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Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9 years, p = 0.0005) and second surgery (1.0 vs. 3.5 years, p < 0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4 years, p = 0.008) and OS (median 10.0 vs. 4.2 years, p = 0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population.

To address a paucity of literature and treatment guidelines regarding the management of butterfly glioblastomas, we performed a ten year retrospective analysis of data from twenty-three consecutive patients treated for this disease at a single institution. Clinical characteristics and outcomes were assessed. Median age was 59 years; 52 % were female; median preoperative Karnofsky performance score (KPS) was 80. Twelve patients underwent biopsy and eleven underwent surgical decompression. The median tumor volume for the biopsy group was 60.6 cm(3) and for the surgically decompressed group 40.5 cm(3). In the biopsy group, five patients received adjuvant therapy but one died prior to its completion; two died prior to the initiation of adjuvant therapy and five were lost to follow up. In the surgical decompression group, seven patients received adjuvant therapy, one died prior to the initiation of adjuvant therapy, two were treated with palliative measures only, and one was lost to follow up. Kaplan-Meier estimates of overall median post surgical-survival of the whole group was 180 days, the biopsy group 48 days, and the surgically decompressed group 265 days (p = 0.14). Our results show that there was a higher median survival in the surgically decompressed group; but a direct correlation could not be established, and that the median KPS did not improve in either group after treatment. A larger multicenter review is required to quantitatively assess the factors, including tumor biomarkers that are associated with patient outcome.

Advanced age and contrast enhancement portend a poor prognosis in diffuse glioma (DG). Diffuse glioma may present as nonenhancing tumors that rapidly progress in weeks to months to a pattern of ring enhancement, characteristic of glioblastoma (GBM). Mutations involving isocitrate dehydrogenase 1 (IDH1) have recently emerged as important diagnostic and prognostic markers in DG. R132H is the most common mutation, expressed in more than 80% of DG and secondary GBM but in less than 10% of primary GBM. Adults older than 50 years with nonenhancing, rapidly progressing DG were identified. A comparison group comprised randomly selected, age-matched patients with nonenhancing, nonprogressing DG. Isocitrate dehydrogenase 1 status was evaluated using anti-IDH1-R132H antibodies (Dianova, Hamburg, Germany). The results were correlated with the clinical outcomes. We identified 4 patients who presented with nonenhancing DG that rapidly progressed to ring-enhancing lesions that were subsequently diagnosed on surgical resection as GBM. This group showed absent IDH1-R132H expression, which is characteristic of primary GBM. The comparison group of 5 patients presented with nonenhancing, nonprogressing DG, and all 5 tumors showed IDH1-R132H expression. In conclusion, negative IDH1-R132H mutation status in nonenhancing DG of older adults is a poor prognostic factor associated with rapid progression to ring-enhancing GBM. The shorter interval of progression and negative IDH1-R132H mutation status suggest a similar molecular pathway as seen in primary GBM.

SummaryTumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.

Papillary craniopharyngiomas are characterized by BRAF V600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. The aim of this study was to establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring inter-observer variability between pre-surgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. The BRAF V600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these three features older than 18 years, absence of calcification, and supradiaphragmatic tumor location we established a rule for predicting BRAF mutation. In cases where all three criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation was 83% and 93%, respectively. In the validation cohort (n=22), the sensitivity was 100% and specificity was 89%. We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAF V600E targeted systemic therapies.

Oligodendroglioma (OD) is a subtype of adult diffuse glioma defined by IDH1/2 gene mutation and co-deletion of chromosomal arms 1p and 19q. Although prognosis in OD tumors is initially relatively favorable, the majority of OD develop outgrowth of a subclone that has undergone malignant transformation. Modeling the molecular mechanisms of this tumor progression is crucial to identify therapeutic targets for malignant disease. However, there are few available patient-derived OD xenograft models, which limit preclinical investigations. Here, we present novel patient derived anaplastic oligodendroglioma (AOD) xenograft models. In a panel of OD at different stages of disease, we harvested two distinct cell samples: those with and without PIK3CA mutation. From the tumor that subsequently rapidly progressed and had a PIK3CA mutation, we established a xenograft model that was lethal to the mouse and retained the PIK3CA mutation. In contrast, xenograft did not form from the other tumor that was clinically stable after resection and had wild-type PIK3CA. We confirmed AOD phenotype and the presence of IDH1 mutation and 1p/19q co-deletion in xenograft tissue, indicating successful capture of these signature OD genetic alterations. We also tested to see if PI3K/AKT/mTOR gene mutation could induce patient-derived OD xenograft formation. In our attempts to establish xenograft models, the presence of activating mutations in PI3K/AKT/mTOR pathway was consistently associated with successful xenograft establishment. OD/AOD tumors that did not form xenograft did not have mutation in the PI3K/AKT/mTOR pathway Importantly, we found progressive tumor cells that harbor mutant PIK3CA were vulnerable to alkylating agents and PIK/AKT/mTOR pathway inhibitors. These findings suggest there is a critical role of PI3K/AKT/mTOR pathway activation in driving progression and xenograft formation in oligodendroglial tumors. Our xenograft models will facilitate dissection of the mechanism of malignant transformation, contributing to the identification of optimal therapeutic strategies for patients with oligodendroglial tumors

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant tumors represent a distinct subtype among diffuse gliomas, with improved prognosis compared to grade-matched IDH wild-type tumors. As a basis for clinical trial design of IDH-targeting drugs, we sought to describe outcomes exclusively within the glioma subgroup defined by IDH1 mutation. METHODS: We retrospectively analyzed 275 IDH mutant glioma patients (48.7% grade II and 51.3% grade III tumors; 65.5% astrocytic and 34.5% oligodendroglial tumors) treated at our institution. We calculated progression and survival statistics, including median time to second progression event following first episode of recurrence, using the method of Kaplan-Meier. Estimated survival proportions were correlated with molecular, histologic and clinical factors. RESULTS: During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression events (54.1%) were observed, with estimated median PFS of 5.7 years (95% CI 4.7–6.4) and median OS of 18.7 years (95% CI 12.2 years - not reached). We validated the effect of grade, molecular diagnosis and treatment paradigms on PFS in our cohort and found results consistent with existing literature. Following the first episode of progressive disease, 79 second progression events occurred during a median follow-up period of 4.1 years. The estimated PFS following first progressive event (PFS-2nd) is 3.0 years (95% CI 2.1–4.1). CONCLUSION: This well-characterized cohort of IDH mutant glioma patients demonstrate progression and survival outcomes reflecting published literature and serves as a reasonable historical control population. Notably, the PFS interval accelerates during disease course, with interval between first to second recurrence (3.0 years) shorter than time from diagnosis to first recurrence (5.7 years). The novel survival statistic PFS-2nd offers an accurate and relevant surrogate outcome for the design of clinical trials investigating experimental drug efficacy at recurrence. These findings highlight that inappropriate comparison to historical baseline PFS may result in prematurely abandoning promising agents.

BACKGROUND: Immunotherapy has been effective therapy for brain metastases (BM) from melanoma and lung cancer, prompting interest in using PD-1 targeting drugs in more patients with BM. However, accurately assessing response in patients undergoing immunotherapy continues to be a challenge. Thus, we prospectively evaluated radiographic characteristics and changes during immunotherapy. METHODS: As part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI.. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. RESULTS: Forty-eight patients have been enrolled of whom 38 have undergone at least baseline advanced MR imaging. Histologies include 16 with breast cancer (12 HER2-, 4 HER2+), 5 with non-small cell lung cancer, 4 with melanoma, and 11 with other cancers. At baseline, the total number of BM was 1–50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 25 evaluable patients include 2 PR, 9 SD, and 14 PD. Cerebral blood volume tended to increase with increasing tumor size. Correlation of volumetric response to patient outcome and standardized response criteria (iRANO) is ongoing. CONCLUSIONS: Pembrolizumab may have activity in metastatic brain cancer. Ongoing analyses are evaluating if physiological MRI can shed light on the biological impact of pembrolizumab and response mechanisms in this patient population.

Progressive meningiomas that have failed surgery and radiation have poor a prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from progressive/high-grade tumors, including matched primary and recurrent samples. We detected frequent alterations in genes residing on the X-chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n= 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n= 2, 8.3%), DDX3X, RBM10 and STAG2 (n= 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3–9.0) vs. median not reached (95% CI 2.9–not reached), p=0.006)]. We also assessed for TERT alterations, which have a known poor prognostic association, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n= 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p=0.033, HR=2.6, 95% CI 1.0–6.6) and TERT alterations (p= 0.005, HR= 3.8, 95% CI 1.5- 9.9) were mutually independent in predicting unfavorable outcomes. Thus, alterations of the mesodermal gene DMD identify a subset of progressive/high-grade meningiomas with worse outcomes.

2007Background: Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). Median survival of patients with LMD is approximately 4-6 weeks and there are no effective tr...

e14028Background: Although a significant proportion of aggressive meningiomas acquire TERT promoter (TERTp) mutations which drive TERT overexpression during progression, alternative mechanisms of t...

e14041Background: The genetic alterations that define PCNSL are beginning to be identified, and the genomic evolution that conveys susceptibility or resistance to treatment in recurrent disease is ...

Three days before admission to this hospital, a 37-year-old, right-handed woman had vertigo, weakness and numbness of the left side, and shaking of the left leg. Magnetic resonance imaging (MRI) at another hospital revealed a mass in the right parietal lobe of the brain. She had had an endometrial biopsy 2 weeks before admission and a dental procedure 1.5 weeks before admission. On transfer to this hospital, she did not have fever, chills, or pain. Examination revealed decreased sensation to touch on the left. Repeat MRI showed enlargement of the brain lesion. A diagnostic procedure was performed.

Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O6-methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O6-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.

Lower-grade gliomas (LGGs) are classified by recurrent mutations in the IDH1/2 and TP53/ATRX genes, the TERT promoter, and chromosome 1p/19q loss. These alterations cluster tumors into three molecular groups with distinct prognoses: the "molecular astrocytic" (group A) defined by co-presence of IDH1/2 and TP53-and/or-ATRX mutation, "molecular oligodendroglial" (group O) defined by presence of IDH1/2 mutation and absence of TP53/ATRX mutations, and "molecular glioblastoma-like"(group G) defined by absence of IDH1/2 mutation. Here, we examined the traditional clinical heuristic of tumor size, assessed by T2/FLAIR and T1 post-gadolinium MRI contrast enhancement (both measured by the product of two orthogonal dimensions on the axial MRI image with the greatest tumor area), within the three molecular groups from cases in the TGCA LGG cohort with available image data in TCIA (n = 172). Upon examination of preoperative MRIs, median tumor measurement by T2/FLAIR was 31.96 cm2 in group A, 19.14 cm2 in group O, and 17.45 cm2 in group G. Notwithstanding this larger size, only 19/85 group A tumors had enhancing area > 10% of the overall tumor size, while 11/47 group O and 24/40 group G gliomas showed similar extent-of-enhancement. Thus, group G gliomas were more frequently enhancing (p = 0.0001 and p = 0.0009 for the comparisons between group A and O respectively, Fisher's exact test). The prognostic impact of contrast enhancement may therefore reflect, in part, this differing distribution between molecular groups. Indeed, WHO grade was also partially linked to enhancement, with 10 of 83 grade II tumors displaying enhancing areas >10% of the overall tumor size, while 44 of 89 grade III tumors were similarly enhancing. Given the inability to identify molecular categories of low-risk tumors from clinical and radiographic factors alone, we conclude that surgical resection or biopsy is indicated in all suspected LGGs, to facilitate molecular group assignment and guide further therapy.

Leptomeningeal carcinomatosis (LM) is a rare complication of melanoma that is associated with a poor prognosis. Given limited data in LM in melanoma, we sought to characterize overall survival in patients with primary melanoma who developed LM. We performed a retrospective review at our institution of LM melanoma patients from 1993 to 2014. Inclusion criteria included patients with documented melanoma and LM as diagnosed by cytology or imaging. Median age was 49.5 years (range, 22-79) in 55 patients, 35 male and 20 female. LM was diagnosed by positive cytology in 20 patients (36.4%) or imaging in 52 patients (94.5%). Median survival from diagnosis of LM to death was 9.7 weeks. Additionally, median time from diagnosis of primary melanoma to LM was 27.3 months (range, 0-109) and from stage IV melanoma 7.5 months (range, 0-46). In univariate analysis, serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) performance status, and LM treatment (no treatment, radiation, chemotherapy) influenced survival. In multivariate analysis, abnormal LDH (p < 0.035) remained a significant predictor of poor survival, while LM treatment with chemotherapy compared to no treatment conferred a survival advantage (p < 0.019). Treatment with radiation and ECOG performance status were no longer significant. Our data offer the largest series of melanoma patients with diagnosed LM and help to characterize the clinical presentation of this devastating late-stage complication of cancer. More effective treatments for this complication are necessary.

Background Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized. Methods Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47Δ were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47Δ. Results We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47Δ efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47Δ significantly extended the survival of mice bearing subdural MN3 tumors. Conclusions We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47Δ for HGM.

BACKGROUND: Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE: To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS: We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS: Neurosurgeons’ individual surgical goals varied significantly (P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor (R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes (P < .01) and nonresectable residual (P < .01), but not resectable residual. CONCLUSION: In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.

Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using 13C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models. Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN–amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts. Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452–65. ©2016 AACR.

Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2016;122:189-197. © 2015 American Cancer Society.

What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? Adult patients with imaging suggestive of a low-grade glioma. Stereotactic biopsy is recommended when definitive surgical resection is limited by lesions that are deep-seated, not resectable, and/or located within eloquent cortex, or in patients unable to undergo craniotomy due to medical co-morbidities to obtain the critical tissue diagnosis needed for targeted treatment planning for patients with low-grade gliomas. What is the best technique for brain biopsy? Adult patients with imaging suggestive of a low-grade glioma. Frameless and frame-based stereotactic brain biopsy for low-grade gliomas are recommended based on clinical circumstances as they provide similar diagnostic yield, diagnostic accuracy, morbidity, and mortality. It is recommended the surgeon consider advanced imaging techniques (e.g., perfusion, spectroscopy, metabolic studies) to target specific regions of interest to potentially improve diagnostic accuracy.

Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma. What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult? Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma. Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues. Patients with histologically-proven WHO grade II diffuse glioma. In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method? IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse glioma, and is recommended as an additional test for classification and prognosis. Patients with histologically-proven WHO grade II diffuse glioma. In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method? 1p/19q loss-of-heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning. Patients with histologically-proven WHO grade II diffuse glioma. In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method? There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population. Patients with histologically-proven WHO grade II diffuse glioma. In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results? Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment.

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed wholeexome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases., Massachusetts Institute of Technology. Department of Biology, National Institutes of Health (U.S.) (National Human Genome Research Institutes of Health Large-scale Sequencing and Analysis Center. Grant U54 HG003067)

Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.

Contains fulltext : 153032.pdf (Publisher’s version ) (Closed access) Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities.

OBJECTIVES To report the 2-year clinical and biochemical follow-up of symptomatic men who had a high prostate-specific-antigen (PSA) level, for whom our policy has been to avoid biopsy in those with a normal repeat PSA, as minimizing negative prostate biopsies is an important goal in managing men with a high PSA, where the decision for biopsy based on one high value may be inappropriate. PATIENTS AND METHODS In all, 101 men (median age 72 years, range 47–85) referred to a urology department over 1 year with a PSA level above the age-specific reference range (but

Immune checkpoint blockade is a treatment option for patients with melanoma brain metastases (MBM). This single institutional analysis investigated the optimal management for patients with MBM undergoing surgical resection and immunotherapy. An IRB-approved, retrospective study identified 142 MBM patients treated with immune checkpoint blockade between 2010 and 2015. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Model building included a prognostic model of OS and the effect of immunotherapy and surgical sequencing on OS. Parallel model-building techniques were used to address the potential for guarantee-time bias. The 2-year OS for patients treated with CTLA-4, PD-1 or combinatorial blockade were 19%, 54%, and 57%, respectively. Accounting for the time-dependent covariate of surgery, factors associated with increased hazard of death included abnormal LDH, presence of extracranial disease at time of brain metastasis diagnosis, and greater than 3 brain metastases. The sequence of therapy was associated with a 2.1-fold increase in the hazard of death amongst patients initially undergoing immunotherapy +/- subsequent surgery compared to surgical patients who went on to receive immunotherapy (HR: 2.1, 95% CI: 1.2 to 3.9, P=0.01). The observed increase in risk is primarily reflected in the subgroup of patients undergoing immunotherapy prior to brain metastases diagnosis +/- surgery, who had a statistically significant, 2.3-fold increase in the hazard of death (HR: 2.29, 95% CI: 1.2 to 4.4, P=0.04). In conclusion, the sequence of surgery and immunotherapy is associated with OS and surgical resection should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve MBM is warranted.

Mutant IDH1 suppresses normal IDH1 activity and alters the cellular metabolic microenvironment. We have previously identified that steady-state NAD+ level is decreased in endogenous IDH1 mutant cancers. Additionally, we found that inhibitors of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) potently depleted NAD+ and selectively induced cytotoxicity in IDH1 mutant cancers. Here, we investigated strategies to further perturb NAD+ metabolism to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. One major source of intracellular NAD+ consumption is mediated by distinct enzyme complexes of poly(ADP-ribose) polymerase (PARP). We found that temozolomide (TMZ), a commonly-used alkylating chemotherapeutic agent, transiently and potently reduced NAD+ to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. Mechanistically, TMZ stimulates an acute burst of NAD+ consumption by PARP via activation of DNA damage repair, and as a result, selectively potentiated NAD+ depletion-induced cytotoxicity in IDH mutant cells. In an in vivo IDH1 mutant cancer model, combined treatment with TMZ and NAMPT inhibitor enhanced efficacy compared to each agent alone. Thus, we find chemotherapy induces metabolic stress in IDH1 mutant cancers which can be exploited for therapeutic gain. Targeting of NAD+ homeostasis via convergent metabolic pathways could improve responses to metabolic therapy.

INTRODUCTION Histone H3 K27M mutations distinguish a subgroup of midline gliomas in children and young adults with devastating prognosis for which there are no effective medical therapies. In a recent phase 2 trial in adult recurrent glioblastoma with ONC201, a small molecule selective antagonist of the dopamine receptor D2 (DRD2) and D3 (DRD3), a 22 year old female with recurrent H3 K27M mutant glioblastoma had tumor regression of 92% that has persisted >15 months. Furthermore, antiseizure medication was discontinued and no ONC201 side effects were observed. Based on this exceptional response, we tested whether H3 K27M mutant gliomas were selectively sensitive to ONC201-induced apoptosis.

Background: Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high grade gliomas, and represents a key molecular mechanism for the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma. Methods: We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC overexpression and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined. Results: The compound screening indentified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of both MMR intact and deficient glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no detectable toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown, whereas PLK1 inhibition had no additive or synergic effect when combined with TMZ. Furthermore, we found that MYC overexpression sensitized glioblastoma cells to PLK1 inhibitors. Conclusions: Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. Thus PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC. Citation Format: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto. PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2017-LB-301

2050 Background: The infiltrating nature of gliomas, particularly into the peritumoral area, is a major barrier to improving clinical outcome as microscopic disease remains even after apparent gross total resection. Conventional T1 post-contrast and T2/FLAIR MRI do not capture full tumor extent. A better imaging biomarker is needed to improve differentiation between tumor, peritumoral area and normal brain. Methods: 4 pre-surgical patients with non-enhancing, FLAIR-hyperintense lesions suspicious for glioma underwent ultra-high gradient diffusion MRI on the Connectome MRI scanner, a unique scanner with maximum gradient strength of 300 mT/m enabling mapping of cellular microstructures on a micron-level scale. The FLAIR area was defined as the tumor region of interest (ROI). Radiographically normal appearing brain up to 1 cm around the FLAIR area was defined as the peritumoral ROI. Using a novel 3 compartment diffusion model (Linear Multiscale Model), the volume fraction of water (VFW) was calculated within restricted (intracellular), hindered (extracellular) and free (CSF) spaces. VFW in the tumor, peritumoral ROI, contralateral normal white matter (WM) and cortex were compared. Results: Within the tumor ROI, the median VFW in the restricted compartment was decreased vs. the peritumoral ROI (↓ 34%), WM (↓ 46%) and cortex (↓ 18%) while median VFW in the hindered compartment was increased vs. the peritumoral ROI (↑ 26%), WM (↑ 54%) and cortex (↑ 25%). Within the peritumoral ROI, median VFW in the hindered compartment was increased compared to WM (↑ 23%). 3 patients had available histopathology revealing isocitrate dehydrogenase-mutant gliomas. Conclusions: Using ultra-high gradient diffusion MRI and a novel diffusion model, we detected distinct diffusion patterns in the tumor and peritumoral area not seen on conventional MRI. Lower VFW in the restricted compartment within the tumor may reflect decreased intracellular water mobility due to enlarged nuclei. Higher VFW in the hindered compartment in the tumor and peritumoral area may reflect higher degree of tissue permeability and edema. MRI-pathology and larger cohort validation studies are underway to elucidate microenvironment changes in response to treatment.

2047 Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

BACKGROUND: Patients with malignant astrocytoma in similar brain regions present with variation in neurocognitive function (NCF). One potential contributor to this variation is the rate at which the tumor progresses or "lesion momentum". IDH1-wild type (IDH1-WT) tumors are more rapidly progressive than IDH1-mutant (IDH1-M) tumors. We hypothesized that patients with IDH1-WT tumors would exhibit worse NCF than patients with IDH1-M tumors. METHODS: The IDH1 status of 119 patients with malignant astrocytoma was determined with immunohistochemistry and genetic sequencing. Patients completed NCF testing prior to surgical resection [WAIS-III: Block Design, Similarities, Digit Span (DS), Digit Symbol; Hopkins Verbal Learning Test-Revised; Confrontation Naming; Controlled Oral Word Association (COWA); Token Test; Trail Making Test (TMT); Grooved Pegboard]. Raw NCF test scores were converted to age-adjusted z-scores. Lesion volume was calculated from preoperative T2/FLAIR MRI. RESULTS: Patients with IDH1-WT tumors (n = 66; mean age = 54.40) were significantly older than those with IDH1-M tumors (n = 53; mean age = 37.74; p < .001). No between group differences were found in years of education, gender, race, lesion location, or lesion volume. IDH1-WT patients performed worse than IDH1-M patients on all NCF tests with statistically significantly lower (p= .025 to .001) performances on HVLT-R Total Recall, HVLT-R Delayed Recall, TMTA, TMTB, COWA, Digit Symbol, Token, and Grooved Pegboard. For IDH1-WT patients, FLAIR volume was significantly associated with 12 of 14 NCF tests (r = -0.33 to -0.51, p < .009 for all). For IDH1-M patients, FLAIR volume was only significantly associated with Naming [r = -0.48, p = .001]. CONCLUSION: Patients with IDH1-WT malignant astrocytoma exhibit worse NCF than those with IDH1-M tumors. FLAIR lesion volume is inversely associated with NCF for patients with IDH1-WT but not IDH1-M tumors. These findings are consistent with the hypothesis that patients with IDH1-WT tumors present with greater NCF dysfunction secondary to greater lesion momentum that may preclude compensatory neuroplasticity and brain reorganization.

Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.

Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy., National Institutes of Health (U.S.) (U24 CA180922)

Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC(2)) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology.

It has been proposed recently that the type of genetic instability in cancer cells reflects the selection pressures exerted by specific carcinogens. We have tested this hypothesis by treating immortal, genetically stable human cells with representative carcinogens. We found that cells resistant to the bulky-adduct-forming agent 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP) exhibited a chromosomal instability (CIN), whereas cells resistant to the methylating agent N -methyl- N ′-nitro- N -nitrosoguanidine (MNNG) exhibited a microsatellite instability (MIN) associated with mismatch repair defects. Conversely, we found that cells purposely made into CIN cells are resistant to PhIP, whereas MIN cells are resistant to MNNG. These data demonstrate that exposure to specific carcinogens can indeed select for tumor cells with distinct forms of genetic instability and vice versa .

Paget's disease of bone (PDB) is a common disorder characterized by focal areas of increased and disorganized osteoclastic bone resorption, leading to bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. Genetic factors play an important role in the pathogenesis of Paget's disease. In some families, the disease has been found to be linked to a susceptibility locus on chromosome 18q21-22, which also contains the gene responsible for familial expansile osteolysis (FEO)--a rare bone dysplasia with many similarities to Paget's disease. Insertion mutations of the TNFRSF11A gene encoding Receptor Activator of NF kappa B (RANK) have recently been found to be responsible for FEO and rare cases of early onset familial Paget's disease. Loss of heterozygosity (LOH) affecting the PDB/FEO critical region has also been described in osteosarcomas suggesting that TNFRSF11A might also be involved in the development of osteosarcoma. In order to investigate the possible role of TNFRSF11A in the pathogenesis of Paget's disease and osteosarcoma, we conducted mutation screening of the TNFRSF11A gene in patients with familial and sporadic Paget's disease as well as DNA extracted from Pagetic bone lesions, an osteosarcoma arising in Pagetic bone and six osteosarcoma cell lines. No specific abnormalities of the TNFRSF11A gene were identified in a Pagetic osteosarcoma, the osteosarcoma cell lines, DNA extracted from Pagetic bone lesions, or DNA extracted from peripheral blood in patients with familial or sporadic Paget's disease including several individuals with early onset Paget's disease. These data indicate that TNFRSF11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosarcoma.

Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute–sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.

Intracerebral hemorrhage (ICH) contributes significantly to the morbidity and mortality of patients suffering from acute leukemia. While ICH is often identified in autopsy studies of leukemic patients, it is rare for ICH to be the presenting sign that ultimately leads to the diagnosis of leukemia. We report a patient with previously undiagnosed acute precursor B-cell lymphoblastic leukemia (ALL) who presented with diffuse encephalopathy due to ICH in the setting of an acute blast crisis. The diagnosis of ALL was initially suspected, because of the hyperleukocytosis observed on presentation, then confirmed with a bone marrow biopsy and flow cytometry study of the peripheral blood. Furthermore, detection of the BCR/ABL Philadelphia translocation t(9:22)(q34:q11) in this leukemic patient by fluorescent in situ hybridization permitted targeted therapy of the blast crisis with imatinib (Gleevec). Understanding the underlying etiology of ICH is pivotal in its management. This case demonstrates that the presence of hyperleukocytosis in a patient with intracerebral hemorrhage should raise clinical suspicion for acute leukemia as the cause of the ICH.

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.Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry.IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P.001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for5 cc residual vs not reached for5 cc, P = .025).The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.

Genetic instability has long been hypothesized to be a cardinal feature of cancer. Recent work has strengthened the proposal that mutational alterations conferring instability occur early during tumour formation. The ensuing genetic instability drives tumour progression by generating mutations in oncogenes and tumour-suppressor genes. These mutant genes provide cancer cells with a selective growth advantage, thereby leading to the clonal outgrowth of a tumour. Here, we discuss the role of genetic instability in tumour formation and outline future work necessary to substantiate the genetic instability hypothesis.

Genetic instability was one of the first characteristics to be postulated to underlie neoplasia1,2,3. Such genetic instability occurs in two different forms. In a small fraction of colorectal and some other cancers, defective repair of mismatched bases results in an increased mutation rate at the nucleotide level and consequent widespread microsatellite instability4,5,6,7. In most colorectal cancers, and probably in many other cancer types, a chromosomal instability (CIN) leading to an abnormal chromosome number (aneuploidy) is observed8. The physiological and molecular bases of this pervasive abnormality are unknown. Here we show that CIN is consistently associated with the loss of function of a mitotic checkpoint. Moreover, in some cancers displaying CIN the loss of this checkpoint was associated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast. The normal mitotic checkpoints of cells displaying microsatellite instability become defective upon transfer of mutant hBUB1 alleles from either of two CIN cancers.

We present a previously unreported set of symptoms in a patient found to have bilateral vertebral dissections. Although visual symptoms are common in vertebral dissection, their pattern does not typically mimic those that commonly precede or accompany migraine headache. When they do occur, they usually take the form of diplopia or blurred vision. The patient we describe had visual symptoms that varied over three episodes of headache and included transient visual field loss and scintillations ("lightning bolts"), both common in migraine. However, our patient's new visual symptoms represented a change in pattern from those that had accompanied her previous migraines. This detailed history-taking prompted an evaluation for an etiology other than migraine and prevented a further delay in diagnosis and treatment.