Radiation dose response of neurologic symptoms during conformal radiotherapy for diffuse intrinsic pontine glioma.

PURPOSE: To estimate the rate and magnitude of neurologic symptom change during radiation therapy (RT) and impact of symptom change on survival outcomes in patients with diffuse intrinsic pontine glioma (DIPG). METHODS: From 2006 to 2014, 108 patients with newly diagnosed DIPG were treated with conventionally fractionated radiation therapy (RT) to 54 Gy (median) at our institution. The presence and severity of neurologic symptoms related to cranial neuropathy (CN) and cerebellar (CB) and long-tract (LT) signs was reviewed before and weekly during RT for each patient. The rate and magnitude of change for each symptom category was evaluated according to accumulated RT dose. The impact of clinical factors and radiation dose-volume parameters was determined using Cox proportional hazards models. RESULTS: Median dose to first sign of symptomatic improvement was 16.2 Gy (CN), 19.8 Gy (LT) and 21.6 Gy (CB). Most patients showed an improvement by 20 Gy. Larger uninvolved brainstem volume, alone or normalized to total brain (TB) or posterior fossa volume (PF), was associated with shorter time to LT sign improvement (P = 0.044, P = 0.033, and P = 0.05, respectively). Patients with any improvement in CN experienced significantly, yet modestly, prolonged progression-free survival (PFS) and overall survival (OS) (P = 0.002 and P = 0.008, respectively). Tumor volume, with or without normalization to TB or PF, was not significantly associated with PFS or OS. CONCLUSIONS: Low cumulative RT doses resulted in neurologic improvement in most patients with DIPG. The volume of brainstem spared by tumor influenced time to symptomatic improvement. Neurologic improvement during RT was associated with superior survival.

Peduncular psychosis.

Psychotic symptoms are rarely documented in association with cortex-sparing central nervous system (CNS) lesions limited to the midbrain. We present the case of a 15-year-old boy with hereditary and environmental risk factors for psychiatric illness, as well as a history of midbrain pilocytic astrocytoma treated with chemotherapy and focused radiation, who presented with non-epileptic seizures, hyper-religiosity and frank psychosis. The space-occupying midbrain lesion has been radiographically stable while the patient has decompensated psychiatrically. Differential aetiology for the patient's psychiatric decompensation is discussed, including psychosis secondary to a lesion of the midbrain. Literature linking midbrain lesions to psychotic features, such as in peduncular hallucinosis, is briefly reviewed. This case suggests that a midbrain lesion in a susceptible patient may contribute to psychosis.

Children with minimal chance for cure: parent proxy of the child's health-related quality of life and the effect on parental physical and mental health during treatment.

To assess health-related quality of life (HRQOL) from the time of diagnosis until disease progression in a cohort of children with diffuse intrinsic pontine glioma (DIPG). The assessment was collected from the perspectives of the child and their parents and evaluated the effect of the child's HRQOL on their parents' physical and mental well-being, thus providing insight into the optimal timing of palliative consultation, including anticipatory grief and bereavement services. This longitudinal study assessed 25 parents and their children, ages 2-17 years of age with DIPG across five time-points, baseline and weeks 2, 4, 6, 16, 24. Assessments included the PedsQL 4.0 Core Scales, PedsQL 3.0 Brain Tumor Scale, and Short-Form 36. HRQOL instruments were completed by the child (age ≥5 years) and parent-proxy (ages 2-17 years), with the parent completing the SF-36. Children's reports and parents' proxy of their child's HRQOL indicated poor physical functioning and increased anxiety at the initiation of therapy. A trending improvement in the children's HRQOL was reported by children and parents from baseline to week 6, with a decline at week 16. The childs' parent proxy reported cognitive problems, procedural anxiety and lower overall brain tumor HRQOL were assoicated with poorer self-reported parental mental status. Palliative care consultation should be initiated at the time of diagnosis and is supported in the high physical and emotional symptom burden reported by our patients, with heightened involvement initiated at 16 weeks. Prompt palliative care involvement, mitigating anxiety associated with clinic visits and procedures, management of brain tumor specific symptoms, advanced care planning, anticipatory grief and bereavement services, and care coordination may maximize HRQOL for patients and ensure positive long-term outcomes for parents of children with DIPG.

Pediatric tectal plate gliomas: a review of clinical outcomes, endocrinopathies, and neuropsychological sequelae.

Pediatric tectal plate gliomas are indolent slow-growing gliomas that often present with increased intracranial pressure or incidentally on routine brain imaging. We investigated clinical outcomes, endocrinopathies, and neuropsychological sequelae associated with tectal plate gliomas. Twenty-six patients with tectal plate glioma were identified in a 20-year retrospective review. Clinical outcomes, treatments, endocrine function, neuropsychological testing outcomes and radiographic imaging were reviewed for possible signs correlating with tumor progression. Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in our cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population.

Long-term quality of life in children treated for posterior fossa brain tumors.

OBJECT: In the face of increasing survival, quality of life (QOL) has become an important indicator of treatment success in children with posterior fossa brain tumors (PFBTs). The authors' objective was to assess the long-term QOL in survivors of PFBT. METHODS: The authors conducted a cross-sectional study of children who, between birth and age 18 years at diagnosis, had previously been treated at their institution for a PFBT. At the time of assessment for this study, children were between 5 and 19 years old and had received standard treatment for PFBT ending at least 6 months before the assessment. The QOL was measured with the Pediatric Quality of Life Inventory (PedsQL) generic score scales and the Health Utilities Index Mark 3 (HUI3). Multivariate analyses were used to assess several variables (patient related, treatment related, and socioeconomic) for association with QOL. RESULTS: A total of 62 children participated in the study (median age at assessment 11.9 years, interquartile range [IQR] 7.8-14.8, and median age at tumor diagnosis of 4.9 years, IQR 2.5-6.9). Median time since active treatment for their PFBT was 5.2 years (IQR 2.4-10.1). Tumor types included cerebellar pilocytic astrocytoma (45.2%), medulloblastoma (30.6%), ependymoma (11.3%), and brainstem astrocytoma (11.3%). Adjuvant therapy included chemotherapy (40.3%) or radiotherapy (14.5% focal and 21.0% craniospinal radiotherapy). Permanent treatment for hydrocephalus was required in 38.7% of the patients. Tumors recurred in 11.3%, requiring repeat treatment in these patients. The median HUI3 utility score was 0.91 (IQR 0.71-1.00) and the median PedsQL total score was 78.3 (IQR 64.1-92.4). Only the following variables were significantly associated with decreased QOL in multivariable model testing (all p < 0.05): need for permanent hydrocephalus treatment, large ventricle size, decreased family functioning, and lower family income. CONCLUSIONS: As a group, long-term survivors of pediatric PFBT appear to have QOL indicators that are similar to those of the general population, although a reasonable minority of patients experience poor outcomes. Although several confounding variables likely remain in this retrospective study, important associations with QOL include the presence of hydrocephalus and socioeconomic factors. The study sample size, however, was limited and the presence of other important factors cannot be excluded.

The landscape of blogging in palliative care.

We present the case of a 30-year-old patient with pontine glioblastoma multiforme, World Health Organisation grade IV (WHO IV). This case is of particular interest in terms of the patient's use of social media as a medium of expression. This popular form of communication raises important clinical, ethical and social issues relating to confidentiality and the nature of the physician-patient relationship in a unique context.

A phase 2 study of pegylated interferon α-2b (PEG-Intron(®)) in children with diffuse intrinsic pontine glioma.

BACKGROUND: Interferon-α is a cytokine that has demonstrated activity in patients with supratentorial gliomas, but its ideal dose and schedule of administration is unknown. Studies suggest that low-dose, continuous exposure is more efficacious than intermittent, high doses. The authors performed a phase 2 study of recombinant interferon α-2b with monomethoxy polyethylene glycol (PEG-Intron(®)) in children with diffuse intrinsic pontine glioma (DIPG), a population with dismal survival despite decades of clinical investigation. The primary objective was to compare 2-year survival with a historic cohort that received radiation therapy alone. METHODS: Patients received weekly subcutaneous PEG-Intron(®) at a dose of 0.3 µg/kg beginning 2 to 10 weeks after the completion of radiation therapy until they developed disease progression. Patients were evaluated clinically and radiographically at regular intervals. Serum and urine were assayed for biomarkers before each cycle. Quality-of-life (QOL) evaluations were administered at baseline and before every other cycle of therapy to the parents of patients ages 6 to 18 years. RESULTS: Thirty-two patients (median age, 5.3 years; range, 1.8-14.8 years) were enrolled and received a median of 7 cycles of therapy (range, from 1 cycle to ≥70 cycles). PEG-Intron(®) was well tolerated, and no decrease in QOL scores was noted in the subset of patients tested. The 2-year survival rate was 14%, which was not significantly improved compared with the historic cohort. However, the median time to progression was 7.8 months, which compared favorably with recent trials reporting a time to progression of 5 months in a similar population. CONCLUSIONS: Although low-dose PEG-Intron(®) therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.

Glioblastoma occurring at the site of a previous medulloblastoma following a 5-year remission period.

We describe a case of a 14-year-old boy who developed a cerebellar and brainstem glioblastoma 5 years after treatment for a medulloblastoma. The patient first presented in 2003 with 9 months of vomiting and a 9-kg weight loss. A head MRI showed a heterogeneously enhancing posterior fossa mass with hydrocephalus. Gross total resection was performed and the tumor was consistent with a classic medulloblastoma. Postoperative chemotherapy and craniospinal radiation was administered. The patient remained tumor-free until 2008, at which time he presented with right-sided weakness and numbness, left eye pain, vomiting and weight loss. Imaging showed abnormalities within the posterior pons, medulla, inferior cerebellar peduncles, cerebellar hemispheres and cervicomedullary junction with expansion of the medulla and cervical spinal cord. Due to the location of the lesion, biopsy was felt to be too risky and was avoided. Despite receiving chemotherapy, his symptoms continued to worsen and he died 4 months later. Post mortem examination limited to the brain and spinal cord confirmed the radiographic extent of the tumor. Microscopic examination showed a highly cellular infiltrative glial neoplasm with extensive palisading necrosis. A diagnosis of glioblastoma was rendered. The question of whether the first and second tumors were related is of potential clinical and academic interest. The first tumor was synaptophysin-positive and GFAP-negative, consistent with medulloblastoma. The second tumor was synaptophysin-negative and focally GFAP-positive, consistent with glioblastoma. The glioblastoma displayed EGF receptor amplification, and interestingly, it also displayed MYCN amplification; both tumors showed low level PTEN deletion. The medulloblastoma displayed a signal pattern consistent with an isochromosome 17q, while the glioblastoma showed some cells with an isochromosome 17q signal pattern amid a background of cells with abundant chromosomal instability. The relationship between these two tumors, particularly with regard to various molecular events, is discussed.

Diffuse pontine glioma in Jordan and impact of up-front prognosis disclosure with parents and families.

For patients with diffuse pontine glioma, our institution offers local radiotherapy and supportive care only. The prognosis and do-not-resuscitate orders are discussed upfront with patients' parents. To investigate the effectiveness of this policy, we retrospectively reviewed records of patients with diffuse pontine glioma treated at the institution over a 49-month period. This study included 19 children (16 girls and 3 boys). The median age at diagnosis was 7 years. One patient remained alive at the end of the study, 2 were lost to follow-up, and 16 were confirmed dead. The median survival was 8.2 months. Do-not-resuscitate discussion was documented for 14 patients and successfully initiated for 11. None of those confirmed dead had been offered life support. Contrary to the common belief, our study showed that do not resuscitate should be addressed in Muslim patients with high-risk malignancies. We also found that diffuse pontine glioma warrants further study in developing countries.

Pathological laughter and behavioural change in childhood pontine glioma.

Children with pontine glioma usually present classically with ataxia, motor deficits and cranial nerve palsies. The pons has generally not been regarded as a structure that mediates complex affective behaviour. However, we report nine children who either at the time of presentation or progression demonstrated marked behavioural changes manifesting as either "pathological laughter" or separation anxiety in the form of school refusal. A mechanism of how pontine lesions can cause such complex affective and cognitive behaviour has been suggested to consist of the disruption of a network of cerebro-ponto-cerebellar pathways and the evidence for this mechanism is discussed.