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma at the Eastern Hepatobiliary Surgery Hospital between 2005 and 2013 were analyzed. Tumor re-recurrence, recurrence-to-death survival, and overall survival were calculated and compared using the Kaplan-Meier method and the log-rank test. Independent risk factors were identified by Cox regression analysis. RESULTS: Operative morbidity and mortality rates were 18.1% and 1.4%, respectively. The 1-, 2-, and 3-year re-recurrence rates were 53.2%, 80.2%, and 92.6%, respectively, and the corresponding recurrence-to-death survival was 82.9%, 53.0%, and 35.3%, respectively. The 1-, 3-, and 5-year overall survival was 97.2%, 67.0%, and 41.9%, respectively. Patients with a time to recurrence of >1 year from the initial hepatectomy achieved higher 1-, 2-, and 3-year recurrence-to-death survival than patients with a time to recurrence of ≤1 year (92.5%, 61.7%. and 46.6% vs 70.4%, 42.2%, and 23.0%, P = .022). Multivariate analysis identified that recurrent tumor >3 cm (hazard ratio: 2.346; 95% confidence interval: 1.288-4.274), multiple recurrent nodules (2.304; 1.049-5.059), cirrhosis (3.165; 1.543-6.491), and a time to recurrence of ≤1 year (1.872; 1.055-3.324) were independent risk factors of recurrence-to-death survival. CONCLUSION: Repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma was safe and produced long-term survival outcomes in selected patients based on prognostic stratification with the presence of the independent risk factors of recurrence-to-death survival.
Asunto(s)
Neoplasias de los Conductos Biliares/cirugía , Causas de Muerte , Colangiocarcinoma/cirugía , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Adulto , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , China , Colangiocarcinoma/mortalidad , Colangiocarcinoma/parasitología , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/patología , Pronóstico , Modelos de Riesgos Proporcionales , Reoperación/métodos , Reoperación/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Splenosis is a benign and relatively uncommon condition caused by trauma or splenectomy or other procedures involving splenic tissue. It is usually asymptomatic, and often diagnosed accidentally, especially misdiagnosed as malignant tumor. METHODS: A 54-year-old man with prior history of chronic hepatitis B virus infection and underwent splenectomy for traumatic splenic rupture following a traffic accident 23 years previously was admitted to our hospital and found a hepatic mass in the right upper quadrant during an imaging examination. The diagnosis of his was not clear and finally he agreed to receive a surgical treatment. RESULTS: During the operation, we found a mass in the right posterior lobe of the liver and a hard nodule on the right side of the diaphragm, both were completely resected, and postoperative histopathologic examination revealed that all excised tissues were proved to have histological structure typical for the spleen. CONCLUSIONS: The occurrence of intrahepatic splenosis is rare with only few cases previously reported in the literature. It is a benign disease and sometimes difficult to distinguish from diseases of the liver. The need for positive surgical resection of splenosis is still controversial.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado , Esplenectomía/efectos adversos , Rotura del Bazo/cirugía , Esplenosis , Accidentes de Tránsito , Hepatectomía/métodos , Humanos , Hallazgos Incidentales , Hígado/diagnóstico por imagen , Hígado/patología , Hígado/cirugía , Masculino , Persona de Mediana Edad , Esplenectomía/métodos , Esplenosis/diagnóstico , Esplenosis/etiología , Esplenosis/fisiopatología , Esplenosis/cirugíaRESUMEN
BACKGROUND/AIMS: To explore the possibility and feasibility of hepatic portal reocclusion for detecting bile leakage during hepatectomy. METHODS: Data were prospectively collected from 200 patients who underwent hepatectomy alone for removal of various benign or malignant tumors between March 2014 and November 2014. The surgical procedure used a conventional method for all patients, and one additional step (hepatic portal reocclusion) was included in group B. The postoperative outcomes of the patients in group A (subjected to the traditional procedure) and group B (subjected to hepatic portal reocclusion) were compared during the same period, and the incidence rates of postoperative bile leakage and other complications in the 2 groups were also analyzed. RESULTS: The incidence of postoperative bile leakage in group B was significantly lower than that in group A (1.0 vs. 9.2%, p = 0.009), although no significant differences in postoperative indicators of liver dysfunction and other complications were observed between the 2 groups (p > 0.05). CONCLUSIONS: Hepatic portal reocclusion effectively reduced the incidence of bile leakage compared to the traditional procedure, without significantly affecting liver function. Therefore, this method might be an alternative to other tests for bile leakage.
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Conductos Biliares/cirugía , Carcinoma Hepatocelular/cirugía , Hepatectomía/métodos , Complicaciones Intraoperatorias/diagnóstico , Neoplasias Hepáticas/cirugía , Complicaciones Posoperatorias/prevención & control , Adulto , Anciano , Bilis , Estudios de Factibilidad , Femenino , Hepatectomía/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Vena Porta , Estudios ProspectivosRESUMEN
BACKGROUND: The relationship between serum carcinoembryonic antigen (CEA) and postoperative prognosis in hepatocellular carcinoma (HCC) has not been reported. METHODS: Data of 5410 consecutive HCC patients who underwent hepatectomy was retrospectively reviewed. Survival curves for overall survival (OS) and tumor recurrence (TR) were depicted using the Kaplan-Meier method and compared using the log-rank test. Independent risk factors of OS and TR were analyzed with Cox hazard regression model. Besides, a one-to-one propensity score-matched (PSM) subset was performed to reduce selection bias. Subgroup analysis was done according to hepatitis B virus (HBV) infection or not. RESULTS: Serum CEA ≥5.1 µg/L was an independent risk factor of OS and TR in the entire cohort and PSM subset (OS-hazard ratio = 1.218, 95 % confidence interval = 1.060-1.400; 1.383, 1.133-1.688, respectively; TR-1.256, 1.114-1.417; 1.258, 1.067-1.484, respectively). Subgroup analysis showed that CEA ≥5.1 µg/L was an independent risk factor of OS and TR in the HBV infection group (OS-1.234, 1.065-1.429; TR-1.231, 1.083-1.399) but not in the non-HBV infection group (OS-1.376, 0.895-2.117; TR-1.437, 0.989-2.088). CONCLUSION: Serum CEA ≥5.1 µg/L was an independent risk factor of OS and TR of HCC patients, and patients with CEA ≥5.1 µg/L had poorer prognosis, especially for HCC patients with HBV infection.
Asunto(s)
Antígeno Carcinoembrionario/sangre , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/sangre , Adulto , Anciano , Carcinoma Hepatocelular/complicaciones , Femenino , Hepatectomía , Hepatitis B/complicaciones , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies. DESIGN: The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy. RESULTS: We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219-2.441) and survival (1.847; 1.291-2.642). CONCLUSION: Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Femenino , Estudios de Seguimiento , Técnicas de Silenciamiento del Gen , Hepatectomía , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Carga Tumoral , Adulto Joven , Tirosina Quinasa del Receptor AxlRESUMEN
Our aim in this study was to develop a prognostic scoring system with which to identify patients most likely to benefit from adjuvant chemolipiodolization (ACL) after liver resection for hepatocellular carcinoma (HCC). Data from 1150 HCC patients who underwent liver resection between 2002 and 2008 at the Eastern Hepatobiliary Surgery Hospital were used to develop the scoring system. Patients were stratified into prognostic subgroups using the new scoring system, and the outcomes of patients who received ACL and those who did not were compared in each subgroup. Using data from 379 patients operated on between 2008 and 2010 for validation, the scoring system had a concordance index (C-index) of 0.75 for predicting post-resectional overall survival (OS). It optimally stratified patients into three prognostic subgroups with scores of 0-5, 6-9 and ≥ 10, having better, medium and worse survival outcomes, respectively. A difference in OS between ACL and non-ACL patients was only detected in the subgroup with scores ≥ 10 (1-, 3-, and 5-year OS rates: 63.9%, 22.6%, and 9.0% vs. 33.8%, 5.6%, and 2.8%, p = 0.001). Our proposed scoring system provides an effective tool for selecting the patients most likely to benefit from ACL.
Asunto(s)
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/mortalidad , Quimioembolización Terapéutica , Quimioterapia Adyuvante/métodos , Terapia Combinada , Aceite Etiodizado/administración & dosificación , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
BACKGROUND: Repeat hepatectomy (re-hepatectomy) is an effective treatment for patients with intrahepatic recurrence following liver resection for hepatocellular carcinoma (HCC). OBJECTIVE: This study aimed to develop nomograms for predicting prognosis after re-hepatectomy. METHODS: The data of 635 patients who underwent re-hepatectomy for recurrent HCC at the Eastern Hepatobiliary Surgery Hospital between 2004 and 2010 were prospectively collected. Multivariable Cox regression analyses based on data obtained before and after re-hepatectomy were performed to select independent predictors of recurrence to death survival (RTDS) which were incorporated into the pre- or post-re-hepatectomy nomograms. Discrimination and calibration of the nomograms were measured using the concordance index (C-index), Kaplan-Meier curves, and calibration plots. RESULTS: The 1-, 3- and 5-year overall survival rates were 96.9, 74.8, and 47.8 %, respectively, and the corresponding RTDS rates were 75.8, 45.7, and 37.6 %, respectively. Tumor size and number at the initial and recurrent stages, time to recurrence from the initial hepatectomy, hepatitis B virus deoxyribonucleic acid level and microvascular invasion were selected into the two nomograms. The C-indexes for predicting RTDS were 0.72 [95 % confidence interval (CI) 0.70-0.74] and 0.77 (95 % CI 0.74-0.80) for the pre- or post-re-hepatectomy nomograms, respectively. The calibration curves for the probability of 5-year RTDS after re-hepatectomy showed optimal agreement between the prediction shown in the nomograms and the actual observations. Both nomograms were able to accurately stratify patients into four distinct incremental prognostic subgroups. CONCLUSION: The proposed nomograms have shown accurate RTDS prediction for patients with intrahepatic recurrent HCC.
Asunto(s)
Carcinoma Hepatocelular/mortalidad , Hepatectomía/mortalidad , Neoplasias Hepáticas/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Nomogramas , Reoperación/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Cuidados Posoperatorios , Cuidados Preoperatorios , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, therapeutic response to sorafenib was not equal among HCC patients. Here we present a novel system to provide quantitative information concerning sorafenib-related targets by simultaneous detection of phosphorylated ERK (pERK) and pAkt expressions in circulating tumor cells (CTCs) isolated from HCC patients. Our results showed that 90.0% of patients had a molecular classification of tissues concordant with that of CTCs. CTC counts showed a shaper decline in patients with pERK+/pAkt- CTCs after two weeks of sorafenib treatment (P < 0.01). Disease control rates were significantly different between patients with pERK+/pAkt- CTCs (11/15; 73.3%) and those without (13/44; 29.5%) (P < 0.05). Univariate and multivariate analysis indicated pERK+/pAkt- CTCs as an independent predictive factor of progression-free survival (PFS) (hazard ratio = 9.389; P < 0.01). PFS correlated with the proportion of pERK+/pAkt- CTCs (r = 0.968, P < 0.01), and was higher in patients with ≥ 40% pERK+/pAkt- CTCs compared to those with < 40% (8.4 vs. 1.3 mo; P < 0.05). In a validation set of twenty HCC patients, CTCs from patients with ≥ 40% pERK+/pAkt- CTCs had significantly higher inhibition rates of spheroid formation compared to those with < 40% (61.2 vs. 19.8%; P < 0.01). Our findings demonstrated that CTCs can be used in place of tumor tissue for characterization of pERK/pAkt expression. pERK+/pAkt- CTCs are most sensitive to sorafenib and an independent predictive factor of PFS in HCC patients treated with sorafenib.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Hepáticas/patología , Células Neoplásicas Circulantes/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes/efectos de los fármacos , Niacinamida/farmacología , Fosforilación/efectos de los fármacos , Pronóstico , Sorafenib , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Notch1 has previously been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). The present study aimed to investigate the prognostic value of Notch1 in early stage HCC patients after hepatectomy. The differential expression of Notch1 in paired tumor and non-tumorous tissue was evaluated by RT-PCR, western blotting and immunohistochemistry. The correlation between Notch1 expression and the surgical outcome of patients at BCLC stage 0/A and its ≤5 cm subgroup was retrospectively investigated in 206 patients from the Eastern Hepatobiliary Surgery Hospital (training cohort), and prospectively validated in 185 patients from the same center and retrospectively verified in 129 patients from the Fujian Medical University (validation cohort 1 and 2, respectively). Compared with paired non-tumorous tissues, loss of Notch1 was observed in tumor tissue. Patients with normal Notch1 had better prognosis than those with loss of Notch1 in the training cohort and ≤5 cm subgroup (time to recurrence: 38.5±6.1 vs. 16.0±3.2 months, P<0.001 and 53.0±6.1 vs. 21.7±3.5 months, P=0.004; 1-, 3-, 5-year survival rates: 91, 64 and 49% vs. 73, 31 and 22%, P<0.001 and 93, 71, 57% vs. 76, 39, 24%, P<0.001). Notch1 expression was an independent factor for recurrence and survival (hazard ratio: 1.901, 2.154; 2.038 and 2.337). Moreover, Notch1 status affected early tumor recurrence, as the 2-year recurrence rate was 61.2 vs. 26.9% (P<0.001) and 51.2 vs. 21.3% (P=0.002) in tumors with reduced or increased Notch1 expression in this cohort and subgroup. These results were fully confirmed by the study in our prospective and retrospective validation cohorts. The status of Notch1 is useful for predicting the prognosis of patients with early stage HCC undergoing hepatectomy.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Recurrencia Local de Neoplasia/genética , Receptor Notch1/genética , Adulto , Anciano , Biomarcadores de Tumor/biosíntesis , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Hepatectomía , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Pronóstico , Receptor Notch1/biosíntesisRESUMEN
BACKGROUND AND AIM: To study the change in serum alpha fetoprotein (AFP) of patients with recurrent hepatocellular carcinoma (HCC) after curative resection and to analyze its effect on the survival. METHODS: We prospectively collected 981 consecutive patients with post-resectional recurrent HCC between 2005 and 2010 at the Eastern Hepatobiliary Surgery Hospital. According to the change of AFP from the initial stage to recurrent stage, the patients were divided into stable-L (20 ng/mL to 20 ng/mL, n = 296), stable-M (20-400 ng/mL to 20-400 ng/mL, n = 102), stable-H (400 ng/mL to 400 ng/mL, n = 212), decreasing (n = 287), and increasing (n = 84) groups. The overall survival (OS) and recurrence to death survival (RTDS) were analyzed using Kaplan-Meier method. Multivariate analysis was performed by Cox proportional hazards regression. RESULTS: The stable-H/increasing and stable-L/decreasing groups had the lowest and highest 5-year OS and RTDS rates (10.8%/18.8% vs 56.3%/55.0%; 3.4%/5.1% vs 37.7%/33.2%; both P < 0.001), while the stable-M group had the lower rates, which were 29.8% and 23.6% (for OS and RTDS: vs stable-L, P < 0.001 and 0.002; vs deceasing, P = 0.001 and 0.012; vs increasing, P = 0.113 and 0.011; vs stable-H, both P < 0.001). Cox regression analysis showed that AFP inconsistency was an independent factor affecting RTDS (decreasing vs stable-L, hazard ratio: 1.10, 95% confidence interval: 0.79-1.54, P = 0.575; increasing vs stable-L, 2.93, 2.06-4.16, P < 0.001). CONCLUSIONS: The AFP inconsistency was an important prognostic factor for recurrent HCC.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , alfa-Fetoproteínas/análisis , Adulto , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/mortalidad , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Estudios ProspectivosRESUMEN
PURPOSE: To assess whether urea-based cream (UBC) has prophylactic benefits on sorafenib-induced hand-foot skin reaction (HFSR) in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: In this randomized, open-label trial, 871 patients with advanced HCC throughout China were treated with 10% UBC three times per day plus best supportive care (BSC; n = 439) or BSC alone excluding all creams (n = 432), starting on day 1 of sorafenib treatment, for up to 12 weeks. HFSR was assessed every 2 weeks and at 14 weeks for patients completing the study. Once HFSR occurred, patients were allowed any cream, including a UBC. RESULTS: The 12-week incidence of any grade HFSR was significantly lower in the UBC group versus the BSC-alone group (56.0% v 73.6%, respectively; odds ratio [OR], 0.457; 95% CI, 0.344 to 0.608; P < .001), as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004). Median time to first occurrence of HFSR was significantly longer in the UBC group than the BSC-alone group (84 v 34 days, respectively; hazard ratio, 0.658; 95% CI, 0.541 to 0.799; P < .001). Elevated AST was associated with increased risk of HFSR but did not alter the treatment effect of UBC. UBC plus BSC, compared with BSC alone, did not affect the sorafenib dose reduction or interruption rate (9.1% v 11.8%, respectively; P = .1937), response rate (11.1% v 10.1%, respectively; P = .6674), or disease control rate (98.8% v 98.2%, respectively; P = .5350) at week 12. CONCLUSION: UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC. Blinded, randomized, placebo-controlled trials to determine the role of UBC on the incidence and severity of HFSR are warranted.
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Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Emulsiones/administración & dosificación , Síndrome Mano-Pie/prevención & control , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Urea/administración & dosificación , Administración Tópica , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/complicaciones , China , Femenino , Síndrome Mano-Pie/tratamiento farmacológico , Humanos , Incidencia , Neoplasias Hepáticas/complicaciones , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Niacinamida/efectos adversos , Oportunidad Relativa , Calidad de Vida , Piel/efectos de los fármacos , Sorafenib , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The selection criteria of hepatectomy for patients with multiple hepatocellular carcinomas (HCCs) remain controversial. METHODS: A scoring system based on preoperative data and independent predictors of overall survival (OS) was developed in a primary cohort of 510 patients who underwent hepatectomy for multiple HCCs from 1998 to 2006, and validated in 177 patients who were operated from 2006 to 2009 at the Eastern Hepatobiliary Surgery Hospital. RESULTS: In the NDR scoring system, tumor number (N) > 3, total tumor diameter (D) > 8 cm, and a ratio of largest/smallest diameter (R) > 6 were independent predictors of OS. Its predictive accuracy as determined by the area under the curve (AUC, 0.718) was larger than the four conventional staging systems (0.524-0.662). It stratified postoperative OS into five levels (0-4 score). The 5-year OS rate of patients with a NDR score 0-2 was 46.5% versus 13.9% in those > 2 (P < 0.001). Patients with a score 0-2 therefore were recommended for hepatectomy. The feasibility of this NDR score 0-2 was compared with the previously reported criteria. If the two more stringent inclusion criteria were adopted, 45.5-75.7% of patients with a NDR score 0-2 would be excluded, but their 5-year OS rates were comparable to those within the criteria (44.7% vs. 52.1%, P = 0.083; 46.6% vs. 46.3%, P = 0.674). If the less stringent criteria were used, an additional 25.9% of patients received hepatectomy, but their 5-year OS rate was 13.9%. CONCLUSIONS: The NDR scoring system was more accurate in selecting patients with multiple HCCs for hepatectomy.
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Carcinoma Hepatocelular/patología , Hepatectomía/mortalidad , Neoplasias Hepáticas/patología , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Postoperative pancreatic fistula is one of the most common complications after pancreatectomy. This study aimed to assess the occurrence and severity of pancreatic fistula after central pancreatectomy. METHODS: The medical records of 13 patients who had undergone central pancreatectomy were retrospectively studied, together with a literature review of studies including at least five cases of central pancreatectomy. Pancreatic fistula was defined and graded according to the recommendations of the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: No death was observed in the 13 patients. Pancreatic fistula developed in 7 patients and was successfully treated non-operatively. None of these patients required re-operation. A total of 40 studies involving 867 patients who underwent central pancreatectomy were reviewed. The overall pancreatic fistula rate of the patients was 33.4% (0-100%). Of 279 patients, 250 (89.6%) had grade A or B fistulae of ISGPF and were treated non-operatively, and the remaining 29 (10.4%) had grade C fistulae of ISGPF. In 194 patients, 15 (7.7%) were re-operated upon. Only one patient with grade C fistula of ISGPF died from multiple organ failure after re-operation. CONCLUSION: Despite the relatively high occurrence, most pancreatic fistulae after central pancreatectomy are recognized a grade A or B fistula of ISGPF, which can be treated conservatively or by mini-invasive approaches.
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Pancreatectomía/efectos adversos , Fístula Pancreática/etiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pancreatectomía/mortalidad , Fístula Pancreática/diagnóstico , Fístula Pancreática/mortalidad , Fístula Pancreática/terapia , Reoperación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Hepatic stellate cells (HSCs), a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma (HCC) development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs (tHSCs) was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition (EMT) phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells (CTCs) in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues (r = -0.256, p < 0.001) or with preoperative CTCs in blood (r = -0.287, p = 0.033), and were significantly correlated with tumor size (p = 0.027), TNM staging (p = 0.018), and vascular invasion (p = 0.008). Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Células Estrelladas Hepáticas/patología , Neoplasias Hepáticas/patología , Animales , Apoptosis , Proliferación Celular/efectos de los fármacos , Trasplante de Células , Transición Epitelial-Mesenquimal , Flavonoides/farmacología , Xenoinjertos , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , PronósticoRESUMEN
BACKGROUND: Long-term outcomes of partial liver resection of hepatocellular carcinoma (HCC) remain satisfactory due to high incidences of recurrence. This study was intended to see whether preoperative transcatheter arterial chemoembolization (TACE) reduces postoperative tumor recurrences and prolongs survival of patients with resectable HCC. METHODS: A computerized literature search was performed to identify relevant articles. The quality of nonrandomized comparative studies (NRCTs) was assessed using the methodological index for nonrandomized studies (MINORS). Data synthesis was performed using Review Manager 5.0 software. RESULTS: Twenty-one studies (4 randomized controlled trials and 17 NRCTs) with a total of 3,210 participants were suitable for analysis. There was no significant difference in disease-free and overall survival at 5-year (32.1% vs. 30.0% and 40.2% vs. 45.2%), and intra- and extra-hepatic recurrence (51.2% vs.53.6% and 12.9% vs.10.3%) between patients with and without preoperative TACE. Postoperative morbidity (28.9% vs. 26.8%) and in-hospital mortality (4.1% vs. 3.1%) were also similar between the two groups. CONCLUSIONS: Preoperative TACE does not seem to improve prognosis and therefore it is prudent to recommend it as a preoperative routine procedure for resectable HCC.
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Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Hepatectomía/métodos , Neoplasias Hepáticas/terapia , Cuidados Preoperatorios/métodos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Ensayos Clínicos Controlados como Asunto , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. PATIENTS AND METHODS: The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. RESULTS: On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all). CONCLUSION: The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy.