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ABSTRACT: Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non-neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro-oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors.
Cancer 01/2011; 117(1):24-38. · 4.77 Impact Factor
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ABSTRACT: This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.
Journal of Neuro-Oncology 07/2009; 95(3):393-400. · 3.21 Impact Factor
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David A Reardon,
Annick Desjardins,
James J Vredenburgh,
Sridharan Gururangan,
Allan H Friedman,
James E Herndon,
Jennifer Marcello,
Julie A Norfleet,
Roger E McLendon,
John H Sampson,
Henry S Friedman
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ABSTRACT: We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
Journal of Neuro-Oncology 07/2009; 96(2):219-30. · 3.21 Impact Factor
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ABSTRACT: The purpose of this study was to determine the safety of tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III-IV malignant glioma patients. Patients were initiated on daily tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and tinzaparin was held if the platelet count decreased to <50,000 and was re-initiated at a platelet count >100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages >or=grade 2. The median time on prophylactic tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.
Journal of Neuro-Oncology 05/2009; 95(1):129-34. · 3.21 Impact Factor
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Hai Yan,
D Williams Parsons,
Genglin Jin,
Roger McLendon,
B Ahmed Rasheed,
Weishi Yuan,
Ivan Kos,
Ines Batinic-Haberle,
Siân Jones,
Gregory J Riggins,
Henry Friedman,
Allan Friedman, David Reardon,
James Herndon,
Kenneth W Kinzler,
Victor E Velculescu,
Bert Vogelstein,
Darell D Bigner
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ABSTRACT: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).
We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.
We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.
Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
New England Journal of Medicine 03/2009; 360(8):765-73. · 53.30 Impact Factor
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ABSTRACT: Performance status (PS) scoring systems are tools of immense clinical importance in the management of patients with malignant disease but these tools are subjective and do not provide an objective evaluation of physical functioning. We conducted a pilot study to explore the feasibility and clinical utility of functional capacity testing to assess physical functioning in recurrent primary malignant glioma patients.
Using a cross-sectional design, consecutive patients with recurrent glioma performed a six minute walk (6MW) test to assess functional capacity. Performance status was assessed using Karnofsky Performance Status (KPS) scoring system. QOL was assessed by the Functional Assessment of Cancer Therapy-Brain scale. Self-reported exercise behavior was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ).
A total of 171 patients were recruited and tested. Seventy percent were diagnosed with glioblastoma multiforme (WHO grade IV) and 85% were undergoing therapy. Median KPS was 90% (range, 70-100%). Median 6MW distance was 400 m (range, 102-630 m), equivalent to 56 +/- 13% (range, 14-87%) of that predicted for age and sex. KPS, self-reported exercise, and QOL increased across 6MW distance quartiles (P < 0.05) although there was considerable variation within each category. 6MW distance and KPS were significantly correlated with each other (r = 0.34, P < 0.01) and several QOL domains (range, r = -0.43 to 0.46, P < 0.05).
6MW distance is a clinically feasible tool that provides an objective measure of physical functioning in select patients with recurrent glioma. Further research is required to investigate the prognostic value of these tests in patients with advanced malignancy.
Journal of Neuro-Oncology 02/2009; 94(1):79-85. · 3.21 Impact Factor
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ABSTRACT: A patient with glioblastoma multiforme underwent serial computerized analysis of tumor-associated vasculature defined from magnetic resonance angiographic (MRA) scans obtained over almost a four year period. The clinical course included tumor resection with subsequent radiation therapy, a long symptom-free interval, emergence of a new malignant focus, resection of that focus, a stroke, and treatment with chemotherapy and anti-angiogenic therapy. Image analysis methods included segmentation of vessels from each MRA and statistical comparison of vessel morphology over 4 regions of interest (the initial tumor site, the second tumor site, a distant control region, and the entire brain) to the same 4 regions of interest in 50 healthy volunteers (26 females and 24 males; mean age 39 years). Results suggested that following completion of focal radiation therapy (RT) vessel shape abnormalities, if elevated at the time of RT completion, may progressively normalize for months in focal regions, that progressively severe vessel shape abnormalities can precede the emergence of a gadolinium enhancing lesion by months, that lesion resection can produce a dramatic but highly transient drop in abnormal vessel tortuosity both focally and globally, and that treatment with anti-angiogenic agents does not necessarily normalize vessel shape. Quantitative measurements of vessel morphology as defined from MRA may provide useful insights into tumor development and response to therapy.
NeuroImage 01/2009; 47 Suppl 2:T143-51. · 5.89 Impact Factor
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Sridharan Gururangan,
Wendy Frankel,
Russell Broaddus,
Mark Clendenning,
Leigha Senter,
Marie McDonald,
James Eastwood, David Reardon,
James Vredenburgh,
Jennifer Quinn,
Henry S Friedman
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ABSTRACT: We describe the case of a patient with transcobalamin II deficiency, hypogammaglobulinemia, absent corpus callosum, and mental retardation who presented at an early age with colorectal cancer and multifocal anaplastic astrocytoma. He was found to have a possible germline mutation of the PMS2 gene, as evidenced by absent protein expression in both normal and tumor tissues. His parents were found to be carriers of a nonsense mutation of the PMS2 gene.
Neuro-Oncology 03/2008; 10(1):93-7. · 5.72 Impact Factor
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Sridharan Gururangan,
Colleen A McLaughlin,
James Brashears,
Melody A Watral,
James Provenzale,
R Edward Coleman,
Edward C Halperin,
Jennifer Quinn, David Reardon,
James Vredenburgh,
Allan Friedman,
Henry S Friedman
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ABSTRACT: We performed a retrospective study of patients with diffuse pontine glioma (DPG) who suffered neuraxis metastasis (NM) and characterized the incidence, clinical features, radiologic findings, and patterns of disease dissemination.
Magnetic resonance imaging (MRI) of brain and spine was used to assess NM. Some patients also underwent magnetic resonance spectroscopy (MRS) (6 patients) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans (13 patients) to further evaluate areas of metastatic disease. Three patients had histologic confirmation of disease at the site of NM.
Between 1986 and 2003, 18 of 96 patients (17.3%) with DPG developed NM. The median age at diagnosis was 8 years (range, 4-17). All patients had adjuvant chemotherapy and/or focal radiotherapy at diagnosis. The NM occurred at a median of 15 months from diagnosis of DPG (range, 3-96). Three patterns of NM were seen on MRI of brain and spine in these patients; 8 (39%) had parenchymal (PM), 4 (22%) leptomeningeal (PM), 2 (11%) subependymal, and in 5 a combination of two or more patterns. The MRS and FDG-PET scan of suspected areas of metastatic disease was consistent with tumor in 6 of 6 and 12 of 13 patients who underwent these procedures respectively. Three patients also had histologic confirmation of malignant glioma at the site of NM. Despite salvage therapy, all 18 patients have died of disease at a median of 5 months (range, 0.5-20) from diagnosis of neuraxis spread.
Our study emphasizes the need for screening patients with DPG for NM at the time of recurrence.
Journal of Neuro-Oncology 05/2006; 77(2):207-12. · 3.21 Impact Factor
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ABSTRACT: Allelic losses of 1p and 19q arms correlate with the oligodendroglial phenotype as well as with sensitivity to radiotherapy and chemotherapy. Furthermore, the DNA repair gene, methylguanine methyltransferase (MGMT), is diminished in 80% of oligodendroglial tumors and represents a possible mechanism for this therapeutic sensitivity. However, the authors questioned the relevance of genetic testing and measuring MGMT levels in tumors that were diagnostic of oligodendroglioma.
The authors performed a retrospective analysis of 1p, 19q, 9p21, TP53, and MGMT status in 46 patients with oligodendrogliomas to address any relations that may exist among these markers with regard to progression-free survival (PFS) and total survival. Methodologies included comparative genomic hybridization; loss of heterozygosity (LOH) on 1p, 19q, and 9p21; TP53 mutational analysis; and immunohistochemistry for MGMT.
The authors found that survival among patients with light microscopically diagnosed oligodendroglial tumors demonstrating LOH of 1p and 19q trended toward statistical significance (P = 0.102 and P = 0.058, respectively). 9p21 LOH was significant as a predictor of PFS only among anaplastic oligodendrogliomas in this cohort (P = 0.033). TP53 mutation was found to be significantly predictive of a shorter survival (P = 0.027) among all patients and exhibited a strong trend toward a shorter PFS (P = 0.060). Low-level MGMT labeling index (LI) (< 20%) was noted in 86% of all oligodendroglial tumors. MGMT LI was not found to correlate with an improved PFS or total survival in this cohort, recognizing that median survival was not reached after a median follow-up of 104 months.
9p21 and TP53 mutational status assisted in developing a stricter subclassification of these tumors with prognostic significance. MGMT levels were decreased in a majority of oligodendrogliomas.
Cancer 11/2005; 104(8):1693-9. · 4.77 Impact Factor
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ABSTRACT: The majority of agents currently used to treat patients with tumors of the central nervous system (CNS) are cytotoxins, developed
initially for their ability to kill cells directly. Subsequent drugs were derived by an analog strategy in which relatively
small chemical modifications were made to the parent drug to either increase its potency or decrease its systemic toxicity,
often with little to no change in the drug’s mechanism of action. This approach has yielded chemotherapeutic agents, notably
DNA damaging agents, such as 2-chloroethylnitrosoureas (CENUs), nitrogen mustard-type drugs, and the platinum analogs that
have been the mainstay of brain tumor chemotherapy to date.
12/2004: pages 359-381;
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Sridharan Gururangan,
Colleen McLaughlin,
Jennifer Quinn,
Jeremy Rich, David Reardon,
Edward C Halperin,
James Herndon,
Herbert Fuchs,
Timothy George,
James Provenzale,
Melody Watral,
Roger E McLendon,
Allan Friedman,
Henry S Friedman,
Joanne Kurtzberg,
James Vredenbergh,
Paul L Martin
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ABSTRACT: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL).
Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR.
A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively.
The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.
Journal of Clinical Oncology 07/2003; 21(11):2187-91. · 18.37 Impact Factor
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Sridharan Gururangan,
Christina M Cavazos,
David Ashley,
James E Herndon,
Carol S Bruggers,
Albert Moghrabi,
Deborah L Scarcella,
Melody Watral,
Sandra Tourt-Uhlig, David Reardon,
Henry S Friedman
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ABSTRACT: To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas.
Eligible patients received carboplatin 560 mg/m(2) intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity.
Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P =.011; 54% v 91% for OS, P =.004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P =.052).
Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.
Journal of Clinical Oncology 08/2002; 20(13):2951-8. · 18.37 Impact Factor
