Showing papers in "Neuro-oncology in 2014"

The epidemiology of glioma in adults: a "state of the science" review.

Abstract: Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors Although relatively rare, they cause significant mortality and morbidity Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5% A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome Genomic analyses of glioma have also produced new evidence about risk and prognosis Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma Many risk factors have been examined as potential contributors to glioma risk Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s) The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults

Detection of circulating tumor dna in early and late stage human malignancies

Abstract: BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in 75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.

Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal

Abstract: c Neurosurgery, d Otolaryngology—Head and Neck Surgery, h Pathology, l Urology, and m Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere main- tenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/ mental retardation syndrome X-linked (ATRX )o rdeath-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telo- merase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequen- cies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carci- nomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggest- ing that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for under- standing the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma

Abstract: Results: Of 259 patients, 203 (78%) died and 156 (60%) had tumor recurrence. The median survival and progression-free survival were 13.4 and 8.9 months, respectively. The median (interquartile range) pre- and postoperative tumor volumes were 32.2 (14.0 –56.3) and 2.1 (0.0 –7.9) cm 3 , respectively. EOR was independently associated with survival (hazard ratio [HR], 0.995; 95% confidence interval [CI]: 0.990– 0.998; P ¼ .008) and recurrence (HR [95% CI], 0.992 [0.983 –0.998], P ¼ .005). The minimum EOR threshold for survival (P ¼ .0006) and recurrence (P ¼ .005) was 70%. RV was also associated with survival (HR [95% CI], 1.019 [1.006– 1.030], P ¼ .004) and recurrence (HR [95% CI], 1.024 [1.001 –1.044], P ¼ .03). The maximum RV threshold for survival (P ¼ .01) and recurrence (P ¼ .01) was 5 cm 3 . Conclusion: This study shows for the first time that both EOR and RV are significantly associated with survival and recurrence, where the thresholds are 70% and 5 cm 3 , respectively. These findings may help guide surgical and adjuvant therapies aimed at optimizing

IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

Abstract: Background IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas—World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma.

Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades.

Abstract: Background.Amideprotontransfer(APT)imagingisanovelmolecularMRItechniquetodetectendogenousmobileproteinsandpeptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. Methods. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1+14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets v ¼ 2 6t o+6 ppm (step 0.5 ppm). dB0 maps were acquired separately for a point-by-point dB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym ¼ (S[23.5 ppm] 2 S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density.

A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool

Abstract: Background. Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. Methods. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. Results. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Conclusions. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma

Abstract: Melanoma is an immunogenic cancer, and numerous immunotherapies have been used to control its progression, including α-interferon, interleukin (IL)-2, and monoclonal antibodies. Ipilimumab is a novel FDA-approved immunotherapy agent that has been used to treat patients with unresectable and/or metastatic melanoma since May 2011. Ipilimumab is a recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, which is an inhibitor of T-cell activation; thereby, ipilimumab potentiates an immune response. Immune-related adverse events (irAEs) may occur in patients treated with ipilimumab, however. Reported neurological irAEs include inflammatory myopathy,1 aseptic meningitis, posterior reversible encephalopathy syndrome,2 Guillain-Barre syndrome, myasthenia gravis–type syndrome, sensorimotor neuropathy,2,3–5 and inflammatory enteric neuropathy.6 We report 3 cases of metastatic melanoma treated with ipilimumab in which the patient developed rare ipilimumab-related adverse events: chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), and concurrent myositis and myasthenia gravis–type syndrome, respectively. We believe these events were due to immunological pathogenesis involving various human leukocyte antigen subgroups and immunotherapy regimens. We report 3 cases of ipilimumab-related irAEs presented with rare neurological symptoms to raise awareness of the wide spectrum of neurological side effects of this medication and provide our experience on their treatment.

New concepts in the management of diffuse low-grade glioma: Proposal of a multistage and individualized therapeutic approach.

Abstract: Diffuse low-grade glioma grows, migrates along white matter tracts, and progresses to high-grade glioma. Rather than a "wait and see" policy, an aggressive attitude is now recommended, with early surgery as the first therapy. Intraoperative mapping, with maximal resection according to functional boundaries, is associated with a longer overall survival (OS) while minimizing morbidity. However, most studies have investigated the role of only one specific treatment (surgery, radiotherapy, chemotherapy) without taking a global view of managing the cumulative time while preserving quality of life (QoL) versus time to anaplastic transformation. Our aim is to switch towards a more holistic concept based upon the anticipation of a personalized and long-term multistage therapeutic approach, with online adaptation of the strategy over the years using feedback from clinical, radiological, and histomolecular monitoring. This dynamic strategy challenges the traditional approach by proposing earlier therapy, by repeating treatments, and by reversing the classical order of therapies (eg, neoadjuvant chemotherapy when maximal resection is impossible, no early radiotherapy) to improve OS and QoL. New individualized management strategies should deal with the interactions between the course of this chronic disease, reaction brain remapping, and oncofunctional modulation elicited by serial treatments. This philosophy supports a personalized, functional, and preventive neuro-oncology.

C11orf95-rela fusions drive oncogenic nf-kb signaling in ependymoma.

Abstract: BACKGROUND: The nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. METHODS: To identify additional genetic alterations that drive ependymoma, we sequenced the whole genomes (WGS) of 41 tumours and matched normal blood, and the transcriptomes (RNAseq) of 77 tumours. The transforming significance of alterations were tested in mouse NSCs that we showed previously to be cells of origin of ependymoma. RESULTS: Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. CONCLUSIONS: Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

Targeting adaptive glioblastoma: an overview of proliferation and invasion.

Abstract: Glioblastoma is one of the most devastating cancers, in which tumor cell infiltration into surrounding normal brain tissue confounds clinical management. This review describes basic and translational research into glioma proliferation and invasion, in particular the phenotypic switch underlying a stochastic “go or grow” model of tumor cell behavior. We include recent progress in system genomics, cancer stem cell theory, and tumor–microenvironment interaction, from which novel therapeutic strategies may emerge for managing this malignant disease. We suggest that an effective therapeutic strategy should target both adaptive glioblastoma cells and the stroma–tumor interaction.

Historical benchmarks for medical therapy trials in surgery- and radiation-refractory meningioma: a RANO review

Abstract: Background The outcomes of patients with surgery- and radiation-refractory meningiomas treated with medical therapies are poorly defined. Published reports are limited by small patient numbers, selection bias, inclusion of mixed histologic grades and stages of illness, and World Health Organization (WHO) criteria changes. This analysis seeks to define outcome benchmarks for future clinical trial design.

Leptomeningeal metastases: a RANO proposal for response criteria.

Abstract: Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use.

Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial

Abstract: Background Outcomes for patients with recurrent glioblastoma multiforme (GBM) are poor and may be improved by immunotherapy. We investigated the safety and efficacy of an autologous heat-shock protein peptide complex–96 (HSPPC-96) vaccine for patients with recurrent GBM.

Single cell derived clonal analysis of human glioblastoma links functional and genomic heterogeneity.

Abstract: BACKGROUND: Glioblastoma (GBM) is a cancer comprised of morphologically, genetically and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. METHODS: We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. RESULTS: Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naive patient tumors included clones that were temozolomide (TMZ) resistant, indicating that resistance to conventional GBM therapy preexists in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were identified with clone-specific drug screening. Genomic analyses identified genes and pathways that associate with specific functional behavior of single clones. In particular, increased expression and signaling of the autocrine/paracrine γ-aminobutyric acid (GABA) receptor GABRA3 correlates with TMZ sensitivity and patient outcome. CONCLUSIONS: Our results suggest that functional clonal profiling used to identify tumorigenic and drug resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies. SECONDARY CATEGORY: n/a.

Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas.

Abstract: Recurrent pediatric low-grade astrocytoma (PLGA) represents a major clinical problem in neuro-oncology, and novel, less toxic and more effective therapies are needed.1 Recently, our increased understanding of the key molecular pathways driving PLGA growth and the increasing availability of targeted therapies for those pathways have led to great interest in exploring molecular targeted therapies for PLGA. Pilocytic astrocytoma (PA) is the most common histological subtype of PLGA. Patients with neurofibromatosis type 1 (NF1) are predisposed to developing PAs, predominantly in the optic tract (ie, optic pathway gliomas [OPGs]).2 NF1 is characterized by the loss of the NF1 gene product neurofibromin, resulting in activation of the RAS/RAF/MEK/ERK signaling pathway.3 The majority of sporadic PAs harbor a unique tandem duplication at chromosome 7q34, which produces a fusion gene between KIAA1549 and the kinase domain of BRAF that result in constitutive BRAF and ultimately MAPK activation. In recent genomic studies, almost all PAs that do not harbor KIAA-BRAF have been shown to harbor other genetic lesions that also result in constitutive MAPK pathway activation, such as activating genetic hits in FGFR1, NTRK2, and RAF1.4,5 PLGAs express pro-angiogenic factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF]), and their receptors (VEGFR and PDGFR).6–8 Bevacizumab, a VEGF inhibitor, has recently shown very encouraging activity in PLGA.9,10 Sorafenib is an oral, small-molecule multikinase inhibitor with potent in vitro activity against both wild-type and mutant (V600E) BRAF.11 Recent preclinical data showed that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with sorafenib.12 Sorafenib also exerts anti-angiogenic activity via inhibition of VEGFR-1/2/3, PDGFRβ, Flt-3, and c-kit, which has been studied in a variety of preclinical models13,14 as well as in clinical studies using dynamic, contrast-enhanced MRI.15 Because sorafenib is a potent inhibitor of several key molecular pathways that are relevant in PLGAs and encouraging preclinical data,12 we conducted this prospective phase II clinical trial to assess the objective response rate to sorafenib in patients with PLGA.

The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

Abstract: BACKGROUND: Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O(6)-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients. METHODS: We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor. RESULTS: Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets. DISCUSSION: The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.

Adjuvant radiotherapy for atypical and malignant meningiomas: a systematic review

Abstract: Atypical meningiomas (AMs) and malignant meningiomas (MMs) are tumors with a lower incidence and poorer prognosis than benign meningiomas. The role of radiotherapy as an adjuvant to surgical resection, especially for AMs, is incompletely defined. In this study, the English-language literature was systematically reviewed for studies that reported tumor characteristics, treatment parameters, and clinical outcomes after adjuvant radiotherapy for AM and MM, including overall survival, progression-free survival, and/or time to recurrence or mortality. Clinical outcomes were further assessed in the context of resection status, timing of administration, and radiation dose. Outcomes after stereotactic radiosurgery were also examined. Treatment toxicity and other potential prognostic or confounding factors were appraised. Ten and 11 studies for AM and MM, respectively, met the inclusion criteria. The median 5-year progression-free survival and overall survival after adjuvant radiotherapy were 54.2% and 67.5%, respectively, for AM and 48% and 55.6% for MM. The complication rates were 11.1% for AM and 5.1% for MM. Incomplete resection and radiation dose <50 Gy conferred significantly poorer 5-year progression-free survival. Most studies were unable to demonstrate a statistically significant prognostic benefit for adjuvant radiotherapy in AM. In conclusion, adjuvant radiotherapy significantly improved local control of AMs and MMs, especially after subtotal resection. Study limitations, including inadequate statistical power, may underlie the studies' inability to demonstrate a statistically significant benefit for adjuvant radiotherapy in AM. Because these tumors preferentially recur within 5 years of surgical resection, future studies should define whether early adjuvant therapy should become part of the standard treatment paradigm for completely excised tumors.

Immunotherapy advances for glioblastoma

Abstract: Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.

H3F3A K27M mutations in thalamic gliomas from young adult patients

Abstract: Results. Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17– 46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally,H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations inTP53,ATRX,NF1, andEGFR. Gliomas withH3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. Conclusion. We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.

Autoimmune encephalitis update

Abstract: Cancer-associated immune-mediated disorders of the central nervous system are a heterogeneous group. These disorders include the classic paraneoplastic neurologic disorders and the more recently described autoimmune encephalitis associated with antibodies to neuronal cell-surface or synaptic receptors that occur with and without a cancer association. Autoimmune encephalitis is increasingly recognized as the cause of a variety of neuropsychiatric syndromes that can be severe and prolonged. In contrast to the classic paraneoplastic disorders that are poorly responsive to tumor treatment and immunotherapy, autoimmune encephalitis often responds to these treatments, and patients can have full or marked recoveries. As early treatment speeds recovery, reduces disability, and decreases relapses that can occur in about 20% of cases, it is important that the immune pathogenesis of these disorders is recognized.

Lactate dehydrogenase A silencing in IDH mutant gliomas.

Abstract: Deregulation of oncogenes and tumor suppressor genes is known to affect the expression and activity of transporters, sensors, and enzymes that regulate metabolism,1 but actual mutations in genes directly involved in metabolism, such as fumarate hydratase and succinate dehydrogenase, which are members of the tricarboxylic acid cycle, have only recently been demonstrated.2 Not surprisingly, then, the discovery of mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2), first in colon cancer and soon thereafter in different subtypes of gliomas, including oligodendrogliomas, astrocytomas, mixed oligoastrocytomas, and secondary glioblastomas,3,4 ignited a feverish interest in cancer cell metabolism. Initially, IDH1/2 mutations were anticipated to directly impact cellular metabolism and promote aerobic glycolysis, the metabolic pathway favored by cancer cells to support rapid proliferation.5,6 However, despite advances in the understanding of the function of the mutant IDH enzyme,7–10 the hypothesis that IDH1/2 mutations directly alter cancer cell metabolism remains unproven. 2-Hydroxyglutarate (2-HG), the product of the neomorphic activity of the mutant IDH1/2 enzymes, competitively inhibits α-ketoglutarate–dependent enzymes,11 including histone demethylases and 5-methylcytosine hydroxylases that are essential for epigenetic regulation of gene expression.12–14 Consequently, via 2-HG–dependent epigenetic remodeling, IDH mutations may interfere with differentiation, proliferation, survival, and metabolism.6 2-Hydroxyglutarate also affects the activity of EGLN prolyl 4-hydroxylases (PHDs), which are responsible for oxygen-dependent degradation of hypoxia-inducible factor (HIF)1α. Although stabilization of HIF1α by 2-HG has been reported,15 a recent study has clarified that 2-HG stimulates PHD activity, leading to the degradation of HIF1α.16 The subsequent downregulation of HIF1α-responsive genes by 2-HG may have unique consequences for human cancer cells, including limitation of the metabolic shift toward aerobic glycolysis, the so-called Warburg effect. A key step in glycolysis is the conversion of pyruvate to lactate, catalyzed by the lactate dehydrogenase (LDH) complex, one subunit of which is LDHA. LDHA enhances the efficiency of the LDH complex, allowing the rapid flux through glycolysis that is necessary to meet the energy needs of rapidly proliferating cells. As such, LDHA is considered a major biomarker of glycolytic activity.17–20 LDHA contains HIF1α binding sites in its promoter and is induced under hypoxic conditions, allowing normal cells to switch to an oxygen-independent glycolytic metabolic phenotype when deprived of oxygen.21,22 LDHA is overexpressed in cancer cells, and silencing of LDHA typically results in accelerated oxygen consumption, increased apoptosis, decreased proliferation, and strong inhibition of tumorigenicity.23–27 Here, we report that multiple HIF1α-responsive genes necessary for glycolysis are underexpressed in IDH mutant (mt) gliomas and brain tumor stem cells (BTSCs) derived from IDHmt tumors, including human BTSCs that have lost the mutant IDH1 allele and no longer produce 2-HG. Due to its central role in glycolysis, we focused our attention on LDHA. Our data suggest that LDHA is silenced through IDHmt-dependent methylation of its promoter. Silencing of LDHA and downregulation of other glycolytic genes is a surprising finding in the context of human cancer cells but may help to explain the slower progression and better prognosis of IDHmt gliomas.

Navigated transcranial magnetic stimulation improves the treatment outcome in patients with brain tumors in motor eloquent locations

Abstract: Background. Neurological and oncological outcomes of motor eloquent brain-tumor patients depend upon the ability to localize functional areas and the respective proposed therapy. We set out to determine whether the use of navigated transcranial magnetic stimulation (nTMS) had an impact on treatment and outcome in patients with brain tumors in motor eloquent locations. Methods. We enrolled 250 consecutive patients and compared their functional and oncological outcomes to a matched pre-nTMS control group (n ¼ 115). Results. nTMS mapping results disproved suspected involvement of primary motor cortex in 25.1% of cases, expanded surgical indication in 14.8%, and led to planning of more extensive resection in 35.2% of cases and more restrictive resection in 3.5%. In comparison with the control group, the rate of gross total resections increased significantly from 42% to 59% (P , .05). Progression-freesurvival for low grade glioma was significantly better in the nTMS group at 22.4 months than in control group at 15.4 months (P , .05). Integration of nTMS led to a nonsignificant change of postoperative deficits from 8.5% in the control group to 6.1% in the nTMS group. Conclusions. nTMS provides crucial data for preoperative planning and surgical resection of tumors involving essential motor areas. Expanding surgical indications and extent of resection based on nTMS enables more patients to undergo surgery and might lead to better neurological outcomes and higher survival rates in brain tumor patients. The impact of this study should go far beyond the neurosurgical community because it could fundamentally improve treatment and outcome, and its results will likely change clinical practice.

Preoperative motor mapping by navigated transcranial magnetic brain stimulation improves outcome for motor eloquent lesions

Abstract: Results. Patients in the nTMS group showed a significantly lower rate of residual tumor on postoperative MRI (OR 0.3828; 95% CI 0.2062 –0.7107). Twelve percent of patients in the nTMS and 1% of patients in the non-nTMS group improved while 75% and 81% of the nTMS and non-nTMS groups, respectively, remained unchanged and 13% and 18% of patients in the nTMS and non-nTMS groups, respectively, deteriorated in postoperative motor function on long-term follow-up (P ¼ .0057). Moreover, the nTMS group showed smaller craniotomies (nTMS 22.4+8.3 cm 2 ; non-nTMS 26.7+11.3 cm 2 ; P ¼ .0023). Conclusions. This work increases the level of evidence for preoperative motor mapping by nTMS for rolandic lesions in a group comparison study. We therefore strongly advocate nTMS to become increasingly used for these lesions. However, a randomized trial on the comparison with the gold standard of intraoperative mapping seems mandatory.

GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity.

Abstract: Gliomas are a heterogeneous group of tumors that show variable proliferative potential, invasiveness, aggressiveness, histological grading, and clinical behavior In this review, we focus on glioblastoma multiforme (GBM), a grade IV glioma, which is the most common and malignant of primary adult brain tumors Research over the past several decades has revealed the existence of extensive cellular, molecular, genetic, epigenetic, and metabolic heterogeneity among tumors of the same grade and even within individual tumors Evaluation of different tumor types has shown that tumors with advanced grade and clinical aggressiveness also display enhanced molecular, cellular, and microenvironmental heterogeneity From a therapeutic standpoint, this heterogeneity is a major clinical hurdle for devising effective therapeutic strategies for patients and challenges personalized medicine In this review, we will highlight key aspects of GBM heterogeneity, directing special attention to regional heterogeneity, hypoxia, genomic heterogeneity, tumor-specific metabolic reprogramming, neovascularization or angiogenesis, and stromal immune cells We will further discuss the clinical implications of GBM heterogeneity in the context of therapy

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

Abstract: Temozolomide plus radiotherapy is standard treatment for newly diagnosed glioblastoma (GBM) patients.1 Recent attempts to improve front-line treatment with bevacizumab2,3 or cilengitide4 have failed to improve survival when combined with standard treatment. Following front-line treatment, nearly all GBMs recur, and there are no effective treatments with durable benefit for recurrent GBM.5 Recurrent GBM has an extremely poor prognosis, with a median overall survival (OS) of ∼9 months and a 12-month OS of 14%.5 Treatment failure is associated with the development of resistance to temozolomide and is primarily mediated by overexpression of specific proteins (O[6]-methylguanine methyltransferase [MGMT] and O[6]-alkylguanine-DNA-alkyl-transferase [AGAT]).6 Nevertheless, temozolomide is well tolerated and may have activity despite prior exposure if novel dose schedules are used.7,8 For example, protracted, low-dose (metronomic) temozolomide may deplete MGMT and AGAT9 and restore temozolomide sensitivity in the recurrent setting. Activation of the ErbB family of receptors, including the epidermal growth factor receptor (EGFR), can initiate downstream signaling pathways involved in cell growth and proliferation.10 ErbB pathway regulation plays an important role in glioma progression, and certain germline EGFR polymorphisms may contribute to the glioma pathogenesis.11 EGFR is amplified and overexpressed in ∼50%–60% of GBMs, and multiple EGFR gene mutations occur in GBM tumors.12,13 The EGFRvIII mutation is expressed in 30% of GBMs, including 41%–60% of those with EGFR amplification.12 HER2 (ErbB2) is a possible low-penetrance gene candidate associated with GBM development.11 The high frequency of EGFR pathway alterations in GBM has triggered interest in therapeutically targeting the ErbB family, including EGFR. EGFR inhibition in vitro has activity against GBM; however, reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have had limited impact on survival of recurrent GBM patients, either as monotherapy or in combination with other agents.14–26 Afatinib is a potent, orally bioavailable ErbB family blocker that irreversibly binds to the ATP binding pocket of the ErbB family of receptors, inhibiting the activity of EGFR (including the EGFRvIII variant), HER, and ErbB4 and blocks transphosphorylation of ErbB3.27,28 Afatinib is active against ErbB family-driven tumors, including lung cancer.29–31 In vitro, afatinib inhibits cells harboring mutations that are frequently found in GBM, including EGFRvIII and EGFR R108K.28,32 Furthermore, unlike erlotinib and gefitinib, cytochrome P450 metabolism of afatinib is negligible.33 Phase I of this study aimed to establish the maximum tolerated dose (MTD) and pharmacokinetics (PKs) of afatinib plus temozolomide among recurrent malignant glioma patients. Phase II assessed the efficacy and safety of afatinib (±temozolomide) versus temozolomide monotherapy in patients with recurrent GBM.

Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma

Abstract: Background Ionizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown. Methods To investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines. Results In 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3β were increased after irradiation in a Snail-dependent manner, and TGF-β was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo. Conclusions We here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials

Abstract: Purpose. To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM). Methods. A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM. Results. A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis. Conclusion. Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.

Prognostic factors associated with survival in patients with symptomatic spinal bone metastases: a retrospective cohort study of 1 043 patients

Abstract: Background Expected survival is a major factor influencing extent of treatment for symptomatic spinal bone metastases (SBM). Predictive models have been developed, but their use can lead to over- or undertreatment.. The study objective was to identify prognostic factors associated with survival in patients with symptomatic SBM and to create a validated risk stratification model.

Significance of interleukin-13 receptor alpha 2–targeted glioblastoma therapy

Abstract: Glioblastoma multiforme (GBM) remains one of the most lethal primary brain tumors despite surgical and therapeutic advancements. Targeted therapies of neoplastic diseases, including GBM, have received a great deal of interest in recent years. A highly studied target of GBM is interleukin-13 receptor α chain variant 2 (IL13Rα2). Targeted therapies against IL13Rα2 in GBM include fusion chimera proteins of IL-13 and bacterial toxins, nanoparticles, and oncolytic viruses. In addition, immunotherapies have been developed using monoclonal antibodies and cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor–modified T cells. Advanced therapeutic development has led to the completion of phase I clinical trials for chimeric antigen receptor–modified T cells and phase III clinical trials for IL-13–conjugated bacterial toxin, with promising outcomes. Selective expression of IL13Rα2 on tumor cells, while absent in the surrounding normal brain tissue, has motivated continued study of IL13Rα2 as an important candidate for targeted glioma therapy. Here, we review the preclinical and clinical studies targeting IL13Rα2 in GBM and discuss new advances and promising applications.