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1.
Otol Neurotol ; 41(6): e759-e762, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32271262

RESUMO

OBJECTIVE: To report and discuss the effectiveness of stereotactic radiosurgery (SRS) or fractionated radiotherapy (FRT) for tumor control following surgical resection of endolymphatic sac tumors (ELST). STUDY DESIGN: Retrospective case series. SETTING: Multi-institutional academic referral centers. PATIENTS: Patients undergoing surgical resection for ELST followed by SRS or FRT. INTERVENTION(S): Surgical resection followed by radiotherapy. MAIN OUTCOME MEASURES: Local tumor control. RESULTS: Two of the five patients experienced tumor recurrence after gross total microsurgical at 78 and 11 months, respectively. The former patient received salvage 3D conformal radiotherapy (3D-CRT) and while the latter patient underwent three courses of salvage SRS for recurrence, two of which were in-field and was disease-free at last follow up. Two additional patients underwent subtotal tumor resection (STR) followed by intensity-modulated radiation therapy (IMRT) and are currently without disease. One patient underwent STR followed by proton-beam therapy (PBT) and was free of disease at most recent follow-up. CONCLUSION: SRS/FRT remains a useful adjuvant for treatment of residual or recurrent ELSTs, where the risk of revision microsurgical resection is high.

2.
Strahlenther Onkol ; 196(7): 664-670, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32006066

RESUMO

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

3.
Otol Neurotol ; 41(2): e262-e267, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789797

RESUMO

OBJECTIVE: Accurate volume assessment is essential for the management of vestibular schwannoma after stereotactic radiosurgery (SRS). A cuboidal approximation for volume is the standard surveillance method; however, this may overestimate tumor volume. We sought to evaluate several volumetric models and their suitability for post-SRS surveillance. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: We evaluated 54 patients with vestibular schwannoma before and after SRS. INTERVENTION(S): Gold-standard volumes were obtained by a radiation oncologist using contouring software. Volume was also calculated by cuboidal, ellipsoidal, and spherical formulae using tumor diameters obtained by a neuroradiologist. MAIN OUTCOME MEASURE(S): Percent error (PE) and absolute percent error (APE) were calculated. Paired t test evaluated bias, and the Bland-Altman method evaluated reproducibility. Linear regression evaluated predictors of model error. RESULTS: All models overestimated volume compared with the gold standard. The cuboidal model was not reproducible before SRS (p < 0.001), and no model was reproducible after SRS (cuboidal p < 0.001; ellipsoidal p = 0.02; spherical p = 0.02). Significant bias was present before SRS for the cuboidal model (p < 0.001), and post-SRS for all models [cuboidal (p < 0.001), ellipsoidal (p < 0.02), and spherical (p = 0.005)]. Model error was negatively associated with pretreatment volume for the cuboidal (PE p = 0.03; APE p = 0.03), ellipsoidal (PE p = 0.03; APE p = 0.04), and spherical (PE p = 0.02; APE p = 0.03) methods and lost linearity post-SRS. CONCLUSIONS: The standard cuboidal practice for following vestibular schwannoma tumor volume after SRS overestimates size. Ellipsoidal and spherical estimations have improved performance but also overestimate volume and lack reliability post-SRS. The development of other volumetric models or application of contouring software should be investigated.

4.
Otol Neurotol ; 41(1): 133-140, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789966

RESUMO

OBJECTIVE: To analyze local control (LC) and toxicity rates between stereotactic radiosurgery (SRS) and intensity-modulated radiotherapy (IMRT) in relation to reported surgical rates in the treatment of paragangliomas (PG) in the upfront, adjuvant, and salvage settings, and to explore factors affecting tumor size reduction, toxicity rates, and symptom control. STUDY DESIGN: Retrospective cohort analysis. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: Thirty patients treated with either linear accelerator-based SRS or IMRT in the definitive, planned adjuvant, or unplanned salvage postsurgery settings. MAIN OUTCOME MEASURES: Local control, toxicities, symptom control, tumor size reduction, and factors affecting each. RESULTS: Median follow-up was 4.16 years. LC rates were 100%. Acute grade >3 toxicity rate was 6.7%, 86.7% of tumors had a reduction in volume, and 76.7% of patients had improvement in at least one tumor-induced symptom by last follow-up. Larger tumor size at presentation and longer time to last follow-up were significantly associated with greater tumor size reduction on multivariate analysis. CONCLUSIONS: SRS and IMRT are safe and effective treatment for PG with high efficacy and low morbidity rates in the upfront, planned adjuvant, and unplanned salvage settings.

6.
Pituitary ; 22(6): 607-613, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31552580

RESUMO

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.


Assuntos
Hipersecreção Hipofisária de ACTH/cirurgia , Hipersecreção Hipofisária de ACTH/terapia , Radiocirurgia/métodos , Adulto , Estudos de Coortes , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
7.
Neurosurgery ; 85(6): E1078-E1083, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215628

RESUMO

BACKGROUND: Fractionated stereotactic radiosurgery (SRS) for vestibular schwannomas (VS) has been theorized to allow for tumor control with higher rates of hearing preservation in selected patients with useful hearing. However, there is a paucity of literature with formal audiologic measures of hearing preservation to support the standard use of fractionated SRS in VS. We hypothesized that fractionation would diminish the amount of hearing damage. OBJECTIVE: To evaluate the relationship between audiologic performance and SRS fractionation scheme. METHODS: We performed an IRB-approved retrospective review of patients treated with 1, 3, or 5 fraction SRS for VS at our institution from 1998 to 2016. Pre- and post-SRS audiograms with speech awareness threshold (SAT) in treated and contralateral ears were obtained. Contralateral ear measurements were used for hearing normalization to account for presbycusis. RESULTS: Fifty-six patients with median audiologic follow-up 2.0 yr (mean 2.66 yr, min-max 0.50-9.45 yr) were included. Patients treated with single fractionation had a significantly worsened SAT (dB) compared to patients treated with 5 fractions (P = .008) and compared to all multifraction patients (P = .009) at 12 to 24 mo follow-up. CONCLUSION: This retrospective analysis supports the use of fractionated SRS to preserve hearing in patients with VS. SAT can be used as an objective metric of hearing response to radiosurgery.


Assuntos
Audiometria/tendências , Fracionamento da Dose de Radiação , Audição/efeitos da radiação , Neuroma Acústico/radioterapia , Radiocirurgia/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Audição/fisiologia , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Neuroma Acústico/diagnóstico , Neuroma Acústico/fisiopatologia , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
8.
World Neurosurg ; 123: 123-127, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30529515

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive soft tissue sarcomas. MPNST intracranial metastasis is exceedingly rare with only 22 documented cases in the literature and, to our knowledge, only 1 case with intraparenchymal brain metastasis. Most have been managed surgically; however, 2 documented cases were treated with Gamma Knife radiosurgery. Excluding this case report, there are no other documented cases of linear accelerator-based stereotactic radiosurgery (SRS) to treat MPNST brain metastasis. CASE DESCRIPTION: A 41-year-old man with MPNST of the lung initially underwent tumor resection. He developed multiple systemic metastases that were managed with directed radiation therapy. A parietal brain metastasis was treated with linear accelerator-based SRS. Following SRS therapy, the patient was treated with a tropomyosin receptor kinase inhibitor. Complete resolution of brain metastasis was seen on brain magnetic resonance imaging 5 months after treatment with SRS. At 11 months after SRS, there was no evidence of recurrence or progression of the intraparenchymal disease. The patient continued to have stable extracranial disease on his ninth cycle of systemic treatment. CONCLUSIONS: This report provides important insights into efficacy of linear accelerator-based SRS to treat MPNST brain metastases.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Neoplasias da Bainha Neural/patologia , Neurofibrossarcoma/patologia , Radiocirurgia/instrumentação , Radiocirurgia/métodos , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Aceleradores de Partículas , Tomografia por Emissão de Pósitrons
9.
World J Clin Oncol ; 9(8): 200-207, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30622928

RESUMO

BACKGROUND: Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade, malignant tumor that constitutes less than one percent of all salivary gland tumors. To date, only one other case report has described radiation-associated EMC in the English language medical literature. CASE SUMMARY: In this report, we describe the case of a 56-year-old male patient who presented with a neck mass diagnosed as EMC of the left submandibular gland approximately 30 years after mantle field radiation and chemotherapy for Hodgkin lymphoma. Treatment included resection, re-resection with nodal dissection, and adjuvant chemoradiotherapy. This patient was also diagnosed with 4 other secondary malignancies, including stage IV diffuse large B cell lymphoma in the abdomen with subsequent brain metastases, low-grade neuroendocrine carcinoma of the lung, Hurthle cell adenoma, and small B cell lymphoma before the patient expired. This case provides important information regarding the pathology, clinical sequelae, and management of a patient diagnosed with radiation-associated EMC amidst four concurrent malignancies. CONCLUSION: Further investigation is needed on the efficacy of adjuvant radiotherapy in EMC, especially atypical EMC.

10.
Neurosurgery ; 81(1): 136-146, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28201783

RESUMO

BACKGROUND: There is no consensus regarding the optimal management of inoperable high-grade arteriovenous malformations (AVMs). This long-term study of 42 patients with high-grade AVMs reports obliteration and adverse event (AE) rates using planned multistage repeat stereotactic radiosurgery (SRS). OBJECTIVE: To evaluate the efficacy and safety of multistage SRS with treatment of the entire AVM nidus at each treatment session to achieve complete obliteration of high-grade AVMs. METHODS: Patients with high-grade Spetzler-Martin (S-M) III-V AVMs treated with at least 2 multistage SRS treatments from 1989 to 2013. Clinical outcomes of obliteration rate, minor/major AEs, and treatment characteristics were collected. RESULTS: Forty-two patients met inclusion criteria (n = 26, S-M III; n = 13, S-M IV; n = 3, S-M V) with a median follow-up was 9.5 yr after first SRS. Median number of SRS treatment stages was 2, and median interval between stages was 3.5 yr. Twenty-two patients underwent pre-SRS embolization. Complete AVM obliteration rate was 38%, and the median time to obliteration was 9.7 yr. On multivariate analysis, higher S-M grade was significantly associated ( P = .04) failure to achieve obliteration. Twenty-seven post-SRS AEs were observed, and the post-SRS intracranial hemorrhage rate was 0.027 events per patient year. CONCLUSION: Treatment of high-grade AVMs with multistage SRS achieves AVM obliteration in a meaningful proportion of patients with acceptable AE rates. Lower obliteration rates were associated with higher S-M grade and pre-SRS embolization. This approach should be considered with caution, as partial obliteration does not protect from hemorrhage.


Assuntos
Malformações Arteriovenosas Intracranianas/radioterapia , Radiocirurgia , Adolescente , Adulto , Idoso , Criança , Protocolos Clínicos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
11.
Prostate ; 76(2): 199-206, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26447830

RESUMO

BACKGROUND: Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS: GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS: GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS: The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis.


Assuntos
Dano ao DNA/fisiologia , Glutationa S-Transferase pi/deficiência , Estresse Oxidativo/fisiologia , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Glutationa S-Transferase pi/genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
12.
J Clin Neurosci ; 24: 143-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26474503

RESUMO

Epithelial-myoepithelial carcinoma (EMC) is a very rare salivary gland malignancy accounting for less than 1% of salivary gland tumors, and classically arises from the parotid gland in females. Spinal cord compression caused by EMC metastasized from the parotid gland has only been described once in the literature to our knowledge. We report the first case of a patient with parotid EMC spinal metastasis undergoing a gross total resection with instrumented fusion. This case illustrates that an en bloc resection with a planned transgression through the spinal canal may be a reasonable option for EMC metastasized to the spine.


Assuntos
Carcinoma/secundário , Mioepitelioma/secundário , Neoplasias Parotídeas/patologia , Neoplasias da Medula Espinal/secundário , Adulto , Carcinoma/patologia , Feminino , Humanos , Compressão da Medula Espinal/etiologia , Neoplasias da Medula Espinal/complicações
13.
World Neurosurg ; 86: 515.e17-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26386456

RESUMO

BACKGROUND: Absent congenital pedicle syndrome is a posterior arch defect characterized by numerous congenital and mechanical abnormalities that result from disconnection of the anterior and posterior columns of the spinal canal. Absent congenital pedicle syndrome is a rare anomaly that is most commonly diagnosed incidentally, after evaluation of minor trauma, or after complaints of chronic neck pain. We report a case of absent congenital pedicle syndrome in a patient who presented with myelopathy and lower extremity weakness and review the literature on the surgical management of this entity. CASE DESCRIPTION: A 32-year-old woman with a history of systemic lupus erythematosus presented to the Neurosurgery Service with progressive weakness in her upper and lower extremities, clonus, and hyperreflexia. Magnetic resonance imaging revealed congenital absence of the pedicles of C2, C3, C4, C5, and C6 with a congenitally narrow canal at C4-5. The patient underwent a staged anterior and posterior cervical decompression and fusion. She was placed in a halo after surgery; at the 1-year follow-up, she was ambulatory with demonstrated improvement in weakness and fusion of her cervical spine. CONCLUSIONS: Absent congenital pedicle syndrome is rare, and most reported cases were treated conservatively. Surgical management is reserved for patients with myelopathy or instability.


Assuntos
Vértebras Cervicais/anormalidades , Vértebras Cervicais/cirurgia , Compressão da Medula Espinal/diagnóstico , Compressão da Medula Espinal/etiologia , Fusão Vertebral , Adulto , Feminino , Humanos , Compressão da Medula Espinal/cirurgia
14.
Global Spine J ; 5(5): 417-24, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26430597

RESUMO

Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patient's predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention.

15.
Case Rep Oncol Med ; 2015: 431819, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26199775

RESUMO

We present a case report of a patient with glioblastoma multiforme (GBM) complicated by extracranial metastasis (ECM) whose survival of nearly four years surpassed the anticipated life expectancy given numerous negative prognostic factors including EGFRvIII-mutation, unmethylated MGMT promoter status, and ECM. Interestingly, while this patient suffered from locally aggressive disease with multiple intracranial recurrences, the proximal cause of death was progressive extracranial disease and complications related to pulmonary metastases. Herein, we review potential mechanisms of ECM with an emphasis upon glioblastoma molecular and genetic profiles and the potential implications of targeted agents such as bevacizumab.

16.
J Clin Neurosci ; 22(9): 1507-10, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26021731

RESUMO

A 25-year-old man with Crouzon syndrome complicated by pseudotumor cerebri and multiple shunt failures presented with progressive back and neck pain, intermittent headaches, and associated vomiting secondary to shunt infection. Due to his previous history of repeated failure of both ventriculoperitoneal and lumboperitoneal (LP) shunting procedures, the decision was made to place a lumboatrial (LA) shunt via an approach through the internal jugular vein. The procedure was uncomplicated and the man's symptoms were relieved. Despite significant improvement, the LA shunt limited his exercise tolerance, and as an avid runner and weight lifter, he requested reconversion back to an LP shunt. At a follow-up of 20months, he continued to do well both clinically and radiographically. This case report summarizes the successful placement and use of an LA shunt for the treatment of intracranial hypertension in the setting of Crouzon syndrome.


Assuntos
Derivações do Líquido Cefalorraquidiano/métodos , Disostose Craniofacial/complicações , Pseudotumor Cerebral/cirurgia , Adulto , Humanos , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/cirurgia , Veias Jugulares/cirurgia , Masculino , Pseudotumor Cerebral/etiologia
17.
World Neurosurg ; 84(2): 314-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25805534

RESUMO

OBJECTIVE: To report five patients who underwent lumbopleural (LPl) shunting for the treatment of idiopathic intracranial hypertension (IIH) and to describe the considerations, complications, and outcomes related to this rarely described procedure. METHODS: The clinical data of five patients treated with LPl shunting over a 23-year period were retrospectively analyzed. Factors including the age at diagnosis of IIH, age at time of LPl shunting, body mass index (BMI), reason for LPl shunt placement, number of revisions before LPl shunt placement, valve type, time to first revision, presence of overdrainage and its management, complications and their management, survival time of LPl shunt, and clinical course at last follow-up were analyzed. RESULTS: All patients were morbidly obese females with an average of 4.6 shunt revisions before an LPl shunt. The average overall survival time of the LPl shunt was 48 months. Two patients experienced failure of their LPl shunts with subsequent replacement within the first year. Four patients experienced complications related to shunt overdrainage, requiring placement of an antisiphon device (ASD) or additional valve. One patient developed a symptomatic pleural effusion, and one patient developed a small pneumothorax, which was managed conservatively. CONCLUSIONS: LPl shunting, though rarely used, is a viable option in the treatment of IIH refractory to standard peritoneal shunting. When pursuing this treatment, a valve and ASD are recommended to mitigate the risks of overdrainage and pleural effusion. Chest imaging should be obtained if the patient becomes symptomatic but can be deferred if the patient remains asymptomatic and is doing well.


Assuntos
Pseudotumor Cerebral/cirurgia , Derivação Ventriculoperitoneal , Adulto , Índice de Massa Corporal , Feminino , Humanos , Seleção de Pacientes , Reoperação , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 109(13): 5028-33, 2012 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-22396593

RESUMO

A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML.


Assuntos
Leucemia/patologia , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Repressoras/metabolismo , Animais , Proliferação de Células , Imunoprecipitação da Cromatina , Citoproteção , Progressão da Doença , Regulação para Baixo/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Inativação Gênica , Genes Neoplásicos/genética , Loci Gênicos/genética , Genoma/genética , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Leucemia/genética , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Complexo Repressor Polycomb 2 , Proteínas do Grupo Polycomb , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo
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