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Medulloblastoma
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Advantage of protons compared to conventional X-ray
or IMRT in the treatment of a pediatric patient with medulloblastoma.
St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM, Loeffler
JS, Tarbell NJ.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, USA.
PURPOSE: To compare treatment plans from standard photon therapy to intensity
modulated X-rays (IMRT) and protons for craniospinal axis irradiation and
posterior fossa boost in a patient with medulloblastoma. METHODS: Proton
planning was accomplished using an in-house 3D planning system. IMRT plans
were developed using the KonRad treatment planning system with 6-MV photons.
RESULTS: Substantial normal-tissue dose sparing was realized with IMRT
and proton treatment of the posterior fossa and spinal column. For example,
the dose to 90% of the cochlea was reduced from 101.2% of the prescribed
posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from
IMRT and protons, respectively. Dose to 50% of the heart volume was reduced
from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons.
Long-term toxicity with emphasis on hearing and endocrine and cardiac function
should be substantially improved secondary to nontarget tissue sparing
achieved with protons. CONCLUSION: The present study clearly demonstrates
the advantage of conformal radiation methods for the treatment of posterior
fossa and spinal column in children with medulloblastoma, when compared
to conventional X-rays. Of the two conformal treatment methods evaluated,
protons were found to be superior to IMRT.
PMID: 14967427 [PubMed - in process]
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Change in neurocognitive functioning after treatment
with cranial radiation in childhood.
Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ.
Department of Psychology, The Hospital for Sick Children, 555 University
Ave, Toronto, ON M5G 1X8, Canada.
PURPOSE: To evaluate the pattern of stability and change over time across
multiple domains of neurocognitive function in radiated survivors of posterior
fossa (PF) tumors. PATIENTS AND METHODS: Thirty-four children (25 males)
treated for malignant PF tumors were observed with serial clinical neuropsychologic
assessments. Thirty patients were treated for medulloblastoma and four
patients were treated for ependymoma. Twelve patients were treated with
reduced-dose and 21 patients were treated with standard-dose cranial radiation.
All patients received an additional boost to the PF. One patient was treated
with PF radiation only. Standardized neuropsychologic tests were administered
at different times after diagnosis for each child. The rate of change in
scores was determined using a mixed model regression. RESULTS: Results
showed a 2- to 4-point decline per year in intelligence scores. For our
relatively young sample, intellectual function declined quickly in the
first few years after treatment, and then more gradually. Significant declines
in visual-motor integration, visual memory, verbal fluency, and executive
functioning were also documented. No decline was evident for verbal memory
and receptive vocabulary. CONCLUSION: Cranial radiation is associated with
a decline in multiple neurocognitive domains, with a few notable exceptions.
Our results must be interpreted in the context of common limitations of
clinical research, including patient variability, changes in test versions,
small sample size, and clinical referral bias.
PMID: 14966095 [PubMed - in process]
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Medulloblastoma in childhood: Impact of radiation technique
upon the outcome of treatment.
Chojnacka M, Skowronska-Gardas A.
1st Department of Radiation Oncology, The Maria Sklodowska-Curie Memorial
Cancer Centre, and Institute of Oncology, Warsaw, Poland. marzanna.ch1@wp.pl
BACKGROUND: Medulloblastoma is an infratentorial primitive neuroectodermal
tumour, diagnosed in paediatric population. The radiotherapy is an essential
method of treatment for these tumours. The impact of technical quality of
radiation therapy on survival was recently considered. In this study treatment-related
variables are analysed with a special focus on radiotherapy technical factors.
PROCEDURE: The population of 158 children with a diagnosis of medulloblastoma
had been undergoing postoperative radiotherapy at MCMCC in Warsaw in the
period 1983-1997. The medical data of these patients were analysed. Simulation
films of the whole-brain irradiation fields were retrospectively reviewed
at 112 patients. The distance from the field margin to the cribriform plate
and to the floor of the temporal fossa was assessed and correlated with supratentorial
relapse. RESULTS: Five-year overall survival (OS) and 5-year disease free
survival (DFS) were 46% and 40%, respectively. In multivariate analysis gender
(P = 0.008), neurological status before radiotherapy (P = 0.029), M-stage
(P < 0.001) and sequence of craniospinal irradiation (P = 0.019) were
significant prognostic factors for OS. For DFS significant factors were M-stage
(P < 0.001) and neurological status (P < 0.001). The cranial fields
were not fully correctly covered at 43% patients. The field incorrectness
was correlated with isolated supratentorial failure (P = 0.049). CONCLUSIONS:
Our results are similar to those published in literature. M0-stage was the
most powerful favourable prognostic factor. Male gender and neurological
status before radiation treatment were associated with poor survival. Also
protracted radiotherapy and quality of radiation technique may have an impact
on the outcome. Copyright 2003 Wiley-Liss, Inc.
PMID: 14752880 [PubMed - in process]
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Medulloblastoma with extensive nodularity: a variant
occurring in the very young-clinicopathological and immunohistochemical
study of four cases.
Suresh TN, Santosh V, Yasha TC, Anandh B, Mohanty A, Indiradevi B, Sampath
S, Shankar SK.
Department of Neuropathology, National Institute of Mental Health and Neurosciences,
560 029, Bangalore, India.
CASE REPORT. Four cases of medulloblastoma with extensive nodularity (MBEN)
are described. The patients were 3 years of age or younger at diagnosis.
Cranial CT scan disclosed multiple coalescing nodules with peculiar 'grape-like'
architecture in three patients. A near total excision of the tumour was
performed in all four patients. The patients are currently receiving radiation
and chemotherapy. Histologically, the tumours were characterized by extreme
nodularity with intranodular uniformity and low proliferative index. The
internodular zones were extremely cellular, composed of undifferentiated,
mitotically active cells. Bcl-2 protein expression was observed in the
cellular zones but was distinctly absent within nodules. DISCUSSION. MBEN
represents a variant that occurs in very young children but has a good
prognosis. The favourable outcome is probably related to its spontaneous
neurocytic differentiation. The pattern of Bcl-2 immunoreactivity in MBENs
indicates that this protein could be a key player in the regulation of
neuronal differentiation in medulloblastomas.
PMID: 14657995 [PubMed - in process]
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Gliosarcoma occurring 8 years after treatment for a
medulloblastoma.
Malde R, Jalali R, Muzumdar D, Shet T, Kurkure P.
Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai-400
012, India.
CASE REPORT. We present a rare case of a gliosarcoma occurring 8 years
following treatment for a medulloblastoma. The patient was diagnosed with
a medulloblastoma at the age of 13 years. We considered the possibility
of a radiation-induced tumour and present evidence supporting this view.
The second cerebral tumour was excised and confirmed to be a gliosarcoma.
The tumour bed was re-irradiated with three-dimensional conformal radiotherapy
(3DCRT). She remained well for 6 months, after which there was clinicoradiological
progression. CONCLUSIONS. During long-term follow-up of patients with medulloblastomas,
the possibility of radiation-induced neoplasms must be borne in mind.
PMID: 14704813 [PubMed - as supplied by publisher]
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Medulloblastomas and central nervous system primitive
neuroectodermal tumors.
McLean TW.
Department of Pediatrics, Wake Forest University School of Medicine, Medical
Center Boulevard, Winston-Salem, NC 27157, USA. tmclean@wfubmc.edu
Significant advances in the treatment of medulloblastoma and primitive neuroectodermal
tumors have been made in the past three decades. Maximal surgical resection
is a mainstay of therapy. However, unlike many other central nervous system
neoplasms, medulloblastoma and primitive neuroectodermal tumors are radiation
and chemotherapy responsive. Despite this response, the prognosis for patients
with these tumors remains variable and is relatively poor in infants and
patients with metastatic disease. These tumors most commonly arise in children,
thus most clinical trials emphasize the reduction of long-term sequelae,
in addition to improving survival. All newly diagnosed patients who are eligible
should be offered participation in a clinical trial. If a patient is ineligible
or declines consent/assent for a clinical trial, the best current treatment
approach is surgical resection, followed by radiation therapy (except for
children younger than 3 years) with weekly vincristine. For high-risk patients,
36 Gy of craniospinal irradiation should be delivered plus a boost of 19.8
Gy to the posterior fossa/primary tumor bed and sites of bulk metastatic
disease. For average-risk patients, the craniospinal irradiation dose may
be lowered to 23.4 Gy plus 32.4 Gy to the posterior fossa/tumor bed. After
radiation therapy, intensive multimodal chemotherapy should be used for all
patients.
PMID: 14585230 [PubMed - in process]
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Effects of radiation treatment planning and patient
fixation on the results of postoperative radiotherapy of childhood medulloblastoma.
Kocsis B, Szekely G, Pap L, Nemeth G.
Department of Radiotherapy, National Institute of Oncology, Budapest, Hungary.
szekelyg@oncol.hu
PURPOSE: To assess the prognostic factors and the benefit of introducing
head fixation and CT-assisted radiation treatment planning following postoperative
radiotherapy in 83 children with medulloblastoma. PATIENTS AND METHODS: In
24 children treated between 1986 and 1994, no head fixation was applied and
boost irradiation was not based on individual radiation treatment planning.
Since 1995, boost irradiation has been assisted by CT-based individual radiation
treatment planning and ORFIT head fixation in 59 patients. The influence
of various factors including age, sex, tumor location, extent, type of surgery,
risk group, radiation dose to posterior fossa and spinal axis, and the effect
of head fixation and CT-assisted radiation treatment planning on 5-year relapse-free
and 5-year overall survival was investigated. RESULTS: Overall and relapse-free
survival rates for all 83 patients were 73.5% and 60.7%. Univariate analysis
identified metastatic disease (p = 0.034) and the application of head fixation
and individual radiation treatment planning (p = 0.013) as significant prognostic
factors for overall survival. Relapse-free survival rates were influenced
by metastatic disease (p = 0.028) and the application of head fixation and
individual radiation treatment planning (p = 0.009). On multivariate analysis,
metastatic disease (p = 0.04) and the application of head fixation and individual
radiation treatment planning (p = 0.045) were significant factors for overall
and relapse-free survival (p = 0.036 and p = 0.041) as well. CONCLUSION:
Metastatic disease appears to be correlated with a worse prognosis in this
analysis. Individual radiation treatment planning and head fixation have
a positive impact on survival. For postoperative radiotherapy of the posterior
fossa, the application of head fixation and individual CT-based radiation
treatment planning is considered indispensable in each case.
PMID: 14652675 [PubMed - indexed for MEDLINE]
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The treatment of adults with medulloblastoma: a prospective
study.
Brandes AA, Ermani M, Amista P, Basso U, Vastola F, Gardiman M, Iuzzolino
P, Turazzi S, Rotilio A, Volpin L, Mazza C, Sainati L, Ammannati F, Berti
F.
Department of Medical Oncology, Azienda Ospedale-Universita of Padova,
Padova, Italy. aabrandes@unipd.it
PURPOSE: To assess in a prospective trial the value of prognostic factors
and the outcome of medulloblastoma in adults. METHODS AND MATERIALS: Patients
(> or =18 years) with a histologic diagnosis of medulloblastoma were staged
according to Chang et al.'s classification (low risk: T1, T2, T3a, M0, and
no residual disease after surgery; high risk: T3b-T4, any M+ or postoperative
presence of residual tumor). In low-risk patients, treatment consisted of
36 Gy to the craniospinal axis, supplemented by a local tumor dose of 18.8
Gy (total dose of 54.8 Gy). In high-risk patients, 2 cycles of "up-front
chemotherapy" were delivered before the same radiation therapy, followed
by maintenance chemotherapy if M1, M2, or M3 disease was present. RESULTS:
Over a 12-year period, 36 evaluable patients were enrolled. Progression-free
survival (PFS) at 5 years was higher in low-risk patients compared to the
high-risk group: 76% +/- 14% (95% confidence interval [CI] = 52%-100%) vs.
61% +/- 11% (95% CI = 42%-87%). Patients with M- disease showed a significantly
better outcome than M+ patients, with 75% showing PFS at 5 years vs. 45%
(p = 0.01). CONCLUSION: The overall PFS observed is comparable to that obtained
in pediatric series and suggests that a more effective therapy must be developed
for high-risk patients.
PMID: 14529781 [PubMed - indexed for MEDLINE]
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From the archives of the AFIP: medulloblastoma: a comprehensive
review with radiologic-pathologic correlation.
Koeller KK, Rushing EJ.
Department of Radiologic Pathology, Armed Forces Institute of Pathology,
14th St at Alaska Ave, Bldg 54, Washington, DC 20306-6000, USA. koeller@afip.osd.mil
Medulloblastoma is the most common pediatric central nervous system malignancy
and the most common primary tumor of the posterior fossa in children. This
highly malignant neoplasm occurs more frequently in males and usually before
10 years of age. Clinical symptoms and signs are generally brief, typically
less than 3 months in duration, and reflect the strong predilection of this
tumor to arise within the cerebellum, most often in the vermis. Although
much less common, the disease may also occur in adults, usually in the 3rd
and 4th decades of life. Surgical resection, radiation therapy, and chemotherapy
have substantially lowered the mortality associated with this tumor, with
5-year survival rates now commonly well above 50%. Still, both dissemination
at the time of diagnosis and recurrence remain obstacles in achieving a cure.
The tumor has characteristic hyperattenuation on unenhanced computed tomographic
scans that reflects the high nuclear-cytoplasmic ratio seen at histologic
analysis. The tumor typically appears heterogeneous on images, findings that
are related to cyst formation, hemorrhage, and calcification and that are
even more pronounced with magnetic resonance (MR) imaging. Evidence of leptomeningeal
metastatic spread is present in 33% of all cases at the time of diagnosis
and is well evaluated with contrast-enhanced MR imaging of the brain and
the spine. Although controversial, postoperative surveillance with MR imaging
is performed at most institutions in the hope of facilitating a better outcome.
With continued research, treatment of these common neoplasms should improve,
perhaps even achieving a cure in the future.
Publication Types:
PMID: 14615567 [PubMed - indexed for MEDLINE]
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A method for reducing ovarian doses in whole neuro-axis
irradiation for medulloblastoma.
Harden SV, Twyman N, Lomas DJ, Williams D, Burnet NG, Williams MV.
Department of Oncology, Addenbrooke's NHS Trust, Addenbrooke's Hospital,
Box 193, Hills Road, Cambridge CB2 2QQ, UK.
BACKGROUND AND PURPOSE: Cranio-spinal irradiation for medulloblastoma can
impair fertility in girls. The literature indicates that an ovarian dose
of 4 Gy causes permanent infertility in 30% of young females and that doses
of <1.5 Gy over the whole treatment are desirable. We report a modified
radiotherapy technique using a non-divergent beam edge inferiorly to reduce
the ovarian dose. PATIENTS AND METHODS: Eight female patients with medulloblastoma
had magnetic resonance imaging (MRI) studies in the treatment position
to identify the position of their ovaries relative to the radiation field.
The information was transferred to the radiotherapy planning system and
plans were generated using conventional spinal fields and modified fields
with a half beam block at the inferior border. RESULTS: Identifying the
position of the ovaries by MRI enabled the dose to be estimated for the
two techniques. Using a non-divergent beam inferiorly, the mean ovarian
dose was reduced in all cases by a median value of 2.45 Gy (range 0.6-19.5
Gy) and the median percentage reduction was 66.8% (range 2.6-84.6%). The
position of the ovary relative to the beam edge was critical in determining
the dose reduction for each case. The modified technique doubled the number
of patients receiving <4 Gy to a single ovary from three to six. With
this alteration, three patients also had an ovary receiving <1.5 Gy
whereas all exceeded this dose with conventional treatment. CONCLUSION:
We recommend using asymmetry at the inferior spinal border to achieve a
non-divergent edge to the treatment field to reduce the dose to the ovary.
Using MRI to localise the ovaries is important in estimating their dose
and in assisting the counselling of patients and their families about future
fertility.
PMID: 14643956 [PubMed - in process]
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Quantitative assessment of inter-clinician variability
of target volume delineation for medulloblastoma: quality assurance for
the SIOP PNET 4 trial protocol.
Coles CE, Hoole AC, Harden SV, Burnet NG, Twyman N, Taylor RE, Kortmann
RD, Williams MV.
Oncology Centre, Addenbrooke's Hospital, Box 193, Hills Road, Cambridge
CB2 2QQ, UK.
BACKGROUND AND PURPOSE: To assess inter-clinician variability amongst specialist
paediatric radiation oncologists in delineating clinical target volumes
for treating medulloblastoma as a quality assurance exercise prior to the
introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy
to the posterior fossa and tumour bed. PATIENTS AND METHODS: Participants
from 17 UK centres attended an educational meeting and then completed a
clinical planning exercise to outline: (1) the whole posterior fossa and
(2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial
positioning and axial planes for each individual was carried out and variation
between individuals analysed. RESULTS: Outlining of the posterior fossa
was reasonably consistent, although most variation was seen in defining
the superior border of the tentorium. A major difference was the decision
whether or not to include the post-surgical meningocoele in the clinical
target volume (CTV). The CTV for the tumour bed was under treated by all
participants due to lack of inclusion of pre-operative tumour extent. CONCLUSIONS:
This exercise demonstrated several ambiguities in the draft protocol and
highlighted particular areas of inter-clinician variation. Consequently
the protocol was revised and improved to take account of these findings.
We recommend that planning exercises, in conjunction with education and
training, should be implemented before the start of any new radiotherapy
trial. In the future, the use of image transfer will allow prospective
peer review of target volumes before treatment commences. These measures
are essential to ensure that alterations in clinical practice are achieved
in a uniform way.
PMID: 14643957 [PubMed - in process]
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Patterns of failure in medulloblastoma after optimal
radiation therapy.
Pratt D, Mansur DB, Michalski JM, Lamoreaux WT, Lockett M, Simpson JR.
School of Medicine, St Louis University, St Louis, MO, USA
PMID: 12965738 [PubMed - in process]
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Adult height and adult sitting height in childhood medulloblastoma
survivors.
Xu W, Janss A, Moshang T.
Divisions of Endocrinology, Department of Pediatrics, University of Pennsylvania,
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104,
USA.
Outcome in adult height and sitting height is poor in children surviving
medulloblastoma due to craniospinal irradiation (CSRT) and chemotherapy.
We evaluated adult height and sitting height in 51 medulloblastoma patients
stratified into four groups: G1, GH-deficient (GHD) patients treated with
23-39 Gy CSRT but not treated with GH [recombinant human (rh)GH]; G2, patients
treated with rhGH; G3, patients who were not GHD; and G4, patients treated
with 18 Gy CSRT and rhGH. Standing/sitting height of each group was compared
with parental height and previously reported outcome studies. The rhGH
dose was 0.3 mg/kg.wk, a higher dose compared with other reports of adult
heights. The adult heights were significantly taller in group G2 [mean
height SD score (SDS) = -1.86] than that achieved in previous studies (P < 0.0001),
but not different from group G3, non-GHD (mean SDS = -1.55). The tallest
stature achieved was in group G4 (18 Gy CSRT), a height SDS of -1.01. Sitting
heights were significantly less than the normal population, with mean SDS
of -2.96 but -1.62 in group G4. We conclude that adult heights but not
sitting heights in medulloblastoma survivors are significantly improved
with the higher dose of rhGH. The lower dose of CSRT further improves not
only adult height but also sitting height.
PMID: 14557440 [PubMed - indexed for MEDLINE]
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Predicting intellectual outcome among children treated
with 35-40 Gy craniospinal irradiation for medulloblastoma.
Palmer SL, Gajjar A, Reddick WE, Glass JO, Kun LE, Wu S, Xiong X, Mulhern
RK.
Division of Behavioral Medicine, St. Jude Children's Research Hospital,
Memphis, TN 38105-2794, USA. shawna.palmer@stjude.org
Fifty children diagnosed with medulloblastoma completed 188 psychological
evaluations using the Wechsler Intelligence Scales for Children (D. Wechsler,
1974, 1991) over a 7-year study period following 35-40 Gy postoperative craniospinal
irradiation. Random coefficient models were used to predict the trend in
the children's intellectual performance as a function of time since diagnosis,
with both patient and treatment variables as parameters of this function.
A quadratic model demonstrated a delay prior to decline in performance for
older patients, whereas the younger patients showed an immediate loss of
performance with a plateau at approximately 6 years postdiagnosis. A steeper
decline was found for those with higher baseline performance. Clinicians
may use the proposed predictive model to identify those patients who are
at risk of significant intellectual decline.
PMID: 14599268 [PubMed - indexed for MEDLINE]
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Pathologically proven cavernous angiomas of the brain
following radiation therapy for pediatric brain tumors.
Baumgartner JE, Ater JL, Ha CS, Kuttesch JF, Leeds NE, Fuller GN, Wilson
RJ.
Division of Pediatric Surgery (Neurosurgery), University of Texas Medical
School, Houston, Tex. 77030, USA. james.e.baumgartner@uth.tmc.edu
Lesions consistent with cavernous angiomas (CAs) of the brain are sometimes
seen on MRI scans of the brains of patients who received radiation therapy
for brain tumors as children. The lesions appear years later within brain
tissue that was included in radiation fields. It is unclear whether these
MRI-detected lesions are true CAs or a pathological variant. This study reports
the clinical, radiographical, and pathological findings in 3 cases of radiation-induced
CAs of the brain. >From 1995 to 1997, 3 patients previously treated with
radiation therapy (45-55 Gy) for pediatric brain tumors (medulloblastoma,
ependymoma, and a presumed midbrain astrocytoma) underwent resections of
symptomatic and enlarging lesions that were consistent with a CA of the brain.
All of the lesions occurred within fields of prior irradiation. None of the
patients had received chemotherapy as part of their cancer treatment. CA-presenting
symptoms included seizures, cranial nerve deficits, and headaches. The lesions
appeared 7-19 years after radiation therapy and slowly enlarged on subsequent
imaging studies. MRI scans of the lesions revealed characteristics typical
of CA. The lesions became symptomatic 1-5 years after they were initially
noted. Surgical resection was performed 1-2 years after symptoms began. The
age at resection ranged from 15 to 23 years (10-21 years after radiation
therapy). Pathological analysis of the three lesions showed typical CA characteristics.
Some CAs may be caused by radiation therapy for pediatric brain tumors. They
are radiologically and pathologically similar to sporadically occurring CAs
of the brain and may enlarge over time and become symptomatic. CAs can be
safely resected using standard microsurgical techniques. Copyright 2003 S.
Karger AG, Basel
Publication Types:
PMID: 12944701 [PubMed - indexed for MEDLINE]
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All-trans-retinoic acid-induced apoptosis in human medulloblastoma:
activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway.
Gumireddy K, Sutton LN, Phillips PC, Reddy CD.
Fels Institute for Cancer Research and Molecular Biology, Temple University
School of Medicine, Philadelphia, PA 19140, USA. reddyd@email.chop.edu
Current treatments for childhood brain tumor medulloblastoma (MB), radiation
and chemotherapy, lead to undesirable side effects. Identification of antitumor
agents that reduce the toxicity will thus have significant therapeutic value.
In this study, we investigated all-trans-retinoic acid (ATRA) as an antitumor
agent. Although high concentrations (1-10 microM) of retinoic acid derivatives
are generally needed for significant antitumor effects in many cancer cells,
we observed that pharmacologically relevant concentrations of ATRA were effective
in inducing cell death in human MB cells. Using 10-fold lower concentrations
(100-500 nM), we found that ATRA inhibits MB (DAOY, D283, D425, and D458)
cell proliferation as determined by cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide] and bromodeoxyuridine incorporation assays. Furthermore, 100 nM
ATRA was potent in inhibiting the anchorage-independent growth of the sensitive
cell lines (D283, D425, and D458) in soft agar assays. We also demonstrate
that the ATRA-induced decrease in cell viability was due to increased cell
death by apoptosis, which was accompanied by a 20-fold induction of caspase-3
activity in the most sensitive cell line, D458. By contrast, induction of
caspase-3 was only 2-fold in the relatively insensitive DAOY cells. Furthermore,
ATRA-induced cell death in D283, D425, and D458 cells was accompanied by
activation of caspase-3, a key executioner of apoptosis. We also demonstrate
that activated caspase-3 resulted in cleavage of 116-kDa poly(ADP-ribose)
polymerase 1 to its signature fragments (85 and 29 kDa). Pretreatment with
a specific caspase-3 inhibitor, DEVD-CHO, significantly reduced ATRA-induced
apoptotic cell death. Thus, we demonstrate for the first time that low concentrations
of ATRA inhibit MB cell proliferation and induce apoptotic cell death in
part by activating caspase-3/poly(ADP-ribose) polymerase 1 effector pathway,
and we show that retinoic acids and novel retinoids are potential antitumor
agents in MB therapy.
PMID: 14519626 [PubMed - in process]
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Second malignancies in pediatric patients: imaging findings
and differential diagnosis.
Vazquez E, Castellote A, Piqueras J, Ortuno P, Sanchez-Toledo J, Nogues
P, Lucaya J.
Department of Pediatric Radiology and Institut de Diagnostic per la Imatge,
Hospital Materno-Infantil Vall d'Hebron, Psg Vall d'Hebron 112-119, Barcelona
E-08035, Spain. evazquez@cs.vhebron.es
Therapeutic advances in the treatment of pediatric neoplasms have improved
the prognosis but have also increased the risk of developing rare second
malignant neoplasms (SMNs). Primary neoplasms that are often associated with
SMNs include lymphoma, retinoblastoma, medulloblastoma, neuroblastoma, and
leukemia. The most common SMNs are central nervous system (CNS) tumors, sarcomas,
thyroid and parotid gland carcinomas, and leukemia, particularly acute myeloblastic
leukemia. Genetic predisposition, chemotherapy, and especially radiation
therapy are implicated as pathogenic factors in SMN. All survivors of childhood
cancer should have lifelong follow-up, preferably with magnetic resonance
imaging, which does not require ionizing radiation and provides greater anatomic
detail and resolution in the head and neck region and the CNS. A new or progressive
lesion may represent recurrence of the primitive neoplastic process, late
radiation injury, or, more infrequently, an SMN. Differential diagnosis can
be very difficult, and outcome is often fatal. Treatment protocols should
be modified to reduce the risk for SMN without compromising the effectiveness
of initial therapy. Clinicians should individualize treatment for patients
who are genetically predisposed to SMN. In addition, radiologists should
be familiar with the long-term consequences of antineoplastic therapy to
facilitate diagnosis and anticipate adverse outcomes. Copyright RSNA, 2003
Publication Types:
PMID: 12975507 [PubMed - indexed for MEDLINE]
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Patterns of failure using a conformal radiation therapy
tumor bed boost for medulloblastoma.
Wolden SL, Dunkel IJ, Souweidane MM, Happersett L, Khakoo Y, Schupak
K, Lyden D, Leibel SA.
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center,
1275 York Ave, Box 22, New York, NY 10021, USA. woldens@mskcc.org
PURPOSE: To assess the patterns of failure for patients with medulloblastoma
receiving a conformal tumor bed boost rather than a boost to the entire posterior
fossa. PATIENTS AND METHODS: From 1994 to 2002, 32 consecutive patients with
newly diagnosed medulloblastoma treated at Memorial Sloan-Kettering Cancer
Center (New York, NY) received a conformal boost to the tumor bed in conjunction
with craniospinal radiation therapy. Twenty-eight patients also received
chemotherapy. The median age was 9 years (range, 3 to 34 years), and the
male to female ratio was 3:1. Twenty-seven patients had standard-risk disease,
and five patients had high-risk disease. Craniospinal doses ranged from 23.4
to 39.6 Gy, and total tumor bed doses ranged from 54 to 59.4 Gy. RESULTS:
With a median follow-up of 56 months, six patients have relapsed; five relapsed
outside of the posterior fossa, and one failed within the posterior fossa,
outside of the high-dose boost volume. Five-year actuarial disease-free and
overall survival rates were 84% and 85%, respectively. Freedom from posterior
fossa failure was 100% and 86% at 5 and 10 years, respectively. Freedom from
distant failure was 84% at 5 years, with a trend for improvement when full-dose
craniospinal radiation (36 to 39.6 Gy) was used compared with a reduced dose
(23.4 Gy) of radiation (100% v 63%, respectively; P =.06). No other predictive
variables were identified. CONCLUSION: Conformal treatment to the tumor bed
allows for significant sparing of critical structures. The posterior fossa
failure rate in this series is similar to that reported when the entire posterior
fossa is treated. This approach should be investigated further in a phase
III trial.
PMID: 12915597 [PubMed - indexed for MEDLINE]
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Nevoid basal cell carcinoma syndrome: relation with
desmoplastic medulloblastoma in infancy. A population-based study and review
of the literature.
Amlashi SF, Riffaud L, Brassier G, Morandi X.
Service de Neurochirurgie, Hopital Pontchaillou, Rennes, France.
BACKGROUND: Patients with nevoid basal cell carcinoma syndrome (NBCCS) are
believed to be predisposed to develop early-onset neoplasms including medulloblastomas
(MB). The desmoplastic subtype of MB is associated most commonly with NBCCS.
The goals of this study were to demonstrate the relation between desmoplastic
MB and NBCCS and to evaluate the concomitant diagnosis of NBCCS and MB. METHODS:
The medical records of 76 consecutive children who received surgical treatment
for MB between 1970 and 2000 were studied. A review of the literature was
performed based on the National Library of Medicine database and bibliographies
of selected articles were scanned. RESULTS: The authors reported three patients
with NBCCS who received surgical treatment for an MB during infancy. The
literature review identified 33 patients with NBCCS who were treated for
MB at a mean age of 28 months. The desmoplastic subtype was the only histopathologic
subtype of MB reported in the NBCCS population. Although patients with NBCCS
are predisposed to develop multiple basal cell carcinomas and intracranial
tumors in the field of irradiation, the prognosis for syndromic MBs was much
better compared with the prognosis for sporadic MBs. CONCLUSIONS: Patients
with NBCCS have an increased risk for other malignancies, especially radiation-induced
neoplasms. Early diagnosis of this syndrome is important for the selection
of appropriate adjuvant treatment and family genetic counseling. The authors
did not advocate the use of radiotherapy as an adjuvant treatment in desmoplastic
MB diagnosed in children younger than 5 years of age. They suggested that
the desmoplastic subtype of MB in children younger than 2 years of age is
a major diagnostic criterion for the diagnosis of NBCCS. Copyright 2003 American
Cancer Society.DOI 10.1002/cncr.11537
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 12879481 [PubMed - indexed for MEDLINE]
-
-
Changes in expression of transferrin, insulin-like growth
factor 1, and interleukin 4 receptors after irradiation of cells of primary
malignant brain tumor cell lines.
Kim KU, Xiao J, Ni HT, Cho KH, Spellman SR, Low WC, Hall WA.
Department of Neurosurgery, Therapeutic Radiology-Radiation Oncology, University
of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
Various immunotoxins have been developed for the treatment of cancer. The
toxin is internalized by target cells through cell-surface receptors, and
it is essential for these receptors to be expressed for the immunotoxin
to have specific anti-tumor activity. Radiation therapy is one of the main
treatment modalities for primary malignant brain tumors. The purpose of
this study was to determine whether radiation influences the expression
of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and
two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing
the cells to a single dose of 5 Gy gamma rays. Expression of transferrin
receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin
4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated
cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute
expression index of transferrin receptors increased during the 24 h after
irradiation with the greatest change of 26% above control at 9 h. The absolute
expression index of IGF1R increased 26.5% above control at 12 h. The absolute
expression index of IL4R decreased 9 h after irradiation. In U373-MG cells
the absolute expression index of transferrin receptors increased during
the 24 h after irradiation, and the greatest increase was 45% above control
at 9 h. The absolute expression index of IGF1R increased during the 12
h after irradiation with a maximum increase of 33% above control at 6 h.
The absolute expression index of IL4R decreased with time after irradiation.
In T98-G cells, the absolute expression index of both transferrin receptors
and IL4R decreased after irradiation. The results suggest that the expression
of growth factor receptors on brain tumor cells may be influenced by radiation.
The effect of ionizing radiation on receptor expression should be considered
when administration of targeted toxin is combined with radiation. Similar
studies with other growth factor receptors used in targeted toxin therapy
are recommended.
PMID: 12859234 [PubMed - indexed for MEDLINE]
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-
Current and future strategies in radiotherapy of childhood
low-grade glioma of the brain. Part I: Treatment modalities of radiation
therapy.
Kortmann RD, Timmermann B, Taylor RE, Scarzello G, Plasswilm L, Paulsen
F, Jeremic B, Gnekow AK, Dieckmann K, Kay S, Bamberg M.
Department of Radiooncology, University of Tubingen, Germany. rdkortma@med.uni-tuebingen.de
BACKGROUND: Treatment of childhood low-grade gliomas is a challenging issue
owing to their low incidence and the lack of consensus about "optimal" treatment
approach. MATERIAL AND METHODS: Reports in the literature spanning 60 years
of radiation therapy, including orthovoltage, megavoltage and recently modern
high-precision treatments, were reviewed with respect to visual function,
survival, prognostic factors, dose prescriptions, target volumes, and treatment
techniques. Based on these experiences, future strategies in the management
of childhood low-grade glioma are presented. RESULTS: Evaluation of published
reports is difficult because of inconsistencies in data presentation, relatively
short follow-up in some series and failure to present findings and results
in a comparable way. Even with the shortcomings of the reports available
in the literature, primarily concerning indications, age at treatment, dose
response, timing and use of "optimal" treatment fields, radiation
therapy continues to play an important role in the management of these tumors
achieving long-term survival rates up to 80% or more. Particularly in gliomas
of the visual pathway, high local tumor control and improved or stable visual
function is achieved in approximately 90% of cases. Data on dose-response
relationships recommend dose prescriptions between 45 and 54 Gy with standard
fractionation. There is consensus now to employ radiation therapy in older
children in case of progressive disease only, regardless of tumor location
and histologic subtype. In younger children, the role of radiotherapy is
unclear. Recent advances in treatment techniques, such as 3-D treatment planning
and various "high-precision" treatments achieved promising initial
outcome, however with limited patient numbers and short follow-ups. CONCLUSIONS:
Radiation therapy is an effective treatment modality in children with low-grade
glioma regarding tumor control and improvement and/or preservation of neurologic
function or vision, respectively. More prospective studies are needed to
address the impact of modern radiation therapy technologies (including intensity-modulated
radiotherapy) on outcome especially in the very young and to define the role
of radiation therapy as a part of a comprehensive treatment approach. The
forthcoming prospective trial SIOP/GPOH LGG RT 2003 is addressing this issue.
Publication Types:
PMID: 14509949 [PubMed - indexed for MEDLINE]
-
Comment in:
Donors with central nervous system malignancies: are
they truly safe?
Buell JF, Trofe J, Sethuraman G, Hanaway MJ, Beebe TM, Gross TG, Alloway
R, First MR, Woodle ES.
Department of Surgery, The Israel Penn International Transplant Tumor Registry,
The University of Cincinnati School of Medicine, OH 45267-0558, USA. Joseph.buell@uc.edu
BACKGROUND: In an era of organ shortage, the use of expanded or marginal
donors has been attempted to increase transplantation rates and diminish
waiting list mortality. One strategy is the use of organs from patients with
a history of or active central nervous system (CNS) tumor. METHODS: Sixty-two
recipients were identified as the recipients of organs from donors with a
history of or active CNS malignancy. Patient demographics, donor tumor management,
incidence of tumor transmission, and patient survival were examined. RESULTS:
Of the organs recovered and transplanted from donors with astrocytoma, 14
were associated with at least one risk factor including high-grade tumor
(n=4), prior surgery (n=5), radiation therapy (n=4), and systemic chemotherapy
(n=4). One tumor transmission was identified at 20 months posttransplant
with the patient expiring from metastatic disease. Twenty-six organs were
transplanted from glioblastoma patients with 15 demonstrating risk factors
including high-grade tumor (n=9) and prior surgery (n=10). Eight transmissions
were identified with a range of 2 to 15 months posttransplant, with seven
patients dying as the result of metastatic disease. Seven organs were used
from donors with a medulloblastoma. Three transmissions were identified at
a range of 5 to 7 months, all associated with ventriculoperitoneal shunts.
Two medulloblastoma recipients died as the result of metastatic disease,
whereas the third is alive with diffuse disease. The rate of donor tumor
transmission, in the absence of risk factors, was 7%, whereas in the presence
of one or more risk factor this rate dramatically rose to 53% (P<0.01).
CONCLUSIONS: Organs from donors with CNS tumors can be used with a low risk
of donor tumor transmission in the absence of the following risk factors:
high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior
craniotomy, and systemic chemotherapy.
PMID: 12883189 [PubMed - indexed for MEDLINE]
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-
Fatal toxicity following radio- and chemotherapy of
medulloblastoma in a child with unrecognized Nijmegen breakage syndrome.
Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G.
Division of Radiobiology, Department of Radiation Oncology, University
Erlangen-Nurnberg, Germany. Luitpold.Distel@strahlen.med.uni-erlangen.de
BACKGROUND: In large-scale pediatric chemo- and radiotherapy trials a proportion
of patients as high as 10-15% is usually reported as having severe treatment
related toxicity occasionally resulting in toxic death. Little is known on
the underlying predisposition of the individual child. Several hereditary
disorders including immunodeficiency (ID) syndromes or repair disorders,
Ataxia Telangiectasia (AT), and Nijmegen breakage syndrome (NBS) were associated
with an elevated risk for severe treatment related toxicity. PROCEDURE: This
report involves the case of a 7-year-old boy with medulloblastoma who suffered
from remarkably severe side effects during and after postoperative radio-
and chemotherapy. Several months following craniospinal radiation with a
total dose of 36 Gy, late normal tissue side effects were observed within
the treated volume. Eighteen months after initiation of treatment the patient
died due to protracted cardiopulmonary failure. RESULTS: To quantify the
intrinsic radiation sensitivity, lymphoblastoid cells were used to examine
chromosomal aberrations by fluorescence in situ hybridization detecting between
two to ninefold higher chromosomal breakage rates in comparison to cells
of average cancer patients. Skin fibroblasts showed in the clonogenic survival
assays a twofold increased sensitivity. Western blotting demonstrated a typical
lack of Nbs1. PCR-SSCP analysis followed by direct sequencing of positive
samples revealed a homozygous truncating mutation of the NBS1 gene (657del5).
CONCLUSIONS: This case highlights that severe treatment related complications
in pediatric cancer patients may be the result of increased intrinsic radio-
and chemosensitivity due to NBS, AT, and other ID syndromes. It is suggested
to exclude such conditions in all patients with anthropometric parameters
below the 3rd centile and other signs suggestive for repair disorders or
ID syndromes. Copyright 2003 Wiley-Liss, Inc.
Publication Types:
PMID: 12764742 [PubMed - indexed for MEDLINE]
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-
Unusual presentation of adult metastatic peritoneal
medulloblastoma associated with a ventriculoperitoneal shunt: a case study
and review of the literature.
Magtibay PM, Friedman JA, Rao RD, Buckner JC, Cliby WA.
Division of Gynecologic Oncology, Department of Obstetrics/Gynecolory,
Mayo Graduate School of Medicine, Mayo Clinic, 200 First Street SW, Rochester,
MN 55905, USA. magtibay.paul@mayo.edu
Patients with medulloblastoma uncommonly develop extracerebral metastases.
We describe an adult patient with the unusual occurrence of intraperitoneal
metastases associated with a ventriculoperitoneal (VP) shunt, as well as
her subsequent treatment with high-dose chemotherapy and bone marrow transplantation.
We review the literature regarding this rare presentation and association
of metastatic spread via VP shunt devices. A 37-year-old woman presented
with a rapidly enlarging pelvic mass. She had a history of medulloblastoma
and had been treated with a combination of surgery, chemotherapy, and radiation
5 years previously, at which time a VP shunt had been placed for cerebrospinal
fluid leakage. At laparotomy, she had unresectable intraperitoneal metastatic
medulloblastoma. After an excellent response to cyclophosphamide, etoposide,
and cisplatin, she underwent a resection of residual disease, followed by
high-dose chemotherapy and a bone marrow transplant. We conclude that adult
onset medulloblastoma with metastasis to the peritoneal cavity is rare and
may be associated with a VP shunt.
Publication Types:
- Case Reports
- Review
- Review, Tutorial
PMID: 12816729 [PubMed - indexed for MEDLINE]
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-
Toxicity of the high-dose chemotherapy CTC regimen (cyclophosphamide,
thiotepa, carboplatin): the Netherlands Cancer Institute experience.
Schrama JG, Holtkamp MJ, Baars JW, Schornagel JH, Rodenhuis S.
Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan
121, 1066 CX Amsterdam, The Netherlands. j.schrama@nki.nl
High-dose chemotherapy (HD-CT) has a role in the potentially curative treatment
of several tumours. The relative efficacies of the different regimens have
not been studied in comparative trials, but it is clear that toxicities differ
significantly between them. We analysed the immediate and long-term toxicity
in the first 100 consecutive patients treated with the CTC regimen (cyclophosphamide
6000 mg m(-2), carboplatin 1600 mg m(-2) (or 20 mg ml(-1) min under the curve
(AUC)) both as daily 1 h infusion, thiotepa 480 mg m(-2) as twice daily 30
min infusion, all divided over 4 consecutive days) followed by peripheral
blood progenitor cell reinfusion (PBPC-Tx). Most patients had high-risk (n=86)
or metastatic (n=4) breast cancer, or a germ cell tumour (n=8). Two patients
(with a medulloblastoma and an aesthesioneuroblastoma, respectively) received
CTC as off-protocol salvage regimen. The main toxicity was bone marrow suppression.
Most patients had PBPC-Tx with granulocyte colony-stimulating factor (G-CSF),
and the median time to neutrophil count 500 x 10(6) l(-1) and platelet count >20
x 10(9) l(-1) without transfusion independence was 10 (range 8-25) and 13
(8-60) days, respectively. The toxic death rate was 1%. Other frequent toxicities
were neutropenic fever requiring antibiotics (n=65), central catheter-related
infection (n=12) or a bleeding episode (n=48), mostly epistaxis (n=26). Reversible
cardiac toxicity was seen in six patients and pulmonary events occurred in
seven patients (infection (n=6), embolism (n=1)). Grade 3-4 gastrointestinal
toxicity was frequent: nausea and vomiting 55%, diarrhoea 28% and mild liver
toxicity (transaminase elevations) 9%. One patient pretreated with cisplatin
had a kidney transplantation 8 years after HD-CT. Late complications included
reversible radiation pneumonitis (n=12) and chronic heart failure (n=2).
We found five second solid malignancies and two myelodysplasias. In conclusion,
the CTC regimen is associated with a moderate, mainly reversible, toxicity.
Future studies need to compare the efficacy and toxicity of the different
HD-CT regimens.
PMID: 12799623 [PubMed - indexed for MEDLINE]
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-
[Growth hormone deficiency after treatment of medulloblastoma
with radiotherapy in childhood: case report]
[Article in Portuguese]
Goldberg TB, Rodrigues MA, Takata RT, Nogueira CR, Faleiros AT.
Faculdade de Medicina Botucatu, Universidade Estadual de Sao Paulo, Botucatu,
SP, Brasil. tamara@fmb.unesp.br
Craniospinal radiation therapy for treatment of brain tumors may result in
growth hormone (GH) insufficiency with resultant linear growth retardation,
one of the most common complications. We report the case of a 10-year-old
boy presenting headache associated to vertigo, nausea and vomiting. A CT
scan showed an homogeneous mass in the left cerebelar hemisphere, that was
surgically removed. The histopathological examination revealed medulloblastoma
and the patient was submitted to craniospinal radiation. He did not present
tumor recurrence nor neurological or cognitive deficits during 4 years, but
evolved to short stature due to GH deficiency. Nowadays, he is being receiving
GH 0,1 U/kg/day and has presented 4cm stature increment after 6 months. The
present case highlights the importance in carefully monitoring of children
after cranial radiation for oncologic treatment, because they may develop
hormonal deficiencies, that can be successfully replaced.
Publication Types:
PMID: 12894290 [PubMed - indexed for MEDLINE]
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-
Medulloblastoma.
Mazzola CA, Pollack IF.
Department of Neurosurgery, University of Pittsburgh Children's Hospital,
3705 Fifth Avenue, Suite 3705, Third Floor, Pittsburgh, PA 15213, USA.
ian.pollack@chp.edu
Medulloblastomas, primitive neuroectodermal tumors of the cerebellum, comprise
20% of all pediatric brain tumors and are the most common solid neoplasm
in children. Primitive neuroectodermal tumors are believed to arise from
cerebellar granule cell precursors. Occasionally, medulloblastoma occurs
in children with genetically linked disorders, such as Turcot's syndrome
or Gorlin's syndrome, which is also called basal cell nevus syndrome. Several
genes have been implicated in the development of medulloblastoma in children,
including Patched-1 and Smoothened. The protein products of these genes function
within the sonic hedgehog molecular signaling pathways, which are important
in neural development and disease. Through analysis of several well-designed
multi-institutional trials, much has been learned about the clinical factors
that influence outcome in children with medulloblastomas. Age younger than
3 years, bulky residual disease postoperatively, and metastasis constitute
adverse prognostic features and indicate patients who are considered "high
risk" for recurrence with standard therapy using 3600 cGy craniospinal
radiation in conjunction with a posterior fossa dose of 5400 cGy. Patients
lacking these features are considered "standard risk." Chemotherapeutic
trials have been developed to assess the safety and efficacy of various multi-agent
therapies to improve the poor results of high-risk patients and to allow
reduction in the dose of radiation needed to cure standard-risk patients,
which may allow a decrease in late cognitive sequelae. Currently, it is policy
to evaluate all children with posterior fossa tumors characteristic of medulloblastoma
with preoperative, staging neuroimaging studies of the craniospinal axis.
Surgical resection is undertaken with the goal of gross total resection.
Postoperative neuroimaging studies are compared with preoperative studies
to determine the amount of residual disease. Cerebrospinal fluid is obtained
from a lumbar puncture done at the conclusion of the surgical resection or
2 weeks after surgery in order to determine microscopic leptomeningeal spread.
Children with tumor histopathology consistent with medulloblastoma are enrolled,
when possible, in open clinical trials. Chemotherapy and radiation are given
as per protocol. The goal of current treatment approaches is to tailor therapy
based on clinical risk factors, with intensification of treatment for children
with high-risk disease and reduction of radiation therapy for those with
standard-risk disease. Evaluation of biologic predictors of outcome, which
may further refine treatment stratification, is in progress.
PMID: 12670407 [PubMed - as supplied by publisher]
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Primary medulla oblongata germinoma: a case report and
review of the literature.
Yen PS, Chou AS, Chen CJ, Jung SM, Chuang HL, Scott RM.
Department of Radiology, Buddhist Tzu Chi General Hospital, Taiwan, ROC.
We describe a case of primary intracranial medulla oblongata germinoma
in a 16-year-old girl who presented with progressive headache and blurred
vision. Magnetic resonance imaging demonstrated a heterogeneous exophytic
mass arising from dorsal aspect of medulla oblongata with extension into
fourth ventricle. The differential diagnosis for this patient had included
ependymoma, exophytic glioma, medulloblastoma and choroid plexus papilloma.
After surgical resection and radiation therapy, she remains alive and recurrence-free
for 7 years.
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 12777087 [PubMed - indexed for MEDLINE]
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-
[Craniospinal radiotherapy in combined therapy of medulloblastoma
in children and adolescents]
[Article in Serbian]
Golubicic I, Bokun J, Nikitovic M, Mladenovic J, Saric M, Bekic Z.
Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Beograd.
PURPOSE: The aim of this study was: 1. to evaluate treatment results of
combined therapy (surgery, postoperative craniospinal radiotherapy with
or without chemotherapy) and 2. to assess factors affecting prognosis (extend
of tumor removal, involvement of the brain stem, extent of disease, postoperative
meningitis, shunt placement, age, sex and time interval from surgery to
start of postoperative radiotherapy). PATIENTS AND METHODS: During the
period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median
8.6 years), were treated with combined modality therapy and 72 of them
were evaluable for the study endpoints. Entry criteria were histologically
proven diagnosis, age under 22 years, and no history of previous malignant
disease. The main characteristics of the group are shown in Table 1. Twenty-nine
patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial
removal. Seventy-two of 78 patients were treated with curative intent and
received postoperative craniospinal irradiation. Radiotherapy started 13-285
days after surgery (median 36 days). Only 13 patients started radiotherapy
after 60 days following surgery. Adjuvant chemotherapy was applied in 63
(80.7%) patients. The majority of them (46; 73%) received chemotherapy
with CCNU and Vincristine. The survival rates were calculated with the
Kaplan-Meier method and the differences in survival were analyzed using
the Wilcoxon test and log-rank test. RESULTS: The follow-up period ranged
from 1-12 years (median 3 years). Five-year overall survival (OS) was 51%
and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses
occurred. Patients having no brain stem infiltration had significantly
better survival (p = 0.0023) (Graph 2). Patients with positive myelographic
findings had significantly poorer survival compared to dose with negative
myelographic findings (p = 0.0116). Significantly poorer survival was found
in patients with meningitis developing in the postoperative period, with
no patient living longer than two years (p = 0.0134) (Graph 3). By analysis
of OS and DFS in relation to presence of the malignant cells in liquor,
statistically significant difference, i.e. positive CSF cytology was not
obtained, which was of statistical importance for survival (p = 0.8207).
Neither shunt placement nor shunt type showed any impact on survival (p
= 0.5307 and 0.7119, respectively). Children younger than three years had
significantly poorer survival compared to those older than 16 years (p
= 0.0473). Although there was a better survival rate in females than in
males this was not statistically significant (p = 0.2386). The analysis
results of treatment showed that significantly better survival occurred
in patients in whom total or subtotal tumor removal was possible (p = 0.0022)
(Graph 4). Patients who started radiotherapy within two months after surgery
have better survival, but again this was not statistically significant,
probably due to the small number of patients receiving delayed radiotherapy
(p = 0.2231) (Graph 5). CONCLUSION: Based on this factors standard and
high risk group could be defined. Combined chemotherapy should to be investigated
particularly for high risk subgroup. Future research should be done to
define new therapeutic modalities (gene therapy, compounds active in tumor
antiangiogenesis etc).
PMID: 14692129 [PubMed - indexed for MEDLINE]
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Atypical teratoid/rhabdoid tumors.
Dang T, Vassilyadi M, Michaud J, Jimenez C, Ventureyra EC.
Division of Neurosurgery, Children's Hospital of Eastern Ontario, University
of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
CASE REPORTS: We describe three cases of atypical ATRT that were identified
at the Children's Hospital of Eastern Ontario. DISCUSSION: Over the past
decade, atypical teratoid/rhabdoid tumors (ATRTs) of the central nervous
system have emerged as a distinct entity. This tumor is typically misdiagnosed
as a primitive neuroectodermal tumor (PNET)/medulloblastoma. The unique
immunohistochemistry profile of an ATRT helps distinguish it from a PNET/medulloblastoma.
This is of clinical importance because the prognosis of a patient with
an ATRT is worse than that of a PNET/medulloblastoma despite aggressive
surgical treatment with or without adjuvant chemotherapy and radiation
therapy.
Publication Types:
PMID: 12682757 [PubMed - indexed for MEDLINE]
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-
Amifostine protects against cisplatin-induced nephrotoxicity
in a child with medulloblastoma.
Hayek M.
Pediatric Hematology-Oncology, Tawan Hospital, Al Ain, United Arab Emirates.
Publication Types:
PMID: 12637222 [PubMed - indexed for MEDLINE]
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-
Stereotactic radiosurgery for brain tumors in pediatric
patients.
Suh JH, Barnett GH.
Brain Tumor Institute, Department of Radiation Oncology, T-28, Cleveland
Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. suhj@ccf.org
Brain tumors represent the most common solid tumor in children. Fractionated
radiation therapy has been an important treatment modality in the multi-disciplinary
management of these tumors. Stereotactic radiosurgery is the precise delivery
of a single fraction of radiation and has been an important treatment option
for adult brain tumor patients. Although the use of stereotactic radiosurgery
in pediatric brain tumors is much less frequent, it represents an important
alternative for patients with recurrent, surgically inaccessible or radioresponsive
tumors. This article will review the results and logistical issues of this
modality in the management of pediatric brain tumors.
Publication Types:
PMID: 12680795 [PubMed - indexed for MEDLINE]
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[Evidence-based radiation therapy for primary brain
tumors]
[Article in Japanese]
Shibamoto Y, Tomita N, Kono T, Tsuji H, Nankoh S, Taniguchi H.
Dept. of Radiology, Nagoya City University Graduate School of Medical Sciences.
Radiation therapy for five primary brain tumors is discussed based on the
results of prospective trials. Many randomized studies have revealed the
usefulness of radiation and radiochemotherapy for treating malignant gliomas,
and the ineffectiveness of many new treatments modalities. However, novel
treatments should be tested further against this tumor. In low-grade gliomas,
the usefulness of radiotherapy was shown but a dose-effect relationship was
not observed in recent randomized studies. In medulloblastoma, the difficulty
in reducing the dose to the cerebrospinal axis has been shown even in low-stage
patients. On the other hand, reliable randomized studies are still lacking
for germinoma and primary central nervous system lymphoma, and the usefulness
of combination chemotherapy remains uncertain. In the future, more prospective
studies are needed for primary brain tumors other than glioma. Establishment
of IMRT and controlled studies to prove its efficacy are important in the
field of neuro-oncology.
Publication Types:
PMID: 12669392 [PubMed - indexed for MEDLINE]
-
Comment on:
In regard to Huang et al.: Intensity-modulated radiation
therapy for pediatric medulloblastoma: early report on the reduction of
ototoxicity. IJROBP 2002;52:599-605.
Soomal R, Saran F, Brada M.
Publication Types:
PMID: 12573781 [PubMed - indexed for MEDLINE]
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Cerebellar liponeurocytoma (lipomatous medulloblastoma).
Akhaddar A, Zrara I, Gazzaz M, El Moustarchid B, Benomar S, Boucetta
M.
Department of Neurosurgery, Mohammed V Military Hospital, Rabat, Morocco.
akhaddar@hotmail.com
Liponeurocytoma (lipomatous medulloblastoma) is an uncommon clinicopathologic
entity. We report a case of cerebellar liponeurocytoma in an adult and attempt
to better characterize this uncommon lesion. A 43-year-old woman presented
with symptoms and signs of increased intracranial pressure and cerebellar
dysfunction. CT and MRI showed a heterogeneous well-circumscribed mass in
the left cerebellar hemisphere with hydrocephalus. Complete surgical excision
of the tumor was accomplished through a suboccipital craniotomy. Pathological
examination with immunohistochemical study revealed a medulloblastoma with
neuronal, astrocytic and lipomatous differentiation. Postoperative radiation
therapy was given. After surgery, the patient was followed up for a 16 month-period;
symptoms improved dramatically and no evidence of tumor recurrence was found.
Careful analysis of the histopathological and immunohistochemical studies
correctly identifies liponeurocytoma (lipomatous medulloblastoma). To our
knowledge, only 16 cases have been reported. Although this lesion appears
to have a better prognosis than the conventional form of adult medulloblastoma,
complete surgical removal with postoperative radiation therapy is recommended.
Publication Types:
PMID: 12717299 [PubMed - indexed for MEDLINE]
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Medulloblastoma with adverse reaction to radiation therapy
in nijmegen breakage syndrome.
Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti
RA, Bhambhani K.
Division of Pediatric Hematology-Oncology, Children's Hospital of Michigan,
Detroit, Michigan 48201, USA.
A 3-year-old child with microcephaly, facial dysmorphism, growth retardation,
and developmental delay was diagnosed with medulloblastoma. Craniospinal
irradiation resulted in severe radiation-induced dermatitis and gastroesophagitis,
unresponsive to further medical therapy. Colony survival assay on the patient's
transformed lymphocytes revealed a high degree of radiosensitivity ex vivo.
The presence of radiation sensitivity, both clinically and ex vivo, in
association with microcephaly and growth retardation, prompted a diagnostic
workup for Nijmegen breakage syndrome. The patient was confirmed to have
a compound heterozygote genotype for the common founder mutation of NBS1
675del5 in exon 6, and 1142delC in exon 10. Because irradiation is an important
component of therapy for brain tumors, caution should be exercised in cancer
patients with associated microcephaly and growth retardation, as they may
turn out to have the rare diagnosis of Nijmegen breakage syndrome.
Publication Types:
PMID: 12621246 [PubMed - indexed for MEDLINE]
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Late delayed postradiation spinal myoclonus or psychogenic
movement disorder?
Loscher WN, Trinka E.
Department of Neurology, Leopold-Franzens University Innsbruck, Innsbruck,
Austria.
We describe a patient with intermittent, at times rhythmic trunk flexion
movements. Neurophysiological assessment excluded a psychogenic movement
disorder. The segmental spinal myoclonus occurred 6 years after radiation
therapy of the brain and entire spinal cord, and we suggest this patient
to be the first case of a late-delayed sequela of spinal cord irradiation
presenting as segmental spinal myoclonus. Copyright 2002 Movement Disorder
Society
Publication Types:
PMID: 12621644 [PubMed - indexed for MEDLINE]
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2-Methoxyestradiol interferes with NF kappa B transcriptional
activity in primitive neuroectodermal brain tumors: implications for management.
Kumar AP, Garcia GE, Orsborn J, Levin VA, Slaga TJ.
Center for Cancer Causation and Prevention, AMC Cancer Research Center
and University of Colorado Comprehensive Cancer Center, Denver, CO 80214,
USA. kumarp@amc.org
Medulloblastoma (MB) is a primitive neuroectodermal tumor (PNET) of the central
nervous system (CNS) and the most common malignant primary brain tumor in
children. Currently, poor risk and recurrent MB patients are treated with
cytotoxic chemotherapy alone or in combination with surgery and irradiation.
In order to improve on therapeutic outcome and reduce toxicity of current
treatment strategies, new and novel therapeutic agents are needed for MB
patients. To that purpose, we have examined the effect of 2-methoxyestradiol
(2-ME), an endogenous non-toxic estrogenic metabolite on the growth of three
medulloblastoma cell lines (DAOY, D341 and D283); and two high-grade anaplastic
astrocytoma/glioblastoma cell lines, U-87MG and T-98-G. We present evidence
to show that 2-ME preferentially inhibits the growth of medulloblastoma cells
significantly by blocking cell cycle progression predominantly in G(2)/M
phase. 2-ME treatment results in phosphorylation of cdc25C without any significant
alterations in the expression of cyclin B1 or p34cdc2. In addition, we observed
a decrease in the levels of 14-3-3 proteins following treatment with 2-ME.
Furthermore, 2-ME-mediated growth inhibition is accompanied by induction
of apoptosis as evidenced by morphological alterations and DNA fragmentation
analysis. Of interest is the finding that 2-ME induced apoptosis is not mediated
through alterations in the expression of p53 or Bax and that transcriptional
activity of NF kappa B and DNA binding activity is reduced indicating that
2-ME disrupts the NF kappa B signaling pathway. These results suggest that
2-ME may prove to be a useful therapeutic agent in the treatment of PNET
brain tumors such as medulloblastoma. In addition, as 2-ME inhibits growth
predominantly through G(2)/M block, it may enhance the effectiveness of radiation
therapy.
PMID: 12584169 [PubMed - indexed for MEDLINE]
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Past, current and future protocols for combined modality
therapy in childhood medulloblastoma.
Kaaijk P, Schouten-van Meeteren AY, Slotman BJ, Kaspers GJ.
VU University Medical Center, Dept. Pediatric Hematology/Oncology, Amsterdam,
The Netherlands. P.Kaaijk@vumc.nl
Radiotherapy plays a major role in the management of brain tumors, together
with surgical resection and more recently, chemotherapy. Improved efficacy
of radiotherapy, ranging from novel techniques of radiotherapy to combination
with (new) chemotherapeutic drugs or agents that selectively target tumor
cells, are currently being explored and offer some hope for improvement of
the prognosis of primary brain tumors. This approach might also enable reducing
radiation doses, thereby potentially decreasing the risk of severe late effects
in pediatric brain tumor patients. This review will evaluate past, current
and future treatment approaches of combined modality therapy in childhood
medulloblastoma.
Publication Types:
PMID: 12597352 [PubMed - indexed for MEDLINE]
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Risk factors for the development of obesity in children
surviving brain tumors.
Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, Burghen GA,
Xiong X, Wu S, Merchant TE.
Departments of Endocrinology, St. Jude Children's Research Hospital, Memphis,
Tennessee 38105, USA. rlustig@peds.ucsf.edu
Hypothalamic obesity, a syndrome of intractable weight gain due to hypothalamic
damage, is an uncommon but devastating complication for children surviving
brain tumors. We undertook a retrospective evaluation of the body mass index
(BMI) curves for the St. Jude Children's Research Hospital brain tumor population
diagnosed between 1965 and 1995 after completion of therapy to determine
risk factors for the development of obesity. Inclusion criteria were: diagnosis
less than 14 yr of age, no spinal cord involvement, ambulatory, no supraphysiologic
hydrocortisone therapy (>12 mg/m(2) x d), treatment and follow-up at St.
Jude Children's Research Hospital, and disease-free survival greater than
5 yr (n = 148). Risk factors examined were age at diagnosis, tumor location,
histology, extent of surgery, hydrocephal | |
