RESUMO
BACKGROUND: Sacroiliac joint (SIJ) dysfunction is an underdiagnosed condition. Several published cohorts have reported favorable midterm outcomes after SIJ fusion using titanium implants placed across the SIJ. Herein, we report 12-month follow-up from SIJ fusion in a standard clinic setting. METHODS: A carefully selected group of 160 consecutive patients with painful SIJ dysfunction were diagnosed at a single center and underwent unilateral or staged bilateral SIJ fusion using triangular titanium implants. Patients were routinely seen in clinic for follow-up every 3 months where they completed visual analog scale (0-10 range) pain ratings and Oswestry Disability Index (ODI). Follow-up CT scan was performed at 1 year. RESULTS: Mean patient age was 58 years, and 68% were women. 30% underwent staged bilateral SIJ fusion. By month 12, SIJ pain decreased from 8.0 to 2.5 (p < 0.0001) and disability (ODI) decreased from 45.3 to 16.4 (p < 0.0001). The proportion with clinically significant improvements in SIJ pain and ODI was high (> 95%). Perioperative adverse events were mild and decreased with increasing surgical experience with the procedure. Subgroup analysis showed slightly smaller improvements in those undergoing bilateral surgery and those with a spinal cord stimulator in place. CT scan at 1 year showed reabsorption along one or more implants in 16% of cases, but there were no breakages or implant removals. CONCLUSIONS: In standard clinical practice, SIJ fusion with triangular titanium implants produces significant improvement in pain and disability related to SIJ dysfunction. These slides can be retrieved under Electronic Supplementary Material.
Assuntos
Articulação Sacroilíaca/cirurgia , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/instrumentação , Adulto , Artralgia/diagnóstico por imagem , Artralgia/cirurgia , Feminino , Seguimentos , Humanos , Dor Lombar/diagnóstico por imagem , Dor Lombar/cirurgia , Masculino , Pessoa de Meia-Idade , Próteses e Implantes , Desenho de Prótese , Estudos Retrospectivos , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/fisiopatologia , Doenças da Coluna Vertebral/diagnóstico por imagem , Fusão Vertebral/métodos , Titânio , Tomografia Computadorizada por Raios X , Escala Visual AnalógicaRESUMO
BACKGROUND AND OBJECTIVE: Primary Ewing's sarcoma of the skull is a very rare malignant neoplasm, predominantly occurring in children and adolescents. We describe here the clinical, neuroradiologic, and histopathologic features of a patient with primary Ewing's sarcoma of the skull and discuss the standards of therapy for this type of tumor. CLINICAL PRESENTATION: This 18-year-old male patient presented with a primary Ewing's sarcoma of the skull, involving the dura of the frontal and parietal lobes of the left cerebral hemisphere. He was treated with gross total surgical excision of tumor, skull reconstruction, chemotherapy, and irradiation. Twelve years after the surgery, the patient has no evidence of local recurrence or distant metastases. Radical surgical excision of the primary tumor with safety margins is thought to play a role in the favorable clinical course. CONCLUSION: The presented case is the longest surviving patient after treatment of primary Ewing's sarcoma of the skull bone. This rare type of tumor may allow better survival rates under adequate management than sarcoma elsewhere in the body.
Assuntos
Sarcoma de Ewing , Neoplasias Cranianas , Criança , Masculino , Adolescente , Humanos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/cirurgia , Crânio , Neoplasias Cranianas/diagnóstico por imagem , Neoplasias Cranianas/cirurgia , Terapia Combinada , Taxa de SobrevidaRESUMO
BACKGROUND: Glioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy. METHODS: We investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines. RESULTS: Our findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy-events that could be prevented by silencing ABCB6 via siRNA treatment. CONCLUSIONS: Our findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aminolevulínico/farmacologia , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioma/metabolismo , Fotoquimioterapia , Protoporfirinas/metabolismo , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Apoptose , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/prevenção & controle , Estudos de Casos e Controles , Proliferação de Células , Fluorescência , Glioma/genética , Glioma/prevenção & controle , Humanos , Luz , Fármacos Fotossensibilizantes/farmacologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
BACKGROUND: Conventional approaches to the thoracic spine can require extensive tissue dissection, bony disruption, and instability that may warrant the need for instrumentation and fusion. Furthermore, anterior approaches may require the involvement of various surgeons from multiple disciplines to ensure a successful operation and mitigate complications. Currently, available minimally invasive approaches still require bony removal and usually rely heavily on computed tomography (CT)-guided imaging without direct gross visualization. Endoscopic spinal procedures have provided an ultra-minimally invasive alternative to access many areas in and around the spinal column. METHODS: We present a 12-year-old boy with a right-sided 2.0 × 3.2-cm paravertebral lesion at the level of T5. The patient successfully underwent an endoscopic approach to the lesion with minimal tissue and bony disruption for tissue diagnosis and tumor resection. RESULTS: At initial and 6-month follow-up, the patient remained asymptomatic and without issues. CONCLUSIONS: We demonstrate here the feasibility and suggest the safety of a posterior ultra-minimally invasive endoscopic spinal approach to obtain a tissue biopsy of an incidentally found ventrolateral paraspinal tumor in the thoracic region in a pediatric patient. This minimal approach can prove to achieve similar results as other approaches that may otherwise necessitate more extensive or transthoracic procedures.
RESUMO
Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is frequently expressed in cancers, including meningiomas and gliomas. Survivin may be associated with tumor progression and poor prognosis of patients with brain tumors. Using ELISA and immunoblot analysis we asked whether survivin is capable of eliciting a humoral immune response in patients with meningiomas and gliomas. Survivin-specific antibodies were detected in 5 of 42 (11.9%) patients with meningiomas and 3 of 35 (8.6%) patients with malignant gliomas of the WHO grades 3 and 4, but not in healthy controls. Tumors of patients with detectable anti-survivin antibodies demonstrated survivin expression in at least 20% of the tumor cells as assessed by immunohistochemistry. We conclude that patients with meningiomas and malignant gliomas can mount a high-titer IgG immune response against the 'universal' tumor-associated antigen survivin. Anti-survivin antibodies may represent attractive tools for diagnosis and follow-up of brain tumors.
Assuntos
Autoanticorpos/sangue , Neoplasias Encefálicas/imunologia , Proteínas Associadas aos Microtúbulos/imunologia , Proteínas de Neoplasias/imunologia , Adulto , Idoso , Apoptose/imunologia , Neoplasias Encefálicas/patologia , Glioma/imunologia , Glioma/patologia , Humanos , Imunoglobulina G/sangue , Proteínas Inibidoras de Apoptose , Meningioma/imunologia , Meningioma/patologia , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Proteínas Recombinantes/imunologia , Valores de Referência , SurvivinaRESUMO
BACKGROUND: The aim of this study was to assess the correlation of overall survival with tumor location (lobar vs. deep grey matter) and with other clinical and imaging variables in a cohort of patients with high grade gliomas. METHODS: Adult patients with newly diagnosed supratentorial WHO grade 3 and 4 gliomas were evaluated. Clinical data included demographics, symptoms at presentation, treatment variables, and overall survival. Radiological data included tumor side, site (deep vs. lobar) and size, extent of peritumoral edema, and presence of midline shift. Biostatistics were carried out using log rank tests and univariate and multivariate Cox regression models. RESULTS: A total of 121 patients were investigated, 23 (19.0%) with WHO grade 3 and 98 (81.0%) with WHO grade 4 gliomas. Tumors had lobar location in 96 cases (79.3%) and deep grey matter location in 25 cases (20.7%). Median survival time for all patients was 26 weeks (IQR: 14-53). Patients with deep tumors survived significantly longer than those with lobar gliomas (log rank test, p=0.0083). Extensive brain edema significantly shortened survival (log rank test, p=0.0003). Presence of midline shift (>1 cm) was a statistically significant risk factor for shorter survival (log rank test, p<0.0001). The univariate Cox regression model demonstrated statistical significance for the variables age, side, site and size of tumor, presence of extensive edema, and presence of mass effect (>1 cm). In the multivariate Cox models, tumor grade, site and size showed statistical significance. CONCLUSIONS: This study suggests that patients with deep grey matter gliomas may survive significantly longer after the initial diagnosis than those with tumors in a lobar location. This is a potentially novel finding, which may corroborate the theory of differential invasion of glioma cells in different microenvironments of the brain, but remains to be confirmed in future prospective studies.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Encéfalo/patologia , Glioma/mortalidade , Glioma/patologia , Adolescente , Adulto , Idoso , Astrocitoma/diagnóstico por imagem , Astrocitoma/mortalidade , Astrocitoma/patologia , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Progressão da Doença , Feminino , Glioma/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico por imagem , Invasividade Neoplásica/patologia , Fibras Nervosas Mielinizadas/patologia , Prognóstico , Análise de Regressão , Taxa de Sobrevida/tendências , Tomografia Computadorizada por Raios X , Reino Unido/epidemiologiaRESUMO
Suicide gene transfer using thymidine kinase (TK) and ganciclovir (GCV) treatment or the cytosine deaminase (CD)/5-fluorocytosine (5-FC) system represents the most widely used approach for gene therapy of cancer. However, molecular pathways and resistance mechanisms remain controversial for GCV-mediated cytotoxicity, and are virtually unknown for the CD/5-FC system. Here, we elucidated some of the cellular pathways in glioma cell lines that were transduced to express the TK or CD gene. In wild-type p53-expressing U87 cells, exposure to GCV and 5-FC resulted in a weak p53 response, although apoptosis was efficiently induced. Cell death triggered by GCV and 5-FC was independent of death receptors, but accompanied by mitochondrial alterations. Whereas expression of Bax remained unaffected, in particular, GCV and also 5-FC caused a decline in the level of Bcl-2. Similar findings were obtained in 9L and T98G glioma cells that express mutant p53, and also underwent mitochondrial apoptosis in both the TK/GCV and CD/5-FC system. Upon treatment of 9L cells with 5-FC, Bcl-xL expression slowly declined, whereas exposure to GCV resulted in the rapid proapoptotic phosphorylation of Bcl-xL. These data suggest that TK/GCV- and CD/5-FC-induced apoptosis does neither require p53 nor death receptors, but converges at a mitochondrial pathway triggered by different mechanisms of modulation of Bcl-2 proteins.
Assuntos
Apoptose/fisiologia , Citosina Desaminase/genética , Flucitosina/farmacologia , Ganciclovir/farmacologia , Genes Transgênicos Suicidas/efeitos dos fármacos , Terapia Genética/métodos , Glioma/terapia , Timidina Quinase/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Mitocôndrias/fisiologia , Mutação/genética , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/fisiologiaRESUMO
PURPOSE: The identification of new molecular markers in astrocytic tumors may help to understand the biology of these tumors in more detail. Informative tumor markers may represent prognostic factors for response to therapy and outcome as well as potential targets for novel anticancer therapies. EXPERIMENTAL DESIGN: Tumor-associated antigens were identified by immunoscreening of a human glioma cDNA expression library with allogeneic sera from patients with diffuse astrocytoma (WHO grades 2-4). The expression of one of the identified antigens, the replication licensing factor minichromosome maintenance protein 3 (MCM3), was analyzed by immunohistochemistry in 142 primary and 27 recurrent astrocytomas (WHO grades 2-4). In addition, 98 serum specimens from patients with primary and secondary brain malignancies and 30 serum specimens from healthy controls were examined by serologic immunoscreening for immunoreactivity with MCM3. RESULTS: MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in 9.3% (9 of 97) of patients with brain tumors (n = 95) and brain metastases (n = 2) but not in healthy controls. Expression of MCM3 in diffuse astrocytoma is significantly associated with age (P < 0.001), histologic grade (P < 0.001), time to recurrence (P = 0.01), and expression of the proliferation marker Ki-67 (P < 0.001) but not with sex (P = 0.800). Univariate and multivariate Cox regression analysis confirmed MCM3 expression as an independent predictor of poor outcome in astrocytoma patients (P < 0.001 for both). CONCLUSIONS: MCM3 may represent a glioma-associated antigen with significant prognostic role as well as have some potential as a target for cancer-directed therapy.
Assuntos
Astrocitoma/imunologia , Astrocitoma/mortalidade , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Proteínas de Ligação a DNA/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrócitos/metabolismo , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Proteínas de Ciclo Celular , DNA Complementar/metabolismo , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Escherichia coli/metabolismo , Feminino , Biblioteca Gênica , Glioma/metabolismo , Humanos , Imuno-Histoquímica , Antígeno Ki-67/biossíntese , Masculino , Pessoa de Meia-Idade , Componente 3 do Complexo de Manutenção de Minicromossomo , Metástase Neoplásica , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Fatores de Tempo , Fatores de Transcrição/metabolismo , Resultado do TratamentoRESUMO
Advances in medical and surgical treatments in the last few decades have resulted in quantum leaps in the overall survival of patients with malignant disease outside the central nervous system, whereas survival of patients with malignant gliomas (World Health Organization Grades III and IV) has remained essentially unchanged. Resection and external-beam fractionated radiotherapy remain the pillars of therapy for malignant gliomas and have shown significant beneficial effects on outcome in many clinical studies. On the other hand, numerous human trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not succeeded in achieving a noteworthy additional extension of survival duration, or have done so only with a considerable deterioration in the quality of life of the treated patients. The concept of local invasiveness of gliomas is not new, but only in the last one to two decades has significant attention been focused on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumor cells has resulted in the introduction and increasing clinical use of local therapies in which practitioners opt for spatially defined delivery methods and tumor-selective agents specifically designed to be used in the environment of a brain invaded by glioma. In this review, the authors summarize the key findings in some of the most important clinical studies of locally administered treatments for malignant glioma. A few such therapies have emerged in the last decade, and have shown considerable antitumor activity and a favorable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection-enhanced delivery, and intra- and peritumorally injected genetically modified viruses conferring glioma-selective toxicity. In addition, areas of possible improvement of these therapies and essential further developments are outlined.
Assuntos
Neoplasias Encefálicas/terapia , Tratamento Farmacológico/tendências , Terapia Genética/tendências , Glioma/terapia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatologia , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Tratamento Farmacológico/métodos , Terapia Genética/métodos , Vetores Genéticos/uso terapêutico , Glioma/genética , Glioma/fisiopatologia , Humanos , Imunotoxinas/uso terapêutico , Polímeros/uso terapêutico , Vírus/genéticaRESUMO
NeoPharm Inc, under license from the National Institutes of Health and the FDA, and in collaboration with the Japanese licensee Nippon Kayaku Co Ltd, is developing cintredekin besudotox, a chimeric human IL-13 conjugated to a genetically engineered Pseudomonas exotoxin molecule, as a potential antitumor agent. This agent is currently undergoing phase III clinical trials.
Assuntos
Exotoxinas/farmacologia , Glioma/tratamento farmacológico , Interleucina-13/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Neoplasias Supratentoriais/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Exotoxinas/genética , Exotoxinas/toxicidade , Humanos , Interleucina-13/genética , Interleucina-13/toxicidade , Camundongos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/toxicidadeRESUMO
KS Biomedix (formerly Avicenna Medica; now a subsidiary of the Xenova group) and Nycomed, together with Japanese licensee Sosei and Chinese licensee PharmaEngine, are developing TransMID, a transferrin-mediated diphtheria toxin delivery system for the potential treatment of adult, recurrent, inoperable, high-grade glioma (as TransMID-107R). It is also under investigation for other forms of brain cancer, including early brain cancer (as TransMID-107N), metastatic brain cancer (as TransMID-107M) and pediatric brain cancer (as TransMID-107P). TransMID is currently undergoing phase III clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Toxina Diftérica/uso terapêutico , Glioma/tratamento farmacológico , Adulto , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Ensaios Clínicos como Assunto , Toxina Diftérica/efeitos adversos , Toxina Diftérica/farmacocinética , HumanosRESUMO
The remarkable migratory and tumor-tropic capacities of neural stem cells (NSCs and/or neuroprogenitor cells) represent a potentially powerful approach to the treatment of invasive brain tumors, such as malignant gliomas. We have previously shown that whether implanted directly into or at distant sites from an experimental intracranial glioma, NSCs distributed efficiently throughout the main tumor mass and also tracked advancing tumor cells, while stably expressing a reporter transgene. As therapeutic proof-of-concept, NSCs genetically modified to produce the prodrug activating enzyme cytosine deaminase (CD), effected an 80% reduction in the resultant tumor mass, when tumor animals were treated with the systemic prodrug, 5-fluorocytosine. We now extend our findings of the tumor-tropic properties of NSCs (using a well-characterized, clonal NSC line C17.2), by investigating their capacity to target both intracranial and extracranial tumors, when administered into the peripheral vasculature. We furthermore demonstrate their capacity to target extracranial non-neural tumors such as prostate cancer and malignant melanoma. Well-characterized NSC lines (lacZ and/or CD-positive) were injected into the tail vein of adult nude mice with established experimental intracranial and/or subcutaneous flank tumors of neural and non-neural origin. The time course and distribution of NSCs within the tumor and internal organs was assessed in various models. Resulting data suggest that NSCs can localize to various tumor sites when injected via the peripheral vasculature, with little accumulation in normal tissues. Our findings suggest the novel use of intravascularly administered NSCs as an effective delivery vehicle to target and disseminate therapeutic agents to invasive tumors of neural and nonneural origin, both within and outside of the brain.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Movimento Celular , Terapia Genética/métodos , Glioma/genética , Glioma/terapia , Sistema Nervoso/citologia , Células-Tronco/fisiologia , Transgenes , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular , Citosina Desaminase/genética , Sistemas de Liberação de Medicamentos , Glioma/patologia , Masculino , Melanoma/patologia , Melanoma/terapia , Camundongos , Camundongos Nus , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , TropismoRESUMO
Cerebellar liponeurocytoma, a rare, newly identified CNS neoplasm of adults, is characterized by advanced neuronal/neurocytic and focal lipomatous differentiation, low proliferative potential and a favorable clinical prognosis. Despite the different age distribution and benign biological behavior, the cerebellar liponeurocytoma shares several features with the cerebellar medulloblastoma, which may include an origin from the periventricular matrix of the fourth ventricle or the external granular layer of the cerebellum. To establish the genetic profile of cerebellar liponeurocytomas, we have formed an international consortium and collected tumor samples from 20 patients. DNA sequencing revealed TP53 missense mutations in 4 (20%) of 20 cerebellar liponeurocytomas, a frequency higher than in medulloblastomas. There was no case with PTCH, APC, or beta-catenin mutations, each of which may be present in subsets of medulloblastomas. Isochromosome 17q, a genetic hallmark of classic medulloblastomas, was not observed in any of the cases investigated by FISH analysis. cDNA array analyses were carried out on 4 cerebellar liponeurocytomas, 4 central neurocytomas, and 4 classic medulloblastomas. Cluster analysis of the cDNA expression data of 1176 genes grouped cerebellar liponeurocytomas close to central neurocytomas, but distinct from medulloblastomas. These results suggest cerebellar liponeurocytoma as a distinct tumor entity that is genetically different from medulloblastoma. Furthermore, the cDNA expression array data suggest a relationship to central neurocytomas, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that their genetic pathways are different.
Assuntos
Neoplasias Cerebelares/genética , DNA de Neoplasias/análise , Lipoma/genética , Neurocitoma/genética , Adulto , Idoso , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/patologia , Diagnóstico Diferencial , Feminino , Genes p53/genética , Humanos , Hibridização in Situ Fluorescente , Lipoma/classificação , Lipoma/patologia , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Neurocitoma/classificação , Neurocitoma/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo Conformacional de Fita SimplesRESUMO
The expression of human leukocyte antigen (HLA) alleles plays an important role in the development and recurrence of benign and malignant diseases. Association of single HLA alleles or haplotypes with neoplastic processes has been investigated previously, and correlation between HLA and solid tumors, such as head and neck cancers or uterine cervical squamous epithelial lesions, were reported. However, there is no published data on the influence of the HLA system on the development of symptomatic cerebral meningioma, a mostly benign intracranial tumor of mesenchymal origin in adults. The present investigation is comparing the frequency of single HLA alleles and haplotypes in 81 adult Caucasian patients with symptomatic central nervous system meningiomas to that of 157 area- and race-matched healthy controls. Both standard serological and molecular genetic (PCR) techniques were used for HLA typing. Our results suggest an association between single HLA alleles and occurrence of clinically symptomatic meningioma. Patients with HLA-A*02 had a 2.5-fold increased risk of meningioma (P = 0.02), and those with HLA-DQB1*05 had a 1.8-fold increased risk of meningioma (P = 0.05). Conversely, HLA-A*01, -B*08, and -DRB1*03 were associated with a 0.4-, 0.5-, and 0.5-fold, respectively, decreased risk of meningioma (P = 0.008, P = 0.05, and P = 0.04). Moreover, the occurrence rate of combinations and estimated haplotypes containing these HLA alleles was strikingly different in meningioma patients compared with controls: significantly increased for the haplotypes HLA-A*02:DRB1*04 (P = 0.02, relative risk = 2.5) and HLA-A*02:DRB1*04:DQB1*0302,DQB1*05 (P = 0.03, RR = 7.5), and significantly decreased for the haplotype HLA-A*01:B*08:DRB1*03 (P = 0.01, relative risk = 0.2). In conclusion, these data suggest that some single HLA alleles and haplotypes may protect from or predispose to developing symptomatic central nervous system meningioma during adult life. These associations may be indicative of the involvement of the immune system in the host antitumor surveillance, recognition, and destruction of de novo arising human tumor cells.
Assuntos
Alelos , Predisposição Genética para Doença , Antígenos HLA/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Haplótipos , Humanos , Masculino , Neoplasias Meníngeas/epidemiologia , Neoplasias Meníngeas/imunologia , Meningioma/epidemiologia , Meningioma/imunologia , Pessoa de Meia-Idade , Probabilidade , Estudos Prospectivos , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
The time course of cytotoxicity induction and the bystander effect of the rabbit cytochrome P450 4B1 (cyp4B1)/4-ipomeanol (4-IM) or 2-aminoanthracene (2-AA) pharmacogene therapy systems were investigated and compared with the herpes simplex virus type 1 thymidine kinase/ganciclovir (HSV-tk/GCV) system. Experiments were performed in rat 9L gliosarcoma cells stably expressing cyp4B1 (9L-4B1), HSV-tk (9L-tk), or their egfp (enhanced green fluorescent protein) fusion genes. Cyp4B1-mediated activation of 2-AA showed a high cell killing efficiency within only 48 hours with an onset after already 15 minutes of prodrug exposure. Residual 9L-4B1 cells were mostly damaged sublethally upon 2-AA treatment showing an S phase arrest by cell cycle analysis. 4-IM treatment of 9L-4B1 cells generated an overall weaker cell killing, especially after prodrug exposure times of less than 48 hours. Residual cells surviving 4-IM treatment showed a G2/M arrest and restarted proliferation after prodrug treatment was stopped. HSV-tk/GCV pharmacogene therapy resulted in a slower cytotoxicity induction than cyp4B1/2-AA treatment with a significantly lower cell killing efficiency after 24 and 48 hours. HSV-tk/GCV-mediated cytotoxicity was widely similar to the cytotoxicity induced by cyp4B1/4-IM with the exception of a continuous 48-hour prodrug exposure where 4-IM treatment showed a significantly higher cell killing rate. Cells surviving HSV-tk/GCV suicide gene therapy were not viable and showed an S-phase arrest. Whereas HSV-tk/GCV induced a strong bystander effect, only moderate bystander cell death depending on cell-to-cell contact was demonstrated in 9L/9L-4B1 cocultures upon 2-AA treatment and was even absent with 4-IM, thereby contrasting with earlier reports. The absence of a strong bystander effect may limit, on one hand, the overall utility of the cyp4B1 systems for cancer gene therapy. On the other hand, the weak bystander effect together with the fast induction of cytotoxicity may provide marked advantages for the use of the cyp4B1 systems as biosafety enhancers for gene marking or replacement studies and donor lymphocyte infusions after allogeneic bone marrow transplantation.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Efeito Espectador/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Pró-Fármacos/farmacologia , Animais , Antracenos/farmacologia , Antivirais/farmacologia , Western Blotting , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Ganciclovir/farmacologia , Terapia Genética/métodos , Gliossarcoma/terapia , Proteínas de Fluorescência Verde , Herpesvirus Humano 1/enzimologia , Humanos , Proteínas Luminescentes/metabolismo , Farmacogenética , Coelhos , Terpenos/farmacologia , Timidina Quinase/genética , Transfecção , Células Tumorais Cultivadas/fisiologiaRESUMO
Molecular events promoting tumourigenesis and anticancer therapeutic strategies have been intensively studied in tumour cell culture models. In the past few years, non-invasive bioluminescence imaging (BLI) has emerged as a powerful strategy for the validation of cell culture findings in animal models of cancer. BLI allows for repetitive and exceptionally sensitive real-time monitoring of a disease course, as well as of tumour response to therapeutic interventions in an individual animal. This review discusses the application of BLI to cancer research in general and to the area of experimental neuro-oncology in particular.
Assuntos
Diagnóstico por Imagem/tendências , Medições Luminescentes , Oncologia/tendências , Animais , Diagnóstico por Imagem/instrumentação , Humanos , Oncologia/instrumentação , Neoplasias Experimentais/patologia , PesquisaRESUMO
BACKGROUND: Suicide gene therapy employing the prodrug activating system Herpes simplex virus type 1 thymidine kinase (HSV-TK)/ ganciclovir (GCV) has proven to be effective in killing experimental brain tumors. In contrast, glioma patients treated with HSV-TK/ GCV did not show significant treatment benefit, most likely due to insufficient transgene delivery to tumor cells. Therefore, this study aimed at developing a strategy for real-time noninvasive in vivo monitoring of the activity of a therapeutic gene in brain tumor cells. METHODS: The HSV-TK gene was fused to the firefly luciferase (Luc) gene and the fusion construct HSV-TK-Luc was expressed in U87MG human malignant glioma cells. Nude mice with subcutaneous gliomas stably expressing HSV-TK-Luc were subjected to GCV treatment and tumor response to therapy was monitored in vivo by serial bioluminescence imaging. Bioluminescent signals over time were compared with tumor volumes determined by caliper. RESULTS: Transient and stable expression of the HSV-TK-Luc fusion protein in U87MG glioma cells demonstrated close correlation of both enzyme activities. Serial optical imaging of tumor bearing mice detected in all cases GCV induced death of tumor cells expressing the fusion protein and proved that bioluminescence can be reliably used for repetitive and noninvasive quantification of HSV-TK/ GCV mediated cell kill in vivo. CONCLUSION: This approach may represent a valuable tool for the in vivo evaluation of gene therapy strategies for treatment of malignant disease.
RESUMO
OBJECTIVE AND IMPORTANCE: Liponeurocytomas are rare cerebellar neoplasms in adults, with benign histological features and a favorable clinical prognosis. Current clinical opinion is based on a total of less than 20 published cases and suggests that gross total resection and long-term follow-up monitoring, with possible additional surgery and radiotherapy for treatment of recurrent tumors, represent the best treatment approach for this relatively benign tumor type. CLINICAL PRESENTATION: A 51-year-old Caucasian woman presented with worsening unsteady gait and headaches, suggesting increased intracranial pressure. INTERVENTION: The patient underwent subtotal resection of a cerebellar liponeurocytoma, followed by fractionated radiotherapy (total dose of 54 Gy). She experienced a local recurrence of the tumor 12 months later and underwent additional surgery for removal of the cerebellar mass. A second recurrent tumor was diagnosed on magnetic resonance imaging scans 3 months later and was surgically resected. The tumor histological findings were consistently devoid of atypical features, apart from leptomeningeal invasion noted in the first surgical specimen. CONCLUSION: This unusual case demonstrated an atypical clinical course of a highly aggressive and radiation-resistant tumor, despite the consistent absence of aggressive histological features. Cerebellar liponeurocytomas may not be as benign as the current literature and typical low-grade cytological and histological features suggest.
Assuntos
Neoplasias Cerebelares/terapia , Lipoma/terapia , Recidiva Local de Neoplasia/terapia , Neurocitoma/terapia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
The human egr-1 gene encodes a zinc finger transcription factor induced by endogenous and exogenous stimuli such as growth factors, cytokines, and mitogens. Egr-1 regulates other genes involved in growth and differentiation. The present study investigated the influence of genotoxic agents, such as chemotherapy drugs and other DNA damaging agents, on egr-1 expression in normal and neoplastic cells. A transcriptional fusion between the human egr-1 promoter and the enhanced green fluorescent protein (EGFP) gene was used for direct visualization of intracellular Egr-1 regulation. The transcriptional activity of the egr-1 promoter in this reporter system faithfully reflects intrinsic egr-1 expression and induction, as demonstrated by FACS analysis of fluorescence and by RT-PCR for egr-1. EGFP was expressed under the control of the egr-1 promoter in stably transfected immortalized cell lines, such as HEK293, T98G, LNZ308, and 9L, which were then treated with genotoxic agents.A multitude of DNA damaging agents and therapeutic drugs caused significant upregulation of egr-1 transcription. Furthermore, cytotoxic compounds without a direct DNA damaging effect, such as resveratrol and vincristine, which interfere with DNA replication and cell division, were also able to activate egr-1 transcription. This suggests that cell cycle arrest rather than DNA damage seems to be the condition triggering egr-1 transcription. Moreover, treatment with the MAP kinase (MAPK) inhibitor SB203580, which specifically blocks the stress inducible p38/SAPK2 pathway, did not alter egr-1 induction. On the other hand, treatment with the inhibitor PD98059, which specifically blocks the MAPK/ERK pathway, partially suppressed the induction effect. In addition, the egr-1 induction effect caused by genotoxic stress was found to be at least in part independent from the cellular p53 status, as it was observed in p53-deficient as well as in wild type p53 cell lines. These results suggest that induction of egr-1, a gene to which until now no relation to DNA repair has been assigned, may belong to the fundamental cellular responses elicited by genotoxic and mitotic stress in normal as well as in neoplastic cells, and that enhanced levels of Egr-1 protein may be needed to regulate genes involved in DNA repair, cell survival, and apoptosis.
Assuntos
Proteínas de Ligação a DNA/genética , DNA/efeitos dos fármacos , Regulação da Expressão Gênica , Proteínas Imediatamente Precoces , Mutagênicos/farmacologia , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Proteína 1 de Resposta de Crescimento Precoce , Genes Reporter , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Mitomicina/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Regiões Promotoras Genéticas , Ratos , Proteínas Recombinantes de Fusão/genética , Resveratrol , Estilbenos/farmacologia , Topotecan/farmacologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Dedos de ZincoRESUMO
Recombinant retroviruses (RV) have been widely used as vectors for clinical gene therapy of malignant brain tumors. Because of the very limited stability of these vectors in vivo, RV producing cells (VPC) are routinely used for intratumoral RV release. The host immune system, however, recognizes the intratumorally grafted allogeneic or xenogeneic VPC, and mounts an immune response against them. Humoral and cellular immune responses eventually result in reduction of VPC numbers and in limited success of RV mediated gene therapy approaches. This study presents a non-pharmacological and spatially limited approach for protection of VPC grafted in the CNS against destruction by host immune responses. Murine fibroblast-derived VPC expressing herpes-simplex-virus type I thymidine kinase (HSV-tk) were genetically modified to co-express a human Fas ligand (CD95L) deletion mutant (DeltaFasL) resistant to enzymatic cleavage and shedding. Direct interactions between Fas (CD95) on lymphocytes and DeltaFasL on VPC upon cell-cell contact rapidly caused apoptosis in lymphocytes. In addition, cultured malignant brain tumor cells (U87, LN18, LN229) transduced with DeltaFasL-RV were rendered apoptotic by Fas/DeltaFasL interaction. DeltaFasL-expressing VPC grafted in a 9L rat brain tumor model survived in significantly higher numbers compared with control VPC, and did not cause an increase in neutrophil infiltration of tumors. Gene therapy of tumor bearing animals grafted with the modified DeltaFasL-VPC and given the prodrug Ganciclovir resulted in significantly increased survival rates compared to treatment with control VPC and Ganciclovir. In conclusion, prolonged intratumoral presence of DeltaFasL-VPC seems to be a direct consequence of the expression of the membrane-bound mutant FasL, and may result in increased total RV output and improved tumor transduction with RV.