- 作者列表："Rinaldo L","Shepherd DL","Murphy ME","Vine RL","Brown RD Jr","Rabinstein AA","Lanzino G
BACKGROUND:The effect of age on risk of intracranial aneurysm rupture is not well understood. We investigated the clinical course of patients 65 years and older with conservatively managed unruptured intracranial aneurysms (UIA) and determined risk factors for rupture in this population. METHODS:We reviewed prospectively collected data on baseline characteristics and long-term follow-up for patients aged 65 years and older with an UIA that were initially managed with observation. The association between patient and aneurysmal characteristics and risk of rupture was performed using a multivariate Cox proportional hazard regression model. RESULTS:There were 214 patients (mean age: 74.7 years, SD: 6.0) included in our study. The median follow-up time was 3.7 years, with a cumulative follow-up time of 883.7 person-years. During the study period, seven patients (3.3%) received interventional treatment of their UIA and eight patients (3.7%) experienced aneurysmal subarachnoid hemorrhage, yielding an annual risk of rupture of 0.9%. All aneurysms that ruptured were at least 10 mm in size. Increasing patient age [unit relative risk (RR) 1.19, 95% CI: 1.07-1.36, P=0.002], larger aneurysmal size (unit RR 1.10, 95% CI: 1.02-1.17, P=0.021), and increasing PHASES Score (unit RR 1.62, 95% CI: 1.32-2.06, P<0.001) were associated with higher risk of rupture. CONCLUSIONS:Our data do not suggest that UIA in older patients carry a high risk of rupture. A conservative approach appears justified in these patients, with the exception of selected patients with larger aneurysms (>10 mm in diameter) and low risk of interventional procedure.
背景: 年龄对颅内动脉瘤破裂风险的影响尚不清楚。我们调查了 65 岁及以上保守治疗的未破裂颅内动脉瘤 (UIA) 患者的临床过程，并确定了该人群破裂的危险因素。 方法: 我们回顾了前瞻性收集的 65 岁及以上 UIA 患者的基线特征和长期随访数据，这些患者最初接受观察。使用多变量 Cox 比例风险回归模型进行患者和动脉瘤特征与破裂风险之间的关联。 结果: 有 214 例患者 (平均年龄: 74.7 岁，SD: 6.0) 纳入我们的研究。中位随访时间 3.7 年，累计随访时间 883.7 人年。在研究期间，7 例患者 (3.3%) 接受了 UIA 的介入治疗，8 例患者 (3.7%) 经历了动脉瘤性蛛网膜下腔出血，每年破裂的风险为 0.9%。所有破裂的动脉瘤大小至少为 10毫米。患者年龄增加 [单位相对危险度 (RR) 1.19，95% CI: 1.07-1.36，P = 0.002]，动脉瘤体积较大 (单位 RR 1.10，95% CI: 1.02-1.17, P = 0.021)，分期评分增加 (单位 RR 1.62，95% CI: 1.32-2.06，P<0.001) 与较高的破裂风险相关。 结论: 我们的数据并不表明老年患者的 UIA 具有很高的破裂风险。在这些患者中，保守治疗似乎是合理的，但选择性动脉瘤较大 (直径> 10毫米) 和介入手术风险较低的患者除外。
METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.
METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.
METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.