Diffuse Pontine Research Articles

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse pontine gliomas treated by radiotherapy

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse pontine gliomas treated by radiotherapy

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse pontine gliomas treated by radiotherapy

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse pontine gliomas treated by radiotherapy

Interstitial infusion of IL13-PE38QQR in the rat brain stem.

Interstitial infusion of IL13-PE38QQR, a tumor specific, chimeric cytotoxin, into the rat brain stem was performed in an effort to assess safety. Six rats underwent stereotaxic cannula placement into the pontine segment of the brain stem followed by a 24-h infusion of IL13-PE38QQR (volume of infusion (Vi) 200 microl) at a concentration of 10 microg/ml. The animals were assessed neurologically and then sacrificed either immediately or after 2 weeks. All animals tolerated the infusions without exhibiting any neurological changes. Postmortem examination of the brains revealed no significant histological changes beyond the site of the cannula tract. These findings indicate that supratherapeutic concentrations of IL13-PE38QQR administered by interstitial infusion into the rat brain stem is well tolerated and may serve as a potential therapeutic strategy for children with diffuse pontine gliomas.

A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma

Purpose To determine the toxicity and maximum tolerated dose of etanidazole administered concurrently with hyperfractionated radiation therapy (HRT) for children with brainstem glioma. Methods and materials Eighteen patients with brainstem glioma were treated with etanidazole and HRT on a dose escalation protocol (Phase I trial) between 1990 and 1996. All patients had MRI confirmation of diffuse pontine glioma and signs/symptoms of cranial nerve deficit, ataxia, or long tract signs of <6 months’ duration. Cervicomedullary tumors were excluded. Patients (median age: 8.5 years; 11 males, 7 females) received HRT to the tumor volume plus a 2-cm margin with parallel-opposed 6–15-MV photons. The total dose was 66 Gy in 44 fractions (1.5 Gy b.i.d., with at least 6 h between fractions) for the first 3 patients and 63 Gy in 42 fractions for the subsequent 15 patients. Etanidazole was administered as a rapid i.v. infusion 30 min before the morning fraction of HRT. Planned doses of etanidazole were 1.8 g/m 2 × 17 doses (30.6 g/m 2) at Step 1 to a maximum of 2.4 g/m 2 × 21 doses (50.4 g/m 2) at Step 8. Dose escalation was planned with 3 patients at each of the 8 levels. Results Three patients were treated at each dose level except Level 2, on which only 1 patient was treated. The highest dose level achieved was Level 7, which delivered a total etanidazole dose of 46.2 g/m 2. Two patients were treated at this level, and both patients experienced Grade 3 toxicity in the form of a diffuse cutaneous rash. Three patients received a lower dose of 42 g/m 2 (dose Level 6) without significant toxicity, and this represents the maximum tolerated dose (MTD). There were 23 cases of Grade 1 toxicity (10 vomiting, 5 peripheral neuropathy, 2 rash, 2 constipation, 1 weight loss, 3 others), 11 cases of Grade 2 toxicity (4 vomiting, 2 skin erythema, 2 constipation, 1 arthralgia, 1 urinary retention, 1 hematologic), and 4 Grade 3 toxicities (2 rash, 1 vomiting, 1 skin desquamation). Grade 2 or 3 peripheral neuropathy was not seen at any dose level. The median survival from the start of treatment was 8.5 months (range: 3–58 months). Conclusion The MTD of etanidazole in children receiving HRT for brainstem glioma is 42 g/m 2, with cutaneous rash as the dose-limiting toxicity. This is in contrast to the adult experience, which demonstrates a 24% lower MTD of 34 g/m 2 limited by peripheral neuropathy.

Prolonged Convection-enhanced Delivery into the Rat Brainstem

Prolonged convection-enhanced delivery was used in an attempt to achieve large volumes of distribution (V(d)) in the rat brainstem. Clinical assessment and histological analysis were performed to establish the safety of this approach. For evaluation of V(d,), 10 rats underwent stereotactic cannula placement into the brainstem. Five rats underwent a 24-hour infusion (volume of infusion [V(i)], 200 microl), and 5 rats underwent a 7-day infusion (V(i), 2 ml) of fluorescein isothiocyanate-dextran. Serial brainstem sections were imaged with ultraviolet illumination, and V(d) was assessed. For assessment of clinical tolerance, 30 additional rats underwent chronic infusions of an isotonic saline solution into the brainstem. Serial neurological examinations were performed, followed by histological analysis after the animals' death. No animal demonstrated clinically recognized neurological deficits. Foci of organizing necrosis were limited to the site of infusion and cannula tract. V(d) increased linearly with increasing V(i) (range, 24.8-130.6 mm(3)). Maximal cross sectional area of fluorescence and craniocaudal extent of fluorescence increased with increasing V(i). Fluorescence was detected throughout the entire brainstem beyond the compact area of highly concentrated tracer. Prolonged convection-enhanced delivery can be applied safely in the rat brainstem with no recognized limitations of V(d) and minimal histological changes beyond the site of infusion. Chronic brainstem infusions may enhance the potential application of convection-enhanced delivery for therapeutic purposes in treating diffuse pontine gliomas.

Convection-enhanced delivery into the rat brainstem

Convection-enhanced delivery (CED) can be used safely to achieve high local infusate concentrations within the brain and spinal cord. The use of CED in the brainstem has not been previously reported and may offer an alternative method for treating diffuse pontine gliomas. In the present study the authors tested CED within the rat brainstem to assess its safety and establish distribution parameters. Eighteen rats underwent stereotactic cannula placement into the pontine nucleus oralis without subsequent infusions. Twenty rats underwent stereotactic cannula placement followed by infusion of fluorescein isothiocyanate (FITC)-dextran at a constant rate (0.1 microl/minute) until various total volumes of infusion (V(i)s) were reached: 0.5, 1, 2, and 4 microl. Additional rats underwent FITC-dextran infusion (V, 4 microl) and were observed for 48 hours (five animals) or 14 days (five animals). Serial (20-microm thick) brain sections were imaged using confocal microscopy with ultraviolet illumination, and the volume of distribution (Vd) was calculated using computer image analysis. Histological analysis was performed on adjacent sections. No animal exhibited a postoperative neurological deficit, and there was no histological evidence of tissue disruption. The Vd increased linearly (range 15.4-55.8 mm3) along with increasing Vi, with statistically significant correlations for all groups that were compared (p < 0.022). The Va/Vi ratio ranged from 14 to 30.9. The maximum cross-sectional area of fluorescence (range 9.8-20.9 mm2) and the craniocaudal extent of fluorescence (range 2.8-5.1 mm) increased with increasing Vi. Convection-enhanced delivery can be safely applied to the rat brainstem with substantial and predictable V(d)s. This study provides the basis for investigating delivery of various candidate agents for the treatment of diffuse pontine gliomas.

Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: The Duke experience

A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.

Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas.

The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas. Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis. Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit. For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy.

High-dose chemotherapy in childhood brain tumours.

New therapeutic strategies are required to improve the prognosis of malignant brain tumours in children, in terms of survival and quality of life. During the last 10 years, high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell rescue has been studied in different types of paediatric brain tumours. The most frequently used combined regimens were busulfan-thiotepa and etoposide-thiotepa along with carboplatin or BCNU. High response rates have been reported in medulloblastoma and germ cell tumours, and HDCT has been further developed as salvage therapy or for consolidation in these diseases. Interesting objective tumour responses have been obtained in supratentorial high-grade glioma, but HDCT has not so far been effective either in ependymoma or in diffuse pontine brain stem tumours. This article reviews the rationale for HDCT in brain tumours and the current clinical results obtained in each tumour type. The place of HDCT in the therapeutic strategy for paediatric brain tumours, especially in young children, is discussed.

Permanent I-125 brain stem implants in children.

Between 1988 and 1997, 28 children have had iodine-125 implants for CNS tumors performed in our institution. Ten had stereotactic implantation in the brain stem region, and nine had the diagnosis of brain stem glioma (8 diffuse pontine, 1 midbrain tumor). Their ages ranged from 1.8 to 12 years. All patients had histological confirmation of malignancy (7 high-grade glioma, 2 low-grade glioma, 1 PNET). Diffuse pontine glioma patients received external beam radiation (50 Gy) followed by a fractionated stereotactic boost of 3 Gyx4 fractions. After 4-6 weeks, patients were reevaluated for stereotactic interstitial I-125 therapy. The planned implant dose was 82.9 Gy to the enhancing tumor (4 cGy per h). Preliminary results indicated that no surgical complications were associated with the catheter placement. Four patients have died (7-9 months from diagnosis) and four patients remain alive (5-38 months from diagnosis, median 10 months). Two autopsies confirmed the presence of progressive glioblastoma multiforme and intralesional necrosis. In one patient who received an implant alone for midbrain LGA, necrosis without tumor was found on biopsy after 36 months. He was successfully treated with hyperbaric oxygen therapy. The implementation of permanent I-125 implants appears to have a role in the management of pediatric CNS malignancy. This study confirms the results of previous reports regarding the safety of stereotactic interstitial brachytherapy in the brain stem. Tumor control for patients with high-grade brain stem glioma remains poor even with high focal radiation doses.

Brain Stem Involvement in Children with Neurofibromatosis Type 1

OBJECTIVE:To evaluate the ability of magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) to distinguish neurofibromatosis Type 1(NF-1) with brain stem enlargement from diffuse pontine glioma (PG) in pediatric patients.METHODS:A chart review was used to identify all pati

Advances and controversies in the management of childhood brain tumors.

Important studies have been reported in the past year on the biology and management of pediatric central nervous system tumors. Pediatric low-grade gliomas and adult gliomas do not share similar molecular genetic features. There may be a role for high-dose chemotherapy with bone marrow rescue in relapsed medulloblastoma and germinoma. Malignant gliomas in infants appear to be distinct entities compared with adult malignant gliomas. Further investigational studies are needed in ependymoma and diffuse pontine gliomas because current therapies have not resulted in improvements in outcomes.

Neuroradiology of Brain Stem and Cervicomedullary tumours

Brain stem and cervicomedullary tumours are typical of paediatric age, 80% of them occurring in patients under 18 years of age, and comprising 10–15% of all childhood and adolescent brain tumours, as well as 20–25% of infratentorial locations.They are characteristically pontine tumours (60% of the cases), but they commonly extend to involve the medulla, midbrain and cerebellum. Although most brain stem tumours are low grade gliomas, their prognosis is extremely severe (no more than 20% of patients are alive 3 years after diagnosis and the 5-year survival rate is 5%) because both the typical infiltrating nature and the neuro-anatomical location usually make them surgically unresectable. Surgery is generally limited to biopsy, partial decompression, or excission of the exophytic components, because of the extremely severe functional sequelae of even minor resections. Thus, the mainstay of therapy has been based on irradiation alone or combined with chemotherapy, doses of 5000–5500 cGy being usually adequate...

Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma.

To evaluate the ability of magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) to distinguish neurofibromatosis Type 1 (NF-1) with brain stem enlargement from diffuse pontine glioma (PG) in pediatric patients. A chart review was used to identify all patients with NF-1 and diffuse brain stem enlargement who were seen at our institution and who had undergone MRI. Comparison groups were as follows: 1) eight patients who did not have NF-1 but who did have diffuse PG, and 2) seven healthy children. Midsagittal diameters of the pons, midbrain, and medulla were measured in all patients, and the results were statistically analyzed. Two MRS variables were also statistically compared: N-acetyl aspartate and the vector sum of the metabolites choline and creatine/phosphocreatine. In MRI-based measurements, only the pontine midsagittal diameter differed significantly between the NF-1 and PG groups (P = 0.002). Altogether, 21 children underwent MRS, including 6 in the NF-1 group. Measures of both MRS variables were significantly lower in patients with PG than in the others (P < or = 0.007). The two MRS variables classified the 21 children into the three respective groups with 100% accuracy. Of the seven patients with NF-1, four presented with symptoms attributable to brain stem involvement. The brain stems of all seven patients with NF-1 were hyperintense on T2-weighted magnetic resonance images, and five were isointense on T1-weighted images; only one exophytic tumor was identified. Four of the patients with NF-1 were followed up clinically without treatment; all remained alive and neurologically stable for a median of 40 months. All eight patients in the PG group were symptomatic at presentation, and all except one died despite therapy. Both MRI measurements and MRS seem to be useful for distinguishing patients with NF-1 and diffuse brain stem enlargement from patients without NF-1 but with diffuse PG. They should be most helpful in differentiating symptomatic patients with NF-1 from patients with PG, thereby minimizing aggressive treatment and its side effects in patients destined to have better outcomes.

Recognition and management of gliomas.

Gliomas are the most frequent primary brain tumours. They include astrocytic gliomas, oligodendrocytic gliomas, ependymomas and gliomas with mixed cell populations. Each glioma type consists of both low-grade and malignant atypical varieties. The low-grade tumours occur predominantly in children and young adults, and the malignant forms in older people. The presenting symptoms are epileptic seizures, headache and mental confusion. Focal neurological symptoms and findings, such as hemiparesis, are mostly associated with the malignant forms. Magnetic resonance imaging (MRI) scan of the brain with and without gadolinium contrast demonstrates the tumour. However, stereotactic biopsy or surgical resection is necessary to obtain the correct pathological diagnosis, except for diffuse pontine astrocytomas, which have an unmistakeable imaging appearance and for which biopsy has substantial risks. Treatment depends on the pathological diagnosis. Complete surgical resection may be curative for low-grade tumours. Postoperative radiotherapy is recommended for partially resected tumours. Most malignant gliomas require aggressive combination therapy with radiotherapy and chemotherapy after maximal surgery. The standard initial regimens are nitrosourea-based chemotherapies, such as carmustine alone, a combination of procarbazine, lomustine and vincristine, or a combination of thioguanine, procarbazine, lomustine and hydroxycarbamide (hydroxyurea). Unfortunately, the prognosis of malignant gliomas is generally poor despite aggressive treatment, because of their infiltrative nature and high relapse rate.

Brain Stem Involvement in Children with Neurofibromatosis Type 1: Role of Magnetic Resonance Imaging and Spectroscopy in the Distinction from Diffuse Pontine Glioma

Brain Stem Involvement in Children with Neurofibromatosis Type 1: Role of Magnetic Resonance Imaging and Spectroscopy in the Distinction from Diffuse Pontine Glioma

Neuroimaging of primary brainstem gliomas: diagnosis and course.

MR imaging is the procedure of choice for identifying brainstem gliomas and classifying them anatomically. Serial studies show a poor prognosis for diffuse pontine gliomas, better outcome for exophytic medullary gliomas and an indolent course for most midbrain gliomas.

Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome.

Although tumors of the brain stem have traditionally been classified as a single entity, these tumors are increasingly being recognized as a heterogeneous group, with some subgroups having better prognoses for long-term survival. Although several systems for classification of brain stem tumors have been proposed, none have been based on data derived from contrast-enhanced magnetic resonance (MR) imaging. In this review, we present a classification scheme based on our review of the literature and of the MR scans of 64 patients with brain stem tumors. In addition, we assess the contribution of gadolinium to the classification of brain stem tumors and correlate the various tumor subtypes, based on MR appearance, with prognosis. Our results suggest that the most important factor in determining prognosis based on MR characteristics is whether the tumor is diffuse or focal. Focal tumors have an excellent prognosis regardless of the site of tumor origin. Diffuse tumors of the mesencephalon and pons have a significantly poorer prognosis than focal tumors (p = 0.0013), with diffuse pontine tumors having the worst prognosis. Differentiation of diffuse and focal medullary tumors was difficult, possibly explaining the lack of significant difference in the survival of patients with diffuse versus focal medullary tumors. The presence or absence of enhancement after the administration of paramagnetic contrast has no significant relation with outcome, overall or within specific tumor subgroups.

Strategies in the treatment of diffuse pontine gliomas: the therapeutic role of hyperfractionated radiotherapy and chemotherapy.

This article will review the current treatment of pediatric patients with diffuse pontine gliomas (DPG) and discuss three potential avenues of therapeutic research including (i) radiotherapy (RT) in combination with radiation sensitizers, (ii) dose-intensive, induction chemotherapy with hematopoietic support followed in sequence with RT applied as a "consolidation' therapy, and (iii) the interleafed application of phase-specific chemotherapeutic agents and hyperfractionated external beam radiotherapy (HFEBRT) referred to as "chemoradiotherapy'.