Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy

Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Children's Hospital of Philadelphia from 2007 to 2015. With a median follow‐up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in‐field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high‐dose RT, indicating the need for improvements in local therapy.     

Micellar formulations of Crizotinib and Dasatinib in the management of glioblastoma multiforme

Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation.     

新型肿瘤电场治疗仪治疗复发脑胶质母细胞瘤的前瞻性、单中心、单臂探索性临床试验方案

多形性胶质母细胞瘤（GBM）是原发性脑肿瘤中恶性程度最高的一种肿瘤,不但进展迅速且预后极差。肿瘤电场治疗（TTF）已被批准用于治疗GBM且具有良好的疗效。但是,尚无有关中国GBM患者采用TTF治疗的临床资料。该文报告一项复发性GMB的前瞻性、单中心、单臂探索性临床试验方案。该试验采用笔者开发的新型肿瘤电场治疗系统ASCLU-300,对参加者进行治疗。主要是评价该治疗系统的安全性和可行性。通过评估与治疗相关不良反应的患者人数,及根据进展时间（TTP）和总生存期（OS）来评价治疗反应;根据神经肿瘤治疗反应评价(RANO)标准进行评估,通过对比MRI检查确定TTP,并通过随访收集OS数据;与治疗相关的不良反应评估将基于描述性方法;通过Kaplan-Meier方法评估TTP和OS。这项初步研究将为进一步的大规模试验打下坚实基础,同时笔者希望新型肿瘤电场治疗系统能够有效治疗GBM,为中国GBM患者提供新的治疗方案。（临床试验注册：NCT0441793;于2020年6月8日注册。）     

Fatal glioblastoma after Gamma Knife radiosurgery for arteriovenous malformation in a child

We describe a fatal case of glioblastoma multiforme that was induced by Gamma Knife radiosurgery (GKS; Elekta AB, Stockholm, Sweden) for an arteriovenous malformation (AVM). A 4-year-old girl presented with repeated convulsions. Imaging studies revealed an AVM located in the right thalamus. One year after initial symptoms, GKS was performed to obliterate the nidus. The maximum and marginal radiation doses were 32 and 16 Gy, respectively. Seventy months after GKS, the patient represented with severe headache. MRI showed a poorly demarcated tumor with heterogeneous gadolinium enhancement in the right thalamus and adjacent to the white matter of the temporal lobe. After a generalised convulsion, the patient deteriorated into a deep coma. CT scans showed severe brain swelling with intratumoral hemorrhage. An emergency craniotomy was performed, and the hematoma was removed. During this surgery, a tumor mass, which was found adjacent to the hematoma, was resected. Microscopic examination revealed glioblastoma multiforme. Despite intensive treatment, the patient died 1 month after surgery. A GKS-induced secondary tumor is a rare but serious complication. It is important to be aware of the adverse effects of GKS, including secondary neoplasms, before its clinical application, especially in young patients.     

Hypofractionated intensity modulated radiotherapy with temozolomide in newly diagnosed glioblastoma multiforme

We conducted a phase I study to determine (a) the maximum tolerated dose of peri-radiation therapy temozolomide (TMZ) and (b) the safety of a selected hypofractionated intensity modulated radiation therapy (HIMRT) regimen in glioblastoma multiforme (GBM) patients. Patients with histological diagnosis of GBM, Karnofsky performance status (KPS) ⩾ 60 and adequate bone marrow function were eligible for the study. All patients received peri-radiation TMZ; 1 week before the beginning of radiation therapy (RT), 1 week after RT and for 3 weeks during RT. Standard 75 mg/m²/day dose was administered to all patients 1 week post-RT. Dose escalation was commenced at level I: 50 mg/m²/day, level II: 65 mg/m²/day and level III: 75 mg/m²/day for 4 weeks. HIMRT was delivered at 52.5 Gy in 15 fractions to the contrast enhancing lesion (or surgical cavity) plus the surrounding edema plus a 2 cm margin. Six men and three women with a median age of 67 years (range, 44–81) and a median KPS of 80 (range, 80–90) were enrolled. Three patients were accrued at each TMZ dose level. Median follow-up was 10 months (range, 1–15). Median progression free survival was 3.9 months (95% confidence interval [CI]: 0.9–7.4; range, 0.9–9.9 months) and the overall survival 12.7 months (95% CI: 2.5–17.6; range, 2.5–20.7 months). Time spent in a KPS ⩾70 was 8.1 months (95% CI: 2.4–15.6; range, 2.4–16 months). No instance of irreversible grade 3 or higher acute toxicity was noted. HIMRT at 52.5 Gy in 15 fractions with peri-RT TMZ at a maximum tolerated dose of 75 mg/m²/day for 5 weeks is well tolerated and is able to abate treatment time for these patients.     

Detoxification of oxidative stress in glioma stem cells: Mechanism,clinical relevance,and therapeutic development

Neural oncogenesis is currently incurable and invariably lethal. The development of innovative treatments for this devastating cancer will require a deeper molecular understanding of how cancer cells survive, proliferate, and escape from current therapies. In high‐grade gliomas (HGGs), glioma stem cells (GSCs) may causally contribute to tumor initiation and propagation, therapeutic resistance, and subsequent recurrence of tumors. Within a tumor mass, GSCs are enriched in a hypoxic niche in which the oxidative stress levels are substantially elevated. Paradoxically, however, recent studies suggest that GSCs appear to generate less reactive oxygen species (ROS), a chemical component responsible for elevation of oxidative stress levels. To date, molecular mechanisms for how GSCs reduce oxidative stress to allow preferential survival in hypoxic areas in tumors remains elusive. This review article summarizes recent studies on the role of ROS‐reducing enzymes, including peroxiredoxin 4, in detoxifying oxidative stress preferentially for GSCs in HGGs. In addition, the therapeutic potential of some of the recently identified antioxidant chemotherapeutic agents and avenues for future research in this area are discussed. © 2014 Wiley Periodicals, Inc.     

Thymoquinone (2-Isopropyl-5-methyl-1, 4-benzoquinone) as a chemopreventive/anticancer agent: Chemistry and biological effects

Cancer remains the topmost disorder of the mankind and number of cases is unceasingly growing at unprecedented rates. Although the synthetic anti-cancer compounds still hold the largest market in the modern treatment of cancer, natural agents have always been tried and tested for potential anti-cancer properties. Thymoquinone (TQ), a monoterpene and main ingredient in the essential oil of Nigella sativa L. has got very eminent rankings in the traditional systems of medicine for its anti-cancer pharmacological properties. In this review we summarized the diverse aspects of TQ including its chemistry, biosynthesis, sources and pharmacological properties with a major concern being attributed to its anti-cancer efficacies. The role of TQ in different aspects involved in the pathogenesis of cancer like inflammation, angiogenesis, apoptosis, cell cycle regulation, proliferation, invasion and migration have been described. The mechanism of action of TQ in different cancer types has been briefly accounted. Other safety and toxicological aspects and some combination therapies involving TQ have also been touched. A detailed literature search was carried out using various online search engines like google scholar and pubmed regarding the available research and review accounts on thymoquinone upto may 2019. All the articles reporting significant addition to the activities of thymoquinone were selected. Additional information was acquired from ethno botanical literature focusing on thymoquinone. The compound has been the centre of attention for a long time period and researched regularly in quite considerable numbers for its various physicochemical, medicinal, biological and pharmacological perspectives. Thymoquinone is studied for various chemical and pharmacological activities and demonstrated promising anti-cancer potential. The reviewed reports confirmed the strong anti-cancer efficacy of thymoquinone. Further in-vitro and in-vivo research is strongly warranted regarding the complete exploration of thymoquinone in ethnopharmacological context.     

Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms

Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti‐inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP‐2 and/or MMP‐9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP‐2 and MMP‐9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP‐2 and MMP‐9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.