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Purpose: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated.Methods: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity.Results: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)].Conclusions: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting. [ABSTRACT FROM AUTHOR]

Introduction: The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. Methods: Thirty-four patients <21 years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. Results: The mean age at diagnosis was 7.9 years (range 1.2-18.3 years) and mean age at RT was 9.8 years (range 3.0-28.9 years). The median follow-up time was 9.8 years after radiation (range 0.8-33.3 years). The estimated 10-year OS and PFS after RT were 92 and 74 %, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1 years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. Conclusion: Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up. [ABSTRACT FROM AUTHOR]

Among brain tumors, the BRAF mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

Purpose: Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFRα2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary. Methods: The expression of GFRα2 and other members of the GFR receptor family (GFRα1, α3, α4) were analyzed using RT-PCR, western blot, and immunohistochemistry in 39 pituitary adenomas, 14 normal pituitary glands obtained at autopsy, and cDNA from 3 normal pituitaries obtained commercially. Results: GFRα2 mRNA was ~2.6 fold under-expressed in functioning adenomas ( p < 0.01) and ~3.5 fold over-expressed in non-functioning adenomas (NFAs) ( p < 0.05) compared to normal pituitary. Among NFAs, GFRα2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only ( p < 0.05). GFRα2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFRα2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFRα2 was localized in Rathke's remnant, the putative pituitary stem cell niche, and in corticotropes. Conclusion: Our results suggest that the pituitary stem cell marker GFRα2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over-expression of GFRα2 in gonadotropinomas might play a role in pituitary tumorigenesis. [ABSTRACT FROM AUTHOR]

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG. [ABSTRACT FROM AUTHOR]

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas. [ABSTRACT FROM AUTHOR]

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5 years ( p = 0.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas ( p = 0.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30 years ( p = 0.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches. [ABSTRACT FROM AUTHOR]

Hypertrophic olivary degeneration (HOD) is caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). We present conventional magnetic resonance and diffusion tensor imaging (DTI) findings in a 6-year-old girl with HOD after surgery for a midbrain pilocytic astrocytoma. To our knowledge, this is the first dedicated DTI analysis of GMT in a child with HOD in the literature. In our patient, we found higher fractional anisotropy (FA) and axial diffusivity values of the inferior olivary nucleus (ION) and lower FA, but higher radial diffusivity (RD) values of all other GMT components compared to age-matched controls. Increased FA values of the ION may be explained by increased packing of white matter fibers. However, associated hyperintense T2 signal is contradictory and the association between increased FA values and hyperintense T2 signal remains unclear. Low FA and high RD values of the other GMT components likely reflect demyelination with axonal degeneration and correlate well with histopathological findings. [ABSTRACT FROM AUTHOR]

The addition of concomitant and adjuvant chemotherapy to radiation therapy after surgical resection has increased significantly the survival of patients with glioblastoma (GB). In conjunction, there has been an increasing fraction of patients who present with new enlarged areas of contrast enhancement and edema on post-treatment imaging that improve without further treatment. It remains to be established how this phenomenon, commonly termed pseudoprogression, can be distinguished from true tumor recurrence defined as the histological presence of active high-grade tumor, as well as its prognostic significance. Data for over 500 patients undergoing surgery for recurrent GB were reviewed. Pathological specimens were categorized as those that contained active high-grade glioma in any amount, and those that did not. Patient survival was compared between these two groups, and independent associations were assessed using Cox proportionate hazards regression analysis. 59 patients met the study criteria including complete pathological and follow-up data. Mean age was 53 ± 11 years. Median survival from suspected recurrence and initial diagnosis were 8 [5-14] and 20 [12-30] months. Seventeen patients (29 %) had no evidence of active high-grade tumor and 42 (71 %) had at least focal active high-grade glioma. Pathologic pseudoprogression at re-operation ( p = 0.03) and gross total resection ( p = 0.01) were independently associated with survival. The histopathological features defined here and used to assess the tumor at reoperation were independently associated with survival. These findings may be important in designing treatment strategies and clinical trial endpoints for patients with GB. [ABSTRACT FROM AUTHOR]

This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co-deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were 'always' or 'almost always' helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently 'never' or 'almost never' helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs. [ABSTRACT FROM AUTHOR]

Rare, generally pediatric oligodendroglioma-like neoplasms with extensive leptomeningeal dissemination have been interpreted variably as glial, oligodendroglial or glioneuronal. The clinicopathologic features have not been fully characterized. We studied 36 patients, 12 females and 24 males with a median age of 5 years (range 5 months-46 years). MRI demonstrated leptomeningeal enhancement, frequently with cystic or nodular T2 hyperintense lesions within the spinal cord/brain along the subpial surface. A discrete intraparenchymal lesion, usually in the spinal cord, was found in 25 (of 31) (81 %). Tumors contained oligodendroglioma-like cells with low-mitotic activity (median 0 per 10 high power fields, range 0-4), and rare ganglion/ganglioid cells in 6 cases (17 %). Tumors were mostly low-grade, with anaplastic progression in 8 (22 %). Immunohistochemistry demonstrated strong reactivity for OLIG2 (7 of 9) (78 %), and moderate/strong S100 (11 of 12) (92 %), GFAP (12 of 31) (39 %) and synaptophysin (19 of 27) (70 %). NeuN, EMA, and mutant IDH1 (R132H) protein were negative. Median MIB1 labeling index was 1.5 % (range <1-30 %). FISH ( n = 13) or SNP array ( n = 2) demonstrated 1p loss/intact 19q in 8 (53 %), 1p19q co-deletion in 3 (20 %), and no 1p or 19q loss in 4 (27 %). Clinical follow-up ( n = 24) generally showed periods of stability or slow progression, but a subset of tumors progressed to anaplasia and behaved more aggressively. Nine patients (38 %) died 3 months-21 years after diagnosis (median total follow-up 5 years). We report a series of a neoplasm with distinct clinicopathologic and molecular features. Although most progress slowly, a significant fraction develop aggressive features. [ABSTRACT FROM AUTHOR]

Therapies that disrupt or repair blood-brain barrier integrity can result in major changes in MRI images even when the tumor volume remains constant. Thus, a reliable blood-based tumor biomarker could significantly improve clinical care and research studies in these patients. This study was performed to assess plasma concentrations of glial fibrillary acidic protein (GFAP) in patients with high- and low-grade gliomas before and after debulking surgery. Pre-operative plasma was collected from 33 patients with radiation- and chemotherapy-naïve gliomas. Additional plasma was collected 24-48 h post-operatively from 23 of these patients. Plasma GFAP (pGFAP) concentrations were determined using an electrochemiluminescent immunoassay and were analyzed as a function of tumor grade, tumor GFAP expression, the integrity of the blood-brain barrier, and post-operative status. Detectable pGFAP levels (≥0.04 ng/mL) were found pre-operatively in 52 % of patients and post-operatively in 96 %. Detectable pGFAP was more common in patients with WHO grade IV (100 %) than WHO grade III (56 %) or WHO grade II gliomas (20 %). No patient with undetectable GFAP had WHO grade IV glioma. Higher pGFAP concentrations were also associated with contrast enhancement but not related to tumor GFAP expression. GFAP is commonly detected in the plasma of patients with high-grade gliomas. pGFAP levels rise rather than fall following debulking surgery which is probably a result of surgical trauma. GFAP remains a potentially informative plasma biomarker for gliomas. Longitudinal studies are required to correlate pGFAP levels with patient outcomes. [ABSTRACT FROM AUTHOR]

Leptomeningeal carcinomatosis (LC) is a devastating complication of cancer. Intrathecal administration of cytotoxic chemotherapy adds little to survival which is measured in weeks. The potential toxicities and efficacy of intrathecally administered anti-angiogenic agents in this setting have not previously been explored. A well-characterized animal model was used to evaluate the neurotoxicity of intraventricularly administered bevacizumab (BCM). Thirty-three New Zealand White Rabbits were studied. Subcutaneous reservoirs and ventricular catheters (SRVC) were placed in eight rabbits, which were randomized to receive weekly intraventricular saline with or without BCM for four weeks. These rabbits were euthanized on day 36 and the brains were examined by a blinded neuropathologist. Twenty-five additional rabbits underwent cisternal injection of VX2 carcinoma cells with or without a single dose of BCM and were followed for survival. No clinical manifestations of neurotoxicity were noted in rabbits treated with intraventricular BCM. Similarly, no evidence of BCM neurotoxicity was identified in autopsied animals. The median survival of evaluable rabbits with LC treated with intraventricular saline ( N = 13) was 15 days compared to 18 days for the animals receiving VX2 and one dose of BCM ( N = 12). Conclusion: Intraventricular BCM can be administered to rabbits without clinical or pathologic neurotoxicity. Survival following one dose of BCM in rabbits with LC should be cautiously interpreted given uncertainties regarding the dose, schedule, and limited expected benefit of this non-rabbit antibody. This neurotoxicity study provides safety data to allow phase I/II studies in humans with treatment refractory LC. [ABSTRACT FROM AUTHOR]

Medulloblastoma with myogenic differentiation (MMD) is a rare and aggressive variant of medulloblastoma, occurring predominantly in children. There have been only two case reports of long-term survival previously published. We report a case of long-term disease-free survival in a 21-year-old diagnosed with MMD. [ABSTRACT FROM AUTHOR]

It has been reported that prolactinomas treated with Bromocriptine (BROM) show fibrosis that may interfere with complete surgical resection. The same has not been reported for Cabergoline (CAB). We retrospectively studied 24 consecutive patients (13 females, mean age 40 years, range 16-60) with histopathologically confirmed prolactinomas undergoing surgical resection at Johns Hopkins Hospital between 1992 and 2009. We compared these prolactinomas to 34 patients (22 females, mean age 42.9 years, range 15-75) with GH-secreting adenoma. The operative notes from 7 different neurosurgeons were reviewed to catalog the tumors as fibrous or not fibrous. Of the 24 prolactinomas, 21 (87.5%) were previously treated with DA. Indication for surgery was: DA resistance (n.5), DA intolerance (n.6), persistent mass effect (n.7) and CSF leak (n.3). Five (14.7%) of GH-secreting adenomas, were exposed to DA and/or somatostatin analogs. We found that 54% of prolactinomas and only 6% of GH-secreting adenomas were described as fibrous. 10/12 (77%) of prolactinomas exposed to BROM for at least 1 month, 2/9 (22%) exposed to CAB only, and 1/3 (33%) not previously treated were fibrous ( P < 0.05). The mean BROM cumulative dose was 406 mg (range 75-1,375), while CAB dose was 28 mg (range 6-70). Only 18% of non-fibrous prolactinomas had been exposed to BROM. Only 3 patients had persistent biochemical remission (2 treated with CAB and 1 not treated). Patients exposed to BROM for at least 1 month are more likely to have tumor fibrosis than patients that are untreated or treated with CAB. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies have demonstrated a high frequency of IDH mutations in adult 'secondary' malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in 'primary' gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas, we questioned whether a subset of these tumors also exhibited IDH mutations. Experimental design: We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children's Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated. Results: IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children ≥14 years, but in 0 of 23 (0%) younger children ( p = 0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86 ± 15% in the IDH-mutated group versus 64 ± 8% in the non-mutated group ( p = 0.03, one-sided logrank test). One-year overall survival was 100% in patients with mutations versus 81 ± 6.7% in those without mutations ( p = 0.035, one-sided logrank test). Conclusions: IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis. [ABSTRACT FROM AUTHOR]

errant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children’s Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival ( p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors. [ABSTRACT FROM AUTHOR]

To characterize a population of pediatric high-grade astrocytoma (HGA) patients by confirming the proportion with a correct diagnosis, and determine prognostic factors for survival in a subset diagnosed with uniform pathologic criteria. Sixty-three children diagnosed with HGA were treated at the Johns Hopkins Hospital between 1977 and 2004. A single neuropathologist (P.C.B.) reviewed all available histologic samples ( n = 48). Log-rank analysis was used to compare survival by patient, tumor, and treatment factors. Median follow-up was 16 months for all patients and 155 months (minimum 54 months) for surviving patients. Median survival for all patients ( n = 63) was 14 months with 10 long-term survivors (survival >48 months). At initial diagnosis, 27 patients were grade III (43%) and 36 grade IV (57%). Forty-eight patients had pathology slides available for review, including seven of ten long-term surviving patients. Four patients had non-HGA pathology, all of whom were long term survivors. The remaining 44 patients with confirmed HGG had a median survival of 14 months and prognostic analysis was confined to these patients. On multivariate analysis, five factors were associated with inferior survival: performance status (Lansky) <80% (13 vs. 15 months), bilaterality (13 vs. 19 months), parietal lobe location (13 vs. 16 months), resection less than gross total (13 vs. 22 months), and radiotherapy dose <50 Gy (9 vs. 16 months). Among patients with more than one of the five adverse factors ( n = 27), median survival and proportion of long-term survivors were 12.9 months and 0%, compared with 41.4 months and 18% for patients with 0–1 adverse factors ( n = 17). In an historical cohort of children with HGA, the potential for long term survival was confined to the subset with less than two of the following adverse prognostic factors: low performance status, bilaterality, parietal lobe site, less than gross total resection, and radiotherapy dose <50 Gy. Pathologic misdiagnosis should be suspected in patients who are long term survivors of a pediatric high grade astrocytoma. [ABSTRACT FROM AUTHOR]

The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide. [ABSTRACT FROM AUTHOR]

The category of mixed glioneuronal tumors of the CNS is rapidly losing its definition as encompassing tumors composed of histologically distinct neuron variants and glia. We encountered five ependymomas with neuronal differentiation seen in two by histology, in two by immunohistochemistry alone, and in one by electron microscopy. Antibodies against GFAP, S-100 protein, neurofilament protein, chromogranin, synaptophysin, Neu-N, and EMA were applied. Ultrastructural studies were also performed. In addition, 33 randomly selected ependymomas of various histologic types were screened for these same antigens. Cases 1 and 2 were anaplastic and showed clearly defined neuropil islands or pale islands as in nodular desmoplastic medulloblastoma, respectively. The tumors affected a 16-year-old male and a 5-year-old female and involved the right frontoparietal lobe and fourth ventricle, respectively. The islands were positive for synaptophysin and Neu-N (cases 1 and 2), and chromogranin (case 1). Cases 3–5, as well as 7 of the 33 screened ependymomas, showed a suggestion of neuronal differentiation by immunohistochemistry alone, including immunoreactivity for Neu-N ( n = 8), synaptophysin ( n = 4), neurofilament protein ( n = 4), and chromogranin ( n = 2). Five tumors each were WHO grade II and III. Electron microscopy performed on the two cases with neuronal islands demonstrated microtubule bundles and dense core granules (case 1) and poorly differentiated cells with high nuclear/cytoplasmic ratios, with intermediate filament accumulation and rare cilia (case 2). Cases identified by immunohistochemistry or electron microscopy demonstrated dense core granules ( n = 5) and aligned microtubules ( n = 3). Neuronal differentiation occurs in ependymomas but is less frequently definitive (histologic, ultrastructural) than merely a limited immunohistochemical finding. The clinical significance of these observations is unknown but deserves further exploration. [ABSTRACT FROM AUTHOR]

Objects: A pilomyxoid astrocytoma (PmA) is considered to be either a more aggressive variant of a pediatric pilocytic astrocytoma (PA) or a tumor of a separate entity. Methods: We present two cases of pediatric optic-chiasmatic PmA. Proton magnetic resonance spectroscopic imaging (MRSI) of the PmA revealed decreased concentrations of total choline (Cho), creatine (Cr), and N-acetyl aspartate (NAA). In contrast, proton MR spectra of PAs showed elevated Cho and decreased Cr and NAA signals. Conclusion: Low metabolite concentrations in PmAs detected by MRSI may therefore help to distinguish PmAs from PAs preoperatively. [ABSTRACT FROM AUTHOR]

Understanding chemoresistance profiles of brain tumors may aid in more educated selection of chemotherapeutic regimens for clinical trials and patient treatment. Although the literature contains many reports of the application of drug resistance assays, little is known about extreme drug resistance (EDR) in primary brain tumors. We undertook this study to determine chemoresistance profiles for brain tumors. From September 1991 to February 1998, we collected 64 brain tumor specimens from patients admitted to the Johns Hopkins Hospital. Tumors were classified according to the revised World Health Organization system. Brain tumor specimens were tested against 13 different chemotherapeutic agents using an extreme drug resistance assay. Results were reported as percent cell inhibition (PCI) (compared to control cultures). A drug resistance profile (extreme, intermediate, or low) was determined based on statistical comparison to a historical database of tumor specimens tested against the same panel of chemotherapeutic agents. Brain tumor specimens were classified histologically as Grade IV astrocytoma (glioblastoma multiforme, n = 35), Grade II/III astrocytoma ( n = 11), oligodendroglioma ( n = 6), meningioma ( n = 9), hemangiopericytoma ( n = 2), and ependymoma ( n = 1). A large percentage of glioblastomas displayed extreme drug resistance to paclitaxel (69%, n = 35), SN38 (75%, n = 28), and vincristine (38%, n = 29). The majority of Grade II/III astrocytomas displayed extreme drug resistance to carboplatin (67%, n = 6), cisplatin (60%, n = 10), and paclitaxel (60%, n = 10). In a similar fashion, oligodendrogliomas displayed extreme drug resistance to vincristine (60%, n = 5) and paclitaxel (50% n = 6). Most meningiomas displayed extreme drug resistance to vincristine (75%, n = 8), dacarbazine (63%, n = 8), and 4-HC (50%, n = 8). Through the continued analysis of brain tumor specimens and compilation of data from multiple institutions, chemoresistance profiles could assist in the development of rationale clinical trials and treatment regimens for patients with brain tumors. [ABSTRACT FROM AUTHOR]

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11–45 μg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 μg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days ( P=0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days ( P=0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days ( P<0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP : SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model. [ABSTRACT FROM AUTHOR]

Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxPtechnology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cellautonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease. [ABSTRACT FROM AUTHOR]

Amplification of the epidermal growth factor receptor (EGFR) gene is found in about 40% of glioblastomas (GBMs) but is rarely detected in GBM cell lines. We confirmed that the exceptional SKMG-3 GBM cell line retained amplified EGFR genes in vitro, and found that these sequences were concentrated on extra-chromosomal DNA particles similar to double-minute chromosomes. The cells contained two other gene mutations that are associated with high-grade astrocytic tumors: extra-chromosomal amplification of the cyclin-dependent kinase-4 (CDK4) gene and a homozygous mutation within the PTEN tumor suppressor gene. Immunoblots revealed very high levels of EGFR, moderately increased expression of CDK4, and no detectable PTEN protein. The over-expressed SKMG-3 EGFRs responded to exogenous ligand and resembled normal rather than mutant receptors. A heterozygous mutation of the p53 gene (p53R282W) correlated with failure of radiation to induce the expression of cyclin-dependent kinase inhibitor p21waf1 or an early G1 cell cycle arrest. Although each of these gene mutations occurs in GBMs, SKMG-3 cells had an unusual genotype in that a p53 gene mutation co-existed with amplified EGFR genes. Nonetheless, the SKMG-3 cell line can be exploited as a model to study how oncogenic EGFR signals in GBM cells interact with over-expressed CDK4 and loss of PTEN to confer the malignant phenotype. [ABSTRACT FROM AUTHOR]

Allelic alterations of chromosomes 1 and 19 are frequent events in human diffuse gliomas and have recently proven to be strong predictors of chemotherapeutic response and prolonged survival in oligodendrogliomas (Cairncross et al., 1998; Smith et al., submitted). Using 115 human diffuse gliomas, we localized regions of common allelic loss on chromosomes 1 and 19 and assessed the association of these deletion intervals with glioma histological subtypes. Further, we evaluated the capacity of multiple modalities to detect these alterations, including loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH). The correlation coefficients for detection of 1p and 19q alterations, respectively, between modalities were: 0.98 and 0.87 for LOH and FISH, 0.79 and 0.60 for LOH and CGH, and 0.79 and 0.53 for FISH and CGH. Minimal deletion regions were defined on 19q13.3 (D19S412-D19S596) and 1p (D1S468-D1S1612). Loss of the 1p36 region was found in 18% of astrocytomas (10/55) and in 73% (24/33) of oligodendrogliomas (P<0.0001), and loss of the 19q13.3 region was found in 38% (21/55) of astrocytomas and 73% (24/33) of oligodendrogliomas (P=0.0017). Loss of both regions was found in 11% (6/55) of astrocytomas and in 64% (21/33) of oligodendrogliomas (P<0.0001). All gliomas with LOH on either 1p or 19q demonstrated loss of the corresponding FISH probe, 1p36 or 19q13.3, suggesting not only locations of putative tumor suppressor genes, but also a simple assay for assessment of 1p and 19q alterations as diagnostic and prognostic markers. [ABSTRACT FROM AUTHOR]

Neovascularization is a common feature of many human cancers, but relatively few molecular defects have been demonstrated in genes regulating angiogenesis. Decreased expression of Thrombospondin-1 (THBS1), a P53 and Rb regulated angiogenesis inhibitor, has been observed in some human tumors, including glioblastoma multiforme (GBM). To study whether methylation-associated inactivation is involved in down-regulating THBS1 expression in cancer, we analysed the methylation status of THBS1 in several cell lines and primary tumors. Three cell lines (RKO, CEM and RAJI) were completely methylated at several CpG sites within the THBS1 5′ CpG island, and had no detectable expression by RT – PCR. THBS1 expression was readily reactivated using the methylation-inhibitor 5-deoxy-azacytidine in all three lines. Furthermore, THBS1 methylation was present in 33% (14/42) of primary GBMs. Thus, de novo methylation may serve as a potential way to inactivate THBS1 expression in human neoplasms. [ABSTRACT FROM AUTHOR]

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Topotecan was studied as a 72 h infusion given every 3 weeks. Treatment began at a dose of 1.0 mg/m2/day and was increased to 1.25 mg/m2/day after the first 6 patients tolerated this higher dose without excessive toxicities. Eighty-eight evaluable children were accrued in 6 strata. There were no complete nor partial responses. Twenty subjects had stable disease (astrocytoma 5/11, malignant glioma 5/13, medulloblastoma 0/12, brain stem tumor 4/19, ependymoma 5/17, and miscellaneous histologies 1/16). Two patients (astrocytoma, ependymoma) completed the maximum 18 topotecan courses. The remaining 68 children developed progressive disease within 2 months. Myelosuppression was the main toxicity. Grade 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 18, 32, 5, and 23 participants, respectively. It was concluded that topotecan as given according to this schedule showed insufficient activity to promote it to frontline protocol usage. [ABSTRACT FROM AUTHOR]

Methylation of promoter-associated CpG islands appears to be a potential way by which tumor suppressor genes are inactivated in cancer. Using Southern blot analysis, we have studied the methylation of several genes in glioblastoma multiforme (GBM), trying to determine their contribution to tumorigenesis. Genes studied included the estrogen receptor (ER), N33, the candidate tumor-suppressors P15, P16 and HIC1 and a control gene, c-abl. Hypermethylation of N33, ER, HIC1, P16, P15 and c-abl were found in 61%, 59%, 60%, 5%, 2% and 0% of GBM respectively. HIC1 methylation was detected in normal brain as well, but appeared to be more extensive in tumors. ER and N33 methylation were significantly more frequent in tumors from individuals over the age of 40 (70% and 88% vs 36% and 14%). In addition, there was a strong association between ER and N33 methylation, which were concordant in 81% of the cases (P<0.01). ER and N33 methylation in GBM may therefore appear as a result of shared etiologic factors, which may relate in part to aging cell populations in the brain. [ABSTRACT FROM AUTHOR]

Past studies of craniopharyngiomas in children have shown overall survival (OS) up to 95% at 5 years and 80% progression-free survival (PFS) at 5 years, although many of these series predate modern neuroimaging and current therapeutic management. Moreover, little mention has been made of failure patterns for craniopharyngioma in children. To obtain a contemporary assessment of outcome among pediatric craniopharyngioma patients, and also to determine the failure patterns for this tumor, we completed a retrospective study of a consecutive cohort of all children with craniopharyngioma diagnosed at the Johns Hopkins Hospital from 1980 to 1996. Resection was performed in 30 children, in 8 of whom gross total resection (GTR) was achieved. Initial treatment took the form of GTR followed by observation for 8, subtotal resection (STR) plus observation in 11, and STR followed immediately by radiotherapy in 8. The timing of radiotherapy following STR was unclear for 3. OS was 95.2% (SE= 4.7%) at 5 years, with only 2 children dying after 4 years from diagnosis. Five-year PFS was 59.4% (SE=10.2%). Before surgery, 19 children had visual loss and 15, endocrine deficits; after surgery, 21 children had visual loss and 29, endocrine deficits. Median time to relapse was 0.98 years (SD=2.5 years). Radiographic ( n=4) and clinical ( n=7) relapses did not differ in time to progression ( P=0.32), but radiographic relapses were significantly associated with age at diagnosis less than 5 years ( P=0.02). Degree of resection was not significantly associated with PFS ( P=0.32) or with postoperative visual or endocrine deficits. Absence of calcification on diagnostic neuroimaging ( n=8) was significantly associated with improved PFS [5-year PFS 100% vs. 42.9% (SE=14.7%), P=0.02], even when adjusted for extent of resection ( P=0.03). Preoperative visual loss was predictive of postoperative visual loss ( P=0.03). Survival for children diagnosed with craniopharyngioma in the current era is outstanding, even with relapse, although postoperative visual and endocrinological morbidities are high. Failures occurred both radiographically and clinically, typically in the first 3–4 years after surgery, suggesting a need for close surveillance initially with neuroimaging, particularly in younger children, and also clinical examination. The short times to relapse observed here may stem from a tendency to delay radiotherapy until recurrence. Lack of calcification at diagnosis is associated with a tendency to remain free of relapse. [ABSTRACT FROM AUTHOR]

Using the monoclonal antibody Ki-67, proliferating cells were demonstrated immunohistochemically in 16 tumors of the nervous system in children, and these findings compared with those in 44 adult tumors. The antibody, which reacts with a nuclear protein expressed during the G1, S, G2, and M phases of the cell cycle, was demonstrated in frozen (13 cases) or smear (3 cases) sections using the peroxidase-antiperoxidase method. The percentage of stained tumor cells in children was in general agreement with the histological grade, ranging from 0.2% in a schwannoma to 12.4% in a juvenile type of glioblastoma. In a medulloblastoma, the fraction of labeled nuclei was 10.2%. In malignant gliomas of children, the percentage of stained cells did not differ from that in adult tumors. However, some cases demonstrated an unusually higher number of positive cells associated with higher cellularity than did adult tumors; this is in agreement with the content of small immature tumor cells in many pediatric tumors. The use of Ki-67 staining could become an important additional criterion for predicting the biologic behavior of nervous system neoplasms in children. [ABSTRACT FROM AUTHOR]

Protein tyrosine kinases (PTKs) are closely related to cell growth, proliferation and differentiation. In keratinocytes, various growth factor receptors and cytosolic proteins, including the EGF and IGF receptors, the proteins of the src family and others, exhibit PTK activity. In psoriatic epidermis an increased level of EGF receptors and their ligand TGF-alpha has been found, and this is thought to be one reason for the pathological hyperproliferation of keratinocytes in this disease. Oral treatment with cyclosporin A (CsA) and FK506 or topical treatment with dithranol lead to an improvement in psoriasis. In the present study we examined the effect of these three drugs on the cellular content of phosphorylated tyrosines in highly proliferative HaCaT keratinocytes. HaCaT keratinocytes can be used as a model for highly proliferative epidermis, e.g. psoriatic epidermis. CsA had no effect whereas FK506 and dithranol reduced the phosphorylation of tyrosine residues in HaCaT keratinocytes. The activation of serine/threonine protein kinase C (PKC) is known to downregulate PTKs. Therefore we incubated keratinocytes with the selective PKC inhibitor Ro 31-8220 in addition to the other drugs. Only after the addition of Ro 31-8220 to FK506-treated keratinocytes was the phosphotyrosine (p-tyr) level elevated, but this was only one-third of the increase measured without additional therapeutic drugs. We assume that an induction of PKC alone is not responsible for the reduced p-tyr level after treatment with dithranol and FK506. FK506 and CsA affect the p-tyr signal transduction pathways of HaCaT keratinocytes in different ways, indicating distinct mechanisms of action of these drugs on keratinocytes. [ABSTRACT FROM AUTHOR]

A microfluorometric analysis was performed to analyse the DNA content of 42 medulloblastomas (MBs) and to seek correlations, if any existed, between the DNA distribution and ploidy values, neoplasm types (i.e. classic vs desmoplastic), histological features of aggressiveness, and immunocytochemical features indicating glial and/or neuronal differentiation. Thirty-one cases were classified as classic and 11 cases as desmoplastic MBs. Ten of 11 desmoplastic MBs had a near-diploid main mode and the remaining 1 case had a near-tetraploid main mode. Moreover, 10 of 11 (90%) cases showed a 'monomodal' DNA distribution diagram. All these cases showed a uniform histology. In contrast, classic MBs represented a heterogeneous group of neoplasms. Twenty-two cases were near-diploid, 5 cases were near-tetraploid and 3 cases were near-triploid. The histogram type distribution showed a similar heterogeneity. Twelve of 31 (39%) cases had a monomodal histogram, 12 (39%) cases had a bimodal diagram and 7 (22%) cases a complex DNA distribution. There was a statistically significant difference ( P<0.001) in terms of prevalence of DNA monomodal histograms between classic and desmoplastic MBs. Significant correlations were not observed among classic MBs between histological features of aggresiveness, type and degree of differentiation and DNA distribution. The present study indicates that desmoplastic MBs represent a homogeneous group of neoplasms in terms of histology and DNA distribution. In contrast, classic MBs are lesions with different degrees of histologically apparent aggressiveness and a complex DNA distribution. [ABSTRACT FROM AUTHOR]

Angiogenesis is the outgrowth of new blood vessels from the preexistent vasculature. In 1971, Folkman hypothesized that solid tumors are dependent on angiogenesis for sustained growthand that anti-angiogenic treatment is a potential antineoplastictherapy. Because glioblastoma multiforma (GBM) frequently shows florid microvascular proliferation (MVP), this tumor has beenconsidered since then as a suitable candidate for such treatmentthat attempts to eradicate or control a neoplasm by interfering withits blood supply. Indeed, in animal models the growth of gliomaxenografts can be inhibited by targeting the angiogenic process.However, unlike many glioma xenografts, human infiltrating gliomassuch as GBMs have a diffuse infiltrative growth pattern, and preexistent vessels may suffice to provide many tumor cells with much of their blood supply, particularly in the critical peripheral infiltrative margins. Thus, while attractive in concept,anti-angiogenic therapy of GBM must address the anatomic vascularrealities of this neoplasm. Even if anti-angiogenic therapy ultimately has a role in infiltrative neoplasms, thereare a host of other intracranial neoplasms whose discrete architecture might make them attractive candidates for anti-angiogenic therapy. This review summarizes the angiogenic process in GBM and suggestsother types of tumors for which the efficacy of anti-angiogenic therapymight be studied. [ABSTRACT FROM AUTHOR]

Although survivals of infants with malignant brain tumors are worse than any other age group, one possible exception to this rule are the malignant gliomas. Eighteen children less than 3 years of age with malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma and malignant glioma) were treated on the Pediatric Oncology Group regimen of prolonged postoperative chemotherapy and delayed irradiation, (1986-1990). Of 10 children evaluable for neuroradiologic response, 6 had partial responses (> 50% reduction) to two cycles of cyclophosphamide and vincristine. Progression free survivals at l, 3 and 5 years were 54.25% ± 12, 43% ± 16 and 43% ± 23 respectively. Survivals at 5 years were 50% ± 14. Four children were not irradiated after 24 months of chemotherapy due to parental refusal and none have developed recurrent disease. Neither degree of surgical resection, presence or absence of metastases, nor pathology influenced survival but this may reflect small sample size. This study suggests that some malignant gliomas in infants are chemotherapy sensitive and may be associated with a good prognosis. Why infants with these high-grade gliomas fare better than adults is not clear. It is likely that there is something intrinsically different about them that cannot be identified on routine pathologic examination. [ABSTRACT FROM AUTHOR]

Three interstitial implant trial groups (one permanent low-dose rateI and two temporary high-dose rateI implants) in glioblastoma patients ('newly diagnosed' and 'failed') were compared to non-randomized similar control groups for efficacy. The results formed the basis for the BTCG 87-01 national implant trial. The 'pilot' trial demonstrated: 1) the effectiveness of a temporary high-dose rateI implant in 'failed' and 'newly diagnosed' patients; 2) the ability of a multicenter consortium to adhere to a standard protocol; 3) a methodology to insure quality assurance; and 4) the possibility of the future adjuvant application of hyperthermia using a single catheter system. [ABSTRACT FROM AUTHOR]

The results of a multi-institutional phase I trial evaluating the safety of surgically implanted biodegradable 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) impregnated polymer as the initial therapy for malignant brain tumors are reported. This is the first study of locally delivered BCNU and standard external beam radiation therapy (XRT) given concurrently. Twenty-two patients were treated at three hospitals. The entry criteria were: single unilateral tumor focus larger than 1 cm; age over 18 years; Karnofsky Performance Score (KPS) of at least 60 h; and an intra-operative diagnosis of malignant glioma. Twenty-one of twenty-two patients had glioblastoma multiforme. After surgery, seven or eight BCNU-loaded polyanhydride polymer discs (7.7 mg BCNU each) were placed in the resection cavity. Postoperatively, all patients received standard radiation therapy; none received additional chemotherapy in the first 6 months. Neurotoxicity, systemic toxicity, and survival were assessed. No perioperative mortality was seen. Neurotoxicity was equivalent to that occurring in other series of patients undergoing craniotomy and XRT without local chemotherapy. Systematically, no significant bone marrow suppression occurred, and there were no wound infections. Median survival in this group of older patients (mean age=60) was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months. Interstitial chemotherapy with BCNU-polymer with subsequent radiation therapy appears to be safe as an initial therapy. Several long-term survivors in this group of older patients with predominantly glioblastoma suggests efficacy in some patients. Dose escalation and efficacy trials are planned to further evaluate interstitial chemotherapy for the initial treatment of malignant gliomas. [ABSTRACT FROM AUTHOR]

Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors. Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M/qod × 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8-62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: To test the efficacy of intra-arterial (IA) cisplatin versus intravenous (IV) PCNU for treating primary brain tumors, in a randomized trial (Brain Tumor Cooperative Group [BTCG] Trial 8420A). Methods: 311 adult patients (ages 19-79 years; median 45) with supratentorial tumors (confirmed histologically) were randomized by nine participating institutions. Patients were required to have completed radiotherapy (4500-6020 cGy to the tumor bed) before randomization. Patients were stratified as either nonprogressive (clinically and radiologically stable) or progressive. Results were analyzed for the 311 patients in the randomized population (RP), and for the 281 patients in the Valid Study Group (VSG) meeting protocol eligibility requirements. 56% of patients in the VSG had glioblastoma multiforme, 33% had other malignant glioma, and 11% had low-grade glioma. 64% were stratified as progressive. 12% had received prior chemotherapy. Results: The group randomized to PCNU had the longer survival (p = 0.06 for the RP, p = 0.07 for the VSG). In the VSG, median survival was 10 months for the cisplatin group, 13 months for the PCNU group. The difference between treatment groups was significant (p ≤0.02) when adjusted for important prognostic factors. PCNU lead to greater hematotoxicity; cisplatin lead to greater renal toxicity and some ototoxicity. Some cisplatin patients experienced complications associated with IA administration, including six cases of encephalopathy. Conclusion: The trial showed a survival advantage to the group randomized to PCNU, although the difference was modest. Coupled with previous BTCG results, these trials suggest that PCNU is an active drug for brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment of de novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies. Methods: During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75-100 mg/m intravenously (IV) every 8 weeks or AZQ 15 mg/m IV once a week for 4 weeks, every 6-8 weeks. All patients who had not received 'full dose' radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review. Results: Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p=0.01) and the VSG (p=0.02). Lifetable analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p=0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups. [ABSTRACT FROM AUTHOR]

Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by comparing release kinetics, safety, and efficacy of escalating BCNU doses in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU 2.5 times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9L-glioma model. A dose-response relationship for BCNU was observed (hazard ratio 0.8354 for each mg/kg increase, P<0.001). The two highest loading doses of BCNU improved survival 40-fold ( P<0.001). The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release. [ABSTRACT FROM AUTHOR]

Elucidation of the pathogenesis and biological significance of MVP in GBMs is essential for developing a rational treatment directed at the abrogation of neovascularization in these neoplasms. The present quantitative study illustrates the striking heterogeneity of the microvasculature in GBMs such that the number of vessels in many tumor areas does not exceed that of normal white matter. Thus, many regions of GBMs may not be overtly angiogenesis dependent and may be difficult to treat by anti-angiogenic therapy alone. Even in areas with florid MVP the efficacy of anti-angiogenic therapy is questionable since the contribution of these aberrant blood vessels to the functional circulation and thus to the viability and growth of GBMs is unclear. [ABSTRACT FROM AUTHOR]

The article presents a study that finds the high rate of concurrent BRAF-KIAA1549 gene fusions and 1p deletions in disseminated oligodendroglioma-like leptomeningeal neoplasm (DOLN), a condition that predominantly affects children. The study demonstrates the differences between oligodendroglioma-like tumors and adult oligodendrogliomas and the role of BRAF abnormalities, common in pediatric low-grade central nervous system (CNS) tumors, in DOLNs.