Treatment Of Low-grade Gliomas Research Articles

Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

Bevacizumab for symptomatic radiation-induced tumor enlargement in pediatric low grade gliomas.

Radiation therapy (RT)-induced effects in children treated for low grade glioma (LGG) can result in worsening of neurologic symptoms and clinical and radiographic deterioration. Treatment for radiation-induced tumor enlargement is based on symptom control and usually involves steroids. We conducted a retrospective review of children with LGG treated with RT who developed symptomatic radiation-induced tumor enlargement and were managed with bevacizumab. Charts were abstracted for onset and duration of RT changes, toxicity and doses of dexamethasone and bevacizumab. Tumor volumes prior to RT, at maximal size following RT, after bevacizumab administration, and at follow-up were evaluated. Five children were treated with bevacizumab for symptomatic radiation-induced tumor enlargement following RT for LGG at a median of 4.2 months (range, 1-11 months) after completion of RT. The median increase in volume of tumor was 195.4% (range, 115.5-309%) compared to the pre-RT volume. Bevacizumab 5-10 mg/kg was administered IV q 2-4 weeks as primary treatment (n = 1) or to assist in weaning patients off steroids (n = 4). All children on high dose steroids (n = 4) were weaned off or to physiologic doses of hydrocortisone. Two children developed avascular necrosis after prolonged steroid use and while on bevacizumab. Radiographically, all children showed significant improvement and are now a median of 31 months (range, 18-50 months) from the completion of radiation without requiring additional tumor-related therapy. Bevacizumab can play an important role in children with symptomatic radiation changes following LGG treatment, allowing patients to avoid or minimize the toxicity of long-term steroid use. Pediatr Blood Cancer 2015;62:240-245. © 2014 Wiley Periodicals, Inc.

GE-15 * CLONAL EVOLUTION AND INTRATUMORAL HETEROGENEITY OF LOW-GRADE GLIOMA GENOMES

Low-grade gliomas frequently recur after surgical resection and may undergo malignant progression to a higher grade with a significantly worse prognosis. Understanding the origin and evolution of recurrences is critical for effectively treating residual disease to delay or prevent recurrence. Here, we extend previous work by sequencing the exomes of over 30 initial low-grade gliomas and their patient-matched recurrences to reconstruct the patterns of clonal evolution. We also sequence multiple spatially distinct samples from both initial low-grade and recurrent high-grade tumors to extensively dissect intratumoral heterogeneity. We identify a broad spectrum of genetic relatedness within tumor pairs, with the unexpected loss of canonical driver mutations upon recurrence. Therefore, resected portions of initial tumors can differ dramatically from tumorigenic portions of adjacent residual disease. The identification of common ancestral clones additionally reveals the order in which key driver mutations are acquired, allowing for a model of low-grade astrocytoma gliomagenesis. We have also previously shown that the treatment of low-grade gliomas with temozolomide induces hypermutation and alters the function of key cancer genes and their cognate pathways, potentially driving malignant progression. We extend that finding with an analysis of the evolution and intratumoral heterogeneity of additional hypermutated glioblastoma recurrences. These evolutionary trajectories have immediate ramifications for the use of mutagenic chemotherapies such as temozolomide, and for personalizing therapy to eliminate residual disease.

ED-32 * OUTCOMES OF PEDIATRIC BRAINSTEM LOW GRADE GLIOMAS: A SINGLE INSTITUTION SERIES

BACKGROUND: Brainstem tumors constitute 10% of primary CNS tumor of children; 80% are malignant pontine gliomas, but 20% are low grade gliomas (LGG) with a more indolent course. Since advances in imaging & neurosurgical techniques, surgical resection is the initial treatment of choice for some of these tumors. However, optimal therapy for those which are incompletely resected or which relapse after surgery is uncertain. METHODS: We reviewed the clinical characteristics, therapy and outcomes of all children with non-tectal brainstem LGGs treated with surgical resection, chemotherapy (CT-carboplatin/VCR or thioguanine/procarbazine/CCNU/VCR), or radiation therapy (RT), at the University of Michigan Mott Children's Hospital over a 20 year period (1993-2013). RESULTS: Median age at diagnosis was 6 years; Histopathologic diagnosis was confirmed in 23/25 tumors; 61% were pilocytic astrocytoma, most often in cervicomedullary brainstem. Twenty one patients underwent initial tumor resection (11 GTR/NTR, 6 STR, 4 PR); 14 of these received no other therapy; 7 received adjuvant therapy (3-CT, 2-RT, 2 CT + RT) after surgery; 6 initially-resected tumors received CT at the time of local tumor relapse, to which all had partial or complete radiographic responses. Among 4 patients who underwent no initial surgical resection, 3 received RT at diagnosis, and 1 has stable disease, untreated for 2 years. All 25 patients are alive in remission with either stable disease or no evidence of disease, at a median follow-up of 12 years. Ten year relapse-free survival is 61 % and overall survival, 100%. DISCUSSION: This single institution retrospective study demonstrates excellent survival rates for children with brainstem LGG, with initial surgery +/- CT or RT, and effective salvage with CT. The efficacy of the well-tolerated chemotherapy in this series supports its role in the treatment of unresectable brainstem LGG, or in those which progress after initial surgical management.

P20 * VARIATIONS IN MANAGEMENT OF LOW GRADE GLIOMAS ACROSS UK NEUROSURGICAL UNITS

INTRODUCTION: Low grade gliomas (LGG) are slow growing tumours, with the potential of transforming into aggressive high grade gliomas. Treatment of LGG must balance risk of malignant transformation against morbidity of early aggressive treatment. We evaluated the variation in management of low grade gliomas in the UK. METHOD: A survey was sent to all adult UK neurosurgery units, addressing surgical technology, treatment choice and surveillance. 23 units participated (82% participation rate). RESULTS: All LGG patients are discussed in an MDT meeting at initial presentation. 11 units manage patients in neurosurgical oncology clinics, and 6 units had dedicated LGG clinics. Others manage patients in general neurosurgical (3), combined (2) and oncology (1) clinics. The majority of centres use intra-operative ultrasound (20) and functional MRI (19) for motor and language mapping. 11 units use intra-operative EMG. Post-operative surveillance imaging intervals range from 3 to 12 months. Most units have multimodal MRI to detect tumour transformation, but do not always use them. Only 5 units use volumetric changes and 5 use PET imaging. Two clinical scenarios were also given: for a peripheral LGG, all units would consider resection followed by surveillance. Variable responses were given for an insular LGG: 9 would manage only with active surveillance, 6 would consider resection followed by surveillance. The rest choose to biopsy, followed by surveillance (4) or radiotherapy (4). CONCLUSION: This study demonstrates variable management of LGG across the UK, particularly surveillance intervals and of tumours in eloquent areas. More research to stratify transformation risk can help guide optimal treatment.

P24 * A RETROSPECTIVE ANALYSIS OF THE TRANSFORMATION OF LOW-GRADE GLIOMAS INTO HIGH-GRADE FROM A SINGLE INSTITUTION

INTRODUCTION: The management and timing of treatment for Low Grade Gliomas (LGG) has been a controversial topic in neuro-oncology for several years. The main aim of this report is to identify what proportion of and the time frame during which LGG will undergo malignant transformation into High-Grade Gliomas (HGG). METHOD: A retrospective analysis of a total of 86 patients from a single institution was conducted. The individual patient medical records were reviewed for date of initial diagnosis and date of recurrence as well as the initial and subsequent disease management. RESULTS: The median age at diagnosis was 41 years (IQR 29 to 51) and the male to female ratio was 47:39. Initial presenting symptoms included epilepsy (65.1%), headache (38.4%), and neurological deficit (14.0%) whereas six cases were identified incidentally. Around half (48.84%) of the patients experienced progression of the disease and required further management with the median time to progression (TTP) being 4.14 years (95% CI, 2.78 to 5.50), whereas the median follow-up time period for the entire population sample was 3.94 years (95% CI, 3.53 to 4.35 years). Univariate analysis revealed that none of the prognostic factors including age at diagnosis, tumour location and histology, gender and surgical approach reached statistical significance. Finally multivariate analysis by means of the Cox proportional hazard model identified statistically significant differences associated with gender and age at diagnosis. CONCLUSION: This study revealed that almost half of the patients diagnosed with LGG will progress to HGG and that the majority of them will do so in the first five years following the diagnosis.

EVEROLIMUS (RAD001) AND THE MTOR PATHWAY IN LOW-GRADE GLIOMAS

BACKGROUND: Low-grade gliomas (LGG) are slow growing, primary brain tumors that frequently recur after primary surgical treatment. Recent work has suggested the activation of the PI3K/mTOR pathway in >50% of LGG, raising the possibility that treatment with mTOR inhibitors such as everolimus (RAD001) may benefit patients with LGG. METHODS: We have an ongoing single-institution phase II clinical trial testing everolimus 10 mg daily in patients with recurrent low-grade gliomas. Primary outcome is 6-month progression-free survival (PFS-6). Secondary outcomes include safety, overall survival, overall response rate, and assessment of the correlation between molecular markers and outcome. A molecularly selected phase II clinical trial for newly diagnosed grade II gliomas is now under development; patients' tumors will be evaluated for 1p/19q chromosomal status as well as PRAS-40 and ribosomal S6 activation as markers of mTOR pathway activation. RESULTS: Accrual in the study for recurrent patients is ongoing, with 48 patients enrolled thus far of 60 total planned. Treatment has been well tolerated. Preliminary PFS-6 for those patients accrued thus far is 72%. Preliminary correlation of results with molecular markers raises the possibility that patients treated with everolimus whose tumors have PRAS-40 activation may have improved PFS vs. treated patients with non-activated tumors (p = 0.03). In contrast, patients with PRAS-40 activated tumors in a historical control trended toward worse PFS than patients with non-activated tumors (p = 0.07). Further molecular characterization, including IDH1/IDH2 status and 1p/19q chromosomal status, is also planned. We will provide updated results at the conference, and will also discuss the design of the study under development for newly diagnosed patients. CONCLUSIONS: Inhibition of the PI3K/mTOR pathway by everolimus is a promising avenue of treatment for low-grade gliomas. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

Surgical Management of Low-Grade Gliomas

Low-grade gliomas represent a wide spectrum of intra-axial brain tumors with diverse presentations, radiographic and surgical appearances, and prognoses. While there remains a role for biopsy, a growing body of evidence shows that aggressive surgical resection of low-grade gliomas may improve symptoms, extend progression-free survival (PFS), and even cure a select few patients. With the application of preoperative functional imaging, intraoperative navigation, and cortical stimulation, neurosurgeons are able to perform more complete resections while limiting the risk to patients. In this article, we describe the surgical management and current operative techniques used in the treatment of low-grade gliomas.

Radiotherapy in low-grade glioma adult patients: a retrospective survival and neurocognitive toxicity analysis

The treatment of low-grade glioma is still debated. Surgery is the first-line approach, and the correct timing of radiation therapy has not yet been defined since "early" radiation therapy improves relapse-free survival but not overall survival. Since a longer progression-free survival is desirable, the main issue related to radiotherapy is the incidence of late neurocognitive toxicity. Ninety-five patients with low-grade glioma were consecutively treated with early (within 3months) or late (at disease progression) post-surgical radiation therapy. Clinical and therapeutic factors were entered into the analysis overall (OS) and progression-free (PFS) survival, and the distribution in two accrual periods identified based on the evolution of imaging procedures and radiotherapy techniques were compared. For 6/18 long survivors (LS) without evidence of disease, neurocognitive evaluation was obtained and the dose to the hippocampus region was retrospectively calculated. Univariate analysis of OS showed a statistically significant advantage for grade 1 and oligodendroglioma histology, better performance status [Karnofsky index (KI)], age <40 years, radical surgery, no steroid treatment; PFS was significantly related with younger age, better KI and "early" radiotherapy. Multivariate analysis of OS confirmed the significance of all variables except surgery; for PFS, only "early" radiotherapy and better KI retained significance. Memory impairment was evident in 4/6 of the LS tested; quality of life was good and executive functions were normal. Radiotherapy remains an essential component in the treatment of low-grade glioma. Prospective studies are needed to evaluate the relative contributions of the disease itself and of surgery, radiation and chemotherapy to long-term neurocognitive damage.

Children &lt;1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: A report from the german multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG)

Children diagnosed with LGG at an age <1 year are reported to have an impaired prognosis in comparison to older patients. Analysis of this subgroup could reveal the necessity to develop risk-adapted treatment approaches. Children <1 year at diagnosis (n = 66, median age 7.3 months, 33 female, none NFI) from the HIT-LGG 1996 cohort were analyzed for risk factors for EFS, PFS and OS. Several children suffered from diencephalic syndrome (DS, n = 22) and primary dissemination (DLGG, n = 9), 50 had a supratentorial midline (SML) location. Extent of resection was complete/subtotal in 12, partial in 15, biopsy in 27. Tumors were pilocytic astrocytoma WHO grade I (n = 33), other WHO grade I (n = 14), pilomyxoid astrocytomas WHO grade II (n = 3), and neuroepithelial tumors WHO grade II (n = 4). One-year EFS was 34.8%. SML-localisation, minor extent of surgery, pilocytic astrocytoma, DLGG and DS were unfavorable predictive factors. No additional non-surgical therapy was applied in 24, 36 were treated with VCR/carboplatin chemotherapy, 6 with radiotherapy (5/6 brachytherapy). Ten-year-PFS-rate following non-surgical therapy was 16.7%; DS and DLGG were unfavorable factors. Ten-year-OS-rate was 72.8%, lower for children <6 months at diagnosis, with DS, or with DLGG. At last follow up in August 2011, vision in 31 living children was often severely impaired. Children <1 year at diagnosis have a conspicuously impaired survival with current treatment approaches. Age <6 months, diencephalic syndrome and dissemination constitute risk factors for even lower PFS and OS. Treatment adaptations are needed to improve outcome and molecular genetics may explain tumor aggressiveness.

The microtubule binding drug EM011 inhibits the growth of paediatric low grade gliomas

Low grade gliomas are a heterogeneous group of tumours representing the most common form of neoplasms in the central nervous system among children. Although gross total resection remains the principal treatment, it is often impractical especially for the resection of tumours within eloquent regions of the brain. Instead Radiotherapy is utilised in such cases, but because of its associated toxicities, it is refrained from use among younger children. These limitations coupled with hypersensitivity and toxicities associated with some commonly used chemotherapeutic agents, have ignited the need to search for safer and more effective treatments for paediatric low grade gliomas. In this study, we investigated the EM011 drug on the growth of two pilocytic and one diffuse paediatric astrocytoma cell lines, using an assortment of cancer assays. We discovered that treatments of low grade gliomas with EM011 abrogated cell viability by inducing a decrease in cell proliferation and an arrest in the S and G2M cell cycle phases, followed by a converse increase in apoptosis in a dose and time dependent manner. The cell migratory and invasion indices, as well as anchorage independent growth in soft agarose, were significantly attenuated. These findings were mechanistically associated with a transient release of AIF, a disruption of microtubule architecture, and a decline in the expression of key genes which drive cancer progression including EGFR, mTORC1, JUN and multiple MMPs. In fact, the activity of MMP2 was also perturbed by EM011. These findings, in conjunction with the insignificant adverse side effects established from other studies, make EM011 an appealing chemotherapeutic agent for the treatment of paediatric low grade gliomas.

Viability screen on pediatric low grade glioma cell lines unveils a novel anti-cancer drug of the steroid biosynthesis inhibitor family

Pediatric low grade gliomas are the most common central nervous system tumors and are still incurable among a subset of patients despite current treatment modalities. Steroid biosynthesis occurs in a wide variety of organs including the brain, to mediate an assortment of functions, including a proposed role in the growth of gliomas. Hence, targeting steroid biosynthesis and/or their signaling pathways, is anticipated as an effective approach for treating gliomas. In this study, we investigated whether our chemical library of steroid inhibitors can modulate the growth of pediatric low grade glioma cell lines (Res186, Res259, R286), and subsequently identified a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 3, referred to as DK16, which functions by attenuating cell viability, proliferation, migration/invasion and anchorage independent growth and conversely induces apoptosis and cell cycle arrest in a dose and duration dependent manner. Further investigations into the mechanisms of how DK16 functions showed that this drug increased the BAX/BCL2 expression ratio, induced phosphatidylserine externalization, and mitochondrial membrane depolarizations culminating to the release and nuclear translocation of AIF. In addition, treatments of low grade glioma cell lines with DK16 increased the expression of pro-apoptotic mediators including CDK2 and CTSL1, and with the converse diminished expression of pro-survival and migratory/invasion genes like PRKCA, TERT, MAPK8, MMP1 and MMP2. Our findings collectively demonstrate the potent anti-neoplastic properties of DK16, a steroid biosynthesis inhibitor, on the growth of pediatric low grade gliomas.

Current treatment of low grade gliomas

Low grade gliomas affect predominantly young adults, and have a relatively favorable prognosis compared to grade III and grade IV gliomas. The challenge for an optimal management of these patients is to find the balance between an optimal survival and the preservation of neurological function including cognition. Because all medical treatments may induce side effects, in young and nearly asymptomatic patients the choices can be difficult. This review summarizes the current strategies: a watch-and-wait policy, surgery, chemotherapy, and radiotherapy.

Response to Weltman and Fleury Malheiros, re Lassman et al.

In Reply to Weltman and Fleury Malheiros: We thank Drs. Weltman and Fleury Malheiros for their comments on our recent article.1 We agree that our analyses were performed on a retrospective dataset, and interpretations are thus subject to limitations and potential biases inherent to any retrospective study. For example, as we discussed in the article, neither central review of pathology nor imaging was performed. Multivariate analyses attempted to control for potential confounding variables, but only a randomized prospective study would definitively address this concern. However, we believe that our conclusions (and cross-comparisons) are supported not only by our own observations but also by recent data and treatment trends in neuro-oncology. For example, in our study, treatment group imbalances did not contribute to differences in outcome in the Cox model. Groups were reasonably well balanced for potential confounders, such as performance status. In addition, Weltman and Fleury Malheiros suggest that standard of care for anaplastic oligoendrogliomas includes radiotherapy as part of the initial treatment regimen. We agree that radiotherapy has well-established efficacy and, for many years, was the standard approach. However, treatment options have evolved since the initial studies during the 1960s–1980s cited by Drs. Weltman and Malheiros. It is now well established that oligodendrogliomas, especially those harboring 1p19q co-deletion, respond to chemotherapy. For example, the recently publicized long-term follow-up of RTOG 9402 demonstrated that chemo-radiotherapy doubled median survival relative to radiotherapy alone in 1p19q co-deleted cases (14.7 vs. 7.3 years).2 Moreover, the German NOA-04 trial of newly diagnosed anaplastic gliomas also suggested that primary chemotherapy is equi-efficacious as primary radiotherapy.3 Furthermore, survival with 1p19q codeleted anaplastic oligodendrogliomas is at least several years. Accordingly, radiotherapy-induced dementia as a late toxicity4 is a real concern. Consequently, many neuro-oncologists advocate for chemotherapy alone and defer radiotherapy until disease progression in 1p19q codeleted cases. The same concern is well established in the controversies surrounding late neuro-cognitive toxicity from early radiotherapy in the treatment of low-grade gliomas, primary central nervous system lymphoma, and resected brain metastases. Therefore, the acknowledged limitations of our retrospective design notwithstanding, our results are concordant with these studies suggesting that overall survival was not compromised by deferring radiotherapy.1 Absent a clear survival advantage, deferred radiotherapy in favor of chemotherapy alone is certainly a reasonable initial strategy. We are not alone. For example, 42% of neuro-oncologists surveyed in 2005 recommended deferring radiotherapy in codeleted cases.5 Similarly, 57% of patients in our retrospective dataset who receive a diagnosis of codeleted tumors since 2005 were treated with chemotherapy alone (almost exclusively temozolomide).6 Therefore, as stated in our publication, “subject to the limitations of study design, our data suggest that initial treatment with chemotherapy alone may be a reasonable option for patients with 1p19q codeleted tumors.”1 Regardless of advised therapy, in our clinical experience, many patients refuse radiotherapy because of perceived concerns about neuro-toxicity. Therefore, although ongoing or future prospective studies may show that deferred radiotherapy adversely affects survival, concerns about cognitive injury are important in determining optimal therapy, and survival may not be the only end point of clinical importance. The CATNON or CODEL phase III trials (for non- or codeleted anaplastic gliomas, respectively) may help to assess quality of life outcomes. Clearly, neuro-oncology is a multidisciplinary field, and treatment requires individualization that depends on discussion among both physicians and patients of risks and benefits of various strategies.

Using different schedules of Temozolomide to treat low grade gliomas: systematic review of their efficacy and toxicity

Low grade gliomas (LGG) contribute to 50% of all central nervous tumors in children and 15% of all gliomas in adults. Temozolomide (TMZ) is an oral alkylating agent with activity in high and LGG. Various regimens of TMZ are currently in use. We attempted to assess the impact of different TMZ regimens on the treatment of LGG. A systematic review of the literature identified all the studies published in Pubmed, EMBASE and Cochrane databases which met the inclusion criteria. The primary outcome measure was the impact of different TMZ regimens on the 12 month progression-free survival (PFS) rates of patients diagnosed with progressive LGG. Secondary outcome measures looked at the ability of the three regimens to elicit an objective response and the associated toxicity. Statistical pooling and calculation of weighted mean average of each proportion (WMAP) was conducted using a random-effects model. 18 studies (736 patients) were analyzed. PFS at 12 months revealed a WMAP of 0.61 (95% CI 0.44-0.78) for regimen A, 0.59 (0.28-0.89) for regimen B, and 0.91 (95% CI 0.83-0.99) for regimen C (Regimen A--200 mg/m(2)/day for 5 days, repeated every 4 weeks; B--75 mg/m(2)/day for 21 days repeated every 4 weeks; C--75 mg/m(2)/day for 7 weeks with 4 weeks of every 11 weeks). In terms of objective response, WMAP were 0.19 (95% 0.13-0.25), 0.27 (95% CI 0.15-0.39) and 0.21 (95% CI 0.10-0.32) for regimen A, B, C respectively. When analyzing hematological toxicity, WMAPs were 0.14 (95% 0.11-0.18), 0.35 (0.14-0.56) and 0.23 (95% CI 0.03-0.43). The bulk of evidence originates from the standard 5 day/month regimen A but with a lack of comparative studies. Analysis revealed significant heterogeneity. Although there is possibly an indication that metronomic regimens of TMZ result in better PFS and response rate when compared to the conventional standard 5 day regimen, insufficient available data and study heterogeneity preclude any safe conclusions. Well designed randomized controlled clinical trials are needed to establish the efficacy of metronomic regimens of TMZ in LGGs.

Management of Patients With Low-Grade Gliomas – A Survey Among German Neurosurgical Departments

The diagnosis and treatment of low-grade gliomas (LGG) are multimodal. Today, there is no defined standard in diagnosis and treatment. Controversies are, in general, about a "wait-and-see" strategy, diagnostic workup, surgical intervention, postoperative imaging, adjuvant treatment, and follow-up. The aim of this study is to gain an overview about management strategies of high-volume German neurosurgical departments treating these patients. A questionnaire including diagnostic, preoperative, perioperative, and postoperative parameters and 5 cases with magnetic resonance imaging data with questions to various treatment options in these patients was sent to all 34 German neurosurgical departments at university hospitals. In total, 24 questionnaires were returned and analysed. Centres were divided into those who generally practice a "wait-and-see" strategy vs. those who do not or only in highly selected cases. Statistical analyses were performed with Fisher test and Chi (2)-test. Interestingly, 50% of all centres routinely follow a "wait-and-see" strategy. Although the management of patients with LGG is complex and a simple questionnaire will not be able to define a standard in diagnosis and treatment, this study offers an overview on strategies at high-volume academic centres dealing with these patients. There is consensus to resect superficially located lobar and circumscribed low-grade lesions. However, the differences between centres become apparent with increasing complexity of the lesions.

Clinical features and management of carboplatin-related hypersensitivity reactions in pediatric low-grade glioma

The effectiveness of carboplatin and vincristine chemotherapy in the treatment of low-grade glioma (LGG) is well established. However, carboplatin hypersensitivity reactions (CHR) are a major problem leading to premature cessation of therapy. We aimed to investigate the clinical features and the management strategies in CHR, retrospectively. Fifty LGG patients treated between October 1997 and January 2008 with carboplatin and vincristine were included in the study. Clinical features, management strategies, influence of demographic factors on CHR, and success rate in terms of continuation with carboplatin therapy were evaluated. CHR were observed in 20 (40%) patients and grade I reactions were the most common. The median number of carboplatin doses administered at the first episode of CHR was nine (range 1-41). Only younger age was found to be correlated with the presence of CHR. Nine patients had carboplatin desensitization protocol; eight patients were given various combinations of premedication while three had no modification. Treatment was terminated in five patients due to CHR. Overall success rate was 75%. This is the largest single-center study conducted to investigate the frequency and the management strategies in patients with CHR who were treated with the same chemotherapy protocol for LGG. Premedication and desensitization were the preferred modifications in case of CHR. Overall, the success rate for carboplatin continuation is high in comparison to previous studies. Carboplatin can be continued successfully in many cases with CHR if reactions are managed in a timely fashion.

Feasibility and efficacy of repeated chemotherapy for progressive pediatric low‐grade gliomas

Chemotherapy is widely accepted as first-line therapy for pediatric low-grade gliomas (LGG). Treatment modalities for further progression are not clearly established. The aim of the study was to determine the feasibility and long-term outcome of repeated chemotherapy for children with recurrent LGG. The study group consisted of patients who received a second line of chemotherapy at progression of their LGG. We compared toxicity, progression-free survival (PFS), and overall survival (OS) of patients treated with chemotherapy at the time of initial diagnosis and patients who received another treatment with chemotherapy at further progression. Between 1985 and 2009, 118 patients received chemotherapy as primary treatment for LGG, 38 had repeated chemotherapy at further progression. Chemotherapy was tolerated extremely well. Ninety-two percent of patients completed their second line protocol and toxicity was comparable between initial and second line chemotherapy. Five-year OS and PFS were 86 ± 6% and 37 ± 8%, respectively, which were similar to first-line chemotherapy (P = 0.14). Repeated chemotherapy courses were not associated with worsening of visual, neuroendocrine, or other long-term organ sequelae. This study demonstrates high feasibility and low mortality of repeated chemotherapy treatment for progressive LGG. The chronic nature of LGG concerning tumor progression justifies consideration of non-toxic second-line treatment regimens at the time of recurrence. Prospective studies focusing on toxicity and long-term outcome are needed to substantiate this approach.

New Insights into Pre-, Intra- and Post-Operative Brain Mapping in Low- Grade Glioma Surgery: Towards a Longitudinal Study of Cerebral Plasticity

Surgery is currently the first treatment for low-grade gliomas (LGG). However, LGG often involves eloquent areas, in patients with no or mild preoperative deficit. Therefore, cortical and subcortical structures, essential, for brain functions must be preserved. Presurgical functional neuroimaging and tractography can show the relationships between eloquent regions and the tumor, but they have several limitations. Consequently, intraoperative electrical mapping is more and more used by neurosurgeons, to tailor the resection according to individual functional boundaries. Nonetheless, due to the invasive feature of LGG, the glioma removal is regularly incomplete to avoid postsurgical permanent deficit. The goal of this review is to provide new insights into cerebral plasticity, that is, the brains ability to reorganize its functional maps consecutively to slow-growing lesions like LGG. Longitudinal studies combining pre-, intra- and post-operative brain mapping methods may enable to analyze functional redistribution over time at the individual scale. Such plastic potential can open the door to multiple surgeries spaced by several months or years, with the aim to optimize the benefit/risk ratio of surgery, i.e. to increase the extent of resection of LGG before anaplastic transformation – thus to increase the overall survival – while preserving and even improving the quality of life. Keywords: Low-grade glioma, awake surgery, functional brain mapping, brain plasticity, functional neuroimaging, LGG, extent of resection, positron emission tomography, magnetoencephalography, hodology, ventral premotor cortex, precentral gyrus

Low-grade oligodendroglioma: current treatments and future hopes

Current treatment modalities for low-grade gliomas include surgery, radiotherapy and chemotherapy. Management of these ultimately incurable tumors remains controversial, particularly the timing and extent of surgery, and the optimal sequence of radiotherapy and chemotherapy thereafter. Two ongoing Phase III trials should provide definitive answers to some of these controversial issues in the treatment of low-grade gliomas and confirm the impact of molecular predictors of response and outcome. This review will discuss recent progress and topical issues in the treatment of low-grade gliomas.