Showing papers in "Neuro-oncology in 2015"

The epidemiology of glioma in adults: a “state of the science” review

Abstract: This is a wide-ranging and comprehensive study.1 However, the section “Nonionizing Radiation: Cellular Phones” has serious deficiencies. It cites 3 incidence time trend studies,2–4 2 cohort studies,5,6 and 1 case control study.7

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Abstract: BACKGROUND Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. METHODS We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. RESULTS Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. CONCLUSION TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials

Abstract: A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems.

Alex's Lemonade stand foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007-2011

Abstract: The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study

Abstract: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, results in a constitutively activated receptor with a novel, highly immunogenic extracelluar epitope. EGFRvIII is present in 25%–30% of glioblastomas1 but is not significantly expressed in healthy tissue. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models.2 In glioblastoma, EGFRvIII has been associated with poor long-term survival, independent of other known significant prognostic factors, such as gross total resection (GTR).3–6 EGFRvIII expression is often heterogeneous in glioblastoma specimens, but EGFRvIII+ cells may influence neighboring EGFRvIII–tumor cells through cytokines and microvesicles, providing a proliferative signal even to nonexpressing cells.7–9 EGFRvIII is also frequently expressed in glioblastoma tumor stem cells.10,11 EGFRvIII and isocitrate dehydrogenase (IDH) 1/2 mutations, the latter associated with long-term survival, rarely coexist in the same patient.12,13 Rindopepimut vaccine consists of the unique 13 amino acid sequence created by the in-frame deletion of EGFRvIII, chemically conjugated to keyhole limpet hemocyanin (KLH) as described by Heimberger and colleagues.14 Rindopepimut is designed to generate a specific immune response against EGFRvIII+ tumor cells, an approach which may be particularly relevant for glioblastoma, where diffuse infiltration of tumor into healthy white matter presents a treatment challenge. Preclinical models have demonstrated that induction of humoral and cellular anti-EGFRvIII immune responses can be effective against EGFRvIII+ intracranial tumors.14 In 2 small single-arm phase II trials conducted at MD Anderson and Duke University (“ACTIVATE” and “ACT II”),6,15 rindopepimut was well tolerated in patients with resected, EGFRvIII+ glioblastoma with promising progression-free survival (PFS) and overall survival (OS) compared with a contemporary cohort of patients matched for major study eligibility. In addition, the vaccine elicited robust anti-EGFRvIII immune responses despite concurrent temozolomide chemotherapy, and EGFRvIII was routinely eliminated in posttreatment tumor samples obtained at recurrence. The current study (“ACT III”) was performed to confirm these results in a larger, multicenter trial.

Immunosuppressive mechanisms in glioblastoma

Abstract: Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches.

The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis

Abstract: Primary brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures. These tumors are an important cause of morbidity and mortality in both adults and children, often generating severe disabilities and producing high burden in both families and health care systems.1,2 The epidemiology of these tumors is poorly understood, as there is a paucity of data published on their incidence and prevalence across the globe. A solid understanding of the incidence and prevalence of primary brain tumors can help with better planning in the allocation of health resources and a better understanding of geographical differences. Only one systematic review on the worldwide incidence of brain tumors has been published within the last 20 years.3 The paper, published in 1998, reviewed the methodology and results of studies including not only primary, but also secondary intracranial tumors. The world age-standardized incidence rate for all primary brain tumors reported in this review ranged from 4.3 to 18.6 per 100 000 per year. Unfortunately, this review had methodological limitations. The authors searched only English-language papers published from 1966 to 1995 (including data collected from 1935 to 1991) and included studies that were not population based in the review, which could result in biased estimates. Only one bibliographical database (Medline) was used for the search, and a formal meta-analysis of incidence rates was not performed. There was also marked heterogeneity in the methodology and results of the different studies included in the review. There is a lack of a comprehensive and up-to-date systematic review of the global incidence and prevalence of brain tumors in the literature. The goal of our study was to systematically review the latest literature on incidence and prevalence of primary brain tumors.

Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma

Abstract: Meningioma is the most common primary brain tumor, comprising 35% of all CNS tumors in the United States.1 Approximately 80% of meningiomas are World Health Organization (WHO) grade I and may be observed expectantly or treated successfully with surgery or radiotherapy. However, the remaining 20% are either WHO grade II (atypical) or grade III (anaplastic or “malignant”) and have high recurrence rates, exceeding 50% for atypical tumors and 80% for anaplastic tumors. Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment, but there is no proven effective chemotherapy for patients with aggressive meningiomas. Studies investigating traditional chemotherapies (temozolomide, hydroxyurea, irinotecan, and triple therapy with cyclophosphamide + doxorubicin + vincristine), hormonal therapies (progesterone and estrogen modulators, somatostatin analogues), interferon alfa-2b, and molecularly targeted therapies, including inhibitors of platelet-derived growth factor receptors (PDGFRs; imatinib) and epidermal growth factor receptor (gefitinib and erlotinib), have all been disappointing.2–19 Although the natural history of these tumors is not well established, the 6-month progression-free survival (PFS6) rate for these patients is poor. A phase II study of imatinib in recurrent meningioma demonstrated a PFS6 of 0% in the atypical/anaplastic cohort.19 PDGF is a ubiquitous growth factor driving cell proliferation in normal development as well as numerous neoplasms, including meningiomas.20–25 Administration of PDGF-BB to meningioma cells in culture results in stimulation of tumor growth, while administration of anti–PDGF-BB antibodies inhibits proliferation.26,27 Vascular endothelial growth factor (VEGF) is upregulated in almost all meningiomas and has been associated with neovascularization, tumor growth, and the development of edema.28,29 Targeting VEGF with different agents has proved effective in several different cancers, including malignant gliomas.30,31 Targeting this pathway may have therapeutic potential in meningioma. Sunitinib malate (SU011248, Sutent, Pfizer) is an orally administered tyrosine kinase inhibitor targeting VEGF receptor (VEGFR), PDGFR, and KIT.32 Inhibiting these targets represents an attractive therapeutic approach for recurrent meningiomas. The FDA-approved and recommended dose for sunitinib in renal cell carcinoma and gastrointestinal stromal tumor is 50 mg daily for 4 of every 6 weeks. We selected this dose because meningiomas are extraparenchymal tumors. Given (i) the strong preclinical rationale for targeting PDGFR and VEGFR in meningiomas, (ii) the efficacy of sunitinib cotargeting VEGFR2 and PDGFR, and (iii) its safety in adults with other solid tumors, we investigated sunitinib in this phase II study for recurrent and progressive meningiomas that had failed prior surgery and radiation.

Intratumoral heterogeneity in glioblastoma: don't forget the peritumoral brain zone

Abstract: Glioblastoma (GB) is the most frequent and aggressive primary tumor of the central nervous system. Prognosis remains poor despite ongoing progress. In cases where the gadolinium-enhanced portion of the GB is completely resected, 90% of recurrences occur at the margin of surgical resection in the macroscopically normal peritumoral brain zone (PBZ). Intratumoral heterogeneity in GB is currently a hot topic in neuro-oncology, and the GB PBZ may be involved in this phenomenon. Indeed, this region, which possesses specific properties, has been less studied than the core of the GB tumor. The high rate of local recurrence in the PBZ and the limited success of targeted therapies against GB demonstrate the need for a better understanding of the PBZ. We present here a review of the literature on the GB PBZ, focusing on its radiological, cellular, and molecular characteristics. We discuss how intraoperative analysis of the PBZ is important for the optimization of surgical resection and the development of targeted therapies against GB.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study

Abstract: Results. Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P ¼ .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P ¼ .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated.

Toward precision medicine in glioblastoma: the promise and the challenges

Abstract: Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system.

Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial.

Abstract: Background. The role of reoperation for recurrent glioblastoma (GBM) remains unclear. Prospective studies are lacking. Here, we studied the association of clinical outcome with extent of resection upon surgery for recurrent GBM in the patient cohort of DIRECTOR, a prospective randomized multicenter trial comparing 2 dose-intensified temozolomide regimens at recurrence of GBM. Methods. We analyzed prospectively collected clinical and imaging data from the DIRECTOR cohort (N = 105). Volumetric analysis was performed on gadolinium contrast-enhanced MRI as well as fluid attenuated inversion recovery/T2 MRI and correlated with PFS after initial progression (PFS2) and post-recurrence survival (PRS). Quality of life was monitored by the EORTC QLQ-C30 and QLQ-BN20 questionnaires at 8-week intervals. Results. Seventy-one patients received surgery at first recurrence. Prognostic factors, including age, MGMT promoter methylation, and Karnofsky performance score, were balanced between patients with and without reoperation. Outcome in patients with versus without surgery at recurrence was similar for PFS2 (2.0 mo vs 1.9 mo, P = .360) and PRS (11.4 mo vs 9.8 mo, P = .633). Among re-operated patients, post-surgery imaging was available in 59 cases. In these patients, complete resection of contrast-enhancing tumor (N = 40) versus residual detection of contrast enhancement (N = 19) was associated with improved PRS (12.9 mo [95% CI: 11.5-18.2] vs 6.5 mo [95% CI: 3.6-9.9], P < .001) and better quality of life. Incomplete tumor resection was associated with inferior PRS compared with patients who did not undergo surgery (6.5 vs 9.8 mo, P = .052). Quality of life was similar in these 2 groups. Conclusion. Surgery at first recurrence of GBM improves outcome if complete resection of contrast-enhancing tumor is achieved.

TERT promoter mutations: A novel independent prognostic factor in primary glioblastomas

Abstract: Background. Activating somatic mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) have been detected in several cancers. In this study we investigated the TERT promoter mutations and their impact on patient survival in World Health Organization grade IV glioblastoma multiforme (GBM). Methods .T heTERT core promoter region containing the previously described mutations and a common functional polymorphism (rs2853669) was sequenced in tumors and blood samples from 192 GBM patients. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was assessed by pyrosequencing in 177 (92.2%) cases. Relevant clinical data were obtained from a prospectively maintained electronic database. Results .W e detected specif ic ( 2124 C. Ta nd2146 C.T) TERT promoter mutations in 143/178 (80.3%) primary GBM and 4/14 (28.6%) secondary GBM (P , .001). The presence of TERT mutations was associated with poor overall survival, and the effect was confined to the patients who did not carry the variant G-allele for the rs2853669 polymorphism. An exploratory analysis suggested that TERT mutations might be prognostic only in patients who had incomplete resections and no temozolomide chemotherapy. Conclusions. In this study, specific TERT promoter mutations were markers of primary GBM and predicted patient survival in conjunction with a common functional polymorphism. The prognostic impact of TERT mutations was absent in patients with complete resections and temozolomide chemotherapy. If confirmed in additional studies, these findings may have clinical implications, that is, TERT mutations appear to characterize tumors that require aggressive treatment.

Descriptive epidemiology of World Health Organization grades II and III intracranial meningiomas in the United States

Abstract: BACKGROUND Because World Health Organization (WHO) grades II and III meningiomas are relatively uncommon, there is limited literature on the descriptive epidemiology of these tumors, and the existing literature predates the 2000 WHO classification revisions. Our purpose was to provide a modern, population-based study of the descriptive epidemiology of WHO II and III meningiomas in the United States. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) was queried for intracranial meningiomas categorized by WHO grade for the 2004--2010 study period. Age-adjusted incidence (95% confidence interval in parentheses) per 100,000 population was calculated by age, sex, race, and ethnicity. Annual percent change (APC) was calculated using Joinpoint. RESULTS From 2004 to 2010, the incidence of WHO II intracranial meningiomas increased from 0.28 (95% CI, 0.27--0.29) to 0.30 (95% CI, 0.28-0.32), representing an APC of 3.6% (95%CI, 0.8%-6.5%). Conversely, from 2000-2010, the incidence of WHO III meningiomas decreased from 0.13 (95% CI, 0.11-0.14) to 0.06 (95%CI, 0.06-0.07), representing an APC of -5.4% (95% CI, -6.8% to -4.0%). From 2004 to 2010, the overall proportion of WHO I, II, and III intracranial meningiomas was 94.6%, 4.2%, and 1.2%, respectively. For WHO II/III meningiomas, females in the 35-64 year age group had a higher incidence than males in the same age group, whereas males in the ≥ 75 year age group ≥ had a higher incidence. Black and Asian Pacific Islander races were both associated with the highest incidence of WHO II/III meningiomas. Hispanic ethnicity was not associated with any difference in incidence. CONCLUSION This study presents the most comprehensive evaluation of the modern descriptive epidemiology of WHO II and III meningiomas. Temporal trends likely reflect the 2000 WHO histological criteria revisions.

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma

Abstract: BACKGROUND We evaluated the diagnostic value of static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET parameters in patients with progressive or recurrent glioma. METHODS We retrospectively analyzed 132 dynamic (18)F-FET PET and conventional MRI scans of 124 glioma patients (primary World Health Organization grade II, n = 55; grade III, n = 19; grade IV, n = 50; mean age, 52 ± 14 y). Patients had been referred for PET assessment with clinical signs and/or MRI findings suggestive of tumor progression or recurrence based on Response Assessment in Neuro-Oncology criteria. Maximum and mean tumor/brain ratios of (18)F-FET uptake were determined (20-40 min post-injection) as well as tracer uptake kinetics (ie, time to peak and patterns of the time-activity curves). Diagnoses were confirmed histologically (95%) or by clinical follow-up (5%). Diagnostic accuracies of PET and MR parameters for the detection of tumor progression or recurrence were evaluated by receiver operating characteristic analyses/chi-square test. RESULTS Tumor progression or recurrence could be diagnosed in 121 of 132 cases (92%). MRI and (18)F-FET PET findings were concordant in 84% and discordant in 16%. Compared with the diagnostic accuracy of conventional MRI to diagnose tumor progression or recurrence (85%), a higher accuracy (93%) was achieved by (18)F-FET PET when a mean tumor/brain ratio ≥2.0 or time to peak <45 min was present (sensitivity, 93%; specificity, 100%; accuracy, 93%; positive predictive value, 100%; P < .001). CONCLUSION Static and dynamic (18)F-FET PET parameters differentiate progressive or recurrent glioma from treatment-related nonneoplastic changes with higher accuracy than conventional MRI.

Localizing seizure-susceptible brain regions associated with low-grade gliomas using voxel-based lesion-symptom mapping

Abstract: Background. Patients afflicted with low-grade glioma (LGG) frequently suffer from seizures. The mechanisms of seizure initiation in these patients remain poorly understood. Tumor location has been correlated with seizure initiation. However, these correlative studies relied on dichotomized data analysis based on arbitrary lobe assignments. As a result, the lesion-symptom correlation may be incorrectly interpreted. Here, we present the first study that used a voxel-wise quantitative lesion analysis to investigate the spatial correlation between tumor location and seizure susceptibility. Methods. We collected the medical records and magnetic resonance images of 410 LGG patients. The dataset was divided into a discovery set and a validation set. A voxel-based lesion-symptom correlative analysis was performed to determine whether tumor location was associated with seizure risk and could be related to the specific type of seizure. Results. For all seizure types, increased seizure risks were identified for LGGs that involved the left premotor area. The LGGs that involved the posterior portion of the left inferior and middle frontal gyrus were associated with increased risk of simple partial seizures. LGGs that involved the right temporal-insular region were associated with an increased risk of complex partial seizures. LGGs that involved the left premotor area were more likely to be associated with seizures that generalize. These correlations were consistently observed in both the discovery and the validation datasets. Conclusions. Our quantitative neuroimaging analyses support the concept that the anatomic location of an LGG is a contributing factor in tumor-related seizure.

Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study.

Abstract: Breast cancer brain metastases (BCBM) are a devastating complication and portend a poor prognosis.1 The role of systemic therapy is limited and secondary for BCBM. The normal blood–brain barrier excludes entry of drugs, and the degree to which it remains patent with a brain metastasis (BM), as the blood–tumor barrier (BTB), is debated.2 Contrast agents show uptake into BCBM, but chemotherapy has been generally ineffective; presumably the BTB prevents attainment of active drug levels. Very limited data exist on drug uptake in human BCBM.1 Evidence for CNS drug penetration is usually based on preclinical xenograft models or evaluation of cerebrospinal fluid in human clinical samples.3–6 In experimental BCBM models, most lesions exhibit drug uptake greater than that of the normal brain, but brain lesion uptake may be heterogeneous and insufficient to mount an apoptotic response.6 Capecitabine and lapatinib have demonstrated efficacy in clinical trials among patients with BCBM.7,8 Capecitabine is an oral prodrug of 5-flourouracil (5-FU), an antimetabolite, and undergoes 3-step enzymatic conversion to 5-FU (Supplementary Fig. S1). Lapatinib is an oral small-molecule tyrosine kinase inhibitor (TKI) that reversibly targets epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). The uptake of lapatinib in BCBM has been demonstrated in a preclinical model.5 Clinical evidence for BM uptake of drugs is scarce, and it is unclear whether preclinical models reflect human BM pharmacokinetics (PK). Prospective evaluation of BM drug uptake in humans is challenging but valuable for future drug development. In this study, we examined the uptake of capecitabine, its metabolites, and lapatinib in BCBM resected from patients undergoing medically indicated craniotomy.

Survival, hypothalamic obesity, and neuropsychological/psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes

Abstract: Background. Quality of life (QoL) and long-term prognosis are frequently, and often severely, impaired in craniopharyngioma (CP) patients. Knowledge of risk factors for long-term outcome is important for optimization of treatment. Methods. Overall survival (OS) and progression-free survival (PFS), body mass index (BMI), neuropsychological status (EORTCQLQC30, MFI-20), and psychosocial status were analyzed in 261 patients with childhood-onset CP diagnosed before 2000 and longitudinally observed in HIT-Endo. Results. Twenty-year OS was lower (P ¼ .006) in CP with hypothalamic involvement (HI) (n ¼ 132; 0.84+0.04) when compared with CP without HI (n ¼ 82; 0.95+0.04). OS was not related to degree of resection, sex, age at diagnosis, or year of diagnosis (before/after 1990). PFS (n ¼ 168; 0.58+0.05) was lower in younger patients (,5y at diagnosis) (n ¼ 30; 0.39+0.10) compared with patients aged 5 –10 years (n ¼ 66; 0.52+0.08) and older than 10 years (n ¼ 72; 0.77+0.06) at diagnosis. PFS was not associated with HI, degree of resection, or sex. HI led to severe weight gain during the first 8– 12 years of follow-up (median BMI increase: +4.59SD) compared with no HI (median increase: +1.20SD) (P ¼ .00). During .12 years of follow-up, patients with HI presented no further increase in BMI. QoL in CP patients with HI was impaired by obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and nonoptimal psychosocial development. Conclusions. OS and QoL are impaired by HI in long-term survivors of CP. HI is associated with severe obesity, which plateaus after 12 years. OS/PFS are not related to degree of resection, but gross-total resection should be avoided in cases of HI to prevent further hypothalamic damage, which exacerbates sequelae.

From the clinician's point of view - What is the status quo of positron emission tomography in patients with brain tumors?

Abstract: The most common type of primary brain tumor is malignant glioma. Despite intensive therapeutic efforts, the majority of these neoplasms remain incurable. Imaging techniques are important for initial tumor detection and comprise indispensable tools for monitoring treatment. Structural imaging using contrast-enhanced MRI is the method of choice for brain tumor surveillance, but its capacity to differentiate tumor from nonspecific tissue changes can be limited, particularly with posttreatment gliomas. Metabolic imaging using positron-emission-tomography (PET) can provide relevant additional information, which may allow for better assessment of tumor burden in ambiguous cases. Specific PET tracers have addressed numerous molecular targets in the last decades, but only a few have achieved relevance in routine clinical practice. At present, PET studies using radiolabeled amino acids appear to improve clinical decision-making as these tracers can offer better delineation of tumor extent as well as improved targeting of biopsies, surgical interventions, and radiation therapy. Amino acid PET imaging also appears useful for distinguishing glioma recurrence or progression from postradiation treatment effects, particularly radiation necrosis and pseudoprogression, and provides information on histological grading and patient prognosis. In the last decade, the tracers O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) and 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine (FDOPA) have been increasingly used for these indications. This review article focuses on these tracers and summarizes their recent applications for patients with brain tumors. Current uses of tracers other than FET and FDOPA are also discussed, and the most frequent practical questions regarding PET brain tumor imaging are reviewed.

Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Abstract: Methods. A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P , .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model’s performance was validated by bootstrapping techniques. Results. A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age ≤3 years, longer symptom duration at diagnosis, and use of oral and intravenous chemotherapy were favorable predictors, while ring enhancement on MRI at diagnosis was an unfavorable predictor. With increasing risk score categories, overall survival decreased significantly. The model can distinguish between patients with very short, average, and increased overall survival (medians of 7.0, 9.7, and 13.7 mo, respectively). The area under the receiver operating characteristic curve was 0.68. Conclusions. We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.

Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas

Abstract: Background The efficacy of novel targeted therapies is often tested at the time of tumor recurrence. However, for glioblastoma (GBM) patients, surgical resections at recurrence are performed only in a minority of patients; therefore, molecular data are predominantly derived from the initial tumor. Molecular data of the initial tumor for patient selection into personalized medicine trials can therefore be used only when the specific genetic change is retained in the recurrent tumor. Methods In this study we determined whether EGFR amplification and expression of the most common mutation in GBMs (EGFRvIII) is retained at tumor recurrence. Because retention of genetic changes may be dependent on the initial treatment, we only used a cohort of GBM samples that were uniformly treated according to the current standard of care (ie, chemo-irradiation with temozolomide). Results Our data show that, in spite of some quantitative differences, the EGFR amplification status remains stable in the majority (84%) of tumors evaluated. EGFRvIII expression remained similar in 79% of GBMs. However, within the tumors expressing EGFRvIII at initial diagnosis, approximately one-half lose their EGFRvIII expression at tumor recurrence. Conclusions The relative stability of EGFR amplification indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor, but care should be taken in extrapolating EGFRvIII expression from the primary tumor, particularly when expressed at first diagnosis.

Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex.

Abstract: Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy, learning difficulties, and behavioral problems. TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth. In normal cells, TSC1 and TSC2 integrate growth signals and nutrient inputs to downregulate signaling to mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase that controls cell growth and cell survival. The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC. Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. Sirolimus, though not approved for TSC, has undergone considerable investigation to treat various aspects of the disease. Everolimus and sirolimus selectively inhibit mTOR signaling with similar molecular mechanisms, but with distinct clinical profiles. This review differentiates mTOR inhibitors in TSC while describing the molecular mechanisms, pathogenic mutations, and clinical trial outcomes for managing TSC.

Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis

Abstract: Background. Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. Methods. We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. Results. A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14‐5.62, P , .001), postoperative KPS (MD 10.4, 95% CI: 6.58‐14.22, P , .001), PFS (MD 2.44 mo, 95% CI: 1.45‐3.43, P , .001), mortality (RR ¼ 0.27, 95% CI: 0.12‐0.61, P ¼ .002), and morbidity (RR ¼ 0.82, 95% CI: 0.46‐1.46, P ¼ .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26‐5.29, P , .001), postoperative KPS (MD 4.91, 95% CI: 0.91‐8.92, P ¼.016), and PFS (MD 2.21 mo, 95% CI: 1.13‐3.3, P , .001) with no difference in mortality (RR ¼0.53, 95% CI: 0.05‐5.71, P ¼.600) or morbidity (RR ¼ 0.52, 95% CI: 0.18‐1.49, P ¼ .223). Conclusions. Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs.

A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K.

Abstract: Background The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.

Convection-enhanced delivery for the treatment of glioblastoma

Abstract: Effective treatment of glioblastoma (GBM) remains a formidable challenge. Survival rates remain poor despite decades of clinical trials of conventional and novel, biologically targeted therapeutics. There is considerable evidence that most of these therapeutics do not reach their targets in the brain when administered via conventional routes (intravenous or oral). Hence, direct delivery of therapeutics to the brain and to brain tumors is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous, low–positive-pressure bulk flow. Investigation in preclinical and clinical settings has demonstrated that CED can produce effective delivery of therapeutics to substantial volumes of brain and brain tumor. However, limitations in catheter technology and imaging of delivery have prevented this technique from being reliable and reproducible, and the only completed phase III study in GBM did not show a survival benefit for patients treated with an investigational therapeutic delivered via CED. Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique.

Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling

Abstract: BACKGROUND: Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2). METHODS: Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices. RESULTS: The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo. CONCLUSIONS: Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies.

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

Abstract: Background. The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. Methods. This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). Results. One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P =. 66). ORR was 14% (combination) versus 6% (monotherapy) (P =. 18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P =. 38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. Conclusions. Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.

Abstract: BACKGROUND: Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response through local delivery of aglatimagene besadenovec (AdV-tk) which synergizes with standard of care (SOC). METHODS: A Phase II trial was designed to evaluate overall survival (OS) after GMCI + SOC compared to a concurrent matched control group meeting protocol criteria and SOC at an institution not active in the treatment trial. Primary efficacy analysis was planned on the null hypothesis of no improvement in the 2-yr survival over the SOC group with planned subset analysis of significant disease prognostic factors. RESULTS: From 2006 to 2010, 48 patients completed SOC + GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Fever, fatigue and headache were the most common GMCI-related symptoms. Median OS was 17.1 and 13.5 months for GMCI + SOC and SOC, respectively (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99, p = 0.0417). Median PFS was 8.1 and 6.5 months for GMCI + SOC and SOC, respectively (HR 0.66, 95% CI 0.48-0.91, p = 0.0100). OS at 1- 2- and 3-years increased from 57%, 22% and 8% to 67%, 35% and 19%, respectively. The improvement was mostly in patients that underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The 2-yr survival rate met the planned statistical threshold for significance. This is the first study to demonstrate a correlation between maximum debulking and a survival advantage using immunotherapy. These data strongly support further evaluation of GMCI for malignant gliomas.

Medical management of brain tumors and the sequelae of treatment

Abstract: Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction.

Growth dynamics of untreated glioblastomas in vivo

Abstract: Methods. By using repeated pretreatment contrast-enhanced T1-weighted MRI scans from 106 patients (aged 26–83 years), we studied the growth dynamics of untreated glioblastomas in vivo. Growth rates were calculated as specific growth rates and equivalent volume doubling times. The fit of different possible growth models was assessed using maximum likelihood estimations. Results. There were large variations in growth rates between patients. The median specific growth rate of the tumors was 1.4% per day, and the equivalent volume doubling time was 49.6 days. Exploring 3 different tumor growth models showed similar statistical fit for a Gompertzian growth model and a linear radial growth model and worse fit for an exponential growth model. However, large tumors had significantly lower growth rates than smaller tumors, supporting the assumption that glioblastomas reach a plateau phase and thus exhibit Gompertzian growth. Conclusion. Based on the fast growth rate of glioblastoma shown in this study, it is evident that poor treatment logistics will influence tumor size before surgery and can cause significant regrowth before adjuvant treatment. Since there is a known association between tumor volume, extent of surgical resection, and response to adjuvant therapy, it is likely that waiting times play a role in patient outcomes.