Dolly Aguilera

Treatment of high-grade glioma in children and adolescents

Pediatric high-grade gliomas (HGGs)--including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma--are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRα and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG.

Dasatinib in chronic myeloid leukemia: a review

Deregulated BCR-ABL tyrosine kinase (TK) activity is the molecular marker for chronic myeloid leukemia (CML), which provides an identifiable target for developing therapeutic agents. Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML. Despite the stunning efficacy of this agent, a small number of patients develop a suboptimal response or resistance to imatinib. In newly diagnosed patients with chronic phase CML, the rate of resistance to imatinib at 4 years was up to 20%, increasing to 70% to 90% for patients in the accelerated/blastic phase. Resistance to imatinib led to the development of novel TK inhibitors such as dasatinib. Several clinical trials have reported more durable complete hematologic and cytogenetic responses with this agent in patients who are resistant or intolerant to imatinib. Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 – most commonly F317L – including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396. Dasatinib is recommended for CML in chronic, blastic or accelerated phase that is resistant or intolerant to imatinib. Dasatinib was approved by the FDA at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients with accelerated or blastic phase CML. Various clinical trial results provided evidence that resistance to one TK inhibitor can be reversed with the use of a different TK inhibitor (TKI). Other second-generation TKIs with activity in CML include nilotinib, bosutinib and INNO 406. New molecules, such as the inhibitor of Aurora family serine-threonine kinases, MK0457, which has antileukemic activity in CML associated with a T315I mutation, are being investigated. Allogeneic hematopoietic stem cell transplantation remains an option for selected patients.

The rationale for targeted therapies in medulloblastoma

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Patients with MB who are classified as having high-risk disease or those with recurrent disease respond poorly to current therapies and have an increased risk of MB-related mortality. Preclinical studies and molecular profiling of MB tumors have revealed upregulation or activation of several key signaling pathways such as the sonic hedgehog and WNT pathways. Although the exact mechanisms underlying MB tumorigenesis remain poorly understood, inhibiting these key pathways with molecularly targeted therapies represents an important approach to improving MB outcomes. Several molecularly targeted therapies are already under clinical investigation in MB patients. We discuss current preclinical and clinical data, as well as data from clinical trials of targeted therapies that are either ongoing or in development for MB.

Bevacizumab and irinotecan in the treatment of children with recurrent/refractory medulloblastoma

Relapsed/refractory medulloblastoma (MB) has a poor outcome regardless of the treatment employed. Novel therapies are needed in an effort to improve survivals. We present two children with recurrent/refractory MB treated with bevacizumab and irinotecan both given every 2 weeks. One patient also received temozolamide. The first patient had stable disease and remains without progression after 30 months. The second patient had a near complete response that was sustained for 18 months. The regimen was well tolerated with minimal toxicity and provided prolonged progression‐free survival in these two patients. Prospective clinical trials are needed to evaluate the effectiveness of this strategy. Pediatr Blood Cancer 2011;56:491–494.

Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.

A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E‐positive residual tumor. Vemurafenib (660 mg/m2/dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy.

Drop metastases to the pediatric spine revealed with diffusion-weighted MR imaging

Identifying drop metastases to the spine from pediatric brain tumors is crucial to treatment and prognosis. MRI is currently the gold standard for identifying drop metastases, more sensitive than CSF cytology, but imaging is not uncommonly inconclusive. Although diffusion‐weighted imaging (DWI) of the brain is very useful in the evaluation of hypercellular tumors, DWI of the spine has not been clinically useful in children because of susceptibility artifacts and lack of spatial resolution. A new technique, readout-segmented echo planar imaging (EPI), has improved these images, allowing for identification of hypercellular drop metastases. We report a case that illustrates the utility of spine DWI in the detection of metastatic disease in children with primary central nervous system (CNS) tumors. This case suggests that DWI of the spine with readout-segmented EPI should be included in the evaluation for drop metastases.

Incidental Resolution of a Radiation-Induced Cavernous Hemangioma of the Brain following the Use of Bevacizumab in a Child with Recurrent Medulloblastoma

Radiation-induced cavernous hemangiomas (RICH) are a known complication of radiation exposure, especially in young children. The current treatment approaches to these lesions include observation and surgical resection. We report the case of a 4-year-old male with recurrent medulloblastoma who had resolution of an incidental RICH lesion while being treated with bevacizumab for his recurrent brain tumor. There was no evidence of worsening hemorrhage with this therapy and the RICH did not recur upon discontinuation of the chemotherapy regimen. This is the first documented case of a RICH lesion responding to antiangiogenic therapy, suggesting the possible use of this class of agents in the treatment of symptomatic patients who are not considered appropriate candidates for surgical resection. Although the risk of bleeding must be taken into consideration, antiangiogenic therapies have the potential to be a novel treatment modality for symptomatic RICH lesions.

Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases.

Background: Diffuse intrinsic pontine gliomas have poor prognosis. Observation: We report on 2 patients with diffuse intrinsic pontine glioma treated with radiation, followed by temozolamide 200 mg/m2/d for 5 days every 28 days and bevacizumab 10 mg/kg/dose every 14 days. Both patients have ongoing PFS of 37 and 47 months from diagnosis. A decrease in tumor size by >65% was observed in both the patients. Both patients continue treatment. No steroid requirement since 10 weeks after radiation. Quality of life is excellent and the chemotherapy regimen is well tolerated. Conclusions: A clinical trial in an expanded cohort is warranted to determine the toxicity and evaluate response.

Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus.

Background: Brain subependymal giant cell astrocytomas (SEGAs) in patients with tuberous sclerosis have been reported to respond to everolimus. Methods: A 15-year-old male patient with intractable seizures and multiple SEGAs of the brain developed leptomeningeal enhancement and multiple metastatic, histologically confirmed SEGAs of the spinal cord. He received daily everolimus at a dose of 3 mg/m2 for 6 weeks, which was then increased to 6 mg/m2. Results: Magnetic resonance image of the brain and spine showed significant reduction in the size of SEGAs after 6 weeks of treatment. The patient has remained free of progression for 24 months. Additional benefits included: excellent seizure control, decrease in the size of cardiac rhabdomyomas, and improved quality of life. Conclusions: We describe a rare case of metastatic SEGA, which was successfully treated with everolimus.

Glioblastoma multiforme in a patient with chronic granulomatous disease treated with subtotal resection, radiation, and thalidomide: Case report of a long-term survivor

We report on a child with chronic granulomatous disease who at the age of 13 years was diagnosed with glioblastoma multiforme of the left thalamus. Therapy included subtotal resection, radiation to the tumor bed (60 Gy), and concomitant chemotherapy with daily thalidomide (250 mg/m2), both during radiation and for 5 years thereafter. Currently, she is 9 years from diagnosis and has no evidence of disease. Therapy with thalidomide did not increase her infection complications and provided excellent quality of life. This is the first report of glioblastoma multiforme in a patient with chronic granulomatous disease treated with surgery, radiation, and thalidomide who is a long-term survivor.