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1.
Radiol Med ; 125(2): 220-227, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31641931

RESUMO

AIMS: To assess toxicity and clinical outcomes of moderately hypofractionated helical tomotherapy (HT) for the curative treatment of localized prostate cancer (PC). METHODS: From December 2012 to May 2018, 170 patients were treated with definitive intent for PC. Thirty-four percent were low risk, 30% intermediate risk (IR) and 36% high risk (HR). All patients received 70 Gy in 28 fractions to the prostate; 61.6 Gy were delivered to the seminal vesicles for IR; pelvic lymph nodes irradiation for a total dose of 50.4 Gy was added in the HR subgroup. Toxicity was assessed using CTCAE V4.0, and biochemical failure was defined following Phoenix criteria. Time-to-event data were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: The median follow-up was 36 months (range 12-78); acute toxicity was as follows: G1 and G2 in 27.6% and 19.4% for GI; 53% and 24% for GU. No G ≥ 3 event was observed. For late toxicity, G ≥ 3 GI and GU rates were, respectively, 3% and 2.4% at 3 years and 3% and 4.8% at 4 years; no G4 occurred. A statistical correlation between acute or late G3 incidence and clinical or dosimetric parameters was not found. At the time of analysis, 2- and 3-year biochemical relapse-free survival rates were 90% and 87.5% and 2- and 3-year overall survival rates were 96.4% and 90%, respectively. The log-rank test revealed no difference between the risk groups in terms of biochemical control (p = 0.16). CONCLUSIONS: Moderately hypofractionated RT with HT for localized prostate cancer reported excellent outcomes with mild acute and late toxicity incidence, with promising biochemical control rates.


Assuntos
Adenocarcinoma/radioterapia , Neoplasias da Próstata/radioterapia , Hipofracionamento da Dose de Radiação , Radioterapia de Intensidade Modulada/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Órgãos em Risco , Qualidade de Vida , Estudos Retrospectivos
2.
Anticancer Res ; 39(5): 2627-2631, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092461

RESUMO

BACKGROUND/AIM: Pineoblastoma of the adult age is an uncommon tumor with only 200 cases reported. A standardized approach for an optimal adjuvant strategy is currently lacking. The case presented herein also deals with the issue of central nervous system tumors in pregnancy. CASE REPORT: A 21-year-old pregnant woman presented with massive hydrocephalus due to a mass in the pineal region detected with MRI. After positioning an urgent ventricular derivation, a cesarean section was performed. During a third ventriculocisternostomy, a biopsy revealed a pineoblastoma. After a maximal safe resection, postoperative craniospinal irradiation for a total dose of 36 Gy plus a sequential boost to the tumor bed to 54 Gy, and adjuvant chemotherapy with CDDP plus CCNU plus vincristine were performed. After one year, the patient is alive with no evidence of disease. CONCLUSION: The use of adjuvant radio-chemotherapy provided excellent outcomes in our case. The advanced gestational age facilitated the choice of the therapeutic strategy.


Assuntos
Quimiorradioterapia Adjuvante , Glândula Pineal/diagnóstico por imagem , Pinealoma/radioterapia , Complicações Neoplásicas na Gravidez/radioterapia , Adulto , Cesárea , Feminino , Humanos , Imageamento por Ressonância Magnética , Glândula Pineal/fisiopatologia , Glândula Pineal/cirurgia , Pinealoma/diagnóstico por imagem , Pinealoma/tratamento farmacológico , Pinealoma/fisiopatologia , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/patologia , Resultado do Tratamento , Ventriculostomia
3.
Biochem Biophys Res Commun ; 320(2): 493-500, 2004 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-15219856

RESUMO

Resistance to chemotherapy is a common feature of malignant gliomas. This resistance is mediated by receptor tyrosine kinase (RTK)-regulated signaling. p21-Ras protein is pivotal in the propagation of the signal originated from many RTKs. Our aim was to investigate whether inhibition of Ras pathway affects the response to cisplatin in malignant gliomas. We found an enhanced sensitivity to cisplatin of two glioblastoma cell lines expressing dominant negative Ras. Moreover, DN-Ras expressing cells, implanted in nude mice, resulted in being extremely sensitive to cisplatin. The growth of all the tumors was significantly inhibited by combining DN-Ras adenovirus infection with cisplatin treatment. The majority of glioma cells expressing DN-Ras underwent apoptosis in response to cisplatin. In vivo, DN-Ras alone did not influence the growth of tumors, suggesting that the effects of Ras-inhibition observed in vitro could not be extrapolated in vivo. The survival signal pathway transduced by Ras was essentially mediated by inhibition of caspase-9 cleavage via PI3K/Akt.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Cisplatino/farmacologia , Glioblastoma/patologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Proteínas ras/antagonistas & inibidores , Proteínas ras/genética
4.
Cancer Cell Int ; 4(1): 1, 2004 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-14711380

RESUMO

BACKGROUND: The aim of this work was to investigate in vitro the putative role of EGR-1 in the growth of glioma cells. EGR-1 expression was examined during the early passages in vitro of 17 primary cell lines grown from 3 grade III and from 14 grade IV malignant astrocytoma explants. The explanted tumors were genetically characterized at the p53, MDM2 and INK4a/ARF loci, and fibronectin expression and growth characteristics were examined. A recombinant adenovirus overexpressing EGR-1 was tested in the primary cell lines. RESULTS: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1-2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus. CONCLUSIONS: Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.

5.
J Biol Chem ; 278(42): 40621-30, 2003 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-12902333

RESUMO

TSH activates its specific receptor in thyroid cells and induces cAMP, a robust stimulator of thyroid cell proliferation. Conversely, cAMP is a potent inhibitor of growth in mouse fibroblasts. To dissect the signals mediating cAMP-dependent growth, we have expressed in mouse fibroblasts the human thyrotropin receptor (TSHR) or a constitutively active mutant, under the control of the tetracyclin promoter. Both TSHR and cAMP levels were modulated by tetracyclin. In the presence of serum, activation of TSHR by TSH induced growth arrest. In the absence of serum, cells expressing TSHR stimulated with TSH, replicated their DNA, but underwent apoptosis. Co-expression of cAMP-dependent protein kinase (PKA) regulatory subunit type II (RIIbeta) inhibited apoptosis and stimulated the growth of cells only in the presence of TSH. Expression of RIIbeta-PKA, in the absence of TSHR, induced apoptosis, which was reversed by cAMP. Growth, stimulated by TSHR-RIIbeta-PKA in mouse fibroblasts, was also dependent on Rap1 activity, indicating cAMP-dependent growth in thyroid cells. As for the molecular mechanism underlying these effects, we found that in normal fibroblasts, TSH induced AKT and ERK1/2 only in cells expressing TSHR and RII. Similarly, activation of TSHR increased cAMP levels greatly, but was unable to stimulate CREB phosphorylation and transcription of cAMP-induced genes in the absence of RII. These data provide a simple explanation for the anti-proliferative and proliferative effects of cAMP in different cell types and indicate that RII-PKAII complements TSHR action by stably propagating robust cAMP signals in cell compartments.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/química , Receptores da Tireotropina/biossíntese , Adenoviridae/genética , Animais , Apoptose , Northern Blotting , Western Blotting , Divisão Celular , Núcleo Celular/metabolismo , Separação Celular , AMP Cíclico/metabolismo , Proteína Quinase Tipo II Dependente de AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Citometria de Fluxo , Genes Dominantes , Marcação In Situ das Extremidades Cortadas , Camundongos , Células NIH 3T3 , Fosforilação , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Tetraciclina/farmacologia , Fatores de Tempo , Transcrição Gênica , Transfecção
6.
Oncogene ; 22(27): 4194-204, 2003 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-12833142

RESUMO

Transcription factor early growth response-1 (Egr-1) is a crucial regulator of cell growth, differentiation and survival. Several observations suggest that Egr-1 is growth promoting in prostate cancer cells and that blocking its function may impede cancer progression. To test this hypothesis, we developed phosphorothioate antisense oligonucleotides that efficiently inhibit Egr-1 expression without altering the expression of other family members Egr-2, Egr-3 and Egr-4. In TRAMP mouse-derived prostate cancer cell lines, our optimal antisense oligonucleotide decreased the expression of the Egr-1 target gene transforming growth factor-beta1 whereas a control oligonucleotide had no effect, indicating that the antisense blocked Egr-1 function as a transcription factor. The antisense oligonucleotide deregulated cell cycle progression and decreased proliferation of the three TRAMP cell lines by an average of 54+/-3%. Both colony formation and growth in soft agar were inhibited by the antisense oligonucleotide. When TRAMP mice were treated systemically for 10 weeks, the incidence of palpable tumors at 32 weeks of age in untreated mice or mice injected with the control scramble oligonucleotide was 87%, whereas incidence of tumors in antisense-Egr-1-treated mice was significantly reduced to 37% (P=0.026). Thus, Egr-1 plays a functional role in the transformed phenotype and may represent a valid target for prostate cancer therapy.


Assuntos
Transformação Celular Neoplásica , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Proteínas Imediatamente Precoces , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Ciclo Celular , Diferenciação Celular , Divisão Celular , Linhagem Celular Transformada , Membrana Celular/metabolismo , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce , Citometria de Fluxo , Técnicas In Vitro , Masculino , Camundongos , Oligonucleotídeos Antissenso/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Fenótipo , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas
7.
J Biol Chem ; 278(14): 11802-10, 2003 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-12556466

RESUMO

In the majority of aggressive tumorigenic prostate cancer cells, the transcription factor Egr1 is overexpressed. We provide new insights of Egr1 involvement in proliferation and survival of TRAMP C2 prostate cancer cells by the identification of several new target genes controlling growth, cell cycle progression, and apoptosis such as cyclin D2, P19ink4d, and Fas. Egr1 regulation of these genes, identified by Affymetrix microarray, was confirmed by real-time PCR, immunoblot, and chromatin immunoprecipitation assays. Furthermore we also showed that Egr1 is responsible for cyclin D2 overexpression in tumorigenic DU145 human prostate cells. The regulation of these genes by Egr1 was demonstrated using Egr1 antisense oligonucleotides that further implicated Egr1 in resistance to apoptotic signals. One mechanism was illustrated by the ability of Egr1 to inhibit CD95 (Fas/Apo) expression, leading to insensitivity to FasL. The results provide a mechanistic basis for the oncogenic role of Egr1 in TRAMP C2 prostate cancer cells.


Assuntos
Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteínas Imediatamente Precoces , Neoplasias da Próstata/patologia , Proteínas Repressoras , Fatores de Transcrição/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Divisão Celular/fisiologia , Sobrevivência Celular/fisiologia , Ciclina D2 , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p19 , Ciclinas/genética , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Proteína Ligante Fas , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Neoplasias da Próstata/genética , Fatores de Transcrição/genética , Ativação Transcricional/fisiologia , Células Tumorais Cultivadas , Receptor fas/genética , Receptor fas/metabolismo
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