Incidence of second malignancies in individuals diagnosed with malignant peripheral nerve sheath tumors.
- 作者列表："Williams LA","Moertel CL","Richardson M","Marcotte EL
BACKGROUND:The incidence of malignant peripheral nerve sheath tumors (MPNSTs) is low in the general population, although individuals with Neurofibromatosis Type I (NF1) are particularly susceptible. These tumors generally have a high probability of metastasis. The rate and types of second malignancies (SMNs) after a primary diagnosis of MPNST are not well characterized. We aimed to quantify the rate of SMNs among individuals with a first primary MPNST using population-based data. METHODS:We estimated age-standardized incidence rates (SIRs) for SMNs among 1,579 primary MPNST cases between ages 0-85+ using SEER 18 (2000-2015). We estimated incidence rate ratios (IRRs) and 95% confidence intervals (95% CI) for SMNs in MPNST cases compared with general population rates. We conducted sex-stratified and age-restricted analyses (< 30 years at diagnosis). RESULTS:Seven percent (108/1579) of MPNST cases developed a SMN (SIR of 4635 cases/million). Compared to the general population, MPNST cases were more likely to develop SMNs (IRR: 29.3; 95% CI 23.8-34.8) and had a much higher rate of second MPNSTs (IRR: 15,992.9; 95% CI 9594.5-22,391.3). Aside from a second MPNST, second cancers were frequently diagnosed in the breast, lung, skin, and soft tissue in females and were myeloid and skin malignancies in males. When restricted to < 30 years of age, second MPNSTs were the most common cancers diagnosed. CONCLUSIONS:The rate of SMNs among MPNST cases is tremendously higher than that observed among individuals with other cancers, particularly for second MPNSTs. These findings suggest rates of SMNs may also be higher in NF1 individuals.
背景: 恶性外周神经鞘瘤 (MPNSTs) 在普通人群中的发病率较低，尽管 I 型神经纤维瘤病 (NF1) 个体尤其易感。这些肿瘤通常有很高的转移概率。初步诊断 MPNST 后第二恶性肿瘤 (SMNs) 的发生率和类型没有得到很好的表征。我们的目的是使用基于人群的数据量化首次原发性 MPNST 个体中 SMNs 的发生率。 方法: 我们使用 SEER 18 (1,579-2000) 估计了 2015 例 0 ~ 85 岁之间的原发性 MPNST 病例中 smn 的年龄标准化发病率 (SIRs)。我们估计了 MPNST 病例中 SMNs 的发病率比 (IRRs) 和 95% 置信区间 (95% CI)，并与普通人群率进行了比较。我们进行了性别分层和年龄限制分析 (诊断时 <30 年)。 结果: 7% (108/1579) 的 MPNST 病例发生 SMN (SIR 为 4635 例/百万)。与普通人群相比，MPNST 病例更容易发生 SMNs (IRR: 29.3; 95% CI 23.8-34.8)，第二次 MPNST 发生率更高 (IRR: 15,992.9; 95% CI 9594.5-22,391.3)。除第二个 MPNST 外，第二个癌症在女性中经常被诊断为乳腺、肺、皮肤和软组织，在男性中是髓系和皮肤恶性肿瘤。当限制到 <30 岁时，第二 MPNSTs 是最常见的癌症诊断。 结论: MPNST 病例中 SMNs 的发生率远远高于其他癌症患者，尤其是第二 MPNST。这些研究结果表明，NF1 个体中 SMNs 的发生率也可能较高。
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.