RESUMO
AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/imunologia , Linhagem da Célula/imunologia , Germinoma/diagnóstico , Germinoma/imunologia , Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica , Germinoma/metabolismo , Humanos , Prognóstico , Transcriptoma , Microambiente Tumoral/imunologiaRESUMO
We have incorporated LiNc-BuO, an oxygen-sensing paramagnetic material, in polydimethylsiloxane (PDMS), which is an oxygen-permeable, biocompatible, and stable polymer. We fabricated implantable and retrievable oxygen-sensing chips (40 % LiNc-BuO in PDMS) using a 20-G Teflon tubing to mold the chips into variable shapes and sizes for in vivo studies in rats. In vitro EPR measurements were used to test the chip's oxygen response. Oxygen induced linear and reproducible line broadening with increasing partial pressure (pO2). The oxygen response was similar to that of bare (unencapsulated) crystals and did not change significantly on sterilization by autoclaving. The chips were implanted in rat femoris muscle and EPR oximetry was performed repeatedly (weekly) for 12 weeks post-implantation. The measurements showed good reliability and reproducibility over the period of testing. These results demonstrated that the new formulation of OxyChip with 40 % LiNc-BuO will enable the applicability of EPR oximetry for long-term measurement of oxygen concentration in tissues and has the potential for clinical applications.
Assuntos
Técnicas Biossensoriais , Dimetilpolisiloxanos/química , Espectroscopia de Ressonância de Spin Eletrônica , Metaloporfirinas/química , Músculo Esquelético/metabolismo , Oximetria/métodos , Consumo de Oxigênio , Oxigênio/metabolismo , Animais , Cristalização , Masculino , Miniaturização , Pressão Parcial , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Alterations of the EGFR gene occur frequently in human gliomas where the most common is an in-frame deletion of exons 2-7 from the extracellular domain, resulting in a truncated mutant receptor (deltaEGFR or de 2-7 EGFR). We previously demonstrated that introduction of deltaEGFR into human U87MG glioblastoma cells (U87MG.deltaEGFR) conferred remarkably enhanced tumorigenicity in vivo. Here, we show by cell-mixing experiments that the enhanced tumorigenicity conferred by deltaEGFR is attributable to a growth advantage intrinsic to cells expressing the mutant receptor. We analyzed the labeling index of the proliferation markers Ki-67 and bromodeoxyuridine and found that tumors derived from U87MG.deltaEGFR cells had significantly higher labeling indexes than those of tumors derived from U87MG cells that were either naive, expressed kinase-deficient mutants of deltaEGFR, or overexpressed exogenous wild-type EGFR. We also utilized terminal deoxynucleotidyl transferase-mediated nick end-labeling assays and showed that the apoptotic index of U87MG.deltaEGFR tumors was more than 4-fold lower than that of parental U87MG tumors. This decrease in cell death was inversely correlated with the expression level of Bcl-X(L), a negative regulator of apoptosis, which was more than 3-fold higher in U87MG.deltaEGFR-derived tumors than in those derived from parental cells. Similar observations were obtained in vitro in serum-free conditions. These results suggest that deltaEGFR exerts its pronounced enhancement of glioblastoma tumorigenicity by stimulating proliferation and inhibiting apoptosis and that the effects are directly attributable to its constitutively active signal.
Assuntos
Apoptose , Receptores ErbB/fisiologia , Glioblastoma/patologia , Animais , Divisão Celular , Receptores ErbB/genética , Glioblastoma/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/análise , Células Tumorais CultivadasRESUMO
The intractability of malignant gliomas to multimodality treatments plays a large part in their extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor (TNF) family that induces apoptosis preferentially in tumor cells through binding to its cognate death receptors, DR4 and DR5. Here we show that the DNA-damaging chemotherapeutic drugs, cis-diamminedichloroplatinum(II) (CDDP) and etoposide, elicited increased expression of DR5 in human glioma cells. Exposure of such cells in vitro to soluble human TRAIL in combination with CDDP or etoposide resulted in synergistic cell death that could be blocked by soluble TRAIL-neutralizing DR5-Fc or the caspase inhibitors, Z-Asp-CH2-DCB and CrmA. Moreover, systemic in vivo administration of TRAIL with CDDP synergistically suppressed both tumor formation and growth of established s.c. human glioblastoma xenografts in nude mice by inducing apoptosis without causing significant general toxicity. The combination treatment resulted in complete and durable remission in 29% of mice with the established s.c. xenografts and also significantly extended the survival of mice bearing intracerebral xenografts. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which the death ligand, TRAIL, is safely combined with conventional DNA-damaging chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Glioma/tratamento farmacológico , Glicoproteínas de Membrana/farmacologia , Receptores do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Animais , Proteínas Reguladoras de Apoptose , Cisplatino/farmacologia , DNA/efeitos dos fármacos , Dano ao DNA , Sinergismo Farmacológico , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Ligante Indutor de Apoptose Relacionado a TNF , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Alteration of chromosome 10 is common in human melanomas and usually entails the loss of an entire chromosome homologue. Although the reasons for monosomy in cancer has remained obscure, one possibility is that multiple tumor suppressor genes residing on this chromosome must be lost in unison during tumor progression, and this is easier to accomplish by chromosome segregation rather than by multiple mutational and/or deletion events. The localization and identification of these genes has been hampered by the monosomy itself, which has resulted in a paucity of small defining deletions in tumors. Here, we have addressed the issue of monosomy in tumor development by using functional complementation mapping to localize and demonstrate the existence of different melanoma suppressor genes on chromosome 10 and assigned each locus a distinct tumorigenic phenotype. We report that a locus on 10q distal to 10q23.1, likely involving the PTEN tumor suppressor, causes a severe reduction in the kinetics of melanoma tumor formation in animals. In contrast, a previously unrecognized region at 10p15.3 has a distinct, but lesser, effect on in vivo melanoma growth. Thus, the loss of both of these regions, which is accomplished by tumor-associated monosomy, provides a significant growth advantage over the individual loss of either region, thereby explaining the monosomy observed in sporadic melanomas.
Assuntos
Cromossomos Humanos Par 10/genética , Genes Supressores de Tumor , Perda de Heterozigosidade , Melanoma/genética , Monossomia , Proteínas Supressoras de Tumor , Animais , Cromossomos Humanos Par 10/ultraestrutura , Progressão da Doença , Humanos , Células Híbridas , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Transplante de Neoplasias , PTEN Fosfo-Hidrolase , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Células Tumorais CultivadasRESUMO
The gene for the major angiogenic factor, vascular endothelial growth factor (VEGF), encodes several spliced isoforms. We reported previously that overexpression of two VEGF isoforms, VEGF(121) and VEGF(165), by human glioma U87 MG cells induced tumor-associated intracerebral hemorrhage, whereas expression of a third form, VEGF(189), did not cause vessel rupture. Here, we test whether these VEGF isoforms have distinct activities for enhancing vascularization and growth of gliomas in mice. U87 MG cells that overexpressed VEGF(165) or VEGF(189) grew more rapidly than the parental cells in both s.c. and intracranial (i.c.) locations. However, cells that overexpressed VEGF(121) only showed enhancement of i.c. tumor growth but had a minimal effect on s.c. glioma progression. At both anatomical sties, VEGF(165) and VEGF(189) strongly augmented neovascularization, whereas VEGF(121) only increased vessel density in brain tumors. In each type of glioma, expression of VEGF receptors -1 and -2 largely phenocopied the tumor vasculature, because increased VEGF/VEGF receptor-activated microvessel densities were strongly correlated with the angiogenicity and tumorigenicity elicited by the VEGF isoforms at both anatomical sites. One notable difference between the sites was the expression of vitronectin, a prototypic ligand of alpha(v)beta(3) and alpha(v)beta(5) integrins, detected in i.c. but not in s.c., gliomas. Endothelial cell migration stimulated by VEGF(121) was potentiated by vitronectin to a greater extent than that stimulated by VEGF(165). This data demonstrates that VEGF isoforms have distinct activities at different anatomical sites and suggest that the microenvironment of different tissues affects the function of VEGF isoforms.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Fatores de Crescimento Endotelial/fisiologia , Glioma/irrigação sanguínea , Linfocinas/fisiologia , Neovascularização Patológica/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Movimento Celular/efeitos dos fármacos , Fatores de Crescimento Endotelial/biossíntese , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Glioma/metabolismo , Humanos , Linfocinas/biossíntese , Linfocinas/farmacologia , Neovascularização Patológica/patologia , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/biossíntese , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Vitronectina/farmacologiaRESUMO
Alterations of the epidermal growth factor receptor (EGFR) occur frequently in malignant gliomas through gene amplification or rearrangement, especially in a large fraction of de novo type glioblastomas. The most common of these mutant EGFRs (variously named de2-7 EGFR, deltaEGFR or EGFRvIII) lacks a portion of the extracellular ligand-binding domain. Here, we review the evidence that shows that expression of deltaEGFR bestows in vivo growth advantages to human glioma cells through its constitutively active tyrosine kinase activity. Thus, deltaEGFR may provide a novel therapeutic target for the most aggressive type of glioblastoma.
Assuntos
Receptores ErbB/fisiologia , Glioma/genética , Transdução de Sinais , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Mutação , Quinazolinas , Tirfostinas/farmacologiaRESUMO
Small-field radiotherapy based on a 6-MeV linac and a conventional head mold is investigated as an alternative to radiosurgery with stereotactic frames. The system requires no additional device and allows fractionated treatment. The dose distributions obtained are comparable to those reported with a Gamma Unit. Overall positioning errors are within 2 mm. Using this approach, seven patients with brain tumors who could not have been treated otherwise, underwent fractionated radiotherapy with total accumulated doses ranging from 70 to 108 Gy. The treatment was tolerated well with no acute toxicity or adverse effect encountered during the follow-up period of 8-14 months. All of the patients remained free from disease progression in the treated volumes. Although the follow-up is brief, the preliminary results suggest that this is a simple and inexpensive but effective system for the treatment of small intracranial malignancies.
Assuntos
Neoplasias Encefálicas/radioterapia , Aceleradores de Partículas , Radioterapia de Alta Energia/instrumentação , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Desenho de Equipamento , Feminino , Humanos , Imobilização , Melanoma/patologia , Melanoma/radioterapia , Melanoma/secundário , Pessoa de Meia-Idade , Projetos Piloto , Dosagem Radioterapêutica , Radioterapia de Alta Energia/métodosRESUMO
OBJECTIVE: A derivative of chloroethylnitrosoureas, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), is a drug of choice for the chemotherapy of human malignant brain tumors. However, the cytocidal effect of ACNU is effectively repressed through repair of ACNU-mediated deoxyribonucleic acid lesions by O6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT). Because a variety of human tumors, including brain tumors, contain high levels of MGMT activity, we investigated the effect of antisense ribonucleic acid (RNA) complementary to MGMT messenger RNA on ACNU resistance in tumor cells. METHODS: We established a stable ACNU-resistant clone, C6AR, from the rat glioma cell line C6 exposed to a stepwise increasing concentration of ACNU. We transfected a plasmid deoxyribonucleic acid-encoding antisense MGMT RNA under the control of the human metallothionein promoter into C6AR cells and determined the effect of the antisense RNA on ACNU resistance of tumor cells by a colony-forming efficiency assay. RESULTS: C6AR cells expressed abundant MGMT messenger RNA, although the transcription level of the MGMT gene in parental C6 cells was below the lower limits of detection under the same assay conditions. ACNU resistance of C6AR cells was significantly repressed by transfected gene-dependent antisense MGMT RNA expression that resulted in decreased survival of the tumor cells. CONCLUSION: ACNU resistance resulting from the expression of MGMT in rat glioma cells is significantly overcome by the expression of antisense MGMT RNA. This result suggests that the antisense MGMT RNA system might be a useful strategy for overcoming ACNU resistance in the treatment of intractable malignant gliomas.
Assuntos
Elementos Antissenso (Genética)/uso terapêutico , Glioma/terapia , Metiltransferases/genética , RNA Complementar/uso terapêutico , RNA Mensageiro/genética , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioma/genética , Glioma/patologia , Nimustina/efeitos adversos , Nimustina/uso terapêutico , O(6)-Metilguanina-DNA Metiltransferase , Biossíntese de Proteínas , Ratos , Transfecção , Células Tumorais CultivadasRESUMO
OBJECTIVE: Sodium butyrate (SB), a differentiation-inducing agent, has been demonstrated to inhibit cellular proliferation in a number of human cell lines. Its precise mechanisms remain to be clarified, however. We investigated molecular mechanisms of SB-induced growth suppression as well as the effects of SB on the invasiveness of human glioma cells. METHODS: Human glioma U87MG and U251MG cells were treated with 1 or 2 mmol/L SB for 48 hours, and the inhibition of cell growth was assessed by spectrophotometric analysis. Cell cycle analysis was carried out by the 5-bromo-2'-deoxyuridine incorporation method, and expression of cell cycle-regulatory proteins was determined by immunoblotting. In addition, invasiveness was assessed using a Transwell chamber (Iwaki, Tokyo, Japan) with extracellular matrix substrate fibronectin or laminin (Iwaki). RESULTS: SB treatment resulted in significantly suppressed proliferation of both U87MG and U251MG cells in a dose-dependent manner. It inhibited the G1-S transition, which was associated with increased expression of p21 and cyclin D1 and reduced pRb phosphorylation. Treatment with antisense oligonucleotide for Rb abrogated SB-induced G1 arrest. p21 up-regulation was independent of the p53 status of the glioma cells. SB treatment also inhibited invasiveness on fibronectin and laminin. CONCLUSION: Our results indicate that SB may suppress the growth of human glioma cells through modulation of cell cycle progression and also may affect their invasiveness on extracellular matrix substrates, which suggests that SB may be a useful therapeutic agent in treating multiple aspects of malignant gliomas.
Assuntos
Neoplasias Encefálicas/patologia , Butiratos/farmacologia , Glioma/patologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/efeitos dos fármacos , Fase G1 , Humanos , Invasividade Neoplásica , Fase S , Células Tumorais CultivadasRESUMO
OBJECT: Activation of signaling by the epidermal growth factor receptor (EGFR) through gene amplification or rearrangement is common in human malignancy, especially in a large fraction of de novo glioblastomas multiforme (GBMs). The most common mutant EGFR, (AEGFR, also known as de2-7 EGFR and EGFRvIII) lacks a portion of the extracellular domain, enhances tumorigenicity in vivo, and causes resistance to the chemotherapeutic drug cisplatin (CDDP). This resistance is due to the suppression of CDDP-induced apoptosis by the constitutively active tyrosine kinase activity of the receptor. The authors have investigated whether inhibition of AEGFR signaling by the tyrosine kinase inhibitor, tyrphostin AG1478, could sensitize tumor xenografts to CDDP and, thereby, enhance its therapeutic efficacy in animals. METHODS: Nude mice were inoculated either subcutaneously or intracerebrally with human GBM cells expressing AEGFR and were then systemically treated with CDDP and/or AG1478. Tumor volumes were monitored and tumor sections were analyzed by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assays or MIB-1 staining. Expression of AEGFR, but not wild-type EGFR, conferred CDDP resistance to the cells in vivo. Inhibition of receptor signaling by the EGFR-specific tyrosine kinase inhibitor, AG1478. sensitized the xenografts to the cytotoxic effects of CDDP. This combined CDDP/AG1478 treatment significantly suppressed growth of subcutaneous xenografts in nude mice in a synergistic manner (p < 0.01 compared with vehicle control) without causing generalized toxicity, whereas treatments with CDDP or AG1478 alone were ineffective. The synergistic growth suppression by the CDDP/AG1478 combination was not observed in xenografts overexpressing wild-type EGFR or kinase-deficient AEGFR. The combined CDDP/ AG1478 treatment induced tumor growth suppression, which correlated with increased apoptosis and reduced proliferation. This treatment also extended the life span of mice bearing intracerebral xenografts (p < 0.01 compared with controls). CONCLUSIONS: The results of this study may provide the basis for the development of a novel and safe therapeutic strategy for the very aggressive AEGFR-expressing GBM.
Assuntos
Neoplasias Encefálicas/genética , Sobrevivência Celular/genética , Cisplatino/farmacologia , Inibidores Enzimáticos/farmacologia , Receptores ErbB/genética , Glioblastoma/genética , Mutação/genética , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Tirfostinas/farmacologia , Animais , Neoplasias Encefálicas/patologia , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Quinazolinas , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The tumor suppressor p16/CDKN2A/INK4a gene is frequently mutated, mostly by homozygous deletions in high-grade gliomas. Although the p16 protein suppresses cell proliferation primarily through inhibition of cell-cycle progression at the G1 phase, other phenotypic changes in glioma cells associated with p16INK4a alterations have not been fully described. To determine the roles of p16 alterations in glioma formation, we have established ecdysone-driven inducible p16 expression in the human glioblastoma cell line CL-4, which were derived from p16-null U87MG cells. Here we show that exogenous p16 expression in CL-4 cells results in morphological changes, with large and flattened cytoplasm, which are associated with increased formation of cytoplasmic actin-stress fibers and vinculin accumulation in the focal adhesion contacts. Adhesion of CL-4 cells to extracellular matrix proteins, such as laminin, fibronectin, and type IV collagen, significantly increased upon exogenous p16 expression, which correlated with increased expression of integrin alpha5 and alphav. Expression of a small GTP-binding protein, Rac, also decreased. Following epidermal growth factor stimulation, phosphorylation of MAP kinases ERK1 and 2 and induction of an early immediate gene product, c-Fos, were significantly reduced in CL-4 cells with p16 expression. These results suggest that the tumor suppressor p16 may exert its antitumor effects through modulation of multiple aspects of glioblastoma phenotypes, including proliferation, invasiveness, and responsiveness to extracellular growth stimuli.
Assuntos
Neoplasias Encefálicas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Glioma/patologia , Bradicinina/farmacologia , Adesão Celular , Meios de Cultura Livres de Soro/farmacologia , Ecdisona/farmacologia , Ecdisterona/análogos & derivados , Ecdisterona/farmacologia , Fator de Crescimento Epidérmico/farmacologia , Proteínas de Ligação ao GTP/biossíntese , Proteínas de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes p16 , Humanos , Insulina/farmacologia , Integrinas/biossíntese , Integrinas/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Pseudópodes/efeitos dos fármacos , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/ultraestruturaRESUMO
Retroflexion of the hypoplastic fused cerebrum is a rare condition in holoprosencephaly. We describe a new case of this entity in a 7-year-old boy with alobar holoprosencephaly whi developed retroflexion of the holosphere 7 years after a ventriculo-peritoneal shunt was placed. The radiological findings revealed retroflexion of the cerebrum anchored to the cranial vault between the precerebral space and the dorsal sac, which were open to each other. In patients with holoprosencephaly, the possibility of retroflexion of the holosphere should be considered after placement of a ventriculo-peritoneal shunt for associated hydrocephalus.
Assuntos
Encéfalo/diagnóstico por imagem , Holoprosencefalia/complicações , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Tomografia Computadorizada por Raios X , Derivação Ventriculoperitoneal/efeitos adversos , Angiografia Cerebral , Criança , Holoprosencefalia/diagnóstico , Holoprosencefalia/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Período Pós-OperatórioRESUMO
The authors report a 57-year-old man with an ossified and calcified epidural hematoma found incidentally 40 years after incurring a severe head injury. Since the introduction of computed tomography (CT) scan, few such cases have been described in the literature. A characteristic intracranial "double-outlined" contour on plain skull x-ray films and CT scans represented bone formation and calcification of the hematoma capsule adjacent to the dura.
Assuntos
Calcinose/patologia , Traumatismos Craniocerebrais/patologia , Hematoma Epidural Craniano/patologia , Calcinose/diagnóstico , Doença Crônica , Traumatismos Craniocerebrais/complicações , Craniotomia , Diagnóstico Diferencial , Hematoma Epidural Craniano/diagnóstico , Hematoma Epidural Craniano/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/irrigação sanguínea , Lobo Parietal/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Glioblastoma multiforme represents one of the most malignant forms of primary intracranial tumors, often intractable to multimodality of treatment including chemotherapy. The unsatisfactory results of chemotherapy are chiefly attributed to chemoresistance. Since various molecules that could confer drug resistance have been elucidated, screening of the amount of such molecules in the tumor cells could provide possibilities for predicting their chemoresistance beforehand and help select more effective drugs. METHODS: We present a 45-year-old woman with recurrent glioblastoma multiforme in the cerebellum and invading the brain stem, treated successfully by postoperative chemotherapy. In this patient, anticancer drugs were determined by measurements of mRNA expression of chemoresistance-related genes, such as O6-methylguanine-DNA methyltransferase (MGMT), mdr1, glutathione S-transferase (GST)-pi, and metallothionein (MT) in the resected tumor. RESULTS: Northern blot analysis demonstrated the moderate mRNA level of MGMT, a major molecule causing ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) resistance. On the other hand, expression levels of mdr1 which codes the P-glycoprotein responsible for multidrug resistance, and GST-pi, a detoxification enzyme, were low. Transcript of MT, another thiol containing molecule for cellular detoxification possibly associated with cisdiamminedichloroplatinum(II) (CDDP) resistance, was only faintly detectable. Postoperatively, the patient was treated initially with intravenous administration of ACNU and etoposide (VP16), resulting in a minor response of tumor regression. For maintenance therapy, we changed ACNU to CDDP according to the findings of the Northern blot analysis. Consequently, the residual tumor showed a marked response and almost disappeared after two courses of systemic chemotherapy with CDDP and VP16. CONCLUSIONS: The successful tumor regression in this case suggests that Northern blot analysis on expression of these chemoresistance-related genes in tumor tissues could provide beneficial information for determination of optimal anticancer agents to improve the efficacy of chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Northern Blotting , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Tronco Encefálico/patologia , Neoplasias Cerebelares/tratamento farmacológico , Quimioterapia Adjuvante , Resistência a Múltiplos Medicamentos/genética , Feminino , Glioblastoma/patologia , Glioblastoma/cirurgia , Glutationa Transferase/genética , Humanos , Metalotioneína/genética , Metiltransferases/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , O(6)-Metilguanina-DNA Metiltransferase , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismoRESUMO
BACKGROUND: Two rare cases of triple primary malignant neoplasms (PMN), including malignant brain tumors, which were glioblastoma multiformes, are described. METHODS: The clinical characteristics and underlying genetic alterations in triple or more PMN, including malignant brain tumors are discussed with intensive review of the literature. RESULTS: The first patient, a 77-year-old male, suffered metachronously from tubular adenocarcinoma of the stomach, transitional cell carcinoma of the bladder, and glioblastoma in the brain. This glioblastoma had loss of heterozygosity in exons 7-8 in p53 gene. The second patient, a 68-year-old male, developed papillary adenocarcinoma of the lung, adenocarcinoma of the rectum, and glioblastoma in the brain during a period of 7 years. In 42 such cases described in the literature, age distribution demonstrated two characteristic peaks, one in the third decade and the other over 50 years of age. The younger group consisted mainly of Turcot's syndrome, and of a case of Li-Fraumeni familial cancer syndrome. On the other hand, neither of these hereditary cancer syndromes were contained in the elder group. Regarding the site of PMN, colorectal cancers were associated most frequently with malignant brain tumors, followed by stomach cancers, and thyroid cancers. Malignant brain tumors, mostly glioblastoma multiforme, tend to occur as the last tumor of triple or more PMN. CONCLUSIONS: These results suggest that genetic background might play an important role in tumorigenesis of PMN in the younger group, whereas epigenetic factors would be more important in the older group. Characteristic organ association and factors influencing carcinogenesis, such as aging, environmental carcinogens, and underlying genetic alterations in these tumors are further discussed.
Assuntos
Polipose Adenomatosa do Colo/epidemiologia , Neoplasias Encefálicas/epidemiologia , Glioblastoma/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Distribuição por Idade , Idoso , Neoplasias Encefálicas/patologia , Neoplasias da Mama/epidemiologia , Carcinoma de Células de Transição/epidemiologia , Comorbidade , Feminino , Glioblastoma/patologia , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Neoplasias da Bexiga Urinária/epidemiologiaRESUMO
This experiment was designed to compare sensitive and insensitive children under psychological stress during performance on a motor skill. A new index for sensitivity based on the psychological and physiological data (heart rate) was introduced. The subjects were 50 Japanese children. Although experimental groups received competitive instruction and were given the mirror-drawing task, a control group did not receive such instruction. The sensitive group made fewer errors than the insensitive group and the control group. These results suggest that the combined index is a more useful measure of psychological stress than a single index.
Assuntos
Ansiedade/psicologia , Nível de Alerta , Desenvolvimento da Personalidade , Estresse Psicológico/complicações , Criança , Feminino , Frequência Cardíaca , Humanos , Masculino , Testes de Personalidade , Desempenho Psicomotor , Tempo de ReaçãoRESUMO
A 6-month-old boy having intraspinal lipoma with lumbosacral subcutaneous lipoma and occult spinal dysraphism is described. CT scan and magnetic resonance imaging (MRI) are demonstrated. On admission, the patient showed no neurological deficits. Lumbosacral hemangioma and subcutaneous lipoma were noticed on physical examination. A plain spinal roentogenogram revealed occult spinal dysraphism extending from L 4 level down to the sacral region. A plain CT scan disclosed a round-shaped low density area surrounded by a relatively high density area corresponding to the neural tissue in the spinal canal. MRI (1.5-T superconducting system) with sagittal views clearly showed an oval-shaped high signal intensity (SI) area-an intraspinal lipoma-with the neural tissue running longitudinally within and on its surface. The lipoma appeared to be attached to the spinal cord at L 1/2 level. On operation, we found an extramedullary lipoma which had a certain connection to the sacral epidural adipose tissue with an opening of the dural sac, as far as the subcutaneous lipoma. Tethered cord and thickened filum terminale were not identified. Generally, lipoma is demonstrated as a low density area of approximately -90 H.U. on a CT scan. In MRI, we can obtain a high contrast between the lipoma, the spinal cord, and the cerebrospinal fluid, since they are shown as a high, an intermediate, and a low SI area respectively, on T1-weighted spin echo images. Furthermore, sagittal section of MRI is regarded as a potent diagnostic modality to get the precise anatomy of the spinal cord lesion. These short spin echo images can be taken in a relatively brief time. It is a great advantage for patients with spinal lipoma, who are usually infants. MRI is considered to be a quite useful modality to diagnose spinal lipoma, and is able to lead to an early diagnosis non-invasively and accurately, facilitating appropriate surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Lipoma/diagnóstico , Imageamento por Ressonância Magnética , Neoplasias da Medula Espinal/diagnóstico , Humanos , Lactente , Lipoma/patologia , Lipoma/cirurgia , Masculino , Métodos , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/cirurgiaRESUMO
A 22-year-old woman harboring recurrent malignant astrocytoma presented with intracranial hypertension by tumor hemorrhage during repeated administration of lymphokine-activated killer (LAK) cells via Ommaya's reservoir. She first suffered from the tumor located at the right occipital lobe at the age of 13. The tumor regressed completely by subtotal removal of the tumor, followed by external irradiation. Nine years later, however, the occipital tumor recurred and was subtotally resected. Pathological diagnosis was astrocytoma grade 3. Postoperatively, LAK cells induced from her peripheral blood lymphocytes incubated with interleukin-2 and anti-CD3 antibody were injected into the tumor cavity via Ommaya's reservoir for eight times. At the end of the LAK therapy, the tumor regrew with massive hemorrhage in the tumor cavity causing intracranial hypertension. At the reoperation, thick granulation tissue covered the surface of the recurrent tumor and dense deposits of clot were noted around the tip of the Ommaya's tube. Histologically the superficial layer of the tumor was infiltrated with macrophages and lymphocytes, mostly CD3-positive T cells, accompanied with capillary hyperplasia. Viable astrocytoma cells were abundant beneath the granulation layer. It should be considered that in local LAK therapy granulation tissue formation with hypervascularization at the surface of the tumor cavity may lead to tumor bleeding as well as resistance to the treatment.
Assuntos
Neoplasias Encefálicas/terapia , Hemorragia Cerebral/etiologia , Glioblastoma/terapia , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Ativadas por Linfocina/transplante , Recidiva Local de Neoplasia , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Feminino , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Invasividade NeoplásicaRESUMO
The present study was designed to investigate the effects of psychological stress upon attention as subjects performed on the MFF test. Thirty-four undergraduate students served as subjects. They participated in two experimental conditions: "stress condition" and "non-stress condition". Main sources of stress were competitive instruction and anxiety caused by unfamiliar experimental setting. Heart rate and state anxiety were measured as the indices of those stressors. Their performance on the MFF test was measured in terms of reaction time and the number of correct responses in each condition. The main results were as follows. Reaction time in stress condition was found significantly shorter than that in non-stress condition. However, there was no significant difference in the number of correct responses between these two conditions. Besides, there was no linear relationship found between either heart rate or state anxiety scores and MFF test performance. These results suggest that attention measured by MFF test differs in its reaction time, depending upon whether stressful instruction exists or not, but it holds constancy in its correct responses throughout the experiment.