Faculty Bibliography

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis

BACKGROUND: Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). PROCEDURES: Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR. RESULTS: Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy. CONCLUSIONS: ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients

Primary CNS germ cell tumors (GCT) arise in the suprasellar and pineal regions. Suprasellar GCT may remain radiographically occult during the early symptomatic period. Although theoretically possible, it is more difficult to identify presymptomatic disease in the pineal region. Given the sensitivity of GCT to cytotoxic therapy, a decrease in size of the "normal" pineal gland following chemotherapy (CHT) could divulge preexisting disease. Such information may impact radiation treatment (RT). The authors reviewed MRIs of 15 patients with suprasellar GCT treated with pre-RT CHT. They defined a > or =50% reduction in volume of the pineal gland as a substantial decrease suspicious for preexisting occult disease. As controls, MRIs of 11 medulloblastoma patients who received cytotoxic therapy were reviewed. Pineal gland volumes could be determined for 12 of 15 patients with GCT and 7 of 11 patients with medulloblastoma. The study radiologists concurred that 2/12 GCT patients and 0/7 medulloblastoma patients had > or =50% volumetric reduction. When radiation is delivered as the sole treatment modality, the pineal region is included in at least the initial volume, but in certain clinical trials RT volume is reduced to only the suprasellar region if a complete response is achieved following pre-RT CHT. Noting changes in the "normal" pineal gland following CHT may indicate disease. CHT alone may not be sufficient to control this disease, even in cases in which a complete response is achieved. If the intent is to deliver RT to all areas of initial disease and this phenomenon can be demonstrated on a larger scale, inclusion of the pineal should be considered for patients demonstrating a substantial decrease in the size of the pineal gland after CHT.

PURPOSE: To assess the activity and tolerability of 2-chlorodeoxyadenosine (2-CDA) in treating mass lesions of the central nervous system (CNS) due to Langerhans cell histiocytosis (LCH). PATIENTS AND METHODS: The records of eight children and four adults with CNS LCH who were treated with 2-CDA were reviewed. The pattern of CNS disease included involvement of the hypothalamic-pituitary axis, gadolinium enhancing parenchymal as well as dural and choroid plexus based mass lesions, and atrophy. 2-CDA (5-13 mg/m(2)/day) was given on 3-5 consecutive days and repeated every 2-8 weeks for a period ranging from 3 to 12 months. RESULTS: Eight patients demonstrated a complete radiographic response to 2-CDA with resolution of all enhancing mass lesions and four patients showed a sustained, partial radiographic response. One patient died from a non-treatment related cause without evidence of LCH on autopsy. With a follow-up ranging from 2 to 10 years after completion of therapy, the 11 surviving patients remain in continuous remission or are progression free. Prolonged bone marrow suppression was the most common toxicity (four patients). Permanent sequelae of CNS LCH, such as panhypopituitarism, diabetes insipidus (DI) and neurocognitive dysfunction, were not found to be reversible with 2-CDA therapy. CONCLUSIONS: 2-CDA is an active agent in patients with CNS LCH, with the possible exception of neurodegenerative disease, and should be further evaluated in a prospective multi-center clinical trial for LCH patients with enhancing mass lesions of the CNS

OBJECTIVE: Diffusion tensor imaging (DTI) allows in vivo delineation of brainstem white matter tracts. The purpose of this study was to determine whether or not abnormalities of DTI metrics and fiber tractography correlate with neurological deficits and clinical status in patients with primary posterior fossa tumors. METHODS: A review of patients with primary posterior fossa tumors who underwent magnetic resonance imaging with DTI was performed. Patients were stratified by tumor type (well-circumscribed or infiltrating lesions). Fractional anisotropy (FA) color maps were used to localize the corticospinal tracts within the brainstem. FA, mean diffusivity, and eigenvalues were measured. Tractography was performed. Correlations between DTI metrics and clinical status and between DTI metrics and neurological examination findings were assessed within each patient group using Bonferroni correction for multiple comparisons. Comparisons of DTI metrics were also made between patient groups (infiltrating lesions versus well-circumscribed lesions). RESULTS: Thirty patients were studied (mean age, 14.1 yr; 16 male, 14 female). Eighteen patients had infiltrating lesions and 12 had well-circumscribed lesions. Twelve patients (four well-circumscribed and eight infiltrating) demonstrated motor weakness on physical examination (four right, three left, five bilateral). Patients with well-circumscribed lesions and weakness had higher mean diffusivity and lower FA in the contralateral corticospinal tract (P < 0.05). No such association was seen in patients with infiltrating tumors. In 102 total patient-years of follow-up (average follow-up period, 4.2 yr), 17 patients (six well-circumscribed and 11 infiltrating lesions) demonstrated complete response or stable disease and six patients (three well-circumscribed and three infiltrating lesions) demonstrated progressive disease or death. No differences were seen in terms of DTI metrics between patients with infiltrating lesions and those with well-circumscribed lesions. Patients with well-circumscribed tumors and a bad outcome had significantly lower transverse eigenvalue measures in the corticospinal tracts compared with those with a more favorable clinical status (P < 0.05). CONCLUSION: In patients with well-circumscribed primary posterior fossa masses, higher mean diffusivity and lower FA in the brainstem corticospinal tract are associated with contralateral motor deficits; lower transverse eigenvalue may be observed with an unfavorable clinical outcome

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years). Eligible patients received TMZ (200 mg/m(2) per day) by mouth for five days every four weeks. Patients received a median of nine cycles (range, 2-12 cycles) of treatment. Best responses in the 26 patients (86%) with optic pathway glioma (OPG)/pilocytic astrocytoma (PA) included partial response in 3 patients (11%), minor response in 1 (4%), stable disease in 10 (38%), and progressive disease in 12 (46%). Only one of four patients with fibrillary astrocytoma had stable disease for 29 months after TMZ. The overall disease stabilization rate in patients with OPG/PA was 54%, and disease control was maintained for a median interval of 34 months. Seventeen of 26 patients had progressive disease either on or off therapy, and three have died of disease. The two-year progression-free and overall survivals in patients with OPG/PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively. Worst toxicity related to TMZ in all 30 patients included grade 2-4 thrombocytopenia in seven patients, grade 2-4 neutropenia in seven, grade 2 skin rash in one, and intratumor hemorrhage in one. TMZ given in this schedule was successful in stabilizing disease in a significant proportion of the patients with OPG/PA, with manageable toxicity.

OBJECT: Cerebellar mutism syndrome (CMS) is a unique postoperative syndrome typically arising 1 to 2 days after resection of a midline posterior fossa tumor; it consists of diminished speech progressing to mutism, emotional lability, hypotonia, and ataxia. Most descriptions have been limited to small institutional series using a retrospective chart review methodology. METHODS: The authors incorporated a CMS questionnaire in two large clinical trials (Children's Cancer Group [CCG] 9931, treatment for high-risk medulloblastoma/primitive neuroectodermal tumor; and CCG/Pediatric Oncology Group [POG] A9961, treatment for average-risk medulloblastoma) to prospectively survey for incidence, severity, and possible causes of CMS in children with newly diagnosed medulloblastoma. Information pertaining to 450 of the 463 patients enrolled in the studies was available for review (82 patients in CCG 9931, and 368 patients in CCG/POG A9961). Cerebellar mutism syndrome occurred in 107 (24%) of 450 children. Symptom intensity was judged to have been severe in 43%, moderate in 49%, and mild in 8% of these 107 patients. Mutism and ataxia were the features most frequently judged as severe. In both cohorts, preoperative brainstem invasion was the only feature that correlated with risk of CMS. One year after diagnosis, nonmotor speech/language deficits, neurocognitive deficits, and/or ataxia persisted in a significant fraction of patients. CONCLUSIONS: Nearly one quarter of patients who underwent resection of a medulloblastoma developed symptoms of CMS, of which 92% were judged to be of moderate or severe intensity. Brainstem invasion by tumor was the only risk factor that correlated positively with CMS occurrence; there was a negative correlation with cerebellar hemisphere tumor location. As more radical resections are attempted for medulloblastoma, the potential for increased morbidity must be carefully weighed against prognostic factors, especially in patients with brainstem invasion.

OBJECT: The goal of this study was to determine the incidence of radiation-induced cavernomas in children treated for medulloblastoma. METHODS: A retrospective chart and film review was performed for all patients treated for medulloblastoma at the Insitute for Neurology and Neurosurgery/Beth Israel Medical Center between August 1996 and the present. The clinical and radiographic histories of pediatric patients (ages 3-21 years at diagnosis) with a histologically confirmed diagnosis of medulloblastoma who received craniospinal radiation therapy were reviewed. Fifty-nine patients were identified, with a mean age at radiation treatment of 7.7 years and a mean follow-up time of 7.2 years. The dose to the craniospinal axis was 24 Gy (31 patients) or 36 Gy (28 patients). The radiation energy in the craniospinal axis was provided by photons in 55 patients and protons in four. All patients received a posterior fossa boost of 54 Gy (46 patients) or 72 Gy (13 patients). Twenty-six lesions developed in 18 patients (31%) during the observation period. The cumulative incidence of lesion development was 5.6, 14, and 43%, at 3, 5, and 10 years, respectively. The sites of occurrence were cerebral (20 cases) and cerebellar (six cases). There was no significant correlation between age at diagnosis, sex, craniospinal radiation dose or energy source, and lesion development. Only one patient required surgical intervention for a symptomatic hemorrhagic lesion in the frontal lobe. Histological analysis in this case was consistent with cavernoma. CONCLUSIONS: Cavernomas are common after cranial irradiation in children, and their incidence increases over time. Most of these lesions follow a benign course and do not require intervention.

We report an atypical teratoid/rhabdoid tumor arising in a ganglioglioma from an 11-year-old male who had been treated over a nine-year period. A combined histologic, immunohistochemical, and molecular genetic analysis confirmed this diagnosis. Molecular genetic studies demonstrated a mutation in exon 9 of the INI1 gene in the tumor, which was not present in the patient's blood. This report is the first to describe progression of a ganglioglioma to atypical teratoid/rhabdoid tumor