Bevacizumab in treating the cystic components of pediatric low-grade gliomas: A report of four patients.

Low-grade gliomas (LGG) are among the most common types of brain tumors in children and young adults. These tumors often consist of solid and cystic components. Bevacizumab is a documented treatment for progressive LGG, yet the impact of therapy on the cystic component of these tumors is unknown. We present four patients with prominently cystic LGG treated with bevacizumab at the time of progression. In each case, the cystic component responded to treatment. This is the first known study to investigate bevacizumab's impact on the cystic component of low-grade gliomas.

Multiregional Tumor Drug-Uptake Imaging by PET and Microvascular Morphology in End-Stage Diffuse Intrinsic Pontine Glioma.

Inadequate tumor uptake of the vascular endothelial growth factor antibody bevacizumab could explain lack of effect in diffuse intrinsic pontine glioma. Methods: By combining data from a PET imaging study using 89Zr-labeled bevacizumab and an autopsy study, a 1-on-1 analysis of multiregional in vivo and ex vivo 89Zr-bevacizumab uptake, tumor histology, and vascular morphology in a diffuse intrinsic pontine glioma patient was performed. Results: In vivo 89Zr-bevacizumab measurements showed heterogeneity between lesions. Additional ex vivo measurements and immunohistochemistry of cervicomedullary metastasis samples showed uptake to be highest in the area with marked microvascular proliferation. In the primary pontine tumor, all samples showed similar vascular morphology. Other histologic features were similar between the samples studied. Conclusion: In vivo 89Zr-bevacizumab PET serves to identify heterogeneous uptake between tumor lesions, whereas subcentimeter intralesional heterogeneity could be identified only by ex vivo measurements. 89Zr-bevacizumab uptake is enhanced by vascular proliferation, although our results suggest it is not the only determinant of intralesional uptake heterogeneity.

Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas.

Background: The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually <6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudoprogression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients who did not present the same evolution. Methods: Multimodal MRIs of 43 children treated for DIPG were retrospectively selected at 4 timepoints: baseline, after radiotherapy, during true progression, and at the last visit. The patients were divided into 2 groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labeling cerebral blood flow (ASL-CBF), and dynamic susceptibility contrast perfusion relative cerebral blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas. Results: After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived >6 months following so-called pseudoprogression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after radiotherapy, but the 90th percentile of those with signs of pseudoprogression had a greater increase of ASL-CBF (P < 0.001). Survival between the 2 groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients who had not experienced pseudoprogression. Conclusions: Pseudoprogression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudoprogression from true progression.

Multimodal Magnetic Resonance Imaging of Treatment-Induced Changes to Diffuse Infiltrating Pontine Gliomas in Children and Correlation to Patient Progression-Free Survival.

PURPOSE: To use multimodal magnetic resonance imaging (MRI) to quantify treatment-induced changes in the whole volume of diffuse infiltrating pontine gliomas and correlate them with progression-free survival (PFS). METHODS AND MATERIALS: This prospective study included 22 children aged 3.3 to 14.7 years (median, 5.9 years). Multimodal MRI was performed at 3 distinct time points: before treatment, the first week following radiation therapy (RT), and 2 months after RT. The imaging protocol included morphologic, multi b-value diffusion; arterial spin labeling; and dynamic susceptibility contrast-enhanced perfusion. Morphologic and multimodal data-lesion volume, diffusion coefficients, relative cerebral blood flow, and relative cerebral blood volume (rCBV)-were recorded at the 3 aforementioned time points. The Wilcoxon test was used to compare each individual parameter variation between time points, and its correlation with PFS was assessed by the Spearman test. RESULTS: Following RT, the tumors' solid component volume decreased by 40% (P<.001). Their median diffusion coefficients decreased by 20% to 40% (P<.001), while median relative cerebral blood flow increased by 60% to 80% (P<.001) and median rCBV increased by 70% (P<.001). PFS was positively correlated with rCBV measured immediately after RT (P=.003), and in patients whose rCBV was above the cutoff value of 2.46, the median PFS was 4.6 months longer (P=.001). These indexes tended to return to baseline 2 months after RT. Lesion volume before or after RT was not correlated with survival. CONCLUSIONS: Multimodal MRI provides useful information about diffuse infiltrating pontine gliomas' response to treatment; rCBV increases following RT, and higher values are correlated with better PFS. High rCBV values following RT should not be mistaken for progression and could be an indicator of response to therapy.

"Occult" post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis?

INTRODUCTION: In diffuse intrinsic pontine gliomas (DIPG), subtracting pre-contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, "occult" enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. METHODS: We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). RESULTS: Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P = .03), within DCWM in the same patient (P = .03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P = .005). CONCLUSION: Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy.

Surgery of brainstem cavernous malformations.

BACKGROUND: Cavernomas are vascular hamartomas made up of thin-walled, grossly dilated blood vessels lined with endothelium. Between 4 and 35 % (mean 15 %) of cerebral cavernomas are located in the brainstem making resection of these lesions one of the most challenging tasks in neurosurgery. METHODS: Patients with cavernomas within the brainstem or deep supratentorial structures were chosen from our prospectively collected database of operated patients with brain cavernomas. The timespan of treatment was between January 1998 and June 2012. Primary outcome was defined as percentage of patients with favourable outcome (Glasgow Outcome Scale (GOS) 4 or 5) at 1 year. Secondary outcome was defined as operation-related morbidity and mortality (drop at least 1 point on GOS at 1 year). RESULTS: A total of 37 patients underwent surgery. The mean age was 34.7 ± 11.7 years. The male to female ratio was 19:16. Thirty-two patients had a solitary lesion and 12 patients harboured multiple lesions. The Glasgow outcome score 4 or 5 was achieved after 34 operations (89.5 %). The mean follow-up was 39 months. We experienced two early post-operative deaths (5.3 %) and decrease in the Glasgow outcome scale postoperatively in 4 patients (10.5 %). CONCLUSIONS: • Favourable outcome was achieved in 89.5 % of cases. • Although M&M appears to be relatively high, surgery is method of choice for surgically accessible lesion which has bled for the first time due to reported high rebleed rate and high probability of poor outcome after cavernoma rebleed. • Radiosurgery should be reserved for those lesions which are deemed unresectable and where surgical intervention is considered favourable to observation alone.

Motor-evoked potentials (MEP) during brainstem surgery to preserve corticospinal function.

BACKGROUND: Brainstem surgery bears a risk of damage to the corticospinal tract (CST). Motor-evoked potentials (MEPs) are used intraoperatively to monitor CST function in order to detect CST damage at a reversible stage and thus impede permanent neurological deficits. While the method of MEP is generally accepted, warning criteria in the context of brainstem surgery still have to be agreed on. METHOD: We analyzed 104 consecutive patients who underwent microsurgical resection of lesions affecting the brainstem. Motor grade was documented prior to surgery, early postoperatively and at discharge. A baseline MEP stimulation intensity threshold was defined and intraoperative testing aimed to keep MEP response amplitude constant. MEPs were considered deteriorated and the surgical team was notified whenever the threshold was elevated by ≥20 mA or MEP response fell under 50%. FINDINGS: On the first postoperative day, 18 patients experienced new paresis that resolved by discharge in 11. MEPs deteriorated in 39 patients, and 16 of these showed new postoperative paresis, indicating a 41% risk of new paresis. In the remaining 2/18 patients, intraoperative MEPs were stable, although new paresis appeared postoperatively. In one of these patients, intraoperative hemorrhage caused postoperative swelling, and the new motor deficit persisted until discharge. Of all 104 patients, 7 deteriorated in motor grade at discharge, 92 remained unchanged, and 5 patients have improved. CONCLUSIONS: Adjustment of surgical strategy contributed to good motor outcome in 33/39 patients. MEP monitoring may help significantly to prevent motor deficits during demanding neurosurgical procedures on the brainstem.

Quantitative diffusion-weighted and dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging analysis of T2 hypointense lesion components in pediatric diffuse intrinsic pontine glioma.

BACKGROUND AND PURPOSE: Focal anaplasia characterized by T2 hypointensity, signal-intensity enhancement on postcontrast T1-weighted MR imaging and restricted water diffusion has been reported in a patient with juvenile pilocytic astrocytoma. We identified T2(HOF) with these MR imaging characteristics in children with DIPG and hypothesized that these represent areas of focal anaplasia; and may, therefore, have increased perfusion properties and should be characterized by increased perfusion. Thus, we used DSC to investigate our hypothesis. MATERIALS AND METHODS: We retrospectively reviewed the baseline MR imaging scans of 86 patients (49 girls, 37 boys; median age, 6.1 years; range, 1.1-17.6 years) treated for DIPG at our hospital (2004-2009). T2(HOF) with the described MR imaging characteristics was identified in 10 patients. We used a region of interest-based approach to compare the ADC, FA, rCBV, rCBF, and rMTT of T2(HOF) with those of the typical T2(HRT). RESULTS: The ADC of T2(HOF) with the specified MR imaging characteristics was significantly lower than that of T2(HRT) (range, 0.71-1.95 µm(2)/ms versus 1.36-2.13 µm(2)/ms; P < .01); and the FA (range, 0.12-0.34 versus 0.07-0.24; P = .03) and rCBV (range, 0.4-2.62 versus 0.23-1.57; P = .01) values of T2(HOF)s were significantly higher. CONCLUSIONS: Our data suggest that T2(HOF) in DIPG may represent areas of focal anaplasia and underline the importance of regional, rather than global, tumor-field analysis. T2(HOF) may be the ideal target when stereotactic biopsy of tumors that present with an inhomogeneous T2 signal intensity is considered.

Three-dimensional susceptibility-weighted imaging and two-dimensional T2*-weighted gradient-echo imaging of intratumoral hemorrhages in pediatric diffuse intrinsic pontine glioma.

INTRODUCTION: We compared the sensitivity and specificity of T2*-weighted gradient-echo imaging (T2*-GRE) and susceptibility-weighted imaging (SWI) in determining prevalence and cumulative incidence of intratumoral hemorrhages in children with diffuse intrinsic pontine glioma (DIPG) undergoing antiangiogenic and radiation therapy. METHODS: Patients were recruited from an institutional review board-approved prospective phase I trial of vandetanib administered in combination with radiation therapy. Patient consent was obtained before enrollment. Consecutive T2*-GRE and SWI exams of 17 patients (F/M: 9/8; age 3-17 years) were evaluated. Two reviewers (R1 and R2) determined the number and size of hemorrhages at baseline and multiple follow-ups (92 scans, mean 5.4/patient). Statistical analyses were performed using descriptive statistics, graphical tools, and mixed-effects Poisson regression models. RESULTS: Prevalence of hemorrhages at diagnosis was 41% and 47%; the cumulative incidences of hemorrhages at 6 months by T2*-GRE and SWI were 82% and 88%, respectively. Hemorrhages were mostly petechial; 9.7% of lesions on T2*-GRE and 5.2% on SWI were hematomas (>5 mm). SWI identified significantly more hemorrhages than T2*-GRE did. Lesions were missed or misinterpreted in 36/39 (R1/R2) scans by T2*-GRE and 9/3 scans (R1/R2) by SWI. Hemorrhages had no clinically significant neurological correlates in patients. CONCLUSIONS: SWI is more sensitive than T2*-GRE in detecting hemorrhages and differentiating them from calcification, necrosis, and artifacts. Also, petechial hemorrhages are more common in DIPG at diagnosis than previously believed and their number increases during the course of treatment; hematomas are rare.

Surgical treatment for hemangioblastomas in the medulla oblongata.

PURPOSE: The purpose of this study was to evaluate the outcome of surgical treatment of hemangioblastomas in the medulla oblongata. METHODS: Between January 2006 and December 2007, 18 patients who underwent surgery for hemangioblastomas in the medulla oblongata in the Neurosurgical Department of Huashan Hospital were retrospectively reviewed. RESULT: The study population was 13 males and five females. The main symptoms were headache, cervical pain, and dizziness. All patients had preoperative and postoperative examination by MRI. There were five cystic tumors and 13 solid tumors. Tumor diameter ranged from 1 to 4.3 cm (mean, 2.6 cm). Complete tumor resection was achieved in all patients, but one patient died. Embolization was done in three patients. According to McCormick scale, postoperative condition was worse in one patient, unchanged in 14 patients, and improved in three patients. In follow-up assessments, no surviving patients remained in a worse condition. Compared with the preoperative condition, 11 patients were unchanged, and six patients exhibited improvement. Tumor recurrence was not observed during follow-up. CONCLUSION: Surgery is the first-line treatment for symptomatic patients with hemangioblastomas in the medulla oblongata. Good results can be achieved for the cystic or small solid tumors. Large solid tumors remain a surgical challenge due to arteriovenous malformation-like vascularization. Preoperative embolization is useful for large solid tumors. For asymptomatic tumors, careful long-term observation or radiosurgery could be chosen.

Perfusion-sensitive MR imaging of gliomas: comparison between gradient-echo and spin-echo echo-planar imaging techniques.

BACKGROUND AND PURPOSE: The different sensitivities to vessel size of gradient-echo echo-planar imaging (GE-EPI) and spin-echo EPI (SE-EPI) might indicate the relative cerebral blood volumes (rCBVs) of different tumor sizes. The techniques of GE-EPI and SE-EPI were compared for detecting low- versus high-grade gliomas. METHODS: Six patients with low-grade gliomas and 19 patients with high-grade gliomas underwent two perfusion-sensitive MR procedures, one produced by a GE- and the other by an SE-EPI technique. Maximum rCBV ratios normalized with rCBV of contralateral white matter were calculated for evaluation. P <.05 was considered statistically significant. RESULTS: Maximum rCBV ratios of high-grade gliomas obtained with the GE-EPI technique (mean, 5.0 +/- 2.9) were significantly higher than those obtained with the SE-EPI technique (mean, 2.9 +/- 2.3) (P =.02). Maximum rCBV ratios of low-grade gliomas obtained with the GE-EPI technique (mean, 1.2 +/- 0.7) were almost equal to those obtained with the SE-EPI technique (mean, 1.2 +/- 0.6), and there was no significant difference (P =.66). The difference in the maximum rCBV ratios between the low- and high-grade gliomas reached significance when obtained with the GE-EPI technique (P =.01). CONCLUSION: The GE-EPI technique seems more useful for detecting low- versus high-grade gliomas than the SE-EPI technique.