Diffuse Brainstem Tumors Research Articles

Clinicopathology & Molecular Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) in Children - Insights from Past, Present, and Future Directions

Diffuse Intrinsic Pontine Glioma, or DIPG, is a rare, highly aggressive, heterogeneous group of brainstem tumors. Around 10-20% of primary brain tumors are considered pediatric brain tumors, of which 10-15% are diffuse brainstem tumors. It is considered untreatable and surgically unremovable due to its intrinsic position within the brain. Over the years, applying radiotherapy and chemotherapy has not shown a better outcome. However, gene-targeted therapy has proven successful, but it is still in the developing phase. This article covers the various aspects of DIPG, from clinical and molecular definitions to a vision for a universally accepted novel approach to beat this severe condition by joining fundamental science and translational research.

Diffuse brainstem tumors in children. Tumor biology and hope for a better outcome. Current state of the problem

Diffuse brainstem tumor is a fatal disease and the main cause of child mortality from neoplasms of central nervous system. So far, no effective therapy has been found for this disease. The authors discuss the modern aspects of clinical data, biology, diagnosis and treatment of patients with diffuse brainstem tumors.

Low Dose Gamma-knife Radiosurgery for Diffuse Brainstem Gliomas

Introduction: Diffuse brainstem glial tumors remain a challenge. Despite many advances in neurosurgical techniques, no effective treatment is currently available. Recently, some authors showed beneficial results with gamma-knife radiosurgery (GK) for focal brainstem tumors. Objective: to analyze safety and effectiveness of GK in patients with diffuse brainstem gliomas. Methods: Eleven patients with diffuse brainstem gliomas treated with Gamma-knife from November 2001 to June 2009 were included. Complete data such as age, gender, symptoms, tumor size, prescription dose, adverse radiation effects and an early late follow-up were analyzed. Results: The mean age was 28.7 years (ranging from 1y 7m to 62y). Six patients were female and 5 were male. The gamma-knife prescription dose ranged from 6 to 7 Gy. All patients had clinical and imaging improvement at an early follow-up, although in 6, there was a late increase in tumor size and death. The others remained clinically stable or better. Larger tumors had a direct relationship with a poorer prognosis. No patient developed complications related to the radiosurgical treatment. Conclusion: Gamma-Knife is a safe and effective treatment for selected patients with diffuse brainstem tumors. The authors propose lower doses. Further studies are mandatory in order to analyze which patients could benefit from this treatment.

Biopsy of Brainstem Gliomas Using Flexible Endoscopes.

To describe our experience and the results obtained in performing transventricular brainstem biopsy with the use of flexible neuroendoscops. We identified patients who underwent a neuroendoscopic procedure with brainstem lesion biopsy to obtain histopathologic diagnosis and to treat obstructive hydrocephalus. All patients had follow-up examinations at months 1, 3, 6, and 12 postsurgery and then annually. Seven patients had a transventricular biopsy of the brainstem performed. Of those, five were pediatric patients. The median age was 10 years (range: 3-26 years). Five of them were female and two male. Four patients presented with secondary obstructive hydrocephalus. The main clinical presentations were intracranial hypertension syndrome in four patients, motor neuron disease in four patients, two with decreased state of alertness, two with gait ataxia, and one with Parinaud syndrome. The types of tumors found in the histopathology and their location were one ventral (pons) and one aqueductal anaplastic astrocytoma, two ventral, one aqueductal, and one attached to the floor of the fourth ventricle pilocytic astrocytoma and one ventral low-grade astrocytoma. The route taken to approach the ventral tumors was made through premammillary fenestration. The tumors of the aqueduct and floor of the fourth ventricle were approached transaqueductally. The use of flexible endoscops for biopsy of ventral, dorsal (tectum lamina quadrigemina), and diffuse brainstem tumors is a useful, effective, and safe procedure that also allows to treat obstructive hydrocephalus secondary to the tumors.

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma

ObjectIntrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution. Material and methodsThe clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata. ResultsRoutine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology. ConclusionDTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive.

Precision of navigated stereotactic probe implantation into the brainstem

The indications for stereotactic biopsies or implantation of probes for local chemotherapy in diffuse brainstem tumors have recently come under debate. The quality of performing these procedures significantly depends on the precision of the probes' placement in the brainstem. The authors evaluated the precision of brainstem probe positioning using a navigated frameless stereotactic system in an experimental setting. Using the VarioGuide stereotactic system, 33 probes were placed into a specially designed model filled with agarose. In a second experimental series, 8 anatomical specimens were implanted with a total of 32 catheters into the pontine brainstem using either a suboccipital or a precoronal entry point. Before intervention in both experimental settings, a thin-sliced CT scan for planning was obtained and fused to volumetric T1-weighted MR imaging data. After the probe positioning procedures, another CT scan and an MR image were obtained to compare the course of the catheters versus the planned trajectory. The deviation between the planned and the actual locations was measured to evaluate the precision of the navigated intervention. Using the VarioGuide system, mean total target deviations of 2.8 +/- 1.2 mm on CT scanning and 3.1 +/- 1.2 mm on MR imaging were detected with a mean catheter length of 151 +/- 6.1 mm in the agarose model. The catheter placement in the anatomical specimens revealed mean total deviations of 1.95 +/- 0.6 mm on CT scanning and 1.8 +/- 0.7 mm on MR imaging for the suboccipital approach and a mean catheter length of 59.5 +/- 4.1 mm. For the precoronal approach, deviations of 2.2 +/- 1.2 mm on CT scanning and 2.1 +/- 1.1 mm on MR imaging were measured (mean catheter length 85.9 +/- 4.7 mm). The system-based deviation of frameless stereotaxy using the VarioGuide system reveals good probe placement in deep-seated locations such as the brainstem. Therefore, the authors believe that the system can be accurately used to conduct biopsies and place probes in patients with brainstem lesions.

Diffuse and focal brain stem tumors in childhood: prognostic factors and surgical outcome

Brainstem tumors (BSTs) are usually gliomas and are divided into diffuse BSTs (DBSTs) and focal BSTs (FBSTs). The aim of this study is to investigate the different outcomes of these two entities. Thirty-one patients with BSTs were admitted to our institution from 1995 to 2003. Patients with DBSTs were treated with locoregional radiotherapy (1.8 Gy/day for 54 Gy) and weekly vincristine for radiosensitization (1.5 mg/sm for six total doses). Patients with FBSTs underwent surgical resection. Chemotherapy and/or radiotherapy were considered in progression. Fourteen patients were diagnosed as having DBSTs. The responses to treatment were ten cases of partial response, three of stable disease, and one of progressive disease. General and/or neurological symptoms improved in more than 80% of patients. The median time from diagnosis to progression and to death were, nonetheless, 8 (range of 3-13) and 13 (range of 4-25) months, respectively, with a 2-year overall survival rate of 12.3% [standard error (SE) 11.2]. Seventeen patients were diagnosed as having FBSTs. Gross total removal was achieved in 4/17 cases, subtotal removal in 7/17, and partial removal in 6/17. There was one surgery-related death. Eight out of 17 patients had adjuvant chemo- and/or radiotherapy after progression: 6/8 are without neurological symptoms and 2/8 have died due to tumor progression. The 4-year overall and disease-free survival rates are 87.4 (SE 8.4) and 58.8% (SE 11.9), respectively, the extent of resection being the most important prognostic factor (p=0.012). DBSTs continue to carry a dismal prognosis, thus demanding new treatment modalities; FBSTs can be treated surgically and patients benefit from a better prognosis.

Advances Toward an Understanding of Brainstem Gliomas

The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.

Treatment of childhood diffuse brain stem tumors: comparison of results in different treatment modalities

Diffuse brainstem tumors in children are rare and its treatment is controversial. Although radiotherapy (RT) used to be the treatment of choice, results remained unsatisfactory. The association of RT with other therapies is common, but lacks scientific data regarding its efficacy. Comparison of results of irradiation alone versus combined treatment modalities is crucial in improving survival. The authors reviewed twenty-four patients with diffuse brainstem tumors, with mean age of 7 years, treated from December 90 to November 99, at the University of Sao Paulo, Brazil. These patients were subdivided in four groups according to the treatment option at the onset of symptoms. Four patients were treated with radiation alone (total dose of 50 Gy to 62.4 Gy), 6 patients with chemotherapy and radiation, 8 with tamoxifen and radiation and 6 with tamoxifen, radiation and chemotherapy. The results of the different groups were them compared. Clinical response was observed in 83.3% of our children, briefly followed by progressive disease. Mean survival was 17 months with no statistically significant differences among the groups. Four patients were alive at the end of the study, with a mean survival of 32.4 months, all of them received combined therapy, but with no statistically significant differences. Neither the association of radiation therapy with chemotherapy, tamoxifen nor both have showed survival improvement. The prognosis of these patients remains very poor and only investigational trials would justify a highly aggressive approach.

Experimental models of brainstem tumors: development of a neonatal rat model

Brainstem tumor models are required to advance the treatment for diffuse pontine gliomas in children. The feasibility of creating an experimental rodent model by inoculating newborn pups with tumor cells was examined. The study was performed to create an animal model for diffuse brainstem tumors. Eighty-two Fischer rat pups aged 12-24 h were anesthetized by hypothermia. The brainstem was injected with saline to identify anatomical coordinates for subsequent tumor cell challenges. The newborn pups were then inoculated with F98 (n=30) or 9L (n=30) glioma cells. Animals were returned to their mother for nursing. Tumor growth was assessed by survival and histopathology. Twenty-one percent of the saline-treated animals (17 out of 82) and 5% of the tumor cell-challenged pups (3 out of 60) were eliminated by their mothers. Inoculations with 9L and F98 cells produced brainstem tumors in 83% (24 out of 29) and 93% of animals (26 out of 28) respectively that were evaluated. Our results demonstrate that neonatal rat models for brainstem tumors can be prepared using known injection coordinates and orthotopic cell lines. Decreasing rates of maternal removal during the course of the work suggests that the method involves a learning curve.

Diffuse brainstem tumors: when is a biopsy necessary?

This study addresses the role of biopsies in diffuse pediatric brainstem tumors. Biopsies have been advocated to confirm the diagnosis, to determine the tumor histology, to obtain prognostic information and because they can be done with low risk. Biopsies are opposed because diffuse brainstem tumors are gliomas, the histology does not correlate with prognosis nor with histology at autopsy, clinical and magnetic resonance scans provide prognostic information, biopsies have risks, and the biopsy does not alter therapy nor improve prognosis. The conclusion is reached that biopsies are not indicated in children with typical clinical and magnetic resonance features of diffuse brainstem gliomas.