RESUMO
OBJECTIVE: Pancreatic cancer is a malignant neoplasm with poor prognosis that might be associated with defective immune function. We aimed to determine the influence on survival of circulating myeloid dendritic cells (c-m-DCs), circulating lymphoid DCs (c-l-DCs), and DCs within the tumor tissue in patients with pancreatic cancer. PATIENTS AND METHODS: Between December 2001 and June 2006, of a total of 110 patients with ductal adenocarcinoma of the pancreas, 42 underwent pancreatectomy, and 68 had unresectable disease. Numbers of c-m-DCs and c-l-DCs were assessed by flow cytometry, and DCs in the tumor tissue by immunohistochemical staining with anti-fascin mAb. RESULTS: The percentage of the c-m-DCs subset in pancreatic cancer patients was significantly lower than in healthy volunteers, and the similar finding was observed between patients who underwent surgical resection and non-resection. Patients with a high percentage of c-m-DCs or with many DCs accumulated in the cancer tissue survived longer than patients with a low percentage or low number in peripheral blood or the tumor, respectively. Moreover, there was a positive correlation between c-m-DCs within peripheral blood mononuclear cells and the number of DCs per field in the cancer tissue. CONCLUSIONS: Preoperative c-m-DCs levels in the PBMC of patients with pancreatic cancer and DCs counts in the cancer tissue can be a prognostic factor after surgical resection. Modulating the distribution of DCs may be an effective therapy in pancreatic cancer patients with a dismal prognosis.
Assuntos
Adenocarcinoma/imunologia , Células Dendríticas/patologia , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Análise de SobrevidaRESUMO
The aim of this study was to evaluate the effects of active hexose correlated compound (AHCC) intake on immune responses by investigating the number and function of circulating dendritic cells (DCs) in healthy volunteers. Twenty-one healthy volunteers were randomized to receive placebo or AHCC at 3.0 g/day for 4 wk. The number of circulating cluster of differentiation (CD)11c(+) DCs (DC1) and CD11c(-) DCs (DC2) were measured. Allogeneic mixed-leukocyte reaction (MLR) was performed. Natural killer (NK) cell activity and the proliferative response of T lymphocytes toward mitogen (phytohemagglutinin [PHA]) were measured. We also measured cytokine production stimulated by lipopolysaccharide [interleukin (IL)-2, IL-4, IL-6, IL-10, interferon gamma-gamma, tumor necrosis factor-alpha). The AHCC group (n = 10) after AHCC intake had a significantly higher number of total DCs compared to that at baseline and values from control subjects (n = 11). The number of DC1s in the AHCC group after intake was significantly higher than at baseline. DC2s in the AHCC group were significantly increased in comparison with controls. The MLR in the AHCC group was significantly increased compared to controls. No significant differences in PHA, NK cell activity, and cytokine production were found between groups. AHCC intake resulted in the increased number of DCs and function of DC1s, which have a role in specific immunity.
Assuntos
Polissacarídeos/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Método Duplo-Cego , Feminino , Citometria de Fluxo/métodos , Humanos , Japão , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Linfócitos T/imunologiaRESUMO
HYPOTHESIS: We hypothesized that no-margin resections for hepatocellular carcinoma do not negatively affect patient outcomes. DESIGN: Inception cohort study. SETTING: Department of surgery at a university hospital. PATIENTS: From January 1992 to December 2005 at our institute, 465 consecutive patients with a preoperative diagnosis of hepatocellular carcinoma with curative potential were evaluated. INTERVENTION: Liver resection performed with or without surgical margins. MAIN OUTCOME MEASURES: Overall survival and no-recurrence survival. RESULTS: Of the 465 patients, 62 underwent resections with exposure of the tumor surface at the cut stump (the cut surface of the remnant liver) with no surgical margins (exposure group), because the tumor adhered to the major hepatic vascular structures. The remaining 365 patients underwent resections without exposure of the tumor surface (nonexposure group). There were no significant differences between the 2 groups regarding the recurrence and overall survival rates. There were also no significant differences between the 2 groups with respect to the recurrence rate at the cut stump or the number and the location of intrahepatic recurrences, despite the less favorable clinical histories in the exposure group. CONCLUSIONS: Limited resection with no margin seems to be the best procedure for patients with tumors close to the major hepatic vessels and with hepatic functions that do not permit wide-margin resections.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Idoso , Perda Sanguínea Cirúrgica , Transfusão de Sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/secundário , Estudos de Coortes , Intervalo Livre de Doença , Eletrocoagulação/instrumentação , Feminino , Seguimentos , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Complicações Pós-Operatórias , Estudos Prospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
One of the longstanding challenges in the treatment of pancreatic cancer, the fifth most common cancer worldwide, is to establish a simple and reliable diagnostic marker for the disease. This study examined whether or not the plasma levels of IgG antibodies (IgGs) reactive to peptides derived from the prostate stem cell antigen (PSCA), which is highly expressed in pancreatic cancer cells, were elevated in patients with pancreatic cancer. Fifty-seven kinds of peptides encoded by PSCA were tested for their reactivity to plasma IgGs of pancreatic cancer patients. The results showed that the levels of IgGs specific to each of the 10 different peptides in the plasma of pancreatic cancer patients were significantly higher than those of non-cancer subjects. Eighty percent of subjects with and 18% of subjects without pancreatic cancer were diagnosed as having pancreatic cancer, respectively, when those cases showing significantly elevated levels of IgGs against at least one of the three peptides of PSCA at positions 2-11, 85-95, and 109-118 were judged as positive for pancreatic cancer. These results indicate that the measurement of IgGs reactive to these PSCA-derived peptides can provide novel information on the host-tumor interaction in pancreatic cancer, and could potentially be used as a new diagnostic tool to screen for pancreatic cancer.
Assuntos
Anticorpos Antineoplásicos/sangue , Carcinoma Ductal Pancreático/imunologia , Imunoglobulina G/sangue , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Pancreáticas/imunologia , Fragmentos de Peptídeos/imunologia , Idoso , Antígenos de Neoplasias , Biomarcadores Tumorais/sangue , Neoplasias do Colo/imunologia , Feminino , Proteínas Ligadas por GPI , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Neoplasias da Próstata/sangue , Neoplasias da Próstata/imunologia , Neoplasias Gástricas/imunologiaRESUMO
OBJECTIVES: To retrospectively evaluate the efficacy and tolerability of 5-fluorouracil and low-dose cisplatin (FP)-based preoperative concurrent chemoradiotherapy (PCRT) and gemcitabine (GEM)-based PCRT in patients with potentially resectable pancreatic cancer. METHODS: Between December 2000 and December 2004, 32 patients with potentially resectable pancreatic cancer were treated with PCRT. All patients received external beam radiotherapy (total dose of 40 Gy) for 4 weeks. Concurrently, chemotherapy was performed intravenously with continuous 5-fluorouracil 200 mg/m2/d and intermittent cisplatin bolus 3 to 6 mg/m2/d for 4 weeks (Arm FP-PCRT, n = 14) or weekly GEM 400 mg/m2 for 3 weeks (Arm GEM-PCRT, n = 18). The patients were restaged 3 to 4 weeks after the end of PCRT and explored for resection in cases without distant metastases. RESULTS: The 3-year survival rates and median survival were 29.4% and 20.5 months for the resected patients (n = 24) and 0% and 5.5 months for unresected patients (n = 8), respectively (P < 0.0001). The 1-, 2-, 3-year survival rates and median survival were 87.5%, 62.5%, 33.3%, and 26 months for the resected patients treated with FP-PCRT and 75%, 40%, 26.7%, and 19.9 months for the resected patients treated with GEM-PCRT (respectively; P = not significant). Most of the toxicities of both regimens were slight and were in grade1 to 2. Grade 1 to 3 leukopenia (43% vs 100%) and thrombocytopenia (0% vs 39%) were significantly different between the FP-PCRT and GEM-PCRT patients. CONCLUSIONS: The PCRT regimens in this article enabled selection of 24 of 32 patients for surgery and resulted in encouraging survival results and acceptable toxicities.
Assuntos
Terapia Neoadjuvante , Neoplasias Pancreáticas/cirurgia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Cuidados Pré-Operatórios , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
OBJECTIVE: To investigate whether circulating dendritic cells in patients with pancreatic cancer is a risk factor for septic complications after pancreatectomy. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Forty-one patients with pancreatic cancer who underwent pancreatectomy from May 2001 to July 2005. Patients were divided into 2 groups depending on whether or not they had a development of postoperative septic complications. MAIN OUTCOME MEASURES: Dendritic cell, natural killer cell, and CD4(+) T-cell, and CD8(+) T-cell counts were measured preoperatively in each patient. Clinicopathologic parameters and immune parameters for each patient, operation, and tumor were compared between the 2 groups. Preoperative risk factors for postoperative septic complications were determined using logistic regression analysis. RESULTS: Circulating dendritic cell count before pancreatectomy in patients with septic complications postoperatively for pancreatic cancer was significantly lower than in patients without septic complications. Multivariate analysis indicated that preoperative circulating dendritic cell count was the only predictive value among the diverse clinical parameters tested in relation to the development of septic complications. Notably, when the circulating dendritic cell count was less than 10.0 x 10(3)/mL in the peripheral blood, the risk of developing postoperative septic complications markedly increased. In such cases, the sensitivity, specificity, positive predictive value, and negative predictive value of total circulating dendritic cell count were as high as 80%. CONCLUSION: In patients with pancreatic cancer, low preoperative circulating dendritic cell count (< 10.0 x 10(3)/mL) is a significant risk factor for the development of septic complications after pancreatectomy.
Assuntos
Células Dendríticas/imunologia , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Sepse/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
The aim of the present study was to investigate the safety and immune responses of personalized peptide vaccination when administered with gemcitabine (GEM) in advanced pancreatic cancer (APC) patients. Thirteen patients with APC were enrolled. Pre-vaccination with peripheral blood mononuclear cells and plasma was carried out to examine cellular and humoral responses to 25 or 23 peptides in human leukocyte antigen A24+(+) or A2++(+) patients, respectively. Only the reactive peptides (maximum of four) were then administered weekly at three different dose settings: 1, 2 and 3 mg of peptide. GEM was administered at 1000 mg/m(2) per week for 3 weeks, followed by 1 week of rest. The combination therapy was well tolerated. Grade 3 toxicities were: anemia (three patients), neutropenia (two patients) and thrombocytopenia (two patients). Of these 13 patients, 11 (85%) showed clinical responses, such as reduction in tumor size and/or level of tumor markers. Augmentation of peptide-specific cytotoxic T lymphocyte activity against pancreatic cancer cells was observed at each dose level, whereas the increment of peptide-specific IgG antibodies was dependent on peptide dose. GEM did not inhibit the immune responses induced by personalized peptide vaccinations, and this new type of immunochemotherapy combination is recommended for further clinical study in APC patients.
Assuntos
Vacinas Anticâncer/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/terapia , Vacinas de Subunidades Antigênicas/uso terapêutico , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Terapia Combinada , Desoxicitidina/uso terapêutico , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Vacinação , Vacinas de Subunidades Antigênicas/administração & dosagem , GencitabinaRESUMO
OBJECTIVE: The aim of this study was to evaluate the tumor necrosis factor alpha (TNF-alpha) releasing capacity in whole blood stimulated by lipopolysaccharide (LPS) in patients with pancreatic cancer during the perioperative period, and before and after chemotherapy. METHODS: The current study involved a total of 39 patients with pancreatic cancer (PC), who were further divided into a PC-Op group (n = 16, underwent pancreatectomy) and a PC-chemo group (n = 23, received chemotherapy). The control groups consisted of patients with hepatocellular carcinoma (n = 27, HCC group) and with benign diseases (n = 15, control group). Serial changes in TNF-alpha in whole blood stimulated by LPS were compared in various clinical settings. RESULTS: Preoperative TNF-alpha levels in the PC-Op group were significantly lower than those in the HCC and control groups (P = 0.034). The TNF-alpha variable surgical index (s-index) was defined as the ratio of the preoperative TNF-alpha level to postoperative level in the PC-Op and HCC groups. Although the TNF-alpha s-index in the PC-Op group was significantly decreased on postoperative day 1 and recovered on postoperative day 3 (P < 0.002), there were no significant changes in the TNF-alpha s-index in the HCC group. The TNF-alpha variable chemotherapeutic index (c-index) was defined as the ratio of the TNF-alpha level before to that after chemotherapy in the PC-chemo group. The TNF-alpha c-index in all 7 patients was reduced to less than 0.3 until leukopenia appeared. Patients who had an increase in TNF-alpha production (TNF-alpha c-index >1.0) on day 3 or 7 after chemotherapy had significantly better cumulative survival than those with no increase (P < 0.033). CONCLUSIONS: TNF-alpha production stimulated by LPS in the whole blood of patients with pancreatic cancer was low. Surgical stress and depressed immunocompetence might induce such profound decreases. A method of assessing the capability of leukocytes, particularly macrophages, to produce TNF-alpha could be useful for prognostis and for monitoring immunocompetence in patients with pancreatic cancer who have undergone chemotherapy.
Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/imunologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Imunidade Celular , Lipopolissacarídeos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pancreatectomia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , GencitabinaRESUMO
BACKGROUND: Dendritic cells (DCs) are important for an immune surveillance. Myeloid DCs (DC1) are important for an effective antitumor immune system. The function and count of circulating DC1 (cDC1) in hosts with a malignant tumor would be defective. This study focused on analyzing the immunological features of cDC1 in patients with pancreatic cancer during the perioperative period. MATERIALS AND METHODS: Thirty-two pancreatic cancer patients who underwent pancreatectomy and 18 age-matched healthy individuals as controls were enrolled in this study. The perioperative cDC count, the stimulatory capacity of cDC1 against allogeneic T cells and TGF-beta1 level in the serum were measured. The cDC count was measured at 12 months after the operation. RESULTS: The preoperative cDC1/cDC2 ratio, cDC1 count, and stimulatory capacity of cDC1 were impaired in patients in comparison to controls (P<0.05). The serum TGF-beta1 level was significantly higher in patients than controls (P<0.001). The stimulatory capacity of cDC1 recovered after pancreatectomy (P<0.05). The serum TGF-beta1 level significantly decreased after the operation (P<0.05); however, they were still significantly higher than controls (P<0.05). Although the cDC1/cDC2 ratio and the cDC1 count did not increase after the pancreatectomy, they recovered as the controls' level at 12 months after the pancreatectomy in disease-free patients (P<0.05) and the serum TGF-beta1 level in those patients at 12 months after the operation significantly decreased compared with those at the postoperative period (P<0.05). CONCLUSION: Surgical resection of pancreatic cancer could be associated with improved cDC1 function. When a patient remained disease free, the recovery of cDC1 counts was observed approximately 12 months after pancreatectomy. Further strategy will be needed to improve immune function in patients with pancreatic cancer.
Assuntos
Contagem de Células Sanguíneas , Células Dendríticas/imunologia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/imunologia , Fito-Hemaglutininas/farmacologia , Período Pós-Operatório , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta1RESUMO
OBJECTIVES: The pancreaticoduodenectomy with extended resection has been frequently performed in patients with pancreatic cancer in Japan. One result of this additional surgical stress may be that postoperative complications in patients with pancreatic cancer are more frequent than in patients with periampullary cancer. METHODS: The 198 patients with pancreatic and periampullary cancer underwent pancreaticoduodenectomy. The operative mortality and morbidity between patients with pancreatic and periampullary cancer were compared, and the risk factors of postoperative complications and in-hospital death were determined. RESULTS: Patients with pancreatic and periampullary cancer made up 52% and 48% of total patients. The duration of surgery and volume of intraoperative blood loss were significantly higher in patients with pancreatic cancer than in patients with periampullary cancer. Additional organ resections were frequently performed in patients with pancreatic cancer. However, significantly lower morbidity rates were observed in patients with pancreatic cancer. Among all complications evaluated, pancreatic fistula and abdominal abscess were found less frequently in patients with pancreatic cancer. Logistic regression analyses showed a positive correlation between periampullary cancer and an increased risk of complications, pancreatic fistula, and abdominal abscess. The in-hospital mortality rate has significantly reduced since 2000. When pancreatic fistula was clinically diagnosed, we immediately started a closed lavage using continuous administration of natural saline at 1000 to 4000 mL/d, after exchange of a nasogastric tube drain. CONCLUSION: Pancreaticoduodenectomy for patients with pancreatic cancer can be a safe procedure in spite of surgical stress. Further surgical strategies will be needed to reduce postoperative complications, especially in patients with periampullary cancer.
Assuntos
Ampola Hepatopancreática , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Complicações Pós-Operatórias , Abscesso Abdominal/epidemiologia , Abscesso Abdominal/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ducto Colédoco/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fístula Pancreática/epidemiologia , Fístula Pancreática/mortalidade , Neoplasias Pancreáticas/mortalidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Reoperação , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: Dendritic cells (DCs) are important for immune surveillance and play a central role in protection against infection and malignancy. DCs comprise two subsets: DC1 (myeloid DC) and DC2 (lymphoid DC). The aim of this study is to determine whether the number and/or function of circulating DCs were decreased in patients with pancreatic cancer and to evaluate the effects of these changes in patients with locally advanced pancreatic cancer before and after chemoradiotherapy (CRT). We examined the circulating DC number and function using the peripheral blood from 29 patients with pancreatic cancer and 20 healthy control subjects. In patients who underwent CRT (n = 20), blood samples were taken before and after CRT. DCs were tested for the ability to stimulate allogeneic T lymphocytes in mixed leukocyte reaction (MLR). CD4/8, NK activity, PHA, and TGF-beta1 were also measured. RESULTS: The number and allostimulatory activity of circulating DC1s in patients were significantly lower than those in controls. In the patients who underwent CRT, the allostimulatory activity of DC1s at post-CRT was significantly increased as compared to those at pre-CRT. The level of TGF-beta1 was also significantly decreased at post-CRT as compared to pre-CRT. There were no changes in CD4/8, NK activity and proliferative response of T lymphocytes at the peri-CRT period. CONCLUSION: These data indicate that the number and function of circulating DCs were impaired in patients with pancreatic cancer. Chemoradiotherapy, however, improved DC function, which might be related to decreased immunosuppressive cytokine levels.