RESUMEN
INTRODUCTION: Since previous in vitro studies suspected the metabolite mycophenolate acyl-glucuronide (AcMPAG) to be responsible for the gastrointestinal side effects, we examined the correlation between AcMPAG blood levels and patient gastrointestinal satisfaction inquiries using a standardized, validated questionnaire. PATIENTS AND METHODS: We enrolled 63 renal transplant patients, however, two discontinued the study and 16 were excluded because of inadequate completion of the questionnaires or missing blood values or discontinuation of enteric coated mycophenolic acid (EC-MPA) therapy, severe side effects or viral infections. The final responses of 45 people were subjects to statistical analysis. Gastrointestinal side effects were examined using the Gastrointestinal Symptom Rating Scale (GSRS) completed at three times: T1 (3-5 days after transplantation), T2 (10-15 days), and T3 (3 months). The GSRS results generated two groups of patients based on cutoff values set at a score of 4 points for each item. Scores less than 4 were assumed to be "no side effects"; ≥4, "side effects." AcMPAG was measured by mass spectroscopy on blood samples obtained at fixed times generating three pharmacokinetic profiles per patient. RESULTS: There was no relation between high AcMPAG blood concentrations and gastrointestinal dissatisfaction. Neither Ac-MPAG area under the curve (AUC) in the absorption phase nor AcMPAG peak values correlated with gastrointestinal dissatisfaction. CONCLUSION: There was no significant correlation between mean AcMPAG and GSRS scores, although previous studies had suggested AcMPAG maximum values or alternatively AcMPAG AUC in the absorption phase to relate to side effects.
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Tracto Gastrointestinal/efectos de los fármacos , Glucurónidos/sangre , Inmunosupresores/sangre , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Área Bajo la Curva , Glucurónidos/farmacocinética , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Ácido Micofenólico/sangre , Ácido Micofenólico/farmacocinética , Satisfacción del Paciente , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: For experimental basic research, standardized transplantation models reflecting technical and immunologic aspects are necessary. This article describes an experimental model of combined pancreas/kidney transplantation (PKTx) in detail. MATERIALS AND METHODS: Donor rats underwent en bloc pancreatectomy and nephrectomy. Revascularization was performed using the aorta with the superior mesenteric artery and the inferior vena cava with the portal vein. Exocrine drainage of the pancreas took place over a segment of the duodenum which was transplanted side-to-side to the jejunum. The kidney vessels were transplanted end-to-side. The ureter was anastomosed by patch technique. Postoperatively, serum parameters were monitored daily. Biopsies for histopathology were taken on days 5, 8 and 12. RESULTS: All 12 recipients survived the combined PKTx without serious surgical complications. One thrombosis of the portal vein led to organ failure. Blood glucose levels were normal by the 3rd postoperative day. The transplanted duodenal segment showed slight villous atrophy, and the kidneys were well perfused without vascular complications. The anastomosis between ureter and bladder was leakproof. CONCLUSIONS: Excellent graft function and survival rates can be achieved due to simplified operation technique and short operation time. It may thus have high clinical relevance to immunologic issues within the scope of basic research.
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Trasplante de Riñón/métodos , Microcirugia/métodos , Trasplante de Páncreas/métodos , Animales , Supervivencia de Injerto/inmunología , Supervivencia de Injerto/fisiología , Humanos , Trasplante de Riñón/inmunología , Trasplante de Riñón/patología , Trasplante de Riñón/fisiología , Masculino , Modelos Animales , Trasplante de Páncreas/inmunología , Trasplante de Páncreas/patología , Trasplante de Páncreas/fisiología , Ratas , Ratas Endogámicas Lew , Trasplante IsogénicoRESUMEN
BACKGROUND: Immunosuppressive therapy increases the incidence of posttransplantation cancer. Primary renal cell carcinoma (RCC) represents 4.6% of all cancers in transplant recipients. The treatment options for RCC in a renal allograft include radical nephrectomy or nephron-sparing surgery. We report the case of a patient who underwent percutaneous radiofrequency ablation (RFA) of a RCC in the grafted kidney. PATIENT AND METHODS: Twelve years after undergoing heterotopic, allogenic kidney transplantation, a de novo lesion was diagnosed in the upper pole of the kidney graft in a 77-year-old patient during routine duplex ultrasonography. The magnetic resonance image showed a spherical lesion of 17 mm in diameter, which undoubtedly showed radiological signs of a RCC. After adequately informing the patient about alternative treatment strategies and the associated risks, we made an interdisciplinary decision for a percutaneous RFA of the lesion. RESULTS: After the intervention, graft function remained unchanged and is still good at 6 months with no signs of local recurrence on follow-up MRI. A small coagulation defect at the site of the former lesion was the only morphological change. There was also no evidence of distant tumor spread. CONCLUSION: Percutaneous RFA seems an acceptable, allograft-preserving treatment option associated with low morbidity and mortality for RCC in a renal allograft considering the significant risks associated with open partial nephrectomy in a kidney graft.
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Carcinoma de Células Renales/terapia , Ablación por Catéter , Neoplasias Renales/terapia , Trasplante de Riñón/efectos adversos , Anciano , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Complicaciones Posoperatorias/terapia , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: It is generally accepted that nitric oxide (NO) plays a crucial role in acute rejection caused by inflammatory responses. Therefore, the purpose of this study was to investigate the effect on survival following arterialized orthotopic rat liver transplantations (o-RLTx) of NO inhibition and consequent blockade of platelet aggregation by application of Aspisol. MATERIALS AND METHODS: Inbred LEWIS-(RT(1)) rats underwent arterialized o-RLTx under ether anesthesia with DA-(RT1av1) rats as organ donors. After liver transplantation, serum parameters were determined and hepatic biopsy specimens were sampled on postoperative days 5, 8, 10, 30, and 90. Sixty-one rats were divided into 5 groups: syngenic controls (group I, n = 12); allogenic controls (group II, n = 11); allogenic with FK506 immunosuppression (group III, n = 12); allogenic with AGH-treatment (group IV, n = 13); and allogenic with AGH/low- dose Aspisol treatment for 5 days after liver transplantation (group V, n = 13) (Bayer, Leverkusen, Germany). RESULTS: Rats of group V with AGH/low-dose Aspisol treatment showed significantly longer graft survival (18.2 days +/- 1.8 days) compared with group II rats with untreated grafts (11.3 days +/- 1.7 days) the allogenic group IV with AGH treatment (11.2 days +/- 1.8 days; P < .05). Histological examination revealed moderate graft rejection among the AGH-treated group IV; however, marked platelet aggregation in sinusoids was present, which was not observed in the AGH/low-dose Aspisol-treated animals (group V). CONCLUSION: Our data suggested that simultaneous treatment with AGH/low-dose Aspisol leads to a significant increase in survival and inhibition of platelet aggregation in the graft after orthotopic liver transplantation.
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Aspirina/análogos & derivados , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Hígado/fisiología , Lisina/análogos & derivados , Óxido Nítrico/antagonistas & inhibidores , Animales , Aspirina/farmacología , Biopsia , Inmunosupresores/uso terapéutico , Trasplante de Hígado/patología , Lisina/farmacología , Modelos Animales , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Ratas , Ratas Endogámicas Lew , Tacrolimus/uso terapéutico , Trasplante Homólogo , Trasplante IsogénicoRESUMEN
BACKGROUND: Activity levels of cytochrome P450 (CYP) provide markers for liver function and graft rejection episodes after orthotopic liver transplantation (OLT). Some in vitro studies have shown decreased CYP activation of inducible nitric oxide synthase (iNOS) in rejecting liver grafts. The aim of this study was to evaluate CYP isoenzyme activity changes in vivo and to examine histopathologic aspects during inhibition of iNOS after treatment with aminoguanidine (AG) using OLT in the rat. MATERIALS AND METHODS: Thirty DA-(RT1av1) rats that served as donors and LEWIS-(RT(1)) rats as recipients were divided into three groups: group I (controls, syngeneic rats; n = 6), group II (allogeneic rats without immunosupression; n = 11), and group III (allogeneic rats with AG treatment; n = 13). On postoperative days 5, 8, and 10 we performed laboratory investigations and liver biopsies for histopathologic investigations. RESULTS: On postoperative day 5, activities of CYP-1A1 and -3A4 were significantly lower (P = .022) in group III and the activity of CYP-1A2 higher (P < .05) compared with group II. At postoperative days 8 and 10, the activities of all CYP isoenzymes were significant higher in AG-treated rats (group III) in contrast with group II after allogeneic OLT without immunosuppression. Histopathologic findings revealed less distinct rejection signs in group III specimens after AG treatment compared with group II. CONCLUSION: Summarizing our results, we concluded that AG treatment led to increased CYP activity and less distinction of graft rejection after OLT in rats.
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Sistema Enzimático del Citocromo P-450/metabolismo , Trasplante de Hígado/fisiología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Animales , Biomarcadores/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Activación Enzimática , Guanidinas/farmacología , Cinética , Modelos Animales , Óxido Nítrico Sintasa de Tipo II/metabolismo , RatasRESUMEN
There is only limited information about recipient risk factors for graft survival in living- donor kidney transplantation. This study aimed to investigate prognostic factors and their impact on living-related and unrelated renal transplant recipients. From October 2000 until October 2004, 81 adult living-related renal transplantations were performed at our institution. Using multivariate analysis, the association of the following variables with kidney graft outcome was studied: ages of donors and recipients, gender and body mass index, cold and warm ischemia, HLA mismatches, identity and compatibility of blood group, duration of dialysis, cytomegalovirus (CMV) status, recipient original disease, surgical and general complications, and status of retransplantation. Multivariate analysis revealed significant reduction of graft function and graft survival in recipients with retransplantation, more than 4 mismatches, and a high body mass index. Thus, living-donor kidney transplantation can be regarded as a safe and standardized operation relating to surgical technique, but further consideration of the recipient body mass index and the number of mismatches are recommended during the preparation for transplantation.
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Trasplante de Riñón/efectos adversos , Trasplante de Riñón/fisiología , Donadores Vivos , Adulto , Incompatibilidad de Grupos Sanguíneos/epidemiología , Femenino , Prueba de Histocompatibilidad , Humanos , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Reoperación/estadística & datos numéricos , Medición de Riesgo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: The application of antibody induction therapy in adult living-related kidney transplantation remains under discussion. The purpose of this study was to compare the outcome of living-related (LRT) and unrelated renal transplant recipients (LURT) using standardized immunosuppressive protocols. From October 2000 to October 2004, 72 adult LRT (TX) were performed at our institution. Thirty-nine LRT (group A) and 33 LURT (group B) recipients received a standardized immunosuppressive therapy consisting of tacrolimus (Tac), steroids and mycophenolate mofetil (MMF) without antibody induction therapy. This prolective analysis included immediate graft function, rejection rate and loss of the transplanted organ. The incidence of post-operative good graft function (>90%) was similar for both groups, as well as the rejection rate showed 57.8% for patients of group A and 58.8% for patients of group B (p < 0.5). However, the number of rejections (>1 rejection) was significantly higher in group B (11.8%) compared to patients in group A (4.4%). No difference concerning loss of transplanted kidney was observed for both groups. Conventional Tac, MMF and steroid-based immunosuppression therapy is equivalent in efficacy of therapy in living-related and unrelated renal transplants. In our opinion, induction therapy in patients without immunologic risk factors has no favourable effect.
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Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Donadores Vivos , Ácido Micofenólico/análogos & derivados , Tacrolimus/uso terapéutico , Adulto , Femenino , Rechazo de Injerto/etiología , Humanos , Incidencia , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The detection of disseminated tumor cells in peripheral blood is limited by the presence of very few tumor cells within a large number of blood cells. Therefore, tumor cell detection calls for enrichment systems with effective depletion of blood cells and high tumor cell recovery. METHODS: We compared the new density gradient centrifugation method OncoQuick with the standard method of Ficoll. The enriched cell fractions were quantified. Tumor cell spiking experiments examined the recovery of tumor cells as detected by immunocytochemistry and cytokeratin-20 reverse transcriptase-polymerase chain reaction (RT-PCR). Clinical application of OncoQuick was evaluated in 37 peripheral blood samples of patients with gastrointestinal carcinomas. RESULTS: The depletion of mononuclear cells (MNCs) in the enriched cell fraction after OncoQuick centrifugation was 632-fold, with an average cell number of 9.5 x 10(4), compared with Ficoll, with a depletion factor of 3.8 and a mean number of 1.6 x 10(7) MNCs. The mean tumor cell recovery rates were 87% for OncoQuick and 84% for Ficoll. The increased depletion of MNCs with OncoQuick centrifugation further simplified immunocytochemical evaluation by reducing the number of cytospins and increasing the tumor cell density. Due to the reduced number of co-enriched MNCs by OncoQuick, the blood volume, which could be analyzed in one RT-PCR reaction, was increased up to 30 ml. Examination of peripheral blood samples from 37 patients with gastrointestinal tumors showed a cytokeratin-20 detection rate of 30% and a significant correlation with the presence of distant metastases (P < 0.02). CONCLUSIONS: OncoQuick significantly reduced the co-enriched number of MNCs, with a high tumor cell recovery rate. Processing blood from tumor patients with OncoQuick increased the chance of detecting circulating tumor cells.
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Centrifugación por Gradiente de Densidad/métodos , Células Neoplásicas Circulantes/patología , Recuento de Células , Separación Celular , Centrifugación por Gradiente de Densidad/instrumentación , Ficoll , Humanos , Inmunohistoquímica , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Queratina-20 , Neoplasia Residual/diagnóstico , ARN Mensajero/metabolismo , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
The cure of a tumor patient with gastrointestinal cancer is dependent on the extension of the primary tumor (TNM-classification) and the option of curative resection (R0-resection) at the time of operation. The additional application of multimodal therapy approaches has lead to an improvement of prognosis in different advanced tumor stages. Nevertheless, despite curative tumor resection about 50% of patients with locally advanced gastrointestinal cancer develop recurrent tumor disease or distant metastases and die tumor-related. A possible explanation is the seed of disseminated tumor cells in blood, bone marrow or lymph nodes pre-, intra- or postoperatively, but also during diagnostic procedures. Several studies have shown in the last years that the presence of minimal residual disease (MRD) influences the course of disease and the patient's prognosis after curative tumor resection. Although several groups have reported the prognostic impact of disseminated tumor cells in the different compartments of bone marrow, lymph nodes and blood, the phenomenon of minimal residual disease is not acknowledged as an established prognostic factor and is not integrated into the classification of the UICC. Therefore, no therapeutic consequences were drawn at present from the detection of disseminated tumor cells in patients with gastrointestinal cancer. A possible explanation are missing multi-center-studies, which confirm the results of the several single-center-studies. Standardization of study designs and methodical procedures and the evidence of reproduction are mandatory in order to value and interpret the multitude of studies and the available data in this field. Only these results will allow to decide if the presence and detection of disseminated tumor cells can alter the tumor staging and individualize or possibly minimize further oncological therapy strategies.
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Médula Ósea/patología , Neoplasias Gastrointestinales/sangre , Neoplasias Gastrointestinales/patología , Ganglios Linfáticos/patología , Neoplasia Residual/sangre , Neoplasia Residual/patología , Biomarcadores de Tumor/análisis , Humanos , Metástasis Linfática , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
The early and clinically occult spread of viable tumour cells to the organism is becoming acknowledged as a hallmark in cancer progression, since abundant clinical and experimental data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies against epithelial cytokeratins or tumour-associated cell membrane glycoproteins, individual carcinoma cells can be detected in cytological bone marrow preparations at frequencies of 10(-5) to 10(-6). Prospective clinical studies have shown that the presence of such immunostained cells in bone marrow is prognostically relevant with regard to relapse-free and overall survival, even in malignancies that do not preferentially metastasise to bone. As current treatment strategies have resulted in a substantial improvement of cancer mortality rates, it is noteworthy to consider the intriguing options of immunocytochemical screening of bone marrow aspirates for occult metastatic cells. Besides improved tumour staging, such screening offers opportunities for guiding patient stratification for adjuvant therapy trials, monitoring response to adjuvant therapies (which, at present, can only be assessed retrospectively after an extended period of clinical follow-up), and specifically targeting tumour-biological therapies against disseminated tumour cells. The present review summarises the current data on the clinical significance of occult metastatic cancer cells in bone marrow.
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Neoplasias de la Médula Ósea/secundario , Neoplasias de la Médula Ósea/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/terapia , Neoplasias de la Médula Ósea/genética , Neoplasias de la Mama/genética , Femenino , Neoplasias Gastrointestinales/genética , Humanos , Masculino , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The detection of epithelial cells in bone marrow, blood or lymph nodes indicates a disseminatory potential of solid tumours. 225 patients with squamous cell carcinoma of the oesophagus were prospectively studied. Prior to any therapy, cytokeratin-positive (CK) cells in bone marrow were immunocytochemically detected in 75 patients with the monoclonal anti-epithelial-cell antibody A45-B/B3 and correlated with established histopathologic and patient-specific prognosis factors. The prognosis factors were assessed by multivariate analysis. Twenty-nine of 75 (38.7%) patients with oesophageal cancer showed CK-positive cells in bone marrow. The analyses of the mean and median overall survival time showed a significant difference between patients with and without epithelial cells in bone marrow (P < 0.001). Multivariate analysis in the total patient population and in patients with curative resection of the primary tumour confirmed the curative resection rate and the bone marrow status as the strongest independent prognostic factors, besides the T-category. The detection of epithelial cells in bone marrow of oesophageal cancer patients is a substantial prognostic factor proved by multivariate analysis and is helpful for exact preoperative staging, as well as monitoring of neoadjuvant therapy.
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Médula Ósea/patología , Carcinoma de Células Escamosas/patología , Células Epiteliales/patología , Neoplasias Esofágicas/patología , Metástasis de la Neoplasia , Células Madre Neoplásicas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Examen de la Médula Ósea , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/terapia , Quimioterapia Adyuvante , Terapia Combinada , Células Epiteliales/química , Neoplasias Esofágicas/química , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/terapia , Esofagectomía , Femenino , Fluorouracilo/uso terapéutico , Humanos , Queratinas/análisis , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Proteínas de Neoplasias/análisis , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Células Madre Neoplásicas/química , Pronóstico , Estudios Prospectivos , Radioterapia Adyuvante , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
At the time of primary therapy (surgery, systemic chemotherapy and/or radiation), disseminated tumor cells in the bone marrow can be found in almost one-third of patients with cancer of the breast, ovary, esophagus, stomach, colon, and other solid tumors. Whereas the prognostic impact of the mere presence of these cells is still a matter of debate, it has been shown that expression of tumor-associated antigens in disseminated tumor cells is linked to more aggressive disease. Therefore, further characterization of disseminated tumor cells at the protein and gene level has become increasingly important. To date, the most common detection method for disseminated tumor cells in the bone marrow is an immunocytochemical approach using cytokeratin-directed antibodies for detection of epithelial cells and the APAAP system for their visualization. We have established a new double immunofluorescence technique enabling simultaneous detection, phenotyping, and antigen quantification of disseminated tumor cells. Mononuclear cells from bone marrow are enriched by Ficoll gradient centrifugation and cytospins are prepared. Double immunofluorescence is performed using antibodies against cytokeratins 8/18/19 (mAb A45B/B3) and the uPA receptor CD87 (pAb HU277). CD87 expression is recorded by confocal laser scanning microscopy (CLSM) using fluorescence labeled latex beads as the reference; staining intensities of all the scans are then summed and quantified (extended focus). This protocol, originally designed for disseminated tumor cells in bone marrow, can also be applied to disseminated tumor cells in blood, to leukapheresis cells or to cells present in malignant ascites or other malignant effusions. The tumor cells detected may be used for gene and mRNA analyses. Furthermore, disseminated tumor cells also represent interesting targets for clinical studies on patient prognosis or prediction of therapy response as well as for specific tumor-biological therapies.
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Biomarcadores de Tumor/análisis , Médula Ósea/patología , Neoplasias/patología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Neoplasias/genética , Neoplasias/terapia , Fenotipo , Activadores Plasminogénicos/análisis , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/genética , Receptores del Activador de Plasminógeno Tipo UroquinasaRESUMEN
OBJECTIVE: To compare prognostic results in patients with gastric stump cancer (GSC) versus those with primary gastric cancer (PGC). SUMMARY BACKGROUND DATA: Gastric stump carcinomas have often been described as having low resectability rates and a poor prognosis. METHODS: Results of surgical treatment of 50 patients with GSC were compared with that of 516 patients with PGC. RESULTS: The resectability rate was 94% for GSC patients and 96.5% for PGC patients, without significant differences in terms of postoperative complications, death rate, and median survival time (31.6 vs. 32.9 months). The multivariate analysis showed an independent prognostic effect for R0 resection, pT1 and pT2 category, and age older than 65 years. CONCLUSION: The prognosis after resection and adequate lymphadenectomy does not differ between patients with GSC and PGC.
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Adenocarcinoma/mortalidad , Muñón Gástrico , Neoplasias Gástricas/mortalidad , Adenocarcinoma/cirugía , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Neoplasias Gástricas/cirugía , Análisis de SupervivenciaRESUMEN
BACKGROUND/AIMS: Liver metastases deriving from colorectal cancer can be treated with curative intention in a select number of patients. Controversy does, however, persist pertaining to the impact of adjuvant treatment strategies. The aim of this study is to elucidate upon the various treatment modalities for patients suffering from liver metastases of colorectal primary tumor as well as to provide a rationale for surgical and adjuvant treatment. METHODOLOGY: From November 1987 to September 1998, a total of 449 consecutive patients suffering from liver metastases deriving from a colorectal cancer were documented at our institution in a prolective study. Prognostic factors providing the most beneficial outcome (whether with surgical and/or adjuvant treatment modalities) were analyzed by univariate and multivariate analysis. RESULTS: Whenever possible, curative (R0) surgical resection of colorectal liver metastases provides the most benefit to the patient. Multivariate analysis revealed tumor infiltration of the lymph nodes of the hepatoduodenal ligament and metachronous occurrence of liver metastases as most independent factors related to survival. CONCLUSIONS: Adjuvant post-operative chemotherapy fails to significantly improve survival following resection of liver metastases when compared to the liver resection only group. In patients with unresectable metastases, regional arterial chemotherapy did not improve survival significantly when compared with systemic chemotherapy.
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Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Dissemination of single tumor cells to the bone marrow is a common event in cancer. The clinical significance of cytokeratin-positive cells detected in the bone marrow of cancer patients is still a matter of debate. In gastric cancer, overexpression of the receptor (uPAR or CD87) for the serine protease urokinase-type plasminogen activator (uPA) in disseminated cancer cells indicates shorter survival of cancer patients. A new immunofluorescence approach, applying confocal laser scanning microscopy, is introduced to locate CD87 antigen in cytokeratin-positive tumor cells and to quantify the CD87 antigen by consecutive scanning. At first, cytokeratin 8/18/19-positive carcinoma cells are identified at excitation wavelength 488 nm using monoclonal antibody A45B/B3 to the cytokeratins and goat anti-mouse IgG labeled with the fluorochrome Alexa488. Next, CD87 in tumor cells is identified by chicken antibody HU277 to the uPA-receptor and goat anti-chicken IgY labeled with fluorochrome Alexa568 (excitation wavelength 568 nm) and the fluorescence signal quantified on a single cell basis using fluorescently labeled latex beads as the fluorescence reference. From 16 patients with gastric or esophageal carcinoma, bone marrow aspirates were obtained, stained for cytokeratins and CD87 and then subjected to laser scanning fluorescence microscopy. Three of six gastric cancer patients had tumor cells present in the bone marrow of which 2 stained for CD87. Three of ten esophageal carcinoma patients had tumor cells in the bone marrow, all three samples stained for CD87. CD87-positive tumor cells were also dissected from stained bone marrow aspirates by laser microdissection microscope to allow analysis of single cells at the gene level.
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Neoplasias de la Médula Ósea/metabolismo , Neoplasias Esofágicas/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Activadores Plasminogénicos/metabolismo , Receptores de Superficie Celular/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adulto , Anciano , Examen de la Médula Ósea/métodos , Neoplasias de la Médula Ósea/secundario , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Humanos , Inmunohistoquímica , Queratinas/metabolismo , Microscopía Confocal , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Sensibilidad y Especificidad , Células Tumorales CultivadasRESUMEN
Minimal residual disease in patients with operable pancreatic carcinoma is frequently missed by current noninvasive tumour staging. We applied an immunocytochemical cytokeratin assay that allows identification of individual pancreatic carcinoma cells disseminated to bone marrow. Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages and an age-matched control group of 33 noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial cytokeratins (CK) using the alkaline phosphatase antialkaline phosphatase method. CK-positive cells were found in 14 (48.4%) of 31 cancer patients treated with curative intent and in 10 (58.8%) of 18 patients with extended disease. The overall frequency of these cells was 1 to 83 per 5x10(5) mononuclear cells with no significant differences between patients at different tumor stages and lymph node involvement. After a median follow-up of 22.8 months (range 3-48 months), 6 (40.0%) of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) had local relapse compared to none of 12 corresponding patients without such cells (p<0.05). Univariate survival analyses revealed that the presence of CK-positive cells was predictive of reduced overall survival. In conclusion, anticytokeratin mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help identify patients with pancreatic cancer and at potentially high risk of early metastatic relapse. The results promise to be of important assistance for determining prognosis and the consequences in therapy of early stage pancreatic cancer.
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Adenocarcinoma/secundario , Neoplasias de la Médula Ósea/secundario , Neoplasias Pancreáticas/patología , Anticuerpos Monoclonales , Femenino , Humanos , Inmunohistoquímica , Queratinas , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
DESIGN: Here we applied an immunocytochemical cytokeratin assay that allows the identification of individual pancreatic carcinoma cells disseminated to bone marrow. PATIENTS AND METHODS: Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages as well as an age-matched control group of 33 non-carcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1 and A45-B/B3 to epithelial cytokeratins (CK), using the alkaline phosphatase anti-alkaline phosphatase method. RESULTS: CK+ cells were found in 25 (52.1%) of 48 cancer patients. The overall frequency of these cells was 1 to 85 per 5 x 10(6) mononuclear cells. 4 (8.3%) cancer patients had specimens that stained with the mAb CK2, compared with 16 (33.3%) patients who displayed KL1+ cells and 9 (18.6%) patients who showed A45-B/B3+ cells. After a median follow up of 22.8 (range 3-48) months, the occurrence of tumor relapse was significantly associated with the outcome of the immunocytochemical screening before the time of primary surgery. 6 (40.0%) out of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) with local relapse as compared to none of 12 corresponding patients without such cells (p < 0.02). Univariate survival analysis revealed that the presence of CK+ cells in bone marrow was predictive of reduced overall survival (p < 0.03). CONCLUSIONS: Anti-CK mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help to identify patients with pancreatic cancer and potential high risk of early metastatic relapse. The results promise to be of important assistance in determining prognosis and consequences in therapy of early stage pancreatic cancer.
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Médula Ósea/patología , Neoplasias Pancreáticas/patología , Humanos , Inmunohistoquímica , Queratinas/análisis , Metástasis de la Neoplasia , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/mortalidad , Estudios Prospectivos , Tasa de SupervivenciaAsunto(s)
Angioplastia Coronaria con Balón , Disección Aórtica/terapia , Enfermedad Coronaria/terapia , Infarto del Miocardio/etiología , Traumatismos Torácicos/complicaciones , Heridas no Penetrantes/complicaciones , Enfermedad Aguda , Adulto , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/etiología , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/etiología , Electrocardiografía , Urgencias Médicas , Humanos , Masculino , StentsRESUMEN
BACKGROUND: The indication for surgical resection of colorectal liver metastases should be guided by technical feasibility and expected prognostic benefit. The aim of the present study was to analyse the frequency and prognostic significance of lymph node involvement of the hepatoduodenal ligament in the resection of colorectal liver metastases. METHODS: A series of 126 prospectively documented patients who underwent hepatectomy for metastases of colorectal carcinoma was analysed. The prognostic factors of patients with complete resection (R0) of the metastases were studied by multivariate analysis. RESULTS: R0 resection was achieved in 94 per cent. The 30-day mortality rate was 2 per cent. In all patients, lymph nodes were excised from the hepatoduodenal ligament, and histological evaluation demonstrated tumour infiltration in 28 per cent of the patients. Multivariate analysis revealed nodal involvement of the hepatoduodenal ligament (P < 0.0001) and synchronous or metachronous appearance of liver metastases (P < 0.005) as independent prognostic factors. The 3- and 5-year survival rates were 3 and 0 per cent for lymph node-positive patients compared with 48 and 22 per cent respectively for the node-negative group. CONCLUSION: Infiltration of lymph nodes in the hepatoduodenal ligament is the most important prognostic factor following R0 resection of colorectal liver metastases.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Neoplasias Hepáticas/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Epithelial cells in the bone marrow of 42 patients with pancreatic carcinoma were identified immunocytochemically with monoclonal antibodies directed to epithelial cytokeratins. The occurrence of tumor relapse in patients who underwent complete surgical resection was significantly associated with cytokeratin-positivity in bone marrow. The presence of these cells in indicative of an increased disseminative capability of the primary tumor and defines a new category of patients for neoadjuvant therapy.