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Cancer  2009;115(14):3243-3253.
A carboplatin-based chemotherapy regimen was used as primary post-operative therapy in infants with central nervous system tumors to limit renal and ototoxicity and to target systemic exposure.
Patients and Methods
53 patients ≤ age 3 years with embryonal CNS tumor medulloblastoma (MB, n=20), ependymoma (EP, n=21), choroid plexus carcinoma (CPCA, n=5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n=7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was utilized only for residual disease at the end of chemotherapy or disease progression.
The response rate after two cycles of chemotherapy was 34% (complete response [CR] 13.8%, partial response [PR] 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The five-year overall survival (OS) was 49 ± 7%, and the progression-free survival (PFS) was 31 ± 7% with a median follow-up of 11.4 yrs (range: 5.2–15.0 years). For medulloblastoma, the five-year PFS is 26% ± 9%; for EP 33 ± 10%; for CPCA, 80 ± 18%; for PNET and atypical teratoid rhabdoid tumor (ATRT) 0%. Localized ependymoma patients with GTR who did not undergo radiotherapy had a 5-year PFS of 57 ±17% and OS of 71 ± 16%. Two patients developed late second malignancies; one associated with germline p53 mutation.
The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five-year survival data are comparable to those reported in other recent studies, including high-dose chemotherapy studies. Of note, is the marked activity in CPCA and gross totally resected ependymoma
PMCID: PMC4307774  PMID: 19484793
Brain tumor; infants; chemotherapy; carboplatin
2.  Phase-I study of vismodegib in children with recurrent or refractory medulloblastoma: a Pediatric Brain Tumor Consortium (PBTC) study 
To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.
Patients and Methods
Initially, vismodegib was administered daily at 85 mg/m2 and escalated to 170 mg/m2. The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67–1.32 m2) or 300 mg for those who were larger (BSA, 1.33–2.20 m2). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with SHH-subtype medulloblastoma.
Thirteen eligible patients were enrolled on the initial study: 6 received 85 mg/m2 vismodegib, and 7 received 170 mg/m2. Twenty eligible patients were enrolled on the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26–0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable and in none of the patients in the other subgroups.
Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only 2 dose-limiting toxicities were observed with flat dosing. The recommended Phase-II study dose is 150 mg or 300 mg, depending on the patient’s BSA.
PMCID: PMC3856244  PMID: 24077351
3.  Processing Speed, Attention, and Working Memory After Treatment for Medulloblastoma: An International, Prospective, and Longitudinal Study 
Journal of Clinical Oncology  2013;31(28):3494-3500.
The current study prospectively examined processing speed (PS), broad attention (BA), and working memory (WM) ability of patients diagnosed with medulloblastoma over a 5-year period.
Patients and Methods
The study included 126 patients, ages 3 to 21 years at diagnosis, enrolled onto a collaborative protocol for medulloblastoma. Patients were treated with postsurgical risk-adapted craniospinal irradiation (n = 36 high risk [HR]; n = 90 average risk) followed by four cycles of high-dose chemotherapy with stem-cell support. Patients completed 509 neuropsychological evaluations using the Woodcock-Johnson Tests of Cognitive Abilities Third Edition (median of three observations per patient).
Linear mixed effects models revealed that younger age at diagnosis, HR classification, and higher baseline scores were significantly associated with poorer outcomes in PS. Patients treated as HR and those with higher baseline scores are estimated to have less favorable outcomes in WM and BA over time. Parent education and marital status were significantly associated with BA and WM baseline scores but not change over time.
Of the three key domains, PS was estimated to have the lowest scores at 5 years after diagnosis. Identifying cognitive domains most vulnerable to decline should guide researchers who are aiming to develop efficacious cognitive intervention and rehabilitation programs, thereby improving the quality of survivorship for the pediatric medulloblastoma population.
PMCID: PMC3782147  PMID: 23980078
4.  International consensus on (ICON) anaphylaxis 
ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction.
They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice.
For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences.
ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available.
ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research.
In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public.
PMCID: PMC4038846  PMID: 24920969
Anaphylaxis; Acute systemic allergic reaction; Epinephrine (adrenaline); H1-antihistamines; H2-antihistamines; Glucocorticoids; Food allergy; Venom allergy; Drug allergy; Exercise-induced anaphylaxis; Idiopathic anaphylaxis
5.  Osteogenesis imperfecta and primary open angle glaucoma: Genotypic analysis of a new phenotypic association 
Molecular Vision  2014;20:1174-1181.
Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by bone fragility. Ocular findings include blue sclera, low ocular rigidity, and thin corneal thickness. However, there are no documented cases linking OI and primary open angle glaucoma (POAG). In this report, we describe three individuals, one isolated case and two from a multiplex family, with OI type I and POAG.
Available family members with OI and POAG had a complete eye examination, including visual acuity, intraocular pressure (IOP), pachymetry, slit-lamp exam, dilated fundus exam, and visual fields. DNA from blood samples was sequenced and screened for mutations in COL1A1/2 and myocilin (MYOC).
All subjects had OI type I. Findings of POAG included elevated IOP, normal gonioscopy, and glaucomatous optic disc cupping and visual field loss. POAG cosegregated with OI in the multiplex family. The multiplex family had a single nucleotide insertion (c.540_541insC) in COL1A1 resulting in a frameshift mutation and a premature termination codon. The sporadic case had a COL1A1 splice acceptor site mutation (c.2452–2A>T or IVS36–2A>T) predicted to result in a premature termination codon due to intron inclusion or a cryptic splice site. None of the glaucoma cases had mutations or sequence changes in MYOC.
We identified two novel mutations in COL1A1 in individuals with OI type I and POAG. Thus, some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.
PMCID: PMC4153423  PMID: 25324685
6.  Environmental assessment and exposure reduction of cockroaches: A practice parameter 
The Journal of allergy and clinical immunology  2013;132(4):10.1016/j.jaci.2013.04.061.
This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the joint Council of Allergy, Asthma & Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing “Environmental assessment and remediation: a practice parameter.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single person, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
PMCID: PMC3864888  PMID: 23938214
Allergy; cockroach; sensitization; disease; morbidity
7.  How parents cope with their child’s diagnosis and treatment of an embryonal tumor: Results of a prospective and longitudinal study 
Journal of neuro-oncology  2011;105(2):253-259.
The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor.
Patients and Methods
Patients (n=219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n=251) completed the Coping Response Inventory at time of their child’s diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates.
At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T=61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (p=.016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (p=.011 and p<.0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T= 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (p=.002). Differences in coping according to age of the patient and parent education level are also discussed.
Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment.
PMCID: PMC3537225  PMID: 21499990
pediatric; brain tumor; medulloblastoma; psychological sequelae
9.  Regional white matter anisotropy and reading ability in patients treated for embryonal tumors 
Brain imaging and behavior  2010;4(2):132-140.
Children treated with cranial irradiation for brain tumors have reduced white matter volume and deficits in reading ability. This study prospectively examined the relationship between reading and white matter integrity within this patient group.
Patients (n=54) were treated with post-surgical radiation followed by 4 cycles of high-dose chemotherapy with stem cell support. At 12 months post-diagnosis, all patients completed a neuropsychology evaluation and a diffusion tensor imaging (DTI) exam. White matter integrity was determined through measures of fractional anisotropy (FA).
Significant group differences in FA were found between above average readers and below average readers within the left and right posterior limb of the internal capsule, and right knee of the internal capsule with a trend within the left temporal-occipital region.
The integrity of the white matter in these regions may affect communication among visual, auditory, and language cortical areas that are engaged during reading.
PMCID: PMC3521043  PMID: 20502994
diffusion tensor imaging; reading; pediatric brain tumors
10.  A Phase II Study of O6-Benzylguanine and Temozolomide in Pediatric Patients with Recurrent or Progressive High Grade Gliomas and Brainstem Gliomas: A Pediatric Brain Tumor Consortium Study 
Journal of neuro-oncology  2011;106(3):643-649.
To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide® (TMZ).
Patients and Methods
Patients received O6BG 120 mg/m2/d IV followed by TMZ 75 mg/m2/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed.
Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas.
The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
PMCID: PMC3518022  PMID: 21968943
glioma; pediatric; resistance; alkylating agent; brainstem glioma; AGT; MGMT
12.  Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018 
Journal of Clinical Oncology  2010;29(3):324-329.
A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics.
Patients and Methods
Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m2/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21).
Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m2/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m2/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied.
Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m2/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.
PMCID: PMC3056466  PMID: 21149652
13.  Diagnosis and management of food-induced anaphylaxis 
Clinical and Translational Allergy  2011;1(Suppl 1):S64.
PMCID: PMC3354295
14.  Dexamethasone, High-dose Cytarabine, and Carboplatin (DAC) Combination is Effective for Childhood Advanced Large-Cell Non-Hodgkin Lymphoma 
Cancer  2008;113(4):782-790.
To purpose of this study was to evaluate the activity and toxicity of dexamethasone, high-dose cytarabine, and carboplatin (DAC) combination therapy in children with newly diagnosed large-cell non-Hodgkin lymphoma (NHL) and to estimate the event-free and overall survival rates achieved when DAC is incorporated into a conventional regimen.
Patients and Methods
From 1991 to 1997, 20 boys and 5 girls aged 4.2 to 17.7 years who had stage III (n=21) or stage IV (n=4) large-cell NHL were treated on this study. DAC therapy was administered at the beginning of the induction phase in 2 sequential cycles and incorporated throughout a continuation phase (modified from the ACOP+ regimen) with doxorubicin, cyclophosphamide, vincristine and dexamethasone. The total duration of treatment was approximately 10 months.
DAC therapy yielded a response in 22 of 25 patients (88%, 95% CI 68%-97%): complete remission in 13 cases (52%) and partial response in 9 (36%). After additional treatment with doxorubicin, cyclophosphamide, vincristine, and dexamethasone, complete remission was attained in 18 patients (72%) and partial remission in 3 (12%). The event-free survival rate (±SE) was 64% ± 9% and the overall survival rate was 80% ± 8% at 5 years.
The DAC regimen is well tolerated and effective for pediatric large-cell NHL.
PMCID: PMC2975596  PMID: 18618501
Dexamethasone; Cytarabine; Carboplatin; Childhood; Large cell; Lymphoma
15.  Proximal dentatothalamocortical tract involvement in posterior fossa syndrome 
Brain  2009;132(11):3087-3095.
Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.
PMCID: PMC2781745  PMID: 19805491
posterior fossa; cerebellum; mutism; medulloblastoma
16.  An Operational Perspective of Challenging Statistical Dogma while Establishing a Modern, Secure Distributed Data Management and Imaging Transport System – The Pediatric Brain Tumor Consortium Phase I Experience 
The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary CNS tumors of childhood. The PBTC was created in 1999 to conduct early phase studies in a rapid fashion in order to provide sound scientific foundation for the Children’s Oncology Group to conduct definitive trials. The Operations and Biostatistics Center (OBC) of the PBTC is responsible for centrally administering study design and trial development, study conduct and monitoring, data collection and management as well as various regulatory and compliance processes. The Phase I designs utilized for the consortium trials have accommodated challenges unique to pediatric trials such as BSA-based dosing in the absence of pediatric formulations of oral agents. Further during the past decade, the OBC has developed and implemented a state-of-the-art secure and efficient internet-based paperless distributed data management system. Additional web-based systems are also in place for tracking and distributing correlative study data as well as neuro-imaging files. These systems enable effective communications among the members of the consortium and facilitate the conduct and timely reporting of multi-institutional early phase clinical trials.
PMCID: PMC2877373  PMID: 20443880
17.  Myeloablative Chemotherapy with Autologous Bone Marrow Rescue in Children and Adolescents with Recurrent Malignant Astrocytoma: Outcome Compared with Conventional Chemotherapy: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2008;51(6):806-811.
Children and adolescents with malignant astrocytomas recurring after initial treatment have a dismal prognosis, with only rare patients surviving one year beyond recurrence. The purpose of this study was to attempt to improve their survival.
Twenty-seven children and adolescents with malignant astrocytomas (17 glioblastoma multiforme and 10 anaplastic astrocytoma) following initial tumor progression, received myeloablative chemotherapy followed by autologous marrow rescue with one of three thiotepa and etoposide-based chemotherapy regimens, administered alone (n=11) or combined with carmustine (n=5) or carboplatin (n=11). Time to progression and death following myeloablative chemotherapy for these patients was compared non-randomly with outcome of a contemporaneously treated cohort of similar patients who received only conventional chemotherapy following initial tumor progression. The two cohorts were compared for age, histology, prior therapies, extent of surgical resection at progression and time from initial diagnosis to progression.
Five of 27 children (two with glioblastoma multiforme and three with anaplastic astrocytoma) survive event-free from 8.3 to 13.3 years (median of 11.1 years) following myeloablative chemotherapy. Of 56 children with recurrent malignant astrocytoma who received conventional chemotherapy following initial progression, no patient survives. Differences in distributions of survival were not significant when stratified by surgical debulking (p=0.39). However, for patients who were surgically debulked, the survival distributions are significantly different (p=0.017).
Myeloablative chemotherapy with autologous marrow rescue can produce durable remissions in children and young adults with recurrent malignant gliomas, in the setting of minimal residual tumor burden achieved surgically.
PMCID: PMC2844080  PMID: 18802947
Myeloablative chemotherapy; autologous bone marrow rescue; recurrent malignant astrocytoma
18.  Phase I Study of SU5416, a Small Molecule Inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGFR) in Refractory Pediatric Central Nervous System Tumors 
Pediatric blood & cancer  2009;52(2):169-176.
SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (Stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110mg/m2 while stratum II started at 48mg/m2. Thirty-three eligible patients were treated on stratum I (n=23) and stratum II (n=10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas and 2 choroid plexus carcinomas. The MTD in Stratum I was initially estimated to be 110mg/m2. The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145mg/m2 dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in Stratum I were 26.1 ± 12.5 liter/h/m2, 41.9 ± 21.4 liter/m2, and 1.11 ± 0.41 h, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum 1 patients.
PMCID: PMC2775441  PMID: 19065567
VEGF; Anti-angiogenesis; Brain tumor; SU5416
19.  A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET 
Neuro-Oncology  2009;11(1):33-40.
We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M0 and tumor size > 1.5 cm2) or disseminated disease in the neuraxis (M1–M3). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36–39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% ± 14% and 73% ± 13%. The 5-year EFS and OS estimates were 75% ± 17% and 88% ± 13%, respectively, for the eight patients with AR disease and 60% ± 19% and 58% ± 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.
PMCID: PMC2718957  PMID: 18796696
autologous stem cell rescue; craniospinal radiotherapy; dose-intensive chemotherapy; event-free survival; risk-adapted therapy; supratentorial PNET
20.  A Multi-Institution Prospective Trial of Reduced-Dose Craniospinal Irradiation (23.4 Gy) Followed by Conformal Posterior Fossa (36 Gy) and Primary Site Irradiation (55.8 Gy) and Dose-Intensive Chemotherapy for Average-Risk Medulloblastoma 
Limiting neurocognitive sequelae of radiation therapy (RT) has been an objective in the treatment of medulloblastoma (MB). Conformal RT to less than the entire posterior fossa (PF) after craniospinal irradiation (CSI) may reduce neurocognitive sequelae and requires evaluation.
Between October 1996 and August 2003, 86 patients, 3-21 years of age, with newly diagnosed, average-risk MB were treated on a prospective, IRB-approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of CSI (23.4 Gy), conformal PF RT (36.0 Gy) and primary site RT (55.8 Gy). The planning target volume for the primary site included the post-operative tumor bed surrounded by an anatomically confined margin of 2 cm which was then expanded with a geometric margin of 0.3-0.5 cm. Chemotherapy was initiated 6 weeks after RT and included 4 cycles of high-dose cyclophosphamide, cisplatin and vincristine.
With a median follow-up of 61.2 months (5.2-115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure were 83.0% ± 5.3% and 4.9% ± 2.4% (±SE), respectively. Targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses above 55Gy compared to conventionally planned RT. Reductions in dose to the temporal lobes, cochleae and hypothalamus were statistically significant.
This prospective trial demonstrates that irradiation of less than the entire PF after 23.4 Gy CSI for average-risk MB results in disease control comparable to treatment of the entire PF.
PMCID: PMC2716663  PMID: 17892918
Radiotherapy; conformal radiotherapy; chemotherapy; pediatrics; CNS neoplasm
21.  Amifostine Protects Against Cisplatin-Induced Ototoxicity in Children with Average-Risk Medulloblastoma 
To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average risk (AR) medulloblastoma treated with craniospinal radiotherapy and 4 cycles of cisplatin-based dose-intense chemotherapy and stem cell rescue.
Patients and Methods
The primary objective was to determine whether, in patients with AR medulloblastoma (n=62), amifostine would decrease the need for hearing aids (defined as ≥ grade 3 ototoxicity in one ear) compared to a control group (n=35), one year from initiating treatment. (Figure 1) Ninety-seven patients received CSI (23.4 Gy) followed by 55.8 Gy to the primary tumor bed, using 3-D conformal technique and 4 cycles of high-dose cyclophosphamide (4000 mg/m2 per cycle), cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5 mg/m2 doses per cycle) and stem cell rescue. When used, amifostine (600 mg/m2 per dose) was given as a bolus immediately prior to and 3 hours into the cisplatin infusion.
The median age of the 97 patients was 8.7 years (range, 3.2–20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 (37.1%) of the control-group versus 9 (14.5%; p=0.005 Chi-Square one-sided test) of the amifostine-treated patients had ≥ grade 3 ototoxicity, requiring hearing aid in at least one ear.
Amifostine administered prior to and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy.
PMCID: PMC2504739  PMID: 18669462
amifostine; ototoxicity; cisplatin
22.  Intraocular Lymphoma:Update on Diagnosis and Management 
Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma (PCNSL) in which lymphoma cells initially invade the retina, vitreous, or optic nerve head, with or without concomitant CNS involvement. The incidence of this previously rare condition has increased dramatically. Given its nonspecific presentation and aggressive course, PIOL provides a diagnostic and therapeutic challenge.
We review the current strategies for diagnosis and treatment of PIOL and present our own experience with PIOL.
Recent developments in the diagnosis of PIOL include immunohistochemistry, flow cytometry, cytokine evaluation, and molecular analysis. However, definitive diagnosis still requires harvesting of tissue for histopathology. Optimal treatment for PIOL remains unclear. Initial therapeutic regimens should include methotrexate-based chemotherapy and radiotherapy to the brain and eye. In addition, promising results have been seen with intravitreal methotrexate and autologous stem cell transplantation for recurrent and refractory disease.
Efforts to further determine the immunophenotype and molecular characteristics of PIOL will continue to assist in the diagnosis of PIOL. Future studies are required to determine the role of radiotherapy and optimal local and systemic chemotherapeutic regimens.
PMCID: PMC1971130  PMID: 15377987
23.  Detection of the bcl-2 t(14;18) Translocation and Proto-Oncogene Expression in Primary Intraocular Lymphoma 
Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells.
Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis.
Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger.
PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lympho-mas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profil-ing, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.
PMCID: PMC1945012  PMID: 16799010
24.  Primary Testicular and Intraocular Lymphomas: Two Case Reports and a Review of the Literature 
Survey of ophthalmology  2006;51(1):41-50.
Testicular lymphoma is a rare neoplasm of the testis that is most commonly seen in older patients. It metastasizes preferentially to extranodal sites, including the skin, central nervous system, Waldeyer ring, contralateral testis, and lung. Two case reports of patients with a history of testicular lymphoma who developed involvement of the vitreous and retina are presented. These are interesting cases as the testis, central nervous system, and eye are all immune privileged organs, which may account for occurrence of disease in these sites. Histopathologic examination of diagnostic vitrectomy specimens from both cases showed atypical lymphoid cells with immunoglobulin heavy chain (IgH) gene rearrangements, consistent with the diagnosis of intraocular B-cell lymphoma. The results of a literature review of all reports of ocular involvement with testicular lymphoma are discussed. Patients with testicular lymphoma are at risk for relapse, particularly in the central nervous system. Clinicians should be suspicious for intraocular lymphoma in patients with a history of testicular lymphoma who present with vitritis or retinal lesions.
PMCID: PMC1930146  PMID: 16414360
immune privileged organ; immunohistochemistry; intraocular lymphoma; microdissection; PCR; retina; testicular lymphoma; vitreous

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