Clinical features of newly developed NF2 intracranial meningiomas through comparative analysis of pediatric and adult patients.
通过对儿童和成人患者的比较分析，新开发的 NF2 颅内脑膜瘤的临床特征。
- 作者列表："Li P","Wu T","Wang Y","Zhao F","Wang Z","Wang X","Wang B","Yang Z","Liu P
OBJECTIVE:NF2 patients can develop new meningiomas throughout their lifetime. Little is known about the clinical features of newly developed NF2 meningiomas. In this study, we analyzed newly developed NF2 meningiomas in a large patient population. PATIENTS AND METHODS:Among 452 NF2 patients, the location patterns of 81 pediatric and 939 adult NF2 meningiomas were compared to find the predominant locations of newly developed meningiomas in adulthood. The clinical features of 39 newly developed meningiomas in 24 NF2 patients were summarized. Clinical risk factors of NF2 meningioma growth rates were analyzed. RESULTS:Pediatric patients had significantly more intracranial meningiomas than adult patients at the skull base (except for the petrosal region) (p < 0.0063). Adult patients had significantly more cranial meningiomas than pediatric patients at the parasagittal, parafalcine (middle & posterior), and frontal/parietal/cerebellar convex surfaces (p < 0.0063). Newly developed NF2 meningiomas in adults tended to occur at different locations than the locations of NF2 meningiomas in pediatric patients. New meningiomas could develop at various ages. Ninety-five NF2 patients were imaged and followed up for at least one year. Twenty-four patients (25.3 %) developed 39 new meningiomas during the follow-up period. They usually had initial meningiomas when new meningiomas occurred. The number of newly developed meningiomas per patient and the petrosal location were significantly associated with both the absolute and relative annual growth rates (p < 0.05). CONCLUSIONS:The number of newly developed NF2 meningiomas seems to be a clinical marker of NF2 disease severity. In adults, new NF2 meningiomas tend to occur in patients with initial meningiomas. The predominant locations of newly developed NF2 meningiomas seem to be the parasagittal, parafalcine (middle/posterior), and frontal/parietal/cerebellar convex surfaces.
目的: NF2 患者可在其一生中发生新的脑膜瘤。对新发展的 NF2 脑膜瘤的临床特征知之甚少。在这项研究中，我们分析了大量患者人群中新开发的 NF2 脑膜瘤。 患者和方法: 在 452 例 NF2 患者中，比较了 81 例儿童和 939 例成人 NF2 脑膜瘤的位置模式，以寻找成年期新发生脑膜瘤的主要位置。总结了 24 例 NF2 患者中 39 例新发生的脑膜瘤的临床特点。分析 NF2 脑膜瘤生长速率的临床危险因素。 结果: 除岩骨区外，儿童颅底脑膜瘤明显多于成人 (p <0.0063)。成人患者在矢状窦旁、旁动脉 (中后侧) 和额叶/顶叶/小脑凸面的颅骨脑膜瘤明显多于儿童患者 (p <0.0063)。成人新发生的 NF2 脑膜瘤往往发生在儿童患者 NF2 脑膜瘤的不同位置。新的脑膜瘤可以在不同年龄发展。对 95 例 NF2 患者进行成像并随访至少 1 年。24 例患者 (25.3%) 在随访期间发生 39 例新发脑膜瘤。当出现新的脑膜瘤时，他们通常有最初的脑膜瘤。每例患者新发生的脑膜瘤数量和岩部位置与绝对和相对年增长率均显著相关 (p <0.05)。 结论: NF2 脑膜瘤的数量似乎是 NF2 疾病严重程度的临床标志。在成人中，新发 NF2 脑膜瘤往往发生在初发脑膜瘤的患者中。新发生的 NF2 脑膜瘤的主要部位似乎是矢状窦旁、旁动脉 (中/后) 和额叶/顶叶/小脑凸面。
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.