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Drenaje , Hepatectomía/efectos adversos , Laparoscopía/efectos adversos , Anciano , Femenino , Hepatectomía/métodos , Humanos , Laparoscopía/métodos , Tiempo de Internación/estadística & datos numéricos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Resultado del TratamientoRESUMEN
BACKGROUND: Long-term immunosuppression is associated with an increased risk of cancer. Especially, the immunosuppression in pancreas transplantation is more intensive than that in other organ transplantation because of its strong immunogenicity. Therefore, it suggests that the risk of post-transplant de novo malignancy might increase in pancreas transplantation. However, there have been few studies of de novo malignancy after pancreas transplantation. The aim of this study was to analyze the incidence of de novo malignancy after pancreas transplantation in Japan. METHODS: Post-transplant patients with de novo malignancy were surveyed and characterized in Japan. RESULTS: Among 107 cases receiving pancreas transplantation in Japan between 2001 and 2010, de novo malignancy developed in 9 cases (8.4%): post-transplant lymphoproliferative disorders in 6 cases, colon cancer in 1 case, renal cancer in 1 case, and brain tumor in 1 case. CONCLUSIONS: We clarified the incidence of de novo malignancy after pancreas transplantation in Japan.
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Neoplasias Encefálicas/etiología , Carcinoma de Células Renales/etiología , Neoplasias del Colon/etiología , Glioblastoma/etiología , Neoplasias Renales/etiología , Trasplante de Páncreas , Complicaciones Posoperatorias , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/epidemiología , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/epidemiología , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/epidemiología , Femenino , Glioblastoma/diagnóstico , Glioblastoma/epidemiología , Humanos , Incidencia , Japón , Neoplasias Renales/diagnóstico , Neoplasias Renales/epidemiología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , RiesgoRESUMEN
BACKGROUND: Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumour recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterise the clinical significance. METHODS: We established gemcitabine-resistant Panc1 cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumourigenicity. The expression was studied in 24 pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining. RESULTS: The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients. CONCLUSIONS: miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.
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Ciclina G2/fisiología , Desoxicitidina/análogos & derivados , MicroARNs/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Antimetabolitos Antineoplásicos , Línea Celular Tumoral , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Humanos , Ratones , Neoplasias Pancreáticas/patología , GemcitabinaRESUMEN
In Japan, absolute shortage of donors still continues even after the law allowing organ transplantation from deceased donors came into force in 1997. With the passage of the waiting period after registration for pancreas transplantation (PTx), both deaths and serious cases of diabetic complications necessitating withdrawal of the registration have undoubtedly increased. Therefore, so-called "marginal donor" (MD) has been considered as a potential solution for shortage of donors in Japan. The aim of the present study is to evaluate feasibility of MD in terms of post-PTx outcomes using data from Japan Organ Transplantation Network. A total of 148 PTx were performed from deceased donors in Japan from 2000 to 2012. MD was defined as follows: (1) >45 years old; (2) hemodynamically unstable at harvest using a high-dose dopamine or more than 2 vasopressors; or (3) non-heart-beating status. Postoperative outcomes after PTx were compared between the MD group and the non-MD group. Among the 148 PTx donors, 108 donors (73.0%) satisfied the criteria of MD. Early graft loss of pancreas graft during 3 months post-transplant was observed in 15 patients (10.1%), and the marginality (MD vs non-MD) was not significantly correlated with the early loss of pancreas graft. The overall patient survival of the MD group (1, 3, 5 years: 94.7%, 94.7%, 94.7%) was not significantly different from that of the non-MD group (1, 3, 5 years: 95.0%, 95.0%, 95.0%). Pancreas graft survival in the MD group (1, 3, 5 years: 80.9%, 73.2%, 66.0%) seemed to be slightly lower than that in the non-MD group (1, 3, 5 years: 92.5%, 85.2%, 77.4%), but no statistically significant differences were found between the 2 groups. These results suggest the feasibility of the use of MD for PTx.
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Trasplante de Páncreas , Donantes de Tejidos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Gemcitabine-based chemotherapy is the standard treatment for pancreatic cancer. However, the issue of resistance remains unresolved. The aim of this study was to identify microRNAs (miRNAs) that govern the resistance to gemcitabine in pancreatic cancer. METHODS: miRNA microarray analysis using gemcitabine-resistant clones of MiaPaCa2 (MiaPaCa2-RGs), PSN1 (PSN1-RGs), and their parental cells (MiaPaCa2-P, PSN1-P) was conducted. Changes in the anti-cancer effects of gemcitabine were studied after gain/loss-of-function analysis of the candidate miRNA. Further assessment of the putative target gene was performed in vitro and in 66 pancreatic cancer clinical samples. RESULTS: miR-320c expression was significantly higher in MiaPaCa2-RGs and PSN1-RGs than in their parental cells. miR-320c induced resistance to gemcitabine in MiaPaCa2. Further experiments showed that miR-320c-related resistance to gemcitabine was mediated through SMARCC1, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. In addition, clinical examination revealed that only SMARCC1-positive patients benefited from gemcitabine therapy with regard to survival after recurrence (P=0.0463). CONCLUSION: The results indicate that miR-320c regulates the resistance of pancreatic cancer cells to gemcitabine through SMARCC1, suggesting that miR-320c/SMARCC1 could be suitable for prediction of the clinical response and potential therapeutic target in pancreatic cancer patients on gemcitabine-based therapy.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/genética , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , MicroARNs/fisiología , Neoplasias Pancreáticas/genética , Factores de Transcripción/fisiología , Anciano , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/cirugía , Línea Celular Tumoral , Supervivencia Celular/genética , Desoxicitidina/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Factores de Transcripción/genética , Transfección , GemcitabinaRESUMEN
We have previously demonstrated that WNT3 and Frizzled7 (FZD7) expression levelswere upregulated in hepatocellular carcinoma (HCC) and that they directly interact to activate the canonical Wnt/ß-catenin pathway in HCC cell lines. In this study, we investigated the functional consequences of WNT3 and FZD7 expression levels in non-transformed hepatic cells to address the question of whether WNT3/FZD7-mediated signal transduction could be involved in cellular transformation. After stable transfection of WNT3 and FZD7, the activation of the Wnt/ß-catenin pathway was confirmed by western blot, immunostaining and quantitative real-time reverse transcriptase-PCR (qRT-PCR) analysis in two non-transformed hepatocyte-derived cell lines. In vitro characteristics of the malignant phenotype were measured, including cell proliferation, migration, invasion and anchorage-independent growth in soft agar. Stable expression of WNT3 and FZD7 in the two cell lines led to cellular accumulation of ß-catenin and expression of downstream target genes activated by this pathway. In the stable WNT3/FZD7-expressing clones, hepatic cell proliferation, migration, invasion as well as soft agar colony formation were enhanced compared with the non-transformed control cells. The epithelial-mesenchymal transition (EMT) factors, Twist, Snail and Vimentin, were increased in cells expressing WNT3 and FZD7. However, the WNT3/FZD7-expressing cells did not form tumors in vivo. We conclude that activation of the WNT3/FZD7 canonical pathway has a role in the early stages of hepatocarcinogenesis by promoting the acquisition of a malignant phenotype with features of EMT.
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INTRODUCTION: The aim of this study was to evaluate whether elderly patients with colorectal cancer benefit from laparoscopic colon surgery (LAC) in comparison to open colon surgery (OC). METHODS: Patients with colon cancer were divided into four groups; >75 years (CC(>75) ) [LAC(>75) (n=36), OC(>75) (n=15)] and ≤75 years [LAC(≤75) (n=90), OC(≤75) (n=26)]. Differences in postoperative short-term outcomes were analyzed among the age and procedure groups. RESULTS: Intraoperative blood loss was significantly less in the LAC(>75) group (68 ± 168 ml) than in the OC(>75) group (118 ± 130 ml, P=0.040). The C-reactive protein of patients in the OC(>75) group (5.4 ± 2.2 mg/dl) tended to be less than that of the LAC(>75) group (6.1 ± 2.8 mg/dl, P=0.080) on postoperative day 1. The time to the first passage of flatus was significantly shorter in the LAC(>75) group (2.0 ± 0.7 days) than in the OC(>75) group (2.7 ± 0.8 days, P=0.003). Postoperative hospital stays were also shorter in the LAC(>75) group (14.2 ± 9.4 days) than in the OC(>75) group (18.0 ± 8.3 days, P=0.038). No mortality was registered in the LAC(>75) group, while one patient in the OC(>75) group died during the postoperative course. The rate of postoperative morbidity was similar between the LAC(>75) and OC(>75) groups [13.9% (5/36) versus 20.0% (3/15), P=0.679]. CONCLUSION: LAC provides some advantages over OC in patients with colon cancer aged >75 years as well as in those aged ≤75 years. LAC can be safely performed in very elderly patients with colon cancer.
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Neoplasias del Colon/cirugía , Laparoscopía , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We reported recently the clinical efficiency of interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC). However, prediction of the response to the combination therapy remains unsatisfactory. The aim of this study was to investigate the anti-tumour effects of microRNA (miR)-21 on the sensitivity of HCC cells to IFN-α/5-FU and whether miR-21 can be used as a predictor of the response to such therapy in HCC. METHODS: Changes in the sensitivity of HCC cells (PLC/PRF/5 and HepG2) to IFN-α/5-FU were examined after transfection with pre-miR-21 or anti-miR-21. The correlation between miR-21 expression level, evaluated by qRT-PCR, and response to the therapy was also investigated in clinical HCC specimens. RESULTS: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-α/5-FU. Annexin V assay showed that the percentage of apoptotic cells was significantly lower in cells transfected with pre-miR-21 than control cells. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-α/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4. miR-21 expression in clinical HCC specimens was significantly associated with the clinical response to the IFN-α/5-FU combination therapy and survival rate. CONCLUSIONS: The miR-21 in HCC cell lines and clinical HCC samples is a significant modulator of the anti-tumour effect of IFN-α and 5-FU. This suggests that miR-21 is a potentially suitable marker for the prediction of the clinical response to the IFN-α/5-FU combination therapy.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , MicroARNs/genética , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , División Celular/efectos de los fármacos , Cartilla de ADN , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Resistencia a Antineoplásicos , Fluorouracilo/antagonistas & inhibidores , Fluorouracilo/uso terapéutico , Humanos , Inmunohistoquímica , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/uso terapéutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , MicroARNs/farmacología , ARN Mensajero/genética , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , TransfecciónRESUMEN
BACKGROUND: A striking efficiency of interferon (IFN)-based anticancer therapy for advanced hepatocellular carcinoma (HCC) has been reported. Because its clinical efficiency greatly depends on each patient's local response, prediction of local response is crucial. METHODS: Continuous exposure of IFN-alpha to parental PLC/PRF/5 cells (PLC-P) and a limiting dilution method resulted in the establishment of IFN-resistant cell clones (PLC-Rs). Microarray analyses of PLC-P and PLC-Rs identified insulin-like growth factor-binding protein 7 (IGFBP7) as one of the most significantly downregulated genes in PLC-Rs. Changes in anticancer effects of IFN-alpha were examined in HCC cells after genetic manipulation of IGFBP7 expression. The correlation between immunohistochemically determined IGFBP7 expression and the response to IFN-alpha/5-fluorouracil (5-FU) therapy was investigated in surgically resected HCC specimens. RESULTS: PLC-R cells showed a remarkable downregulation of IGFBP7 and resistance to IFN-alpha, compared with PLC-P. Parental PLC/PRF/5 cells transfected with short hairpin RNA against IGFBP7 showed a significant resistance to IFN-alpha relative to control cells (IC(50) fold increase=14.38 times). Insulin-like growth factor-binding protein 7 transfection into PLC-R restored sensitivity to IFN-alpha. In resected specimens, IGFBP7 expression significantly correlated with the response to IFN-alpha/5-FU therapy. CONCLUSION: IGFBP7 could be a useful predictor of the response to IFN-based therapy in advanced HCC.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/genética , Resistencia a Antineoplásicos/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Interferón-alfa/farmacología , Neoplasias Renales/genética , Biomarcadores de Tumor/análisis , Western Blotting , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Fluorouracilo/uso terapéutico , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Inmunoprecipitación , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Estimación de Kaplan-Meier , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Neoadjuvant chemotherapy may improve survival of responders in esophageal cancer patients but is useless and harmful in non-responders. Thus, it is important to predict the effect of the chemotherapy, and that any predictor must be applicable clinically. The aim of this study is to examine the correlation between pretherapeutic hypercoagulopathy as determined by plasma d-dimer levels and response to chemotherapy. In 71 patients with esophageal cancer who underwent neoadjuvant chemotherapy (cisplatin, adriamycin and 5-fluorouracil) followed by surgery, plasma d-dimer levels were measured before chemotherapy and the clinical and pathological responses to chemotherapy were assessed at 4 weeks after therapy (after surgery). Pretherapeutic plasma d-dimer level was significantly lower in clinical responders (complete response/partial response [CR/PR]; 0.62 +/- 1.10 microg/mL, mean +/- SD) than in non-responders (no change/progressive disease [NC/PD]; 1.15 +/- 1.08 microg/mL, P = 0.0491), and in pathological responders (Grade 1b-3; 0.62 +/- 1.11 microg/mL) and non-responders (Grade 0-1a; 1.15 +/- 1.05 microg/mL, P = 0.0107). The optimal cut-off level of the plasma d-dimer levels for predicting clinical and pathological responses was 0.6 microg/mL. Then, sensitivity and specificity for the prediction of CR/PR were 68% and 73%, and those for Grade 1b-3 were 91% and 69%, respectively. Our results suggested that pretherapeutic plasma d-dimer level correlated significantly with clinical and pathological responses to chemotherapy. Pretherapeutic plasma d-dimer level can be used as a predictor for chemosensitivity.