Jerome Graber

Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma

Objective: To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP). Methods: This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ2 or Fisher exact test. Results: Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06–1.0). Conclusions: Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.

MRI perfusion in determining pseudoprogression in patients with glioblastoma

We examine the role of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion in differentiating pseudoprogression from progression in 20 consecutive patients with treated glioblastoma. MRI perfusion was performed, and relative cerebral blood volume (rCBV), relative peak height (rPH), and percent signal recovery (PSR) were measured. Pseudoprogression demonstrated lower median rCBV (P=.009) and rPH (P<.001), and higher PSR (P=.039) than progression. DSC MRI perfusion successfully identified pseudoprogression in patients who did not require a change in treatment despite radiographic worsening following chemoradiotherapy.

Biomarkers of disease activity in multiple sclerosis.

As therapeutic options for multiple sclerosis widen, validated biomarkers of clinical disease activity are urgently needed. Reliable biomarkers would assist in choosing initial therapy, monitoring response to therapy, detecting subclinical disease activity, predicting and possibly preventing therapeutic failure, and hopefully improving both short (relapses) and long-term (disability) outcomes. The presence of oligoclonal bands in the cerebrospinal fluid is a well-validated biomarker that is useful in initial diagnosis. Neutralizing antibodies to interferon-beta are also useful in identifying treatment failure and possibly guiding changes in therapy. The discovery of antibodies to aquaporin-4 in patients with neuromyelitis optica delineates patients with a fundamentally different underlying pathophysiology and clinical course who may require alternate therapeutic approaches. While numerous other candidate biomarkers in serum and cerebrospinal fluid have been described, none so far have the validated reliability necessary for widespread clinical use. The availability of multiple genetic and protein microarray technology may assist in identifying more reliable candidate biomarkers or patterns of multiple biomarkers and improve specificity. The heterogeneity of multiple sclerosis may necessitate individualized biomarkers and therapeutic decisions within distinct subsets of patients.

Pretreatment Dynamic Susceptibility Contrast MRI Perfusion in Glioblastoma: Prediction of EGFR Gene Amplification

Background and PurposeMolecular and genetic testing is becoming increasingly relevant in GBM. We sought to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion imaging could predict EGFR-defined subtypes of GBM.Materials and MethodsWe retrospectively identified 106 consecutive glioblastoma (GBM) patients with known EGFR gene amplification, and a subset of 65 patients who also had known EGFRvIII gene mutation status. All patients underwent T2* DSC MRI perfusion. DSC perfusion maps and T2* signal intensity time curves were evaluated, and the following measures of tumor perfusion were recorded: (1) maximum relative cerebral blood volume (rCBV), (2) relative peak height (rPH), and (3) percent signal recovery (PSR). The imaging metrics were correlated to EGFR gene amplification and EGFRvIII mutation status using univariate analyses.ResultsEGFR amplification was present in 44 (41.5 %) subjects and absent in 62 (58.5 %). Among the 65 subjects who had undergone EGFRvIII mutation transcript analysis, 18 subjects (27.7 %) tested positive for the EGFRvIII mutation, whereas 47 (72.3 %) did not. Higher median rCBV (3.31 versus 2.62, p = 0.01) and lower PSR (0.70 versus 0.78, p = 0.03) were associated with high levels of EGFR amplification. Higher median rPH (3.68 versus 2.76, p = 0.03) was associated with EGFRvIII mutation.ConclusionDSC MRI perfusion may have a role in identifying patients with EGFR gene amplification and EGFRvIII gene mutation status, potential targets for individualized treatment protocols. Our results raise the need for further investigation for imaging biomarkers of genetically unique GBM subtypes.

Seizures and Epilepsy in Cancer Patients

Seizures in the general population may occur for a variety of reasons, including vascular, infectious, autoimmune, genetic, and traumatic causes. In the cancer population, seizures arise mainly as a result of an infiltrative neoplastic process in the brain. However, seizures as a result of cancer treatment, metabolic causes, or paraneoplastic diseases may occur in patients with systemic cancer, even in the absence of a cerebral lesion. The etiology of seizures in brain tumor patients includes primary cerebral neoplasms and metastatic brain lesions. The treatment for seizures in this population is multifaceted and involves surgery, radiation, chemotherapy, and antiepileptic drugs. All treatments have potential adverse effects, especially when combined. The treatment for brain tumor-associated seizures and epilepsy almost always is geared toward treating the tumor, but subsequent treatment of seizures often is necessary. A pragmatic approach to this problem is essential to mitigate potential complications from treatment.

Potential role of preoperative conventional MRI including diffusion measurements in assessing epidermal growth factor receptor gene amplification status in patients with glioblastoma.

BACKGROUND AND PURPOSE: Epidermal growth factor receptor amplification is a common molecular event in glioblastomas. The purpose of this study was to examine the potential usefulness of morphologic and diffusion MR imaging signs in the prediction of epidermal growth factor receptor gene amplification status in patients with glioblastoma. MATERIALS AND METHODS: We analyzed pretreatment MR imaging scans from 147 consecutive patients with newly diagnosed glioblastoma and correlated MR imaging features with tumor epidermal growth factor receptor amplification status. The following morphologic tumor MR imaging features were qualitatively assessed: 1) border sharpness, 2) cystic/necrotic change, 3) hemorrhage, 4) T2-isointense signal, 5) restricted water diffusion, 6) nodular enhancement, 7) subependymal enhancement, and 8) multifocal discontinuous enhancement. A total of 142 patients had DWI available for quantitative analysis. ADC maps were calculated, and the ADCmean, ADCmin, ADCmax, ADCROI, and ADCratio were measured. RESULTS: Epidermal growth factor receptor amplification was present in 60 patients (40.8%) and absent in 87 patients (59.2%). Restricted water diffusion correlated with epidermal growth factor receptor amplification (P = .04), whereas the other 7 morphologic MR imaging signs did not (P > .12). Quantitative DWI analysis found that all ADC measurements correlated with epidermal growth factor receptor amplification, with the highest correlations found with ADCROI (P = .0003) and ADCmean (P = .0007). CONCLUSIONS: Our results suggest a role for diffusion MR imaging in the determination of epidermal growth factor receptor amplification status in glioblastoma. Additional work is necessary to confirm these results and isolate new imaging biomarkers capable of noninvasively characterizing the molecular status of these tumors.

Teaching NeuroImages: “Penguin” or “hummingbird” sign and midbrain atrophy in progressive supranuclear palsy

An 82-year-old man presented to us with a 2-year history of progressive difficulty walking. On examination, he had bradykinesia, bradyphrenia, …

Continuing the search for MR imaging biomarkers for MGMT promoter methylation status: conventional and perfusion MRI revisited

Dear Sir: It is with great interest that we read the recent investigation by Moon et al. [1] that assessed the value of preoperative imaging in the prediction of methyl-guanine methyl transferase (MGMT) promoter methylation status in 24 patients with high-grade gliomas. By evaluating preoperative computed tomography (CT), conventional magnetic resonance (MR) imaging, perfusion MR imaging, and diffusion tensor imaging (DTI), they found that MGMT promoter methylation was associated with ill-defined tumor margins, lower CT attenuation, higher apparent diffusion coefficient (ADC), and lower fractional anisotropy (FA). The remainder of the qualitative conventional MR imaging measures (ring versus nodular tumor enhancement, presence of a cystic portion, and heterogeneity of the signal intensity on the T2-weighted images) as well as perfusion MR imaging (as assessed by relative cerebral blood volume) were not found to be different between groups. Their results are relevant given the recently described prognostic significance of MGMT promoter methylation status in the survival of patients with high-grade gliomas [2, 3]. An imaging biomarker for MGMT methylation could serve as a surrogate for histopathology in those cases where pathology sampling is suboptimal, or could be of value if future preoperative treatment regimens are developed and based on presumed MGMT status. However, a major confounding factor in that study is the fact that both WHO grade III tumors and grade IV tumors were included, with a relatively small number of patients in each group. WHO grade III and IV tumors are a highly heterogeneous group in terms of histological findings, biological behavior, and radiographic characteristics. In that study, a total of 57.1% of grade III tumors were methylated versus only 41.1% in the grade IV tumors. Although this difference has not reached statistical significance, likely reflecting small sample sizes, the possibility that radiographic differences found between the methylated and unmethylated groups could at least in part reflect differences in histological grade cannot be excluded. The radiographic differences among the different types of malignant gliomas such as anaplastic oligodendrogliomas, grade III astrocytomas, and glioblastomas have been well described and cannot be ignored. The distribution of the different radiographic parameters according to tumor type and grade was not provided in that paper. We would like to take this opportunity to report our experience with attempting to find MR imaging parameters that may predict MGMT promoter methylation status. We examined the preoperative MR imaging of patients with malignant glioma treated at our institution and who had the MGMT promoter methylation status determined. To improve the homogeneity of the sample, we restricted the analysis to patients with glioblastomas (WHO grade IV tumors). The cohort of 77 patients all underwent preoperative conventional MR imaging with standard sequences (axial diffusion, T1-weighted, T2-weighted, FLAIR, gradient-echo or susceptibility-weighted, and triplanar post-gadolinium T1-weighted images). We qualitatively assessed, by consensus of experienced neuroradiologists (6 and 11 years experience), the following signs: (1) enhancing border sharpness; (2) cystic/necrotic change; (3) hemorrhage; (4) T2-isointense signal; (5) diffusion restriction; (6) nodular enhancement; (7) subependymal enhancement; and (8) multifocal discontinuous enhancement. In addition, 49 of the 77 patients had T2* dynamic susceptibility contrast perfusion-weighted MR imaging, where rCBV was recorded using maximal region-of-interest (ROI) technique (in a fashion similar to the manner described by Moon et al. [1]) as well as additional perfusion metrics including peak height (PH), relative peak height (rPH), and percentage signal recovery (PSR). Similar to Moon et al. [1], we found that 31 of our 77 patients (40.2%) had methylation of the MGMT promoter, compared with 46 (59.8%) with unmethylated MGMT promoter. Despite measuring additional perfusion metrics such as PH, rPH, and PSR, we also found MR perfusion-weighted imaging to have no value in predicting MGMT promoter methylation, with p values ranging from 0.66 to 0.87 (Table 1). Table 1 Relationship between perfusion metric and MGMT methylation status However, none of our conventional MR imaging signs was significantly associated with MGMT methylation promoter status, with p values ranging from 0.14 to 0.97 (Table 2). Moon et al. [1] found that ill-defined tumor margins were associated with methylation of the MGMT promoter, which could be potentially explained by the fact that some lower-grade tumors tend to have ill-defined margins and have higher frequency of MGMT promoter methylation. Moon’s findings also disagree with a study performed by Drabcyz et al. [4] in 59 patients, which found that ring enhancement was highly associated with unmethylated MGMT promoter status (p=0.006) and in an elegant texture analysis found T2-weighted texture features to be important (p<0.05). Moreover, an additional study by Eoli et al. [5] in 86 patients found that ring enhancement was associated with unmethylated MGMT status (p<0.005). Clearly, additional studies are needed to settle this question. Table 2 Relationship between MRI sign and MGMT methylation status We did not perform DTI in our patients. It is interesting that Moon et al. found that reduced FA is associated with methylation of the MGMT promoter. They performed DTI by applying six different directions of orthogonal diffusion gradients. They do not specify the number of excitations (NEX) used, but we estimate that at 3 T with a commonly applied NEX=6 that this sequence required approximately 2–3 min. We have considered adding DTI as a routine sequence for preoperative imaging at our institutions, but our standard DTI protocol prescribes 15 to 33 non-collinear gradient directions that may add 5–11 min to total scan time. The authors measured ROIs in the enhancing solid portions of the tumors and obtained ratios relative to ROIs in the contralateral homologous normal-appearing brain parenchyma. This technique helps mitigate but does not completely eliminate potentially dramatic regional and anatomy-specific variations in FA. Given these limitations, incorporating DTI into routine clinical practices in all preoperative imaging of high-grade gliomas may be challenging, and further validation would be needed. Given the variability of these reports, we would urge caution in attempting to predict MGMT status based on preoperative MR imaging sequences. Our cohort of 77 patients showed no significant differences after qualitative assessment of MR imaging signs. It is therefore our opinion that, despite the interesting preliminary findings of Moon et al. and previous reports, additional studies are needed to address this critical clinical question. Although the potential role of DTI or quantitative ADC measurements in predicting MGMT status is important and warrants further investigation, qualitative measures performed at the picture archive and communication system (PACS) station that do not require sophisticated time-consuming post-processing are more likely to be adopted in standard clinical practice and are therefore more valuable to practicing radiologists. Clearly, more work is needed in this area before neuroradiologists can suggest with any reasonable degree of confidence the likely MGMT status of a high-grade glioma based on standard, conventional MR imaging sequences.

Primary central nervous system lymphoma: is there still a role for radiotherapy?

PURPOSE OF REVIEW Adding high-dose methotrexate to whole-brain radiotherapy improves survival in primary central nervous system lymphoma. However, the high neurotoxicity rates observed, especially in the elderly, raised interest in exploring other alternatives such as reduced-dose radiotherapy and chemotherapy-only treatments. RECENT FINDINGS Phase II studies suggested that omitting radiotherapy decreases progression-free survival (PFS) but not overall survival. A randomized phase III trial testing chemotherapy with/without radiation found similar results. However, interpretation of that trial has been difficult because of the chemotherapy regimen used (methotrexate with/without ifosfamide), intrinsic methodological problems and lack of neuropsychological evaluation. It also remains unclear whether chemotherapy-only treatments could ultimately result in worse cognitive outcomes in comparison with combined chemotherapy and radiotherapy because the higher rates of relapses could result in additional neurotoxicity from salvage treatments and brain damage by relapsing tumor. Given differences in relapses and neurotoxicity rates according to age, it is also unclear how results apply to younger versus older patients. SUMMARY Given the lack of better data, omitting radiotherapy currently seems a justifiable choice in routine practice, particularly in the elderly, but the question remains unsettled. Ongoing studies are investigating other consolidation options, including reduced-dose radiotherapy and high-dose chemotherapy with stem-cell rescue, aiming at improving disease control and decreasing neurotoxicity.

Diffusion-Weighted MR Imaging and MGMT Methylation Status in Glioblastoma: A Reappraisal of the Role of Preoperative Quantitative ADC Measurements

Methylation of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) has been well described as one the most significant biomarkers of glioblastoma (GBM) patient prognosis and response to standard first-line chemotherapy treatment with temozolomide.[1][1] As such, we read with great