Ian F. Pollack

Induction of CD8+ T-Cell Responses Against Novel Glioma–Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma

PURPOSE A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. PATIENTS AND METHODS Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays. RESULTS The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression. CONCLUSION These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.

Intracranial ependymomas of childhood: long-term outcome and prognostic factors.

A detailed outcome analysis was performed on 40 children with intracranial ependymomas treated at our institution between 1975 and 1993 to identify those factors that were predictive of overall and progression-free survival. Three patients (7.5%) who were treated in the first 5 years of the study died within 3 months of surgery and were excluded from further outcome assessments. Eight (22%) of the 37 patients who survived the perioperative period had evidence of leptomeningeal dissemination at presentation, on the basis of either imaging (three children) and/or cytological (six children) results. The 5- and 10-year progression-free survival rates among these 37 patients were 45.1 and 36.1%, respectively; overall survival rates were 57.1 and 45.0%, respectively. The site of progression was local in 17 of 19 patients with progressive disease. Three factors were found to have a significant association (P < or = 0.05) with the outcome on both univariate and multivariate analyses: 1) the extent of the resection, 2) the age of the patient at diagnosis, and 3) the duration of the symptoms before diagnosis. The 5-year progression-free and overall survivals were 8.9 and 22%, respectively, among patients who had evidence of residual disease on postoperative imaging studies, compared with 68 and 80% rates among patients with no apparent residual disease (P = 0.0001 and P < 0.0001, respectively). Patients younger than 3 years fared significantly worse than older children (5-year progression-free and overall survival rates of 12 and 22%, respectively, in the younger children versus 60 and 75% in older children (P = 0.003 and P = 0.01, respectively). In addition, patients with a duration of symptoms before diagnosis of < 1 month had a worse outcome than those with a more protracted course (5-year progression-free and overall survival rates of 33 and 33%, respectively, versus rates of 53 and 64%, respectively (P = 0.02 for both). Neither the finding of evidence for dissemination at presentation nor the detection of anaplastic histological features (e.g., dense cellularity or high numbers of mitoses) were associated with a significantly worse outcome in this series. The combination of variables that had the strongest association with both favorable and unfavorable outcomes was the combination of the age of the patient and the resection extent. Only 2 of 17 patients older than 3 years with gross total resections have died, whereas 13 of 20 children who were either younger than 3 years or had radiologically incomplete resections have died (P < 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology.

MUTISM AND A variety of other neurobehavioral symptoms have been reported anecdotally after the removal of posterior fossa mass lesions. To determine the incidence and clinical spectrum of this syndrome, a detailed review was performed of patients undergoing resection of infratentorial tumors at our institution during the last 9 years; 12 of 142 patients (8.5%) manifested this syndrome, the largest series of such patients reported to date. Each child had a lesion that involved the vermis; seven had medulloblastomas, three had astrocytomas, and two had ependymomas. The incidence among children with vermian neoplasms was 13%. Ten children underwent division of the inferior vermis during tumor resection, and three had a superior vermian incision; one child underwent both superior and inferior vermian incisions. In 10 children, mutism developed in a delayed fashion postoperatively. The speech disturbance was associated with poor oral intake in 9 children, urinary retention in 5, long-tract signs in 6, and bizarre personality changes, emotional lability, and/or decreased initiation of voluntary movements in all 12. Neuropsychiatric testing, performed in seven children, confirmed impairments not only in speech but also in initiation of other motor activities. Ten children regained normal speech, bladder control, and neurological functioning, other than ataxia and mild dysarthria, within 1 to 16 weeks; two children had significant residual deficits. Characteristically, affect and oral intake returned to their preoperative baseline before the speech difficulties began to resolve. A detailed radiological review of these cases in parallel with 24 cases of vermian tumors without mutism identified only one factor that was significantly associated with the mutism syndrome, bilateral edema within the brachium pontis (P < 0.01). Neither the size of the tumor nor the length of vermian incision was associated with the development of mutism. The clinical features of this syndrome in the context of these imaging findings suggest that the mutism syndrome results from transient impairment of the afferent and/or efferent pathways of the dendate nuclei that are involved in initiating complex volitional movements. The clinical courses of our patients are presented and compared with those of similar cases in the literature in an attempt to evaluate the validity of this hypothesis.

Spinal cord injury without radiographic abnormality in children--the SCIWORA syndrome.

Spinal cord injury in children frequently occurs without fracture or dislocation. The clinical profiles of 55 children with spinal cord injury without radiographic abnormalities (SCIWORA) are reported in detail to illustrate features of this syndrome. No patient had vertebral fracture or dislocation on plain films and tomographies. There were ten upper cervical (C1-C4), 33 lower cervical (C5-C8), and 12 thoracic cord injuries; of these, 22 were complete or severe lesions and 33 were mild lesions. The mechanism of the neural injury probably relates to the inherent elasticity of the juvenile spine, which permits self-reducing but significant intersegmental displacements when subjected to flexion, extension, and distraction forces. The spinal cord is therefore vulnerable to injury even though the vertebral column is spared from disruption, and this vulnerability is most evident in children younger than 8 years. All but one of the 22 children with profound neurologic injuries were younger than 8 years (p less than 0.000001), whereas 24 of 33 children with mild injuries were older. Younger children were also more likely to have severe upper cervical lesions (p less than 0.05); lower cervical lesions were distributed evenly through the ages of 6 months to 16 years. Thoracic injuries most commonly resulted from distraction or crushing. Distraction invariably involved violent forces, and crush injuries were usually caused by children being run over while lying prone, when the spinal column was acutely bowed towards the spongy abdominal and thoracic cavities. Fifteen children had delayed onset of neurologic deficits; nine of these had transient warning symptoms of paresthesia, subjective paralysis, and Lhermittes phenomenon 30 minutes to 4 days before the onset of deterioration. Eight other children suffered a second SCIWORA 3 days to 10 weeks after the initial SCIWORA. The spines in these children were presumably rendered incipiently unstable by the initial injury and thus were susceptible to additional, often more severe, neurologic trauma. The long-term neurologic outcome in children with SCIWORA is solely determined by their admission neurologic status. Realistically, the outcome can thus only be improved by: 1) ruling out occult fractures and subluxation which will require surgical fusion; 2) identifying patients likely to have delayed deterioration; and 3) preventing recurrent SCIWORA. Our experience and recommendations in these regards are discussed.

Mutism and Pseudobulbar Symptoms after Resection of Posterior Fossa Tumors in Children

MUTISM AND A variety of other neurobehavioral symptoms have been reported anecdotally after the removal of posterior fossa mass lesions. To determine the incidence and clinical spectrum of this syndrome, a detailed review was performed of patients undergoing resection of infratentorial tumors at our institution during the last 9 years ; 12 of 142 patients (8.5%) manifested this syndrome, the largest series of such patients reported to date. Each child had a lesion that involved the vermis ; seven had medulloblastomas, three had astrocytomas, and two had ependymomas. The incidence among children with vermian neoplasms was 13%. Ten children underwent division of the inferior vermis during tumor resection, and three had a superior vermian incision ; one child underwent both superior and inferior vermian incisions. In 10 children, mutism developed in a delayed fashion postoperatively. The speech disturbance was associated with poor oral intake in 9 children, urinary retention in 5, long-tract signs in 6, and bizarre personality changes, emotional lability, and/or decreased initiation of voluntary movements in all 12. Neuropsychiatric testing, performed in seven children, confirmed impairments not only in speech but also in initiation of other motor activities. Ten children regained normal speech, bladder control, and neurological functioning, other than ataxia and mild dysarthria, within 1 to 16 weeks ; two children had significant residual deficits. Characteristically, affect and oral intake returned to their preoperative baseline before the speech difficulties began to resolve. A detailed radiological review of these cases in parallel with 24 cases of vermian tumors without mutism identified only one factor that was significantly associated with the mutism syndrome, bilateral edema within the brachium pontis (P < 0.01). Neither the size of the tumor nor the length of vermian incision was associated with the development of mutism. The clinical features of this syndrome in the context of these imaging findings suggest that the mutism syndrome results from transient impairment of the afferent and/or efferent pathways of the dendate nuclei that are involved in initiating complex volitional movements. The clinical courses of our patients are presented and compared with those of similar cases in the literature in an attempt to evaluate the validity of this hypothesis.

O6-Methylguanine-DNA Methyltransferase Expression Strongly Correlates With Outcome in Childhood Malignant Gliomas: Results From the CCG-945 Cohort

PURPOSE O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined. METHODS We examined the association between MGMT expression and survival duration using tumor samples from the Childrens Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens. RESULTS Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location. CONCLUSION Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.

Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma

PURPOSE Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. PATIENTS AND METHODS We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. RESULTS TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. CONCLUSION Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group

An open-label phase II study (ACNS0126) testing the efficacy of chemoradiotherapy with temozolomide (TMZ) followed by adjuvant TMZ was conducted by the Childrens Oncology Group. During the period from July 6, 2004 through September 6, 2005, 63 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) were enrolled in the study. All patients received TMZ at a dosage of 90 mg/m(2)/day for 42 days to a dose of 59.4 Gy. Four weeks following irradiation, TMZ was given at a dosage of 200 mg/m(2)/day for 5 days every 28 days, for a total of 10 cycles. The primary objective of the statistical analysis was to determine whether the current treatment produced a 1-year event-free survival (EFS) rate higher than the historical baseline of 21.9% observed in CCG-9941. The mean 1-year EFS (± standard deviation) was 14% ± 4.5%, compared with 21.9% ± 5% for CCG-9941. The P value of the test of comparison of 1-year EFS, based on a 1-sided, 1-sample test of proportions, was .96. There was no evidence that temozolomide produced a 1-year EFS rate higher than 21.9%. The mean 1-year OS (± standard deviation) was 40% ± 6.5%, compared with 32% ± 6% for CCG-9941. The median time to death was 9.6 months. Chemoradiotherapy with TMZ followed by adjuvant TMZ is not more effective than previously reported regimens for the treatment of children with DIPG.

The management of brainstem gliomas in patients with neurofibromatosis 1

The appropriate management of brainstem tumors in patients with neurofibromatosis 1 (NF1) has been problematic because the natural history of these lesions remains poorly defined.To formulate rational guidelines for the evaluation and treatment of these tumors, we reviewed the outcome of 21 patients with brainstem mass lesions followed in our NF clinic during the last 9 years. We subdivided the imaging features of these lesions into four groups: (1) diffuse enlargement of the brainstem with hypointensity on T1-weighted MR images and hyperintensity on T2-weighted images (n = 9); (2) focal enhancing masses (n = 7); (3) intrinsic tectal tumors (n = 5); and (4) focal nonenhancing areas of hypointensity on T1-weighted MR images (n = 2). Two cases exhibited two types of lesions. Twelve patients presented with, or developed, symptoms that were referable to the mass; in nine, the lesion was asymptomatic. A distinguishing feature of these tumors was their generally indolent biological behavior. With a median follow-up of 3.75 years, only 10 patients have had radiographic (n = 9) or clinical (n = 3) evidence of disease progression. In seven of these patients, the tumor subsequently stabilized in size or regressed without intervention. Only four patients, each with a focal enhancing tumor, received specific therapy for the tumor; this consisted of biopsy (n = 1), excision (n = 3), and adjuvant radiotherapy (n = 2). Each of these lesions was a low-grade glioma histologically and each remained stable in size after treatment (median follow-up = 4.25 years). Four patients with tectal tumors underwent insertion of a CSF shunt for hydrocephalus, but required no specific treatment for the tumor. None of the patients with diffuse brainstem lesions or focal areas of hypointensity required any intervention for the tumor. All 21 patients are presently alive and well. We conclude that the biological behavior of brainstem lesions in patients with NF1 differs significantly from that of lesions with a similar appearance in patients without this disorder.Although these lesions may at some time in their course exhibit clinical and radiographic progression, most do not require specific intervention. The lesions that are most likely to progress and require therapy are focal enhancing tumors; however, even lesions in this subgroup may stabilize in size or regress spontaneously without intervention. Based on these results, we recommend that intervention be limited to those lesions that exhibit rapid or unrelenting growth on serial images or that produce significant clinical deterioration. NEUROLOGY 1996;46: 1652-1660

Frameless stereotactic guidance for surgery of the upper cervical spine.

OBJECTIVE The goal was to evaluate and describe the use of a frameless, computed tomography-guided, stereotactic technique in complex procedures involving the craniocervical junction. METHODS Eleven procedures, including transoral odontoid resection, posterior atlantoaxial fusion with transarticular C1-C2 screw fixation, and spinal tumor resection, were performed in the preceding 26 months. In each case, frameless stereotaxy was used to plan the incision, to define resection margins, and to determine the appropriate orientation of instrumentation. RESULTS There were no intraoperative complications noted. Each patient underwent adequate resection of the pathological lesion and satisfactory placement of instrumentation. The stereotactic system provided detailed anatomic visualization, which increased the confidence of the surgeon during the procedure. The system limited the need for extensive surgical exposure, reduced fluoroscopy time, and decreased the risk of neurovascular injury. CONCLUSION Frameless stereotaxy provided the surgeon with intraoperative information regarding the extent of bone and soft tissue resection. It provided a multidimensional view of anatomic relationships in the operative field, which significantly increased surgical accuracy and safety.