Multifocal Glioblastoma Research Articles

Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma.

2055 Background: Patients with unresectable or multifocal glioblastomas (GBs) have a poor prognosis with median survival of 6-10 months. Given the angiogenic phenotype of GB, we conducted two phase II trials of upfront 5-day temozolomide (TMZ) and Bevacizumab (BV) with or without Irinotecan in patients with newly diagnosed unresectable or multifocal GB. Methods: Before radiation, patients received up to 4 cycles of temozolomide at 200 mg/m2/d days 1-5 and BV at 10 mg/kg on days 1 and 15 in each 28-day cycle. In the second trial, Irinotecan was added on days 1 and 15 at 125 mg/M2 for patients not on an enzyme-inducing anti-epileptic drug (EIAED), or 340 mg/M2 for patients on an EIAED. An MRI was performed monthly and therapy continued as long as there was no tumor progression, grade 4 non-hematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary endpoint was tumor response using the RANO criteria. Results: In the initial trial of TMZ and BV, 41 patients were enrolled from 10/07 to 9/08. MRI’s were available from 31 patients. There were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4 (12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with three grade 4 hematologic toxicities. There were 3 venous thromboembolic complications. There were 2 CNS hemorrhages. The median PFS was 5.2 mos (3.2, 9.0 months) and the median OS was 11.7 months (7.1, 15.6 months). In the second trial, Irinotecan was added to TMZ and BV and 41 patients were enrolled between 12/09 and 11/10. The partial response rate was 41%, 44% had stable disease and 15% had progression. 16 of 41 patients completed four cycles without tumor progression. There were 4 patients with grade 4 hematologic toxicity, 7 patients with venous thromboembolic complications and 1 with CNS hemorrhage. The median PFS was 6.7 months (2.0, 10.5 months) and median OS was 10.5 months (7.2, ND months). Conclusions: Upfront TMZ and BV was well tolerated. Adding Irinotecan to TMZ and BV does not appear to improve survival. Upfront therapy for unresectable or multifocal GB is an excellent platform to determine clinical activity.

O(6)-methylguanine DNA-methyltransferase (MGMT) in glioblastoma: Analysis on first and following surgeries.

2097 Background: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Outcome has recently improved with the introduction of post-operative concomitant chemoradiotherapy (CRT) followed by 6 cycles of temozolomide (TMZ). MGMT expression has already been encoded as an independent prognostic factor and predictive for TMZ sensitivity, but few data are available on the modifications of MGMT status after CRT. Methods: From January 2005 to November 2010 at Modena University Hospital and Nuovo Ospedale Civile S. Agostino-Estense, 15 consecutive patients (pts) with GBM and treated with at least 2 subsequent surgeries were included in this retrospective study. Aim of the present analysis is to evaluate if methylation status may change between first and following determinations. Results: Fifteen pts (M/F=10/5; median age: 48, range: 40-67 years) underwent a first surgery for GBM. MGMT status was: methylated in 5 (33%); unmethylated in 10 pts (77%). Two unmethylated pts presented an early relapse and underwent a second surgery after 41 and 46 days, respectively. MGMT analysis confirmed the absence of methylation. One pt with multifocal GBM was treated after the first surgery on right frontal lobe with TMZ, operated on left frontal lobe, submitted to CRT, then re-operated for a relapse in the first site of surgery (right frontal lobe). In this case MGMT status evaluated in the site of relapse (right frontal lobe) changed from unmethylated to methylated. MGMT on the lesion of left frontal lobe was unmethylated. The remaining 12 pts underwent post-operative concomitant CRT followed by monthly TMZ (median number of cycles: 8.5; range: 2-24). MGMT status on second surgery was: 5 methylated (42%) and 7 unmethylated (58%), with a 100% concordance. Two pts received a third surgery: in one case MGMT status changed from unmethylated to methylated. Overall median survival was 15.8 months. The two patients with “MGMT switch” have a median survival of 35.8 months. Conclusions: in 2 on 13 cases (15%) after CRT, MGMT status changed from unmethylated to methylated and these pts have a median overall survival similar to methylated pts. This observation may be confirmed on larger series.

Multiple craniotomies in the management of multifocal and multicentric glioblastoma

Multiple craniotomies have been performed for resection of multiple brain metastases in the same surgical session with satisfactory outcomes, but the role of this procedure in the management of multifocal and multicentric glioblastomas is undetermined, although it is not the standard approach at most centers. The authors performed a retrospective analysis of data prospectively collected between 1993 and 2008 in 20 patients with multifocal or multicentric glioblastomas (Group A) who underwent resection of all lesions via multiple craniotomies during a single surgical session. Twenty patients who underwent resection of solitary glioblastoma (Group B) were selected to match Group A with respect to the preoperative Karnofsky Performance Scale (KPS) score, tumor functional grade, extent of resection, age at time of surgery, and year of surgery. Clinical and neurosurgical outcomes were evaluated. In Group A, the median age was 52 years (range 32-78 years); 70% of patients were male; the median preoperative KPS score was 80 (range 50-100); and 9 patients had multicentric glioblastomas and 11 had multifocal glioblastomas. Aggressive resection of all lesions in Group A was achieved via multiple craniotomies in the same session, with a median extent of resection of 100%. Groups A and B were comparable with respect to all the matching variables as well as the amount of tumor necrosis, number of cysts, and the use of intraoperative navigation. The overall median survival duration was 9.7 months in Group A and 10.5 months in Group B (p = 0.34). Group A and Group B (single craniotomy) had complication rates of 30% and 35% and 30-day mortality rates of 5% (1 patient) and 0%, respectively. Aggressive resection of all lesions in selected patients with multifocal or multicentric glioblastomas resulted in a survival duration comparable with that of patients undergoing surgery for a single lesion, without an associated increase in postoperative morbidity. This finding may indicate that conventional wisdom of a minimal role for surgical treatment in glioblastoma should at least be questioned.

Heterogeneity of response to bevacizumab in multifocal and multicentric glioblastomas.

2019 Background: Bevacizumab (BEV) is approved for treatment of recurrent glioblastoma (GBM). However, whether the subset of pts with multifocal (MF) or multicentric (MC) GBM respond favorably to BEV has not been described. Hypothesizing that MF/MC lesions may represent an initially more invasive and biologically heterogeneous phenotype in GBM which may exhibit varied responses to BEV, we examined their patterns of radiologic response and correlation with clinical outcome. Methods: Clinical and MRI data from pts with recurrent GBM who received BEV were reviewed to identify those with MC or MF disease who had adequate baseline and follow-up MRI. Enhancing and nonenhancing (FLAIR) disease were analyzed for response to BEV and categorized in each pt as homogeneous (similar changes in all lesions) or heterogeneous (varied across lesions) in response or progression. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method and log rank test. Results: Of the 179 evaluable pts, 31 (17.3%) had multiple lesions (16 pts - MF, 15 pts - MC) prior to BEV treatment. Patients with MC/MF lesions had a significantly worse outcome than those with unifocal lesions in both PFS (Median 19 wks vs. 24.4 wks, p = 0.0124, HR 1.84, CI [1.14, 2.9]) and OS (Median 31 wks vs. 45.9 wks, p = 0.0011, HR 2.42, CI [1.42, 4.12]). Unlike previous reports of BEV response in recurrent GBM pts, MRI responders (homogenous or heterogeneous) among pts with MC/MF lesions did not have a better OS compared with nonresponders. In addition, no significant difference was seen in PFS or OS between patients with homogenous versus heterogeneous progression. There was no significant difference in median PFS (median 17.6 wks vs. 18.4 wks) or median OS (median 27.7 wks vs. 32.3 wks) between pts with MC versus MF GBM. Conclusions: The subset of GBM pts with MF/MC lesions had a worse outcome to BEV treatment compared with those with unifocal disease. Although a homogenous radiological response of all lesions to BEV was the commonest pattern on MRI, neither radiologic response nor pattern of radiologic progression correlated with improved PFS or OS. Our data also suggests that outcome of pts MC/MF GBM may need to be analyzed separately in studies with BEV containing regimens. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IMEDEX Celgene, Lilly, MGI Pharma, Pfizer

Cerebellar glioblastomas: pathophysiology, clinical presentation and management

Glioblastoma multiforme usually affects the cerebral hemispheres with the peak age of onset in the sixth or seventh decade, while cerebellar glioblastoma multiforme is a rare tumour especially in younger patients. Most result from de-differentiation from low grade astrocytoma (secondary glioblastoma) or can develop de novo (primary glioblastoma). Primary glioblastomas develop in older patients while secondary glioblastomas develop in younger patients and contain TP53 mutations as the earliest detectable change. We report a 28 year old patient with primary multi-focal cerebellar glioblastoma multiforme and review the pathophysiology, clinical presentation, diagnosis and treatment of cerebellar glioblastomas.

Multifocal Glioblastoma with Remote Cutaneous Metastasis: A Case Report and Review of the Literature

Remote extracranial mestastases of glioblastoma multiforme (GBM) are uncommon, while cutaneous seeding at a distance from the operative site appears to be even more unusual. A 63-year-old man presented with focal seizures and mental impairment. Computed tomography (CT) scan revealed a left frontoparietal mass. He underwent a gross total removal of the tumor. The tissue diagnosis was that of a GBM. Seven months later, the patient developed a left scapular subcutaneous mass. Fine-needle aspiration cytology (FNAC) was performed and the cytological findings disclosed again a GBM. One month later, after clinical deterioration, a repeat magnetic resonance imaging (MRI) scan was carried out which demonstrated two new distinct lesions in the opposite hemisphere, as in a multifocal GBM. Both lesions were biopsed under stereotactic guidance and the recurrence of GBM was confirmed. The patient died ten months after the primary diagnosis of the intracranial GBM. Improved diagnostic modalities and prolonged survival have increased the likelihood of detection of extracranial mestastases from GBM. This potential may be greater in multifocal GBM. FNA is a valuable method for the definite diagnosis of metastatic GBMs. Although several theories have been postulated, the route of remote cutaneous dissemination and the mechanism of multifocal recurrence remain to be elucidated.

Multifocal epithelioid glioblastoma mimicking cerebral metastasis: case report

Epithelioid glioblastoma is a rare morphologic subtype of glioblastoma that closely mimics metastatic carcinoma or metastatic melanoma histologically. All previous case reports of this unusual glioblastoma variant have been solitary lesions. We report here the first case to our knowledge of multifocal epithelioid glioblastoma mimicking cerebral metastasis. A 67-year-old man with a prior history of mycosis fungoides, a common form of cutaneous T-cell lymphoma, presented with memory loss and impaired peripheral vision. Two discrete brain lesions highly suspicious for metastases were identified by magnetic resonance imaging (MRI). The patient underwent two separate craniotomies; both lesions were successfully resected in toto with an excellent post-surgical outcome. Epithelioid glioblastoma is one of the rarest morphologic subtypes of glioblastoma. Here we describe the first case to our knowledge of multifocal epithelioid glioblastoma that convincingly mimicked a secondary metastatic process. Multifocal epithelioid glioblastoma should be included in the differential diagnosis of patients who present with multiple discrete brain lesions. An attempt at gross total resection is recommended when anatomically feasible for definitive histopathological diagnosis and to improve progression free survival of patients who present with similarly ambiguous and potentially misleading multiple lesions.

Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression

To assess the progression patterns in patients with multifocal glioblastoma multiforme who had undergone whole brain radiotherapy (WBRT), the historical standard, versus three-dimensional conformal radiotherapy, and to identify predictive treatment and pretreatment factors. The records of 50 patients with multifocal glioblastoma multiforme treated with RT were reviewed. Univariate analyses were performed using survival methods and the Cox proportional hazards regression method. Multivariate analyses were performed using the Cox proportional hazards regression method. The mean age was 61 years, and 71% had a Karnofsky performance status (KPS) score of > or =70. Of the 50 patients, 32% underwent WBRT and 68%, three-dimensional conformal RT. Progression was local in all evaluable patients, as determined by imaging in 38 patients and early neurologic progression in 12. The median time to progression (TTP) was 3.1 months, and the median survival time (MST) was 8.1 months. The significant independent predictors of TTP on multivariate analysis were a KPS score <70 (p = 0.001), the extent of surgery (p = 0.040), a radiation dose <60 Gy (p = 0.027), and the lack of chemotherapy (p = 0.001). The significant independent predictors of a reduced MST were a KPS score <70 (p = 0.022) and the absence of salvage surgery (p = 0.011) and salvage chemotherapy (p = 0.003). Local progression was observed in all patients. On multivariate analysis, no significant difference was found in the TTP or MST between three-dimensional conformal radiotherapy and WBRT. The KPS was a consistent independent predictor of both TTP and MST. On the basis of the progression pattern, we do not recommend WBRT as a mandatory component of the treatment of multifocal glioblastoma multiforme.

Antibodies to endostatin in a multifocal glioblastoma patient

Endostatin, a C-terminal fragment of collagen XVIII is involved in the regulation of neovascularisation in solid tumours in mice. However, few data are available on the concentration of endostatin protein in patients with cancer. Paradoxical results obtained in this way prompted us to investigate an antibody to endostatin. We detected antibodies to endostatin in the serum and in the tumour brain tissue of a patient with a multifocal glioblastoma, and in the serum samples from two patients with aggressive tumours. These data suggest that endostatin overexpression by tumour tissue might induce a humoral immune response.

Whole-body [18F]FDG PET in the management of metastatic brain tumours.

To determine its roles in the diagnosis and the systemic evaluation of metastatic brain tumours, whole-body positron emission tomography (PET) using [18F]FDG was performed in 20 consecutive patients. All patients were thought to be suffering or needing to be differentiated from metastatic brain tumours. Nine patients had multiple brain lesions; six were older and showed a rim-enhancing lesion with surrounding oedema; seven had homogeneously enhancing periventricular lesion(s) on computed tomography (CT) and/or magnetic resonance (MR) imaging, thought to be central nervous system lymphomas. Two patients had skull mass(es) and two patients had a solid mass suspected to be, respectively, a haemorrhagic metastasis and a metastatic malignant melanoma. All of them received whole-body [18F]FDG PET and conventional systemic work-up for metastasis in order to compare the results of the two methods. Metastatic brain tumours were diagnosed on whole-body [18F]FDG PET in eleven patients who had extracranial and intracranial hypermetabolic lesions. In nine of these, a conventional work-up also detected primary lesions which on whole-body [18F]FDG PET were seen to be hypermetabolic foci. Systemic lymph node metastases were detected by whole-body [18F]FDG PET only in two patients and histological diagnosis was possible by biopsy of lymph nodes rather than of brain lesions. In the remaining nine patients who had only intracranial hypermetabolic foci, histological diagnosis was made by craniotomy or stereotactic biopsy. It was confirmed that seven of nine patients were suffering from a primary brain tumour and two from metastatic carcinoma. None of the nine showed evidence of systemic cancer on conventional work-up. Histological diagnoses of the primary brain tumours were four cases of primary central nervous system lymphoma and one each of multifocal glioblastoma, Ewing's sarcoma, and cavernous angioma. Patients felt no discomfort during the whole-body [18F]FDG PET procedure and there were no complications. The false negative rate in [18F]FDG PET and in conventional work-up was 15.4% and 30.7% respectively. There were no false positives on either [18F]FDG PET or conventional work-up. It is suggested that whole-body [18F]FDG PET is a safe, reliable, and convenient method for the diagnosis and systemic evaluation of patients thought to be suffering or needing to be differentiated from a metastatic brain tumour.

Multifocal giant cell glioblastoma: Case report

Glioblastoma multiforme (GM) of the cerebellum is a rare tumour. A variant of GM, a multifocal giant cell glioblastoma, initially presenting in the cerebellum, has not previously been reported. A giant cell glioblastoma occurring in a 46-year-old man who presented initially with a cerebellar tumour is described. One month after excision of the tumour, the patient had a grand mal seizure. Computed tomography (CT) showed a low-density lesion in the left temporal lobe. Four months later he developed dysphasia and right-sided hemiparesis. Repeat CT scan revealed a large temporal lobe tumour which was excised, and histologically found to be a giant-cell glioblastoma with histopathological similarities to the original cerebellar tumour. The clinical course, computed tomographic and pathological features of this tumour are described and discussed

Stereotaxic Implantation of Autologous Adrenal Medulla Into Caudate Nucleus in Four Patients With Parkinsonism

Four patients with levodopa-responsive parkinsonism (aged 26, 35, 45, and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days, during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case, the stereotaxic implantation missed the basal ganglia, resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases, a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.

Multifocal glioblastoma with liver metastases in the absence of surgery

A patient with two intracerebral glioblastomas of differing histology with metastases to the liver in the absence of surgery is reported. The gliomatous nature of the lesions was confirmed by staining for glial fibrillary acidic protein. Histological and immunohistochemical evidence suggests that the metastases arose from the more poorly differentiated of the intracerebral tumors. One of the intracerebral tumors had enhanced expression of the ras p21 oncogene as compared to the other tumors and as compared to nonmalignant brain tissue from this patient.

Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies

To study the progression of astrocytic neoplasms and to provide practical information about the topography of the glioblastoma multiforme, the distribution of eight defined cell types was mapped from whole brain sections of 18 glioblastomas studied postmortem. Based on the densities and topographic distributions of well-differentiated and anaplastic cells, three principal categories of neoplasms were defined. In one group of three cases, multifocal glioblastomas appeared to be emerging in the background of a better differentiated, and presumably precursory, astrocytic neoplasm. In another group of nine cases, the neoplasms were more intimate mixtures of well and poorly differentiated cells. The third group of five cases was composed of neoplasms that were largely undifferentiated without a component of better differentiated cells. The study suggests that progression from a better differentiated neoplasm to one composed largely of undifferentiated cells is common in the fibrillary astrocytic neoplasms. Although some glioblastomas appear largely undifferentiated and consistent with the de novo appearance of overt malignancy, the size of these neoplasms and the patterns of necrosis leave open the possibility that a preexisting better differentiated neoplasm had been obliterated by necrosis and the overgrowth of the anaplastic component. The potential topographic variation of cellular constituency in a glioblastoma underscores the care that must be exercised in utilization of the needle biopsy technique in the diagnosis and grading of astrocytic neoplasms.

Multicentric and isolated multifocal glioblastoma multiforme simulating metastatic disease

Single case reports of multicentric glioblastoma multiforme and multifocal glioblastoma multiforme tumours are presented. Multicentric glioblastoma multiforme tumours are those which have no macroscopic or microscopic connection. Multifocal gliomatous tumours, on the other hand, are those with either gross or microsopic continuity or evidence of cerebral spinal fluid spread and/or local metastases. The cerebral scintigram findings, cerebral angiogram studies and pathological description of these entities are presented. These lesions may be mistaken for metastases. In patients with multiple cerebral lesions multiple primary malignancies of brain should be considered when there is no clinical or radiographical evidence for extracranial primary neoplasms.