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Congenital hypomyelinating neuropathy central dysmyelination and WaardenburgЦHirschsprung disease Phenotypes linked by SOX10 mutation.

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Congenital Hypomyelinating
Neuropathy, Central
Dysmyelination, and
Waardenburg–Hirschsprung
Disease: Phenotypes Linked
by SOX10 Mutation
Ken Inoue, MD, PhD,1 Konstantin Shilo, MD,2
Cornelius F. Boerkoel, MD, PhD,1 Carol Crowe, MD,3
Joram Sawady, MD,2 James R. Lupski, MD, PhD,1,4
and Dimitri P. Agamanolis, MD5
A unique phenotype of Waardenburg–Hirschsprung disease (WS4) accompanied by peripheral neuropathy and
central dysmyelination has been recognized recently in
association with SOX10 mutations. We report an infant
boy with lethal congenital hypomyelinating neuropathy
and WS4 who had a heterozygous SOX10 mutation
(Q250X). Histopathological studies showed an absence of
peripheral nerve myelin despite normal numbers of
Schwann cells and profound dysmyelination in the central nervous system. These observations suggest that some
SOX10 mutations such as Q250X may allow Schwann
cells and oligodendrocytes to proliferate but interfere
with further differentiation to form myelin. In contrast
with the SOX10 loss-of-function mutations causing only
WS4, mutations associated with both peripheral and central dysmyelination may affect pathology through a
dominant-negative mechanism.
Ann Neurol 2002;52:836 – 842
Congenital hypomyelinating neuropathy (CHN) is a
genetically heterogeneous severe peripheral neuropathy
characterized by little or no development of peripheral
myelin. Mutations causing CHN have been identified
in myelin protein zero (MPZ)1 and peripheral myelin
protein 22 (PMP22),2,3 myelin structural proteins, and
From the 1Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, TX; 2Departments of Pathology and
3
Pediatrics (Genetics), MetroHealth Medical Center and Case Western Reserve University, Cleveland, OH; 4Department of Pediatrics,
Baylor College of Medicine, Houston, TX; and 5Department of Pathology, Children’s Hospital Medical Center of Akron, and Northeastern Ohio Universities College of Medicine, Rootstown, OH.
Received Apr 9, 2002, and in revised form Aug 13. Accepted for
publication Aug 13, 2002.
Address correspondence to Dr Agamanolis, Department of Pathology, Children’s Hospital Medical Center of Akron, One Perkins
Square, Akron, OH 44308. E-mail: dagamanolis@chmca.org
836
© 2002 Wiley-Liss, Inc.
the early growth response gene 2 (EGR2),4 a transcription factor regulating Schwann cell differentiation. In
addition to causing CHN, mutations in these proteins
can cause a spectrum of peripheral demyelinating neuropathies including Dejerine–Sottas neuropathy (DSN;
MIM 145900) and Charcot–Marie–Tooth disease type
1(CMT1).5
Recently, Inoue and colleagues6 and Pingault and
colleagues7 reported two patients with Waardenburg–
Hirschsprung disease (WS4; MIM 277580) in whom
the SOX10 mutations caused peripheral neuropathy,
CMT1 and CHN; one patient also had central dysmyelination.6 These observations suggested that some mutations of SOX10, a transcription factor important for
neural crest development, affect the central (oligodendrocyte) and peripheral (Schwann cell) myelin lineage
in addition to other neural crest derivatives. To explain
the association of myelin deficiency with only a subset
of SOX10 mutations, Inoue and colleagues proposed
that SOX10 loss-of-function mutations result in WS4
whereas dominant-negative mutations result in an expanded phenotype encompassing WS4 as well as central and peripheral dysmyelination.6 We report a neuropathological study of a patient with a SOX10
mutation causing CHN, central dysmyelination, and
WS4; our observations support the hypothesis that heterozygous dominant-negative SOX10 mutations interfere with Schwann cell and oligodendrocyte differentiation and myelin development.
Case Report
The patient, a male infant (BAB1580), was the first child of
unrelated parents. The pregnancy was complicated by urinary tract infection, asymmetrical fetal growth retardation,
leaking amniotic fluid, and decreased fetal movements. The
mother was induced at 38 weeks because of fever, urinary
tract infection, and rupture of membranes. Apgar scores were
3 and 6 at 1 and 5 minutes, respectively. The infant weighed
2,290gm (3%), measured 49cm (75%), and had a head circumference of 36cm (90%). On physical examination, he
had a white forelock and hyperpigmented and hypopigmented patches on the face, body, and extremities. On neurological examination, he had little spontaneous respiratory
or other movement, severe hypotonia, multiple contractures,
undetectable tendon reflexes, and tongue fasciculations. He
did not react to sound. He never passed meconium and required repeated segmental small and large bowel resections
for treatment of ileus. He remained ventilator dependent his
entire life and died at 83 days of Pseudomonas aeruginosa sepsis.
We obtained nerve conduction velocities (NCVs) of 2.1
and 1.9m/sec from the right median nerve and right tibial
nerve at 29 days of life, respectively. Follow-up testing at 6
weeks showed no excitability in the distal extremities; pickup
responses were barely obtained at proximal positions; however, NCV could not be determined. His brainstem auditory
evoked responses were undetectable. His electroencephalogram and head ultrasound were normal. Brain magnetic res-
onance imaging at 2 days of age showed marked delay in
myelination. The brainstem, hilus of the dentate nucleus,
posterior limbs of the internal capsules, and thalamus that
normally are myelinated at this age showed no trace of myelin. The skeletal survey showed osteopenia and numerous
fractures. The upper gastrointestinal series showed reflux and
poor peristalsis, and the lower gastrointestinal series showed
decreased colon and terminal ileum caliber and dilated small
bowel loops. His rectal biopsy showed sparse ganglion cells,
and his muscle biopsy showed myofiber atrophy. He had
normal organic acids, carnitine, lactate to pyruvate ratio, very
long chain fatty acids, thyroid function studies, and karyotype analyses. Molecular testing for spinal muscular atrophy,
peripheral neuropathy (PMP22, MPZ, and EGR2), and cystic fibrosis was normal.
Materials and Methods
We extracted genomic DNA from a flash-frozen postmortem
liver sample from the patient and from maternal blood using
standard methods. We amplified each coding exon of SOX10
by the polymerase chain reaction and sequenced the products
using an automated DNA sequencer (ABI377; Applied Biosystems, Foster City, CA), as described.6
Autopsy was performed 3 hours after death. Paraffinembedded, formalin-fixed tissues were processed for conventional morphological studies by light microscopic examination. Sections of cerebrum, brainstem, and spinal cord from
the patient and from two 3-month-old neurologically normal
infants who died of sudden infant death syndrome were
stained with Luxol fast blue and Weil myelin stains. Immunohistochemistry using antibodies to myelin basic protein
(MBP; SMI 94; Sternberger Monoclonals, Baltimore, MD)
and glial fibrillary acidic protein (Dako) was also performed.
Cross-sections of the common peroneal nerve were examined
by electron microscopy.
Results
SOX10 Mutation Analysis
We identified a single heterozygous nucleotide substitution (748C3 T) in exon 5 of the SOX10 gene that
destroys a PstI restriction enzyme recognition site. This
transition mutation results in a premature termination
at codon 250 (Q250X), encoding the region between
the high mobility group and the transactivation domain (Fig 1). We did not detect a SOX10 mutation in
the mother by DNA sequencing or PstI endonuclease
digestion. The father was not available for testing. We
did not observe this mutation in 100 normal control
chromosomes derived from healthy North American
individuals.
Autopsy Findings
GENERAL PATHOLOGY. The autopsy showed segmental
bowel dilatation and thinning with multiple peritoneal
adhesions. Myenteric and submucosal ganglion cells
were severely diminished throughout the entire colon
and much of the small bowel. There were abnormal
Inoue et al: CHN with WS4 and SOX10 Mutation
837
Fig 1. DNA sequence chromatograms and PstI endonuclease confirmation of the SOX10 alteration identified in patient BAB1580
of family HOU644. (A) The family exhibits sporadic inheritance. Filled circle indicates congenital hypomyelinating neuropathy. (B)
Patient 1580 is heterozygous for mutation 748C3 T that by conceptual translation causes the nonsense mutation Q250X. (C) Because mutation 748C3 T abolishes a PstI restriction site, heterozygosity for the mutation in the patient and absence of the mutation in the mother was confirmed by PstI digestion of the polymerase chain reaction amplicon of SOX10 exon 5. bp ⫽ base pairs;
MW ⫽ molecular weight markers; UD ⫽ undigested. (D) Structure of SOX10 (horizontal bar) with corresponding coding exons
and distribution of SOX10 mutations (triangles). Mutations resulting in WS4 are listed at the top, and those causing WS4 with
myelin deficiencies, or with uncharacterized neurological phenotypes, are shown at the bottom. (open triangle) Q250X mutation;
(filled triangles) mutations previously reported.
hypertrophic nerves in the intestinal serosa, but no hypertrophic nerves were found in the enteric plexuses.
The brain weighed 550gm and
was grossly normal. The gyral pattern was normal, and
the central white matter was normal in mass. The cortical cytoarchitecture was normal. The spinal cord had
a normal number of anterior horn neurons. Clusters of
heterotopic sensory ganglion cells were present in the
spinal subarachnoid space. Myelin stains and MBP immunostains showed absence of central myelin. Specifically, in the posterior columns, corticospinal tracts, medial lemnisci, medial longitudinal fasciculi, cerebellar
peduncles, transverse fibers of the pons and optic
tracts, no myelin was found in the patient in contradistinction to the age-matched controls (Fig 2). Oligodendrocytes were reduced in number but present in
these white matter tracts. The white matter of the centrum semiovale in the patient showed mild gliosis.
MBP staining was observed in close proximity or in
contact with small round nuclei, presumably oligodendrocytes. No evidence for myelin degradation or macrophages infiltration was observed.
NEUROPATHOLOGY.
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Annals of Neurology
Vol 52
No 6
December 2002
The common peroneal nerve showed virtually total
absence of myelin (Fig 3A). The extremely rare myelinated axons that were present had very thin myelin.
Most large axons were surrounded by the cytoplasm of
a single Schwann cell without myelin formation.
Rarely, two Schwann cells surrounded large axons.
Some large axons were only partially enveloped by
Schwann cell cytoplasm, but they had a continuous
basement membrane. Endoneurial collagen was markedly increased, and Schwann cell processes enveloped
bundles of collagen and axons but made no myelin (see
Fig 3B). Axons ranged from 0.5 to 15␮m in diameter.
The density of large axons was normal. Small axons
were markedly decreased, and the remaining ones were
packed into tight fascicles (see Fig 3C). These small
axons were individually ensheathed by Schwann cell
processes. Scattered excessively large axons were
present. Some of these had a normal structure, but
most were densely packed with neurofilaments, and the
largest among them were traversed by irregular membranous septa that extended from the axolemma (see
Fig 3D). Such axons were surrounded by basement
membrane but were not in contact with Schwann cell
Fig 2. Myelin basic protein immunostains. (A) Spinal cord of the patient; (B) spinal cord of a 3-month-old control (neurologically
normal child who died of the sudden infant death syndrome); (C) optic tract of the patient (⫻24 magnification); (D) optic tract of
the 3-month control, ⫻12 magnification. Essentially no myelin can be appreciated in the spinal cord, spinal roots, or optic tract in
the patient under low magnification. In contrast, the control shows abundant myelin in the central nervous system and in spinal
roots.
cytoplasm. No onion bulb formations were seen. There
was increased endoneurial collagen. Skeletal muscle
showed group atrophy and fiber-type grouping.
Discussion
CHN is characterized by a deficiency of peripheral
nerve myelin formation. The clinical phenotype consists of nonprogressive weakness, hypotonia, areflexia,
respiratory failure, and remarkably slow NCV from
birth. Microscopic analysis shows prominent hypomyelination without myelin degeneration. Our case fits
this clinical and pathological phenotype.
SOX10 mutations have been identified in WS4 patients with peripheral myelinopathies6,7 but not in peripheral neuropathy patients without features of WS4
(C.F. Boerkoel, K. Inoue, and J.R. Lupski, unpublished results; Pingault and colleagues8). The patient
described by Inoue and colleagues (1400del12, resulting in disruption of the normal stop codon and an 82–
amino acid extension) had WS4, a CMT1-type peripheral neuropathy, and severe central nervous system
dysmyelination consistent with Pelizaeus–Merzbacher
disease.6 Although no biopsy findings were provided,
NCV and clinical presentation suggested a much
milder peripheral nerve phenotype than our patient.
The patient described by Pingault and colleagues
(759delG) had WS4 and thin myelin sheaths in the
nerve biopsy, consistent with hypomyelination; however, clinical and electrophysiological findings improved over 8 years.7
In contrast with the two previously described patients, our patient exhibited a complete deficiency of
peripheral myelin development. Although present in
nearly normal numbers and often aligned next to axons
in a one-to-one relationship, Schwann cells never
formed myelin. This observation suggests that the
SOX10 mutation did not affect Schwann cell migration
or proliferation but rather inhibited differentiation of
the myelin sheath. Furthermore, the axons showed dystrophic changes, which likely resulted from loss of trophic axon–myelin interactions. This also may affect
unmyelinated axons as observed in our case. Interest-
Inoue et al: CHN with WS4 and SOX10 Mutation
839
Fig 3. (A) A fascicle of the common peroneal nerve shows no myelinated axons and scattered abnormal large axons. Epoxy section,
toluidine blue stain (⫻440 magnification). (B) Schwann cell processes wrap around a nonmyelinated axon (bottom) and a collagen bundle (top). Uranyl acetate and lead citrate (⫻11,000 magnification). (C) Tightly packed small unmyelinated axons and
increased endoneurial collagen. Uranyl acetate and lead citrate (⫻5,500 magnification). (D) Dysplastic large axon with densely
packed filaments and septa. Adjacent axon is shown in top right corner with thin myelin. Uranyl acetate and lead citrate (⫻7,000
magnification).
ingly, similar differentiation defects in Schwann cells
were observed in mouse models lacking the transcription factors Egr29 and Oct6,10 in agreement with the
fact that SOX10 acts synergistically with EGR2 and
840
Annals of Neurology
Vol 52
No 6
December 2002
OCT6.11 Our case also showed central dysmyelination
that is compatible with the prominent dysmyelination
observed in association with the 1400del12 mutation.6
Of note, the case with 759delG mutation presented
with no clinical features of central nervous system dysmyelination.7 These findings indicate that SOX10 also
plays an important role in central myelin development,6,12 but the consequent clinical manifestations
may vary with different mutations. The prominent
pathological findings in the present case correspond
well with the severe clinical phenotype.
The SOX family of transcription factors is characterized by a high-mobility group DNA binding domain.11
SOX10 is selectively expressed in neural crest cells during the early stages of development and in the
Schwann cell and oligodendrocyte lineages later in development and continuing into adulthood.13 To date,
various studies have suggested that SOX10 likely controls the expression of genes in the Schwann cell and
oligodendrocyte lineages, including ERBB3, MPZ,
CX32 (GJB1), PLP, and MBP.12,14 –16 Accordingly,
early migration defects of both Schwann cell and oligodendrocyte lineages were observed in Sox10⫺/⫺
mice.12,14
In humans, the clinical spectrum conveyed by
SOX10 mutations supports the hypothesis that haploinsufficiency is the genetic mechanism underlying some
cases of WS4.17 However, other patients with SOX10
mutations have peripheral and central nervous system
dysmyelination in addition to WS4. The expanded
phenotype likely results from a distinct pathogenic
mechanism such as dominant-negative interference
with wild-type SOX10 activity.6 Mutations associated
with such dysmyelination or with a “neurological phenotype”18,19 result in premature terminations in the
last exon (see Fig 1D). The mRNA from these mutations may escape the RNA surveillance system and be
translated into mutant proteins that interfere with the
function of the wild-type SOX10 protein.20 In contrast, those associated with WS4 alone cause premature
terminations in upstream exons and are presumably
subjected to RNA surveillance and subsequent degradation and thus not translated into mutant protein.20
Q250X found in our patient belongs to the former
group of mutations. Thus, we hypothesize that the severe and lethal CHN associated with WS4 may result
from the dominant-negative action of the mutant
SOX10 protein.
This study was supported in part by grants from the National Institute of Neurological Disorders and Stroke, NIH (R01 NS27042,
J.R.L.), Muscular Dystrophy Association (J.R.L.), and the National
Institute of Diabetes, Digestive, and Kidney Diseases, NIH (K08
DK02738, C.F.B.) and by the Research Development Grant from
the Muscular Dystrophy Association (K.I.).
We thank the family described for their cooperation. We also thank
Dr D. L. Armstrong (Texas Children’s Hospital) for her critical advice in neuropathology and T. Campbell (Children’s Hospital Medical Center of Akron) for his help with the figures.
References
1. Warner LE, Hilz MJ, Appel SH, et al. Clinical phenotypes of
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2. Simonati A, Fabrizi GM, Pasquinelli A, et al. Congenital hypomyelination neuropathy with Ser72Leu substitution in
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5. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. Scriver CR, Sly WS, Childs B,
Beaudet AL, Valle D, Kinzler KW, Vogelstein B. eds. The metabolic and molecular basis of inherited diseases. 8th ed. New
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6. Inoue K, Tanabe Y, Lupski JR. Myelin deficiencies in both the
central and the peripheral nervous systems associated with a
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7. Pingault V, Guiochon-Mantel A, Bondurand N, et al. Peripheral neuropathy with hypomyelination, chronic intestinal
pseudo-obstruction and deafness: a developmental “neural crest
syndrome” related to a SOX10 mutation. Ann Neurol 2000;48:
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8. Pingault V, Bondurand N, Le Caignec C, et al. The SOX10
transcription factor: evaluation as a candidate gene for central
and peripheral hereditary myelin disorders. J Neurol 2001;248:
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1994;371:796 –799.
10. Jaegle M, Mandemakers W, Broos L, et al. The POU factor
Oct-6 and Schwann cell differentiation. Science 1996;273:
507–510.
11. Wegner M. From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 1999;27:1409 –1420.
12. Stolt CC, Rehberg S, Ader M, et al. Terminal differentiation of
myelin-forming oligodendrocytes depends on the transcription
factor Sox10. Genes Dev 2002;16:165–170.
13. Kuhlbrodt K, Herbarth B, Sock E, et al. Sox10, a novel transcriptional modulator in glial cells. J Neurosci 1998;18:
237–250.
14. Britsch S, Goerich DE, Riethmacher D, et al. The transcription
factor Sox10 is a key regulator of peripheral glial development.
Genes Dev 2001;15:66 –78.
15. Peirano RI, Goerich DE, Riethmacher D, et al. Protein zero
gene expression is regulated by the glial transcription factor
Sox10. Mol Cell Biol 2000;20:3198 –3209.
16. Bondurand N, Girard M, Pingault V, et al. Human Connexin
32, a gap junction protein altered in the X-linked form of
Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. Hum Mol Genet 2001;10:2783–2795.
17. Pingault V, Bondurand N, Kuhlbrodt K, et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat
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phenotype in Waardenburg syndrome type 4 correlates with
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Inoue et al: CHN with WS4 and SOX10 Mutation
841
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Association of Chromosome
10 Losses and Negative
Prognosis in
Oligoastrocytomas
Lorena Bissola, PhD,1 Marica Eoli, MD,2
Bianca Pollo, MD,2 Bianca Maria Merciai, PhD,3
Antonio Silvani, MD,2 Ettore Salsano, MS,1
Carmelo Maccagnano, MD,1
Maria Grazia Bruzzone, MD,1
Anna Maria Fuhrman Conti, PhD,3
Carlo Lazzaro Solero, MD,4 Sergio Giombini, MD,4
Giovanni Broggi, MD,4 Amerigo Boiardi, MD,2
and Gaetano Finocchiaro, MD1
Oligoastrocytomas are mixed gliomas harboring different
genetic alterations and with heterogeneous clinical evolution. We have looked for correlations between genetic
losses and clinical evolution in 34 oligoastrocytomas. Loss
of heterozygosity (LOH) with different microsatellite
markers was studied on chromosomes 1p, 10q, 17p, and
19q. LOH on 1p was found in 44% of the tumors, on 10q
in 24%, on 17p in 18%, and on 19q in 38%. LOH on 1p
and 19q was combined in 29% of the patients. LOH on
1p was associated with significantly longer overall survival
(p ⴝ 0.0092) and LOH on 10q with shorter overall survival (p ⴝ 0.0206). The observation that LOH on 10q predicts a short survival in oligoastrocytomas is novel and
provides further evidence that genetic analysis may help to
predict the clinical evolution of different gliomas, giving a
more rationale basis to therapeutic options.
Ann Neurol 2002;52:842– 845
Oligoastrocytomas are composed of a mixture of neoplastic cells resembling atypical astrocytes and oligodendrocytes. The pathological criteria for tumoral diagnosis are not univocal. Genetic alterations of these
mixed gliomas include loss of heterozygosity of chromosomes 1p and/or 19q, typical of oligodendrogliomas, and mutations of the p53 tumor suppressor gene,
located on chromosome 17p, frequent in astrocytomas.1– 6
Oligoastrocytomas may respond to chemotherapy
but less frequently than oligodendrogliomas.7–9 Indeed
oligoastrocytomas are heterogeneous for their clinical
evolution, and this often makes their clinical management uncertain. Thus, there is hope that a wider
knowledge of their genetic alterations may help to
characterize these tumors thoroughly, giving a more
rational basis to their treatment. With this aim, we
have examined 34 oligoastrocytomas for allelic losses
on chromosomes 1p, 19q, 17p, and 10q (where
PTEN and possibly other tumor suppressor genes are
located10), and we have correlated our findings with
their clinical evolution.
The results show that significant correlations exist
and stress the positive and the negative role that chromosome 1p and 10q losses, respectively, may play as
prognostic factors.
Patients and Methods
Tumor Specimens and DNA Extraction
Tumor and corresponding blood samples were obtained
from 34 patients treated at the Istituto Nazionale Neurologico “C. Besta,” Milano, between 1992 and 2000. Tumor
classification, in agreement with World Health Organization
(WHO) guidelines,11 was performed by two neuropathologists of our institution. To make the diagnosis, we identified
at least 25% of the neoplastic cells as astroglial or oligodendroglial. Tumors included 9 oligoastrocytomas (OAs, WHO
grade II) and 25 anaplastic oligoastrocytomas (AnOAs,
WHO grade III). DNA was extracted from frozen tissues
(n ⫽ 30) or from paraffin-embedded material (n ⫽ 4) using
established methods.12 Control DNA was extracted from
blood lymphocytes.
Clinical Parameters
From the Departments of 1Experimental Neurology and Diagnostics and 2Clinical Neurology, Istituto Nazionale Neurologico Besta;
3
Department of Biology and Genetics for Medical Sciences, University of Milan; and 4Department of Neurosurgery, Istituto Nazionale
Neurologico Besta, Milan, Italy.
Received Jun 14, 2002, and in revised form Aug 23. Accepted for
publication Aug 23, 2002.
Published online Nov 22, 2002 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10405
Address correspondence to Dr Finocchiaro, Unit of Neuro-Oncology
and Gene Therapy, Istituto Nazionale Neurologico Besta, Via Celoria
11, 20133 Milano, Italy. E-mail: gaetano.finocchiaro@libero.it
842
© 2002 Wiley-Liss, Inc.
Clinical data included age, gender, date of surgical resection
and pathology of the specimen, extent of surgery (assessed by
comparison of preoperative computed tomography/nuclear
magnetic resonance with scans taken within 24 hours after
surgery and 2 months later), Karnofsky performance score
(assessed on the seventh day after surgery), treatment (chemotherapy and/or radiation therapy), time of tumor progression (defined as the time of the first sign of radiological progression13), time of the last follow-up, and status of the
patient (living/deceased) at the time of the last follow-up.
Clinical and neuroradiological controls were performed every
6 months at our institution. Because many patients were
alive at the last follow-up, time to tumor progression (TTP)
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