RESUMEN
PURPOSE: To evaluate the effectiveness and safety of percutaneous vesselplasty in pathological vertebral fractures of the thoracolumbar spine in selected tumor patients. MATERIALS AND METHODS: Eleven pathological vertebral fractures in nine patients were treated with vesselplasty (Vessel-X®, MAXXSPINE). Nine of eleven vertebras (81.8 %) had major posterior wall deficiency (> 30 %). Clinical and radiological (CT) measures were obtained before and 3 months after the procedure. RESULTS: The mean VAS improved significantly from preoperative to postoperative (6.9 ± 2.2 to 3.7 ± 2.3; p < 0.05), as did the ODI (59.7 %± 19.2 % to 40.3 %± 24.0 %; p < 0.05). The physical component summary of the SF-36 was significantly improved by the operation (19.2 ± 8.0 to 31.0 ± 16.5; p < 0.05). Symptomatic cement leakage or other operation-associated complications were not observed. Three patients were primarily treated with concomitant minimally invasive stabilization via fixateur interne. One patient had to undergo minimally invasive stabilization via fixateur interne 4 months after vesselplasty due to further collapse of the treated vertebral body. CONCLUSION: From these preliminary results, vesselplasty appears to be a treatment option worth considering in pathological vertebral fractures, even in the case of posterior wall deficiency. Selected tumor patients might benefit from vesselplasty as a minimally invasive procedure for stabilization of the fractured vertebra, pain control, and improvement in body function and quality of life. Long-term prospective studies with a larger sample size are required to validate these results.
Asunto(s)
Fracturas Espontáneas/diagnóstico por imagen , Fracturas Espontáneas/cirugía , Cifoplastia/instrumentación , Cifoplastia/métodos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/cirugía , Prótesis e Implantes , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/secundario , Neoplasias de la Columna Vertebral/cirugía , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Anciano , Anciano de 80 o más Años , Cementos para Huesos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico por imagen , RadiografíaRESUMEN
OBJECT: Cerebellar hemorrhage is a life-threatening condition that requires immediate surgical intervention. Open craniectomy, hemorrhage evacuation and posterior fossa decompression is the treatment of choice. Patients with aspirin antithrombotic medication, however, face an increased risk of postoperative rebleeding, because it is impossible to normalize blood coagulation in time. To sufficiently treat these patients, we have developed a minimally-invasive, free-hand, bedside catheter evacuation technique. CLINICAL PRESENTATION: In a retrospective analysis, two patients with a mean age of 68 years and antithrombotic aspirin medication with cerebellar hemorrhage were treated. On admission, mean hemorrhage volume was 30.25 mL or 3.7x4.75x3.03 cm, mean GCS was 7.5, initial aspiration drained a mean 24 mL of blood. After a mean of 2.5 days of urokinase lysis, mean hemorrhage volume was 3.7 mL or 2.25x2.0x1.15 cm and mean EGOS on discharge was 4.5. After a mean follow-up of 408 days, the mean EGOS was 5.5, and both patients were alive. CONCLUSION: We conclude from these data that, in selected cases, bedside catheter placement and consequent urokinase lysis is a successful way to drain posterior fossa hemorrhage. However, experience in catheter positioning is crucial and the technique therefore should only be performed by experienced neurosurgeons.
Asunto(s)
Catéteres de Permanencia/normas , Enfermedades Cerebelosas/cirugía , Hemorragias Intracraneales/cirugía , Procedimientos Neuroquirúrgicos/instrumentación , Procedimientos Neuroquirúrgicos/métodos , Anciano , Aspirina/efectos adversos , Aspirina/uso terapéutico , Enfermedades Cerebelosas/patología , Enfermedades Cerebelosas/fisiopatología , Cerebelo/irrigación sanguínea , Cerebelo/patología , Cerebelo/cirugía , Fosa Craneal Posterior/diagnóstico por imagen , Fosa Craneal Posterior/patología , Fosa Craneal Posterior/cirugía , Descompresión Quirúrgica/instrumentación , Descompresión Quirúrgica/métodos , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Hidrocefalia/etiología , Hidrocefalia/fisiopatología , Hidrocefalia/prevención & control , Hemorragias Intracraneales/patología , Hemorragias Intracraneales/fisiopatología , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/fisiopatología , Hipertensión Intracraneal/prevención & control , Masculino , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Sistemas de Atención de Punto/normas , Sistemas de Atención de Punto/tendencias , Hemorragia Posoperatoria/inducido químicamente , Hemorragia Posoperatoria/fisiopatología , Hemorragia Posoperatoria/prevención & control , Estudios Retrospectivos , Terapia Trombolítica/métodos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéuticoRESUMEN
OBJECTIVE: After the implementation of the G-DRG system in Germany, doubts arose whether and how interdisciplinary pain therapy centers should be restructured to remain profitable and maintain medical excellence for patients with a long ordeal of malaise. METHODS: To reveal structural deficits, we performed a detailed economic analysis of all patients treated at an interdisciplinary pain therapy center of a German University hospital in 2004. RESULTS: 3,672 patients were treated: 2,163 outpatients, 753 at the daycare clinic, 619 as consults and 132 inpatients. The costs for personnel were euro 736,645, consumables euro 105,061, and infrastructure euro 277,762. We calculated fixed costs of euro 236, and consumables of euro 24 per patient. The costs for surgery were euro 1,595, and for a neuroradiological examination euro 245 per patient. Overall treatment costs were euro 319 per patient. We calculated an overall loss of euro 476,752 or euro 109.19 per patient. Outpatients caused a total loss of euro 456,665.83 or euro 211 per patient, consults a total loss of euro 161 683.16 or euro 261.20 per patient, daycare patients a slight profit of euro 30,370 or euro 40 per patient and inpatients a total profit of euro 111,225 or euro 135 per day. CONCLUSION: Managerial optimization can yield considerable cost reductions in the G-DRG coding system, without any change in treatment strategies, selection of profitable patients or dismissal of personnel. Inversely, additional personnel are needed to accomplish the implementation process. Board certification was unveiled to constitute the key structural implementation that ensures the economic survival of the department and continuing medical excellence for the patients.
Asunto(s)
Legislación Médica , Clínicas de Dolor/economía , Clínicas de Dolor/normas , Manejo del Dolor , Dolor/economía , Enfermedad Crónica , Costos y Análisis de Costo , Centros de Día , Alemania , Hospitales Universitarios , Humanos , Pacientes Ambulatorios , Clínicas de Dolor/organización & administraciónRESUMEN
The allograft inflammatory factor-1 (AIF-1) is a 17-kDa IFN-gamma inducible Ca(2+)-binding EF-hand protein that is encoded within the HLA class III genomic region and is involved in immune dysfunction and smooth muscle cell activation. We used immunohistochemistry double labelling experiments to analyse the spatial distribution and cell-type-specific localization of AIF-1 in the brains of patients who died as a result of sporadic Creutzfeldt-Jakob disease (CJD) and neuropathologically unaltered controls. Significantly more AIF-1 immunoreactive macrophages/microglial cells and, interestingly, neurones were observed in CJD patients compared to controls. Western blotting confirmed more prominent AIF-1 immunoreactive bands of approximately 50 kDa in four CJD patients compared to three controls. Chaotropic SDS-PAGE of the recombinant AIF-1 resulted in almost complete reduction of the 50 kDa band and mass spectrometry revealed only AIF-1-specific tryptic protein fragments suggesting that trimerized AIF-1 is the predominant form in vivo. Finally, we analysed mechanisms of neuronal AIF-1 induction. Following H2O2 challenge, a model of general cell stress, we observed the gradual induction of AIF-1 and, more interestingly, release to the supernatant of SKNSH neurones. Parallel reverse transcriptase polymerase chain reaction and sequencing was used to confirm AIF-1 mRNA expression.
Asunto(s)
Química Encefálica , Proteínas de Unión al Calcio/análisis , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Encéfalo/patología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al ADN , Femenino , Humanos , Macrófagos/química , Macrófagos/fisiología , Masculino , Proteínas de Microfilamentos , Microglía/química , Microglía/fisiología , Persona de Mediana Edad , Neuroblastoma , Neuronas/química , Neuronas/fisiología , ARN Mensajero/análisis , Células Tumorales CultivadasRESUMEN
The allograft inflammatory factor (AIF-1/daintain) is a hormone-like peptide produced by activated monocytic cells in a variety of traumatic, inflammatory and degenerative lesions. Gut-derived AIF-1 has been shown to modulate insulin production and to attenuate autoimmune diabetes. As the localization of this gastrointestinal peptide in the porcine duodenum is not known and the pig is a convenient model for the study of nutritional modulation of the mucosal immune compartment, we have localized expression of AIF-1 by immunohistology in the duodenum of either malnourished (energy and protein supply 50% of demands, n = 5) or optimally fed pigs (n = 5). AIF-1 macrophages were predominantly located at the villus tip. The number of positively stained cells per high-power field was significantly (P < or = 0.001) higher in the malnourished pigs (74.6 +/- 2.44; least square means +/- SEM) compared to optimally fed pigs (32.56 +/- 1.99). It is likely that the effect in malnourished pigs can be explained by a more pronounced antigen contact of macrophages due to loss of epithelial integrity. Thus, AIF-1 is a novel marker for the study of the nutritional regulation of the mucosal immune system of the pig. AIF-1 expression in the duodenum was further validated by polymerase chain reaction and sequencing. Surprisingly, we detected a slight deviation from the original sequence (probably representing an allelic variation) and an AIF-1 splice variant, previously not known to occur in pigs.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Mucosa Intestinal/metabolismo , Trastornos Nutricionales/veterinaria , Enfermedades de los Porcinos/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/genética , ADN Complementario/química , Duodeno/citología , Duodeno/inmunología , Duodeno/metabolismo , Inmunidad Mucosa , Inmunohistoquímica/veterinaria , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Datos de Secuencia Molecular , Trastornos Nutricionales/inmunología , Trastornos Nutricionales/metabolismo , Reacción en Cadena de la Polimerasa/veterinaria , Homología de Secuencia de Aminoácido , Porcinos , Enfermedades de los Porcinos/inmunologíaRESUMEN
Plasminogen belongs to the plasminogen activator system of cell signaling proteins and has recently been identified to bind to pathological prion protein PrPSC, but not to its normal conformer, PrPC. Plasminogen binds specifically to the urokinase-type plasminogen activator receptor (uPAR) to promote pericellular proteolysis, regulate integrin function, and mediate cell signaling. By using immunohistochemistry, we observed that significantly more cortical neurons in eight postmortem brains of patients who died with sporadic Creutzfeldt-Jakob disease (CJD) are immunoreactive for uPAR compared with controls. These data provide the pathophysiological basis for detailed analyses of the role of the plasminogen activator system in CJD and related diseases.
Asunto(s)
Corteza Cerebral/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Neuronas/metabolismo , Plasminógeno/metabolismo , Proteínas PrPSc/metabolismo , Receptores de Superficie Celular/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Astrocitos/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Síndrome de Creutzfeldt-Jakob/patología , Síndrome de Creutzfeldt-Jakob/fisiopatología , Femenino , Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunohistoquímica , Masculino , Microcirculación/metabolismo , Microcirculación/patología , Microglía/metabolismo , Microglía/patología , Persona de Mediana Edad , Neuronas/patología , Fosfopiruvato Hidratasa/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Transducción de Señal/fisiologíaRESUMEN
In order to elucidate the reason for conflicting results that have been published previously on galectin-3 expression in human gliomas, we used single labeling and double labeling immunohistochemistry experiments to identify cellular origin and extent of galectin-3 positivity in 53 glioma-samples (16 glioblastomas, 21 anaplastic astrocytomas, 16 low-grade astrocytomas). Galectin-3 positivity was observed in neoplastic astrocytes, macrophages/microglial cells. endothelial cells and some B- and T-lymphocytes. The quantitative analysis showed that the percentage of galectin-3 positive cells was significantly higher in the tumor parenchyma of glioblastomas than in anaplastic (p = 0.0371) and low-grade astrocytomas (p = 0.0042). Single labeling with anti-CD68 antibodies revealed a significant correlation between CD68 and galectin-3 immunoreactivity (p = 0.0092). Endothelial cells were labeled in all low-grade and anaplastic astrocytomas, but only in 10/16 glioblastomas (p = 0.0003). This detailed analysis demonstrates that galectin-3 positivity in human gliomas is considerably influenced by tumor-infiltrating macrophages. The differential expression on endothelial cells raises the question if galectin-3 plays a role in tumor angiogenesis of human gliomas.
Asunto(s)
Antígenos de Diferenciación/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Endotelio Vascular/metabolismo , Galectina 3 , Glioma/clasificación , Glioma/patología , Humanos , Técnicas para Inmunoenzimas , Macrófagos/metabolismo , Estadificación de Neoplasias , Organización Mundial de la SaludRESUMEN
BACKGROUND: Endostatin is a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. Its occurrence and localization has not yet been examined in human brain tumors. The authors report the production of a monoclonal antibody and detection of endostatin in rat and human gliomas by immunohistochemistry. METHODS: The authors analyzed localization and tissue distribution of endostatin in 41 paraffin embedded glioma samples (18 glioblastoma multiforme, 7 WHO Grade III astrocytomas, 13 fibrillary, and 3 protoplasmic WHO Grade II astrocytomas) of human origin and 21 rat C6 gliomas by immunohistochemistry. Double labeling experiments confirmed the origin of endostatin-labeled cells. RESULTS: Endostatin immunoreactivity was detected in tumor cells, endothelial cells, macrophages, and lymphocytes of both rat and human gliomas. The percentage of cells labeled with the endostatin antibody was significantly lower (P = 0.0126) in the tumor parenchyma of human glioblastomas than in WHO Grade II astrocytomas. CONCLUSIONS: Endostatin was present in various cell types in rat and human gliomas in vivo. Lower levels in glioblastomas than in WHO Grade II astrocytomas might have reflected the shift of a probable regulatory balance between promoters and inhibitors of angiogenesis towards facilitation of neovascularization.
Asunto(s)
Neoplasias Encefálicas/patología , Colágeno/análisis , Glioma/patología , Neovascularización Patológica , Fragmentos de Péptidos/análisis , Adulto , Anciano , Animales , Anticuerpos Monoclonales , Neoplasias Encefálicas/irrigación sanguínea , Modelos Animales de Enfermedad , Endostatinas , Femenino , Glioma/irrigación sanguínea , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-DawleyRESUMEN
Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Adulto , Anciano , Animales , Química Encefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Trasplante de Células , Femenino , Glioma/genética , Glioma/patología , Humanos , Inmunohistoquímica , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Trasplante de Neoplasias , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
Following surgical removal of glioblastoma multiforme (GBM), radiochemotherapy impedes neoplastic outgrowth and relapse formation. Macrophages/microglial cells are believed to be potent mediators of the host defense system in GBM. However, little is known about their alteration by postsurgical therapies. We have now analyzed expression of LCA (leucocyte common antigen), CD68 (phagocytic cells), HLA-DR, -DP, -DQ (MHC class II), MRP-8 (myeloid-related protein, S100A8), MRP-14 (S100A9), LCF (lymphocyte chemoattractant factor, IL-16) and NOS II (inducible nitric oxide synthase) in macrophages/microglial cells in 39 GBM relapses and their matched primary tumors. Following surgery of the primary tumors, 15 patients received irradiation and chemotherapy, 17 irradiation and 7 no treatment. In irradiated relapses, we observed significantly more macrophages/microglial cells expressing MRP-14 compared to untreated GBM relapses. Furthermore, we observed a significant increase of CD68 expressing macrophages/microglial cells in patients without postsurgical treatment, but not in those with radiochemotherapy. In conclusion, our findings suggest that radiochemotherapy alters the number of MRP-14 expressing cells. The lacking increase of CD68 expressing cells in patients with radiochemotherapy suggests depletion of this cell type by postsurgical therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/patología , Irradiación Craneana , Glioblastoma/patología , Macrófagos/patología , Microglía/patología , Recurrencia Local de Neoplasia/patología , Adulto , Antígenos de Diferenciación/análisis , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Recuento de Células , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Glioblastoma/cirugía , Humanos , Macrófagos/química , Macrófagos/efectos de los fármacos , Macrófagos/efectos de la radiación , Masculino , Microglía/química , Microglía/efectos de los fármacos , Microglía/efectos de la radiación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugíaRESUMEN
Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of edema, impeding blood flow and immunomodulation in the pathologically altered brain. Two COX iso-enzymes have been associated with brain disease, the constitutively expressed COX-1 and the cytokine-inducible COX-2. We have used single and double labeling immunohistochemistry to analyse COX-1 and COX-2 expression in twenty-six primary WHO grade II oligodendrogliomas, sixteen primary WHO grade III anaplastic oligodendrogliomas, twenty-seven matched recurrences and ten neuropathologically unaltered brains. COX-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of COX-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in primary anaplastic oligodendrogliomas (P<0.0001) and in anaplastic oligodendroglioma relapses (P=0.011). Patients with low COX-1 labeling scores in the primary tumors had significantly longer time to progression and overall survival (P=0.0285) than those with high COX-1 labeling scores. COX-2 immunoreactivity was predominantly observed in disseminated neurons and astrocytes. In glioblastoma multiforme relapses, accumulation of COX-2 expressing astrocytes was observed surrounding areas of focal necrosis. The number of COX-2 expressing astrocytes was significantly (P=0.0471) lower in primary oligodendrogliomas than in high grade oligodendroglioma relapses. These data provide convincing evidence for the differential accumulation of cyclooxygenase isoforms during oligodendroglioma progression in vivo.
Asunto(s)
Astrocitos/enzimología , Neoplasias Encefálicas/metabolismo , Isoenzimas/biosíntesis , Macrófagos/enzimología , Microglía/enzimología , Oligodendroglioma/metabolismo , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Adulto , Anciano , Astrocitos/patología , Neoplasias Encefálicas/patología , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Progresión de la Enfermedad , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Macrófagos/patología , Masculino , Proteínas de la Membrana , Microglía/patología , Persona de Mediana Edad , Oligodendroglioma/patologíaRESUMEN
Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB- 1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p = 0.013). Irradiation caused the reduction of MIB-1+ (p = 0.0015), DO-7+ (p = 0.0043) and the increase of Bcl-2+ cells (p = 0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p = 0.0186) and no treatment (p = 0.0158), low ISNT scores (p = 0.0018) and high DO-1 scores (p = 0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-I and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.
Asunto(s)
Neoplasias Encefálicas/patología , Quimioterapia Adyuvante , Irradiación Craneana , Regulación Neoplásica de la Expresión Génica , Genes bcl-2 , Genes , Glioblastoma/patología , Recurrencia Local de Neoplasia/patología , Radioterapia Adyuvante , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Biomarcadores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Terapia Combinada , Ciclofosfamida/análogos & derivados , Ciclofosfamida/uso terapéutico , Citarabina/administración & dosificación , Progresión de la Enfermedad , Femenino , Proteínas de Unión al GTP/biosíntesis , Proteínas de Unión al GTP/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Genes/efectos de los fármacos , Genes/efectos de la radiación , Genes bcl-2/efectos de los fármacos , Genes bcl-2/efectos de la radiación , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/radioterapia , Glioblastoma/cirugía , Humanos , Antígeno Ki-67/biosíntesis , Antígeno Ki-67/genética , Tablas de Vida , Lomustina/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/efectos de la radiación , Nimustina/administración & dosificación , Nimustina/uso terapéutico , Proteína Glutamina Gamma Glutamiltransferasa 2 , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesisRESUMEN
Heme oxygenase (HO-1, HSP32) catalyzes the oxidation of heme to biliverdin and carbon monoxide, a putative neurotransmitter. In the brain, HO-1 expression has been associated with neuroprotection during oxidative stress and hypoxia. However, consecutive downstream mediation is involved in neoangiogenesis and consequent neoplastic outgrowth. We have analyzed HO-1 expression in 69 oligodendroglioma tissue samples, in rat intracranially transplanted C6 gliomas, and neuropathologically unaltered control brains by immunohistochemistry. Double labeling experiments confirmed the nature of HO-1 expressing cells. Reverse transcription-polymerase chain reaction was used to demonstrate HO-1 gene expression. HO-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of HO-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in their matched relapses (P<0.0001) and lower in primary anaplastic oligodendrogliomas than in their relapses (P=0.0006). Prominent accumulation of HO-1 expressing macrophages/microglial cells was observed in perinecrotic areas of both experimental rat and human glioblastoma relapses. HO-1 expressing neurons, macrophages/microglial cells and astrocytes were scattered in areas of infiltrative tumor growth. Surprisingly, HO-1 mRNA was detected in only one glioblastoma multiforme relapse. We conclude from these data that HO-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression in areas of focal necrosis. However, overall biological function of this phenomenon remains to be determined.
Asunto(s)
Glioblastoma/enzimología , Hemo Oxigenasa (Desciclizante)/metabolismo , Macrófagos/enzimología , Microglía/enzimología , Proteínas de Neoplasias/metabolismo , Oligodendroglioma/enzimología , Adulto , Anciano , Animales , Femenino , Hemo-Oxigenasa 1 , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , ARN Mensajero/metabolismo , Ratas , Células Tumorales CultivadasRESUMEN
Blood-brain barrier disintegration and inflammatory cell recruitment are key processes in the pathogenesis of cerebral malaria (CM). Recent data provide convincing evidence that the serine protease urokinase-type plasminogen activator receptor (uPAR) is a key molecule in promoting cell adhesion and spreading. We have now analyzed expression of urokinase-type plasminogen activator receptor (uPAR, CD87), which is part of a cell surface associated proteolytic system, in brains of eight CM patients and seven neuropathologically unaltered and diseased controls by immunohistochemistry. Double labeling experiments with antibodies directed against CD68 (macrophages/microglial cells), myeloid-related protein (MRP8), and glial fibrillary acid protein (GFAP) confirmed the nature of uPAR expressing cells. We observed focal accumulation of uPAR expressing macrophages/microglial cells in Dürck's granulomas and adjacent to petechial hemorrhages, in astrocytes, and in endothelial cells. In contrast, focal uPAR expression in macrophages/microglial cells but not in astrocytes was found in microglial nodules of toxoplasmic encephalitis and in the cellular infiltrate of bacterial meningitis. Normal brains showed only faint uPAR expression in endothelial cells. We conclude from these data that lesion-associated uPAR expression at least in part contributes to blood-brain barrier alteration and immunologic dysfunction in CM patients.
Asunto(s)
Malaria Cerebral/inmunología , Malaria Cerebral/patología , Receptores de Superficie Celular/inmunología , Adulto , Anticuerpos Monoclonales , Antígenos CD/análisis , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/análisis , Antígenos de Diferenciación Mielomonocítica/inmunología , Astrocitos/química , Astrocitos/inmunología , Astrocitos/microbiología , Barrera Hematoencefálica/inmunología , Encéfalo/inmunología , Encéfalo/microbiología , Encéfalo/patología , Química Encefálica/inmunología , Endotelio/química , Endotelio/citología , Endotelio/metabolismo , Proteína Ácida Fibrilar de la Glía/análisis , Proteína Ácida Fibrilar de la Glía/inmunología , Humanos , Meningitis Bacterianas/inmunología , Meningitis Bacterianas/patología , Microglía/química , Microglía/inmunología , Microglía/microbiología , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/biosíntesis , Receptores del Activador de Plasminógeno Tipo UroquinasaRESUMEN
Allograft inflammatory factor-1 (AIF-1) is a Ca2+-binding peptide that constitutes a potential modulator of macrophage activation and function during the immune response of the brain. Peptides termed microglia response factor-1 or ionized calcium-binding adaptor molecule- have been reported to be identical with AIF-1. We have investigated the expression of AIF-1 in the rat C6 glioblastoma and 9L gliosarcoma tumor models and additionally assessed AIF- expression in a diverse range of human astrocytomas by immunohistochemistry. AIF-1 was expressed by activated microglial cells and a subset of infiltrating macrophages in areas of infiltrative tumor growth and in compact tumor areas in both rat and human gliomas. Double-labeling experiments in rats and humans characterized the nature and the functional status of AIF-1+ cells. AIF-1 expression was detected in cells expressing major histocompatibility complex class II molecules and in a subset of activated macrophages/microglial cells. All MRP-8+ cells coexpressed AIF-1. In humans, there was a strong correlation of AIF-1-expressing activated macrophages/microglial cells with tumor malignancy (P < 0.0001). These results suggest that AIF-1 defines a distinct subset of tumor-associated activated macrophages/ microglial cells.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/metabolismo , Glioma/metabolismo , Glioma/patología , Macrófagos/metabolismo , Macrófagos/patología , Microglía/metabolismo , Microglía/patología , Adulto , Anciano , Animales , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/fisiopatología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/fisiopatología , Glioma/fisiopatología , Humanos , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Datos de Secuencia Molecular , Ratas , Homología de Secuencia de Ácido Nucleico , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patologíaRESUMEN
In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P=.0003) more TGF-beta1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P=.0081) more TGF-beta2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Dürck's granulomas, and significantly (P=.0022) more TGF-beta3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-beta1, -beta2, and -beta3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.
Asunto(s)
Encéfalo/metabolismo , Malaria Cerebral/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Enfermedad de Alzheimer/metabolismo , Humanos , Meningitis Bacterianas/metabolismo , Esclerosis Múltiple/metabolismo , Isoformas de Proteínas/metabolismoRESUMEN
Intravascular sequestration and altered cytokine expression patterns are key determinators of CNS lesion formation in patients with cerebral malaria (CM). Among others, altered prostaglandin concentrations were revealed by clinical trials in peripheral blood of CM patients. Prostaglandin synthesis is controlled by cyclooxygenases (COX, prostaglandin endoperoxide synthase, PGG/H synthase) and COX expression has been attributed a key role in immunomodulation, hemostasis and inflammation in a wide variety of pathologically altered brain tissues. We have now analyzed expression of COX-1 and COX-2 in brains of patients with CM by immunohistochemistry. Double labeling experiments were used to verify the cellular identity of COX-1 and COX-2 expressing cells. Compared to healthy controls, significant (P=0.0006) accumulation of COX-1 expressing macrophages/microglial cells was detected in Dürck's granulomas. Accumulations of COX-2 expressing endothelial cells (P=0.0006) and COX-2 expressing astrocytes (P=0.0012) were detected in CM brain parenchyma. The restricted expression and accumulation of COX-1 and COX-2 in CM brains adds convincing evidence for the participation of cyclooxygenases in the formation of fever, inflammation and granuloma in these patients.
Asunto(s)
Encéfalo/enzimología , Isoenzimas/metabolismo , Malaria Cerebral/enzimología , Neuronas/enzimología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Encéfalo/patología , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Humanos , Inmunohistoquímica , Malaria Cerebral/patología , Proteínas de la Membrana , Valores de ReferenciaRESUMEN
Secretion of regulatory peptides by macrophages in injured skeletal muscle constitutes a pivotal determinator of tissue homeostasis. We analyzed expression of a novel Ca2+- binding peptide expressed by activated macrophages, the allograft inflammatory factor-1 (AIF-1), in rat devascularized skeletal muscle. AIF-1 expression was observed in 94% of all macrophages at the site of the injury 48 hours postdevascularization. The physiological function of AIF-1 in injured skeletal muscle was analyzed using a rat in-vitro model of satellite cell proliferation and differentiation. Addition of AIF-1 to the culture medium resulted in a concentration-dependent and reversible reduction of the total number of cells expressing M-cadherin (p < or = 0.0001), a mediator of the differentiation process of skeletal muscle cells, the proliferation associated PCNA (p < or = 0.0001), and the initiator of muscle differentiation myogenin (p < or = 0.0001). These results provide convincing evidence that activated AIF-1 expressing macrophages constitute the predominant cell type in skeletal muscle 48 hours postinjury, and that AIF-1 regulates reduced proliferation, differentiation, and activation of satellite cells.
Asunto(s)
Proteínas de Unión al Calcio/biosíntesis , Diferenciación Celular , Macrófagos/metabolismo , Músculo Esquelético/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Cadherinas/biosíntesis , Proteínas de Unión al Calcio/antagonistas & inhibidores , Proteínas de Unión al Calcio/farmacología , Recuento de Células/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Isquemia/metabolismo , Activación de Macrófagos/fisiología , Macrófagos/citología , Masculino , Proteínas de Microfilamentos , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Miogenina/biosíntesis , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Ratas , Ratas Endogámicas Lew , Ratas Wistar , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/farmacologíaRESUMEN
BACKGROUND: Heat shock proteins (HSP) are cytoprotective, antiapoptotic proteins which may predict clinical prognosis in various types of cancer. Here, we asked whether the differential response to radiochemotherapy and different overall prognosis for astrocytic and oligodendroglial tumours can be accounted for by differences in HSP expression. MATERIAL AND METHODS: We examined aB-crystallin, HSP27, HSP70, HSC70 (HSP73) and HSP90 expression in 44 human gliomas (5 anaplastic and 5 low-grade astrocytomas, 5 anaplastic and 5 low-grade oligodendrogliomas and 24 glioblastomas) by immunohistochemistry. RESULTS: HSP were expressed in the tumour parenchyma of all high-grade and most low-grade gliomas, including oligodendrogliomas. Endothelial cells were more often positive for HSC70 and HSP90, but more often negative for HSP27, in glioblastomas than in the other tumours. HSP were also observed in macrophages/microglial cells, but not in a tumour-specific pattern. CONCLUSION: Different patterns of HSP expression seem not to account for the differential response of these tumours to adjuvant cytotoxic therapy.
Asunto(s)
Astrocitoma/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Neoplasias/metabolismo , Oligodendroglioma/metabolismo , Proteínas Portadoras/metabolismo , Cristalinas/metabolismo , Proteínas del Choque Térmico HSC70 , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , PronósticoRESUMEN
BACKGROUND: Altered expression of Bcl-2 family proteins has been associated with tumorigenesis and tumor progression as well as resistance to radiotherapy and chemotherapy. In the current study, Bcl-2 family protein expression was examined in oligodendrogliomas and anaplastic oligodendrogliomas, and an attempt was made to determine whether these proteins accumulate during disease progression and to search for protein expression patterns predictive of time to progression and overall survival. METHODS: A total of 42 oligodendroglioma tissue samples, 26 de novo World Health Organization (WHO) Grade 2 oligodendrogliomas, and 16 de novo WHO Grade 3 anaplastic oligodendrogliomas were studied. Nineteen Grade 2 tumors progressed: 10 again were Grade 2 oligodendrogliomas and 8 had progressed to higher grade lesions. Eight anaplastic oligodendrogliomas progressed: five again were WHO Grade 3 tumors and three were glioblastoma multiforme. Expression of Bcl-2, Bax, Bcl-X, and Mcl-1 proteins and of the proliferation marker Ki-67 was evaluated by immunohistochemistry. Apoptotic cells were quantified by in situ nick translation (ISNT). RESULTS: De novo WHO Grade 2 oligodendrogliomas had higher Bcl-2 scores (P = 0.037), lower MIB-1 scores (P = 0.0012), and lower ISNT scores (P = 0.049) compared with de novo WHO Grade 3 anaplastic oligodendrogliomas. In de novo oligodendrogliomas, low numbers of Bax positive cells were associated with a short time to disease progression (P = 0.043). In de novo anaplastic oligodendrogliomas, low numbers of Bcl-2 positive cells correlated with short survival (P = 0.029). In tumors that had progressed from WHO Grade 3 anaplastic oligodendrogliomas, the authors found significantly more Bcl-X positive (P = 0.005), Mcl-1 positive (P = 0.002), and Bax positive (P = 0.03) cells. CONCLUSIONS: The results of the current study show that progression of oligodendrogliomas and anaplastic oligodendrogliomas is associated with an enhanced expression of antiapoptotic Bcl-2 family proteins.