Edmond A. Knopp

Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival

OBJECT Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas. METHODS Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/ kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy. RESULTS At a median follow-up of 7.5 months (range 1-19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1-7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval [CI] 2.3-7.7) and 9 (95% CI 7.6-10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease. CONCLUSIONS Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.

Feasibility and Response to Induction Chemotherapy Intensified With High-Dose Methotrexate for Young Children With Newly Diagnosed High-Risk Disseminated Medulloblastoma

PURPOSE To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas. PATIENTS AND METHODS From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue. RESULTS Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively. CONCLUSION This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies.

Experimental and clinical assessment of the adequacy of partial bypass in maintenance of spinal cord blood flow during operations on the thoracic aorta.

We studied both experimentally and clinically the efficacy of partial bypass techniques in maintaining spinal cord blood flow and physiological function during surgical procedures on the thoracoabdominal aorta. We attempted to define the level of distal aortic pressure required to safely ensure normal neurological function in the absence of critical intercostal occlusion. Six dogs underwent left thoracotomy with baseline measurements of spinal cord blood flow and spinal cord impulse conduction (somatosensory evoked potentials). Following exclusion of the entire descending thoracic aorta from the left subclavian artery to the T-13 level, partial left atrium-femoral artery bypass was instituted, and baseline levels of proximal and distal aortic pressure were maintained during a 30-minute stabilization period. Mean distal aortic pressure then was progressively altered at 30-minute intervals to 100, 70, and 40 mm Hg. Measurements of spinal cord blood flow and somatosensory evoked potential were repeated at the end of each interval for comparison with baseline. No significant changes in spinal cord blood flow or somatosensory evoked potential were observed in any animal with a distal aortic pressure greater than or equal to 70 mm Hg. With a pressure of 40 mm Hg, normal flow and somatosensory evoked potentials were maintained in 5 of the 6 dogs. Loss of somatosensory evoked potential, with simultaneous loss of spinal cord blood flow at the T-6 level, occurred in 1 dog. Restoration of distal aortic pressure to 70 mm Hg in all animals resulted in immediate return of somatosensory evoked potential. Loss of somatosensory evoked potential routinely occurred in animals with a distal aortic pressure less than 40 mm Hg. Clinically, 9 patients have undergone operation for lesions of the thoracoabdominal aorta using shunt or bypass techniques. Normal somatosensory evoked potentials were preserved in 7 patients with maintenance of adequate distal aortic pressure (greater than or equal to 60 mm Hg) without evidence of postoperative neurological deficit. Two patients showed hypotensive somatosensory evoked potential loss (distal aortic pressure less than 40 mm Hg). Prolonged distal hypotension (85 minutes of aortic cross-clamping) in the latter resulted in paraplegia. We conclude that maintenance of a distal aortic pressure greater than 60 to 70 mm Hg will uniformly preserve spinal cord blood flow in the absence of critical intercostal exclusion. Should distal aortic pressure be inadequate, early reversible changes in the somatosensory evoked potential will alert the surgeon. Failure to institute measures to reverse these changes may result in paraplegia.

Treatment-related change versus tumor recurrence in high-grade gliomas: a diagnostic conundrum--use of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI.

OBJECTIVE The purpose of this article is to address radiation necrosis, pseudoprogression, and pseudoresponse relative to high-grade gliomas and evaluate the role of conventional MRI and, in particular, dynamic susceptibility contrast-enhanced perfusion MRI in assessing such treatment-related changes from tumor recurrence. CONCLUSION Posttreatment imaging assessment of high-grade gliomas remains challenging. Familiarity with the expected MR imaging appearances of treatment-related change and tumor recurrence will help distinguish these entities allowing appropriate management.

Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

INTRODUCTION Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma. METHODS AND MATERIALS Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m(2). Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m(2) for 12 months. Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed. RESULTS Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. CONCLUSION Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.

Dynamic susceptibility contrast MR imaging: Correlation of signal intensity changes with cerebral blood volume measurements

Cerebral blood volume (CBV) maps derived from dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging provide valuable information regarding intracranial microhemodynamics and have been helpful in characterizing primary brain tumors and guiding stereotactic biopsy. Another parameter, the maximum signal drop (MSD) during the first pass of intravascular contrast bolus due to T2* effect, can also be measured directly without extensive post‐processing and data manipulation. The purpose of our study is to determine whether MSD maps provide information similar to CBV maps in patients presenting with intracranial mass lesions. Twenty‐nine patients with various intracranial mass lesions were studied with DSC MR imaging prior to stereotactic biopsy or volumetric resection. Maps of both CBV and MSD are calculated on a pixel‐by‐pixel basis and displayed as color overlays over the raw images. Relative CBV (rCBV) and MSD (rMSD) values were measured in regions of interest (ROIs) within areas of abnormality and compared. In addition, computer‐generated noise was added to the data to estimate the sensitivity of each measurement to noise. The rMSD values were strongly correlated with rCBV values (r = 0.87, P = 0.0001). CBV values were much more sensitive to added noise than MSD values (P < 0.01). MSD maps derived from DSC MR imaging provide information similar to CBV maps in patients with intracranial mass lesions. MSD maps are a simple and reliable indicator of vascularity that can easily be incorporated into routine MR imaging. J. Magn. Reson. Imaging 2000;11:114–119.

Primitive Neuroectodermal Tumors of the Brainstem: Investigation of Seven Cases

Objective. We discuss the clinical aspects, pathology, and molecular genetics of 7 patients with primitive neuroectodermal tumors (PNETs) arising in the brainstem that were treated at our institution from 1986 through 1995. Most neuro-oncologists avoid performing biopsies in children with pontine tumors. This article raises the question as to whether biopsies should be performed, because treatment recommendations might differ if a PNET was diagnosed rather than a pontine glioma. Patients and Methods. We reviewed the clinical neuro-oncology database and the files of the Division of Neuropathology at New York University Medical Center from 1986 through 1995 and identified 7 histologically confirmed PNETs arising in the brainstem among 146 pediatric brainstem tumors. The clinical, neuroradiological, and neuropathological data were reviewed. Postmortem examinations were performed in 2 cases. Formalin-fixed, paraffin-embedded tumor tissues were also available in 6 of 7 patients that were tested for p53 gene mutations using single-strand conformation polymorphism analysis. We also tested 9 cerebellar PNETs, 9 brainstem gliomas, and 3 normal brains for p53 gene mutations as controls. Results. All 7 patients presented with focal cranial nerve deficits, and 2 were also hemiparetic. The median age at diagnosis was 2.7 (1–8 years). Magnetic resonance imaging (MRI) characteristics included a focal intrinsic exophytic nonenhancing brainstem lesion that had low T1-weighted and high T2-weighted signals. Hydrocephalus was present in 5 patients at diagnosis, 3 of whom had leptomeningeal dissemination. Meningeal dissemination occurred later in the course of the disease in 3 other patients. Five children required shunts at diagnosis and another 2 at recurrence. Despite therapy, all 7 PNET patients died within 17 months of diagnosis with a mean survival of 8 (4–17) months. No mutation in the p53 gene was detected. Conclusions. Brainstem PNETs tend to arise at a younger age than brainstem gliomas and medulloblastomas. The MRI pattern suggests a localized rather than a diffuse intrinsic nonenhancing brainstem tumor. Like other PNETs, brainstem PNETs have a high predilection to disseminate within the central nervous system. The absence of p53 mutations is similar to other PNETs. Despite their origin close to the cerebellum, brainstem PNETs exhibit a more aggressive behavior and result in worse clinical outcomes than do cerebellar PNETs.

Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

PURPOSE Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. METHODS AND MATERIALS A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. RESULTS At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R(2) = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). CONCLUSION Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

Magnetic field correlation as a measure of iron-generated magnetic field inhomogeneities in the brain.

The magnetic field correlation (MFC) at an applied field level of 3 Tesla was estimated by means of MRI in several brain regions for 21 healthy human adults and 1 subject with aceruloplasminemia. For healthy subjects, highly elevated MFC values compared with surrounding tissues were found within the basal ganglia. These are argued as being primarily the result of microscopic magnetic field inhomogeneities generated by nonheme brain iron. The MFC in the aceruloplasminemia subject was significantly higher than for healthy adults in the globus pallidus, thalamus and frontal white matter, consistent with the known increased brain iron concentration associated with this disease. Magn Reson Med 61:481–485, 2009.

Brain MRI: Tumor evaluation

The designation “brain tumors” is commonly applied to a wide variety of intracranial mass lesions that are distinct in their location, biology, treatment, and prognosis. Since many of these lesions do not arise from brain parenchyma, the more appropriate term would be “intracranial tumors.” The term “tumor” is used to include both neoplastic and non‐neoplastic mass lesions, and should be considered in its broadest sense to simply indicate a space‐occupying mass. This review describes an imaging‐based approach for evaluating intracranial tumors. Conventional MRI is discussed in the setting of a regional classification system. This system provides a framework for analysis, and imaging clues can then be applied to narrow the differential possibilities. Emphasis is placed on advanced MRI techniques and their utility for deciphering common diagnostic problems. J. Magn. Reson. Imaging 2006.