A. Differential Diagnosis of CNS Mass Lesions

1. Tumor
   1. Metastatic - 18% of all cancers have CNS metastasis
   2. Primary
2. Cerebrovascular Disease
   1. Occlusion
   2. Hemorrhage
   3. Arteriovenous Malformation (AVM)
   4. Aneurysm
3. Focal Encephalitis
   1. Herpes Simplex Virus (HSV), usually Type 2
   2. Toxoplasmosis
4. Inflammatory - Sarcoidosis

B. Effects of Mass Lesions

1. Compression/Destruction of adjacent nervous system structures
2. Seizures
   1. Local irritation leads to focal or generalized seizures
   2. ~10% of patients presenting with new seizures will have a brain tumor
3. Intracranial pressure (ICP) Elevation
   1. Mass lesion
   2. Edema
   3. Hydrocephalus

C. Symptoms of Elevated ICP

1. Headache (HA) constant and dull
2. Pupillary dilation (may be unilateral)
3. Blurred disc margins, hyperemia, retinal hemorrhage
4. Change in mental state (Delta MS) - lethargy and stupor
5. Nausea and Vomiting
6. Risk of herniation through foramen magnum
7. Late/Severe - Motor changes, increased pulse pressure, slow pulse
8. Cushing Reflex - bradycardia and hypertension
9. Elevated ICP usually present with rapidly growing tumors
10. Slowly growing tumors more likely to cause seizures

D. Evaluation

1. History and Physical
2. Computerized Tomography (CT) or MRI [5]
   1. Magnetic Resonance Imaging (MRI) is preferred as better modality
   2. CT is most useful when speed is critical, or MRI contraindicated
3. Angiography
   1. Usually for tumors which are close or encircle blood vessels
   2. Cerebral angiography is somewhat risky with increased stroke incidence
   3. Magnetic resonance angiography (MRA) has largely replaced invasive angiography
4. Search for primary tumor
5. Spinal Fluid Analysis: Lumbar Puncture (LP)
   1. Assessment for focal signs
   2. If no signs of increased ICP, then usually safe to do LP
   3. Prefer that MRI or CT done prior to LP
6. Biopsy
   1. CT guided stereotaxic needle biopsy is preferred method
   2. Craniotomy may be required for certain tumors (especially posterior fossa)
7. Surgical Biopsy Indication
   1. No known primary tumor
   2. Single CNS lesion accessible
   3. No other treatment options

E. Typical Therapy

1. Mostly palliative for malignant tumor, metastasis
2. Surgical removal of some benign tumors can be curative
3. Surgical Debulking - usually for primary brain tumors
4. Radiotherapy - up to 6000 Rads in 6 weeks
5. Glucocorticoids
   1. Reduction of intracranial pressure (ICP), edema
   2. Kill lymphoid tumor cells
   3. High doses are used, for example, 6-10mg dexamethasone q6 hours IV
6. Systemic Chemotherapy
7. Impending Herniation
   1. Mannitol therapy
   2. Forced ventilation
   3. Glucocorticoids

1. Overall incidence is ~20 per 100,000 persons per year
   1. Estimated ~16,800 primary brain tumors in USA in 1999
   2. ~50% of these are gliomas
   3. Malignant brain tumors have 3rd worst 5 year survival of all adult tumors
   4. Primary cancer of CNS caused 13,100 deaths in USA in 1999
2. Bimodal peak ages 0-4 years and increasing incidence after age 24 years
3. Normal Cell and Derived Tumor Types
   1. Astrocyte: astrocytomas, glioblastomas
   2. Ependymocyte: ependymoma, ependymoblastoma
   3. Oligodendrocyte: oligodendroglioma
   4. Arachnoidal fibroblasts: meningioma
   5. Nerve cell: ganglioneuroma, neuroblastoma, retinoblastoma
   6. External granular cell or neuroblast: medulloblastoma
   7. Pituitary: adenoma
   8. Endothelial cell: hemangioblastoma
   9. Primitive germ cell: germinoma, pinealoma, teratoma, cholesteatoma
   10. Pineal prachenymal cell: pinealcytoma
   11. Schwann cell: Schwannoma, neuroma (peripheral nervous system only)
   12. Melanocyte: melanotic carcinoma, uveal melanoma
   13. Choroid epithelial cell: choroid plexus papilloma or carcinoma
   14. Notochordal remnants: chordoma
   15. Primary CNS lymphoma [7]
4. Etiology of Brain Tumors
   1. Ionizing radiation is the only unequivocal risk factor
   2. Brain irradiation for acute lymphoblastic leukemia [9]
   3. Various chemical exposures, especially vinyl chloride
   4. No clear association with magnetic fields
   5. No increased risk of brain tumors with handheld cellular phone use [10,11]
   6. Incidence may be increased in patients with TPMT mutations [9]
   7. Increased risk (2.5X) associated with simian virus 40 (SV40) infection [17]

B. Presentation and Diagnosis

1. Focal or generalized symptoms
2. Depend primarily on location, size and type of brain tumor
3. Generalized Symptoms
   1. Often due to increased intracranial pressure (ICP)
   2. Headache
   3. Nausea and vomiting
   4. Sixth nerve palsey (CN VI)
   5. Obtundation
   6. Coma
   7. Death
4. Focal Symptoms
   1. Hemiparesis
   2. Aphasia
   3. Seizure - usually begin focally, may generalize
   4. Visual field deficit
5. Cognitive dysfunction - tumor is primary contributor [28]
6. Radiographic Evaluation
   1. Magnetic Resonanace Imaging (MRI) is the only test required
   2. MRI with gadolinium enhancement is the test of choice
   3. Computerized tomographic (CT) scan is not indicated nor useful
7. Obtaining Tissue for Diagnosis [5]
   1. Stereotactic biopsy versus craniotomy
   2. Biopsy for deep-seated or unresectable tumor, multiple lesions, unclear radiographic diagnosis, no mass effect, normal intracranial pressure, patient with systemic disease
   3. Craniotomy for superficial or resectable tumor, single lesion, clear radiographic diagnosis, new diagnosis, mass effect, raised intracranial pressure, therapeutic potential
8. Frequency of Presenting Symptoms [1] Table: Frequency of Presenting Symptoms for Common Brain Tumors (Ref[1])*

   Glioma LG	Glioma HG	Meningioma	P-CNS	Lymphoma
   Headache	40%	50%	~35%	35%
   Seizure	~80%	~20%	40%	~15%
   Hemiparesis	~10%	~40%	~20%	~25%
   Mental Status	10%	~50%	~20%	~60%
   Abnormalities

1. Most common primary brain tumors
   1. Lilkely derived from neural stem cells in adults
   2. Block on differentiation of multipotent stem cells in human brain
   3. Potential to transform into gliomas or astrocytomas
   4. Most neural stem cells found in subventricular zone, site of most gliomas
   5. Precursor cells with mutated K-ras or Akt genes likely lead to malignant tumors
   6. Graded pathologically on basis of most malignant area identified
   7. Grades I (low) - IV (high) may arise denovo or from lower grade tumors
   8. Presence or absence of nuclear atypia, mitosis, microvascular proliferation, necrosis
   9. Accurate pathological grading critical because it defines treatment and prognosis
   10. Genetic alterations correlate with progression and grade [2]
2. Astrocytoma (Grades I and II Gliomas)
   1. Relatively low grade neoplasms of astrocytes, usually in younger persons (ages 20-40)
   2. Highly infiltrative but nondestructive on surrounding tissue
   3. Presents with seizures or progressive neurologic dysfunction
   4. Low grade fibrillary astrocytoma (WHO Grade II) is less benign than counterparts
   5. Pilocytic (Grade I) and pleomorphic (Grade II) are more benign than fibrillary forms
   6. 75% with headaches, 35% with change in mental state
   7. Presentation usually with seizures
   8. Usually occur in cerebral hemispheres; may also occur in cerebellum or spinal cord
   9. Brainstem gliomas are <10% of gliomas in adults; ~15% in children
   10. PET scans may supplement MRI scans which help assess grade of tumor
   11. Surgical resection with delayed low dose radiation when progression occurs
   12. Most astrocytomas progress to high-grade malignant gliomas
   13. The 10 year survival rate is 10-20% depending on success of resection
   14. Deferring radiotherapy (as for oligodendrogliomas) had same survival as immediate radiotherapy, but seizure control and time to progression were poorer [32]
3. Glioblastoma [1]
   1. Grades III ("anaplastic astrocytoma") and Grade IV (Glioblastoma multiforme, GBM)
   2. Mean age 55, slight male predominance
   3. Highly malignant, aggressive tumors of astrocytes
   4. Grade III have 28-36 month median survival
   5. Grade IV have 8-12 month median survival
   6. Conversion from Grade III to IV accompanied by marked angiogenesis
   7. Grade IV GBM are some of the most highly vascularized of all neoplasms
   8. Vascularization driven by high hypoxia inducing factor 1 (HIF-1) levels
   9. Irregular contrast enhancement on MRI, usually of ring type
   10. Abnormal growth factor receptor, p16 deletions, and mutations in PTEN tumor suppressor
   11. Tumor necrosis is a predictor of short survival
   12. Surgical resection is initial modality followed by immediate radiation therapy
   13. Radiotherapy in patients >70 years with glioblastoma increased survival from 16.9 weeks with supportive care to 29.1 weeks [37]
   14. Routine use of chemotherapy in addition to radiation is controversial
4. Other Gliomas
   1. Oligodendroglioma
   2. Ependymoma
5. Genetic Changes in Gliomas [2]
   1. P16/CDKN2A common early (~50%)
   2. Loss of heterozygosity (LOH) at chromosomes (chr) 1p and 19q
   3. PTEN mutations
   4. Mutations in p53 (TP53) mid to late event
   5. RB mutations also seen in late stage (~20%)
   6. LOH 10q (later)
   7. EGF-R overexpression in up to 40% of late stage, high grade tumors
   8. Glioblastomas often express EGFRvIII, a constitutively active genomic deletion variant
6. Treatment Overview
   1. Usually palliative
   2. Surgical resection followed by postoperative radiotherapy is standard
   3. Radiation therapy alone
   4. Chemotherapy - mainly alkylating agents
   5. Radiotherapy + concomitant adjuvant temozolomide superior to radiotherapy alone [30]
   6. High dose glucocorticoids for mass effects - dexamethasone 4-64mg per day iv (po)
7. Resection
   1. Resection (~20% are totally resectable) and radiation therapy are main therapies
   2. Resection generally cannot be safely performed on spinal cord and brainstem tumors
   3. Implantation of carmustinet impregnated "wafers" improves survival [14]
8. Radiation Therapy [28]
   1. Low doses for typically used for astracytomas
   2. Higher doses for glioblastomas
   3. Memory dysfunction occurs in low-grade glioma patients receiving >2 Gy in fractional doses
   4. Radiotherapy in patients >70 years with glioblastoma increased survival from 16.9 weeks with supportive care to 29.1 weeks [37]
   5. Anti-epileptic drugs also impair cognitive function, moreso than radiation
9. Chemotherapy [22]
   1. Systemic chemotherapy with alkylating agents improves survival
   2. High rates of side effects due to need for very high doses
   3. First line therapy usually includes carmustine or lomustine + procarbazine + vincristine
   4. However, newer chemotherapy with carboplatin has milder side effects
   5. Local release of chemotherapies with slow-release polymers may be effective
   6. Temozolomide has been approved for recurrent anaplastic astrocytoma (see below)
   7. Expression of DNA repair enzyme methylguanine-DNA methyltransferase (MGMT) inhibits killing of brain tumor cells by alkylating agents [23]
   8. Expression of MGMT is reduced by methylation of the MGMT promoter
   9. Presence of methylated MGMT promoter sequences is a good prognostic factor for both time to progression and to overall survival [23]
   10. Adding chloroquine 150mg/day for 12 months following surgery improved median survival from 11 months (placebo) to 24 months [34]
   11. Chloroquine has shown chemotherapy (carmustine) potentiating activity in vitro
10. Temozolomide (Temodar®) [19,20]
    1. Oral agent for treatment of recurrent anaplastic astrocytoma
    2. Used for relapse after nitrosourea (lomustine or carmustine) and procarbazine
    3. Also used to treat glioblastoma multiforme (frist line setting)
    4. Appears to be quite beneficial in first-line adjuvant setting with radiotherapy with 2 year survival 25% versus 10% with radiotherapy alone [30]
    5. Patients with gliobalstoma containing methylated MGMT (O6-methylguanine-DNA methyl- transferase) promoter benfit from temozolomide added to radiotherapy [31]
    6. Progression-free survival in recurrent disease: 46% at 6 months, 24% at 12 months
    7. Overall survival at 6 months 75% and 56% at 12 months
    8. Thrombocytopenia and neutropenia are side effects, but overall well tolerated
11. Carmustine Wafers (Gliadel®) [14]
    1. Carmustine impregnated polymers with slow-release properties
    2. These wafers are implanted at the tumor site after surgery
    3. These impregnated wafers deliver high local levels of chemotherapy
    4. They improve survival to >30% at 2 years
    5. Some increase in cerebral edema, seizures and infections at surgical site with use
    6. FDA approved for recurrent brain tumors
    7. Recent cohort study in recurrent glioblastoma showed no survival benefit [21]
    8. However, may consider use at initial surgery (great side effect profile) [22]
12. EGF-R Kinase Inhibitors [33]
    1. ~15% of patients have response to gefitinib or erlotinib
    2. Coexpression of EGFRvIII and PTEN by glioblastoma cells associated with response
13. Mean survival <1 year; 2 year survival is <6% for grades III and IV gliomas

D. Oligodendrogliomas

1. Tumors of CNS myelinating cells, representing ~20% of glial neoplasms
   1. Low grade tumors (more common) are usually slow growing and calcified
   2. Anaplastic oligodendrogliomas grow rapidly and require immediate therapy
2. These tumors are uniquely sensitive to chemotherapy
3. Symptoms include seizures, often over many years
4. May be pure or mixed with malignant astrocytes
5. Surgical decompression with multiple resections over many years
6. Radiotherapy (Palliative) [32]
   1. 54 Gy total in 1.8Gy fractions improves symptoms and probably survival
   2. Deferred radiotherapy for slow growing tumors does not affect survival
   3. Deferring radiotherapy does reduce seizure incidence, severity
   4. Immediate radiotherapy improves time to progression versus delayed radiotherapy
7. Procarbazine + lomustine + vincristine for anaplastic forms [22]
8. Median lifespan for low grade tumors is ~16 years (due to early MRI diagnosis)

E. Meningioma [24]

1. ~20% of all Intracranial tumors: incidence is 7.8 per 100,000
2. Higher in females than males (3:2 or 2:1)
3. Presentation
   1. Due to growth of tumor affecting local neurological function or structure
   2. Local or generalized seizures
   3. Neurologic deficits
   4. Psychiatric symptoms
   5. Increasing incidence due to wider use of CT and MRI scans (often asymptomatic)
4. Most are benign tumors derived from meninges
   1. Usually occur at base of skull
   2. Characteristic attachment to dura mater on CT scan ("dural trail")
   3. Typically compresses nearby structures
   4. Diagnosis with CT or MRi characteristics
5. Associated Syndromes
   1. Multiple meningiomas associated with von Recklinghausen's Neurofibromatosis
   2. Increased incidence in patients with lymphangioleiomyomatosis [25]
6. Pathology
   1. The cells often express progesterone receptors (may explain higher female)
   2. Divided into 3 grades (WHO Grades I - III) with specific pathologies
   3. Grade I: meningothelial, psammomatous, secretory, fibroblastic, angiomatous, transitional, lymphoplasmocyte-rich, microcystic, metaplastic
   4. Grade II: clear cell, chordoid, atypical
   5. Grade III: papillary, rhabdoid, anaplastic
   6. Rate of proliferation of tumor and tumor recurrence after surgery increases with grade
   7. Grade I recurrence ~15%, grade II ~35%, grade III has histologic invasion, always recurs
7. Molecular Genetics
   1. Loss or mutation of neurofibromatosis 2 (NF2) gene on chr 22q12 early in all meningiomas
   2. Next most common mutations are deletions of chr 1p, 3p, 6q, 9p, 10q, 14q
   3. Altered expression of growth factor receptors and various other genes
8. Surgery is definitive therapy
   1. However, complete resection associated with 20% recurrence after 10 years
   2. >80% recur after partial resection
   3. Stereotactic surgery may be useful for removal of tumor foci
9. Endovascular treatment with selective microvascular embolization has been used
10. Radiation therapy for incomplete resection, recurrence, or high degree of tumor atypia
11. Malignant meningiomas should be treated with surgery + radiation

F. Craniopharyngioma

1. Slow growing, suprasellar tumors
2. Often present with visual changes
3. May be cystic and amenable to surgical resection

G. Schwannoma

1. Nerve sheath tumor
2. Most common brain schwannoma is an Acoustic Neuroma
   1. Also called vestibular schwannoma
   2. Hearing Loss - usually asymmetric
   3. Tinnitus
   4. Vertigo
   5. Facial Weakness and Sensory Loss
   6. Most common cerebellopontine angle tumors
3. Treatment of Acoustic Neuromas [16]
   1. Microsurgical resection or stereotactic radiosurgery
   2. Radiosurgery preserves neurological function in >70% of persons
   3. Damage to the facial or trigeninal nerves are most common complications
4. Also occur on spinal nerve roots and other peripheral nerves [18]
   1. May be confused with neurofibroma (less common)
   2. However, patients with neurofibromatosis are more likely to have neurofibromas
   3. Peripheral schwannomas are often benign but can cause severe pain or motor symptoms
   4. Surgical resection of peripheral schwannomas leads to resolution of pain in 88% of cases
   5. Motor function is typically spared or improved after surgery

H. Medulloblastoma

1. Most common brain tumor in children
2. Etiology
   1. Embryonal tumor (neuroectoderm) from external granular layer of cerebellum
   2. Usually arises from midline cerebellar structures
   3. These cells are frequently multipotent
3. Genetic Abnormalities
   1. Chromosomal abnormalities (such as inv17q)
   2. PTCH basal tumor suppressor gene mutations [13]
   3. Oncogene amplifications
4. Symptoms
   1. Headache
   2. Behavioral changes
   3. Seizures
   4. Frequent hydrocephalus due to proximity to 4th ventricle
5. Treatment
   1. Craniotomy and resection
   2. Highly radiosensitive - high dose craniospinal irradiation (but significant side effects)
   3. Chemotherapy for many years
   4. Chemotherapy initially with lomustine + cisplatin + vincristine [22]
   5. Intensive chemotherapy with cyclophosphamide, vincristine, methotrexate, carboplatin and etoposide with intravesicular methotrexate is increasingly used
   6. Postoperative intensive chemotherapy alone in children without metastases has shown good outcomes without the need for radiotherapy [12]
6. Prognosis [12]
   1. irls have much better outcome than boys
   2. Radiation therapy causes a good deal of leukoenceaphlopathy and cognitive defects
   3. Postoperative chemotherapy alone for non-metastatic disease appears effective
   4. Five year survival with complete resection+post-operative chemotherapy 93%
   5. Five year survival with residual tumor+post-operative chemotherapy 56%
   6. Five year survival with macroscopic metastases+post-operative chemotherapy 38%

I. Pituitary Tumors

1. Represent ~15% of primary brain tumors
2. Usually benign tumors derived from hormonally active secretory cells
   1. Microadenomas are tumors <10mm in diameter
   2. Macroadenomas are tumors >10mm in diameter
3. Symptoms / Signs Due to Mass Effects
   1. Mass effects in specific anatomic location (usually macroadenomas)
   2. Headache - may be severe [4]
   3. Photophobia
   4. Cranial Nerve III problems - double vision
   5. May mimic aseptic meningitis
   6. Pituitary rupture and hemorrhage ("apoplexy") have similar symptoms
4. Symptoms Related to Hormone Production
   1. Prolactinoma is most common type of pituitary tumor --> hyperprolactinemia [29]
   2. Growth hormone excess --> acromegaly [36]
   3. Thyroid hormone excess
   4. FSH or LH excess
   5. Hypercortisolism --> Cushing's Disease
5. Diagnosis
   1. Hormone radioimmunoassay
   2. MRI visualization of lesion is generally preferred to CT scan
   3. About 10% of asymptomatic adults have pituitary mass by MRI
6. Treatment Modalities [8]
   1. Treat by transphenoidal surgery (with operating microscope)
   2. Radiation therapy for recurrent tumors leads to ~100% regression [6]
   3. Many of these tumors are responsive to somatostatin (Octreotide®) therapy [27]
   4. Dopamine agonists are also sometimes useful
7. Pituitary Dysfunction may occur after irradiation for brain tumors

J. CNS Lymphoma [2,7]

1. Diffuse Non-Hodgkin's Lymphoma limited to cranium and/or spine
2. Represents 2-3% of all primary brain tumors
3. B Cell lymphomas in nearly all cases, many associated with presence of EBV DNA
4. Risk Factors
   1. Congenital immunodeficiency
   2. AIDS and other acquired immunocompromised conditions
   3. Risk increasing in immunocompetent patients for unclear reasons
5. Symptoms
   1. Mental status changes and/or cognitive dysfunction (~60%)
   2. Headache (~35%)
   3. Seizures (~17%)
   4. Visual changes
   5. Other symptoms associated with elevated intracranial pressure such as nausea
   6. Difficulty walking
6. Detection
   1. Formerly, by computerized tomography (CT)
   2. In HIV negative persons, CT shows no ring enhancement
   3. In HIV+ disease, ~50% are ring enhancing lesions
   4. Multiple lesions seen on MRI
7. Therapy [1,7]
   1. Radiation and/or chemotherapy are the mainstays of therapy
   2. Radiation + dexamethasone fairly effective, especially in HIV negative persons
   3. Chemotherapy increases survival in HIV+ and HIV- persons
   4. High dose methotrexate is most commonly used chemotherapy
   5. Radiation therapy combined with high dose methotrexate is generally recommended [2]
   6. Combination chemoradiotherapy is poorly tolerated in persons >60 years
   7. Surgical resection is not useful
   8. HIV+ patients should remain on HAART therapy
8. Median survival is now 30-60 months with combined chemoradiotherapy
9. Median survival after initial relapse is 14 months

K. Pineal Tumors

1. Most commonly a germ cell tumor
2. Amenable to radiation therapy
3. Neuroblastomas and parenchymal pineal tumors are less common
4. Neuroblastomas usually arise from sympathetic ganglia

L. Ependymoma

1. Glial Cell Tumor usually arising from central canal of spinal cord
2. Less commonly arises from ventricles
3. Undifferentiated cells

M. Spinal Cord Tumors - Summary

1. 55% are Schwannomas or Meningiomas
2. Clinical Manifestations
   1. Pure sensorimotor (cord) syndrome
   2. Painful radicular syndrome
   3. Syringomyelic syndrome
3. Syringomyelia
   1. Spinal cord - longitudinal cavities lined by dense gliogenous tissue
   2. Not caused by vascular insufficiency
   3. Marked clinically by pain and paresthesias followed by muscular atrophy
   4. Analgesia with thermal anesthesia in the hands and arms

1. Lung
2. Breast
3. Melanoma
4. Leukemia (Lymphoma)

B. Spread

1. Carcinomas spread primarily by hematogenous routes
2. Subarachnoid spread is called syndrome of carcinomatous meningitis
3. Subarachnoid spread is common with leukemias and lymphomas
   1. May involve multiple cranial nerve roots
   2. Leukemic or lymphomatous meningitis

C. Carcinomatous Meningitis

1. Etiology
   1. Subarachnoid spread of tumor - radicular involvement
   2. Obstruction of CSF resorption by involvement of arachnoid
   3. This causes increased intracranial pressure (ICP)
2. Symptoms of Carcinomatous Meningitis
   1. Change in Mental status - Increased ICP
   2. Cranial nerve palsies
   3. Weakness of extremities, sensory loss, deep tendon reflex loss
   4. Seizures and Focal signs

D. Treatment

1. Single Brain Metastases [15]
   1. Generally treatable
   2. Surgical resection is more effective than whole brain radiotherapy (WBRT)
   3. Stereotactic radiosurgery (SRS) is usually used for single lesions
   4. Adding WBRT to surgery reduces recurrence rate and death from brain disease
   5. Late sequellae of WBRT is neurological damage due to radiation necrosis
2. One to Four Brain Metastases [35]
   1. SRS and WBRT are used
   2. Adding WBRT to SRS does not improve survival, but reduces brain recurrences
   3. No significant differences with WBRT+SRS and SRS on neurologic or systemic complications
3. Carcinomatous meningitis is usually treated with intrathecal chemotherapy
   1. Regimens include high dose systemic glucocorticoids
   2. Outcomes are generally poor for carcinomas
   3. However, lymphomatous or leukemic meningitis is responsive to intrathecal therapy

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