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Glioblastoma is the most common malignant brain parenchymal tumor yet remains challenging to treat. The current standard of care—resection and chemoradiation—is limited in part due to the genetic heterogeneity of glioblastoma. Previous studies have identified several tumor genetic biomarkers that are frequently present in glioblastoma and can alter clinical management. Currently, genetic biomarker status is confirmed with tissue sampling, which is costly and only available after tumor resection or biopsy. The purpose of this study was to evaluate a fully automated artificial intelligence approach for predicting the status of several common glioblastoma genetic biomarkers on preoperative MRI. We retrospectively analyzed multisequence preoperative brain MRI from 199 adult patients with glioblastoma who subsequently underwent tumor resection and genetic testing. Radiomics features extracted from fully automated deep learning-based tumor segmentations were used to predict nine common glioblastoma genetic biomarkers with random forest regression. The proposed fully automated method was useful for predicting IDH mutations (sensitivity = 0.93, specificity = 0.88), ATRX mutations (sensitivity = 0.94, specificity = 0.92), chromosome 7/10 aneuploidies (sensitivity = 0.90, specificity = 0.88), and CDKN2 family mutations (sensitivity = 0.76, specificity = 0.86).

SUMMARY: The olfactory bulbs and tracts are central nervous system white matter tracts maintained by central neuroglia. Although rare, gliomas can originate from and progress to involve the olfactory apparatus. Through a Health Insurance Portability and Accountability Act–compliant retrospective review of the institutional teaching files and brain MR imaging reports spanning 10 years, we identified 12 cases of gliomas involving the olfactory bulbs and tracts, including 6 cases of glioblastoma, 2 cases of anaplastic oligodendroglioma, and 1 case each of pilocytic astrocytoma, diffuse (grade II) astrocytoma, anaplastic astrocytoma (grade III), and diffuse midline glioma. All except the pilocytic astrocytoma occurred in patients with known primary glial tumors elsewhere. Imaging findings of olfactory tumor involvement ranged from well-demarcated enhancing masses to ill-defined enhancing infiltrative lesions to nonenhancing masslike FLAIR signal abnormality within the olfactory tracts. Familiarity with the imaging findings of glioma involvement of the olfactory nerves is important for timely diagnosis and treatment of recurrent gliomas and to distinguish them from other disease processes.

INTRODUCTION It is estimated that 25 to 35% of patients experience treatment-induced effects that can mimic recurrent high-grade gliomas. This diagnostic challenge is complicated by the coexistence of treatment-related changes and recurrent tumor within the same lesion which limits the accuracy of classification based on summary metrics of multi-parametric MRI. This study aimed to determine whether different MR features were relevant for distinguishing pathological features of recurrent tumor from the effects of treatment in the contrast enhancing and non-enhancing lesions of recurrent high-grade gliomas. METHODS Leveraging our unique dataset of image-guided tissue samples that directly maps pathology to MR characteristics, we analyzed 291 tissue samples (222 recurrent tumor; 69 treatment effect) with known coordinates on imaging from 139 patients that underwent preoperative 3T MRI and surgery for a suspected high-grade recurrent tumor. 8 MR parameter values from perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging at each tissue sample location were tested for association with histopathological outcome using univariate and multivariate generalized estimating equation models for enhancing and non-enhancing tissue samples. Individual cutoff values were determined and evaluated using ROC-Curve analysis with 5-fold cross-validation. RESULTS In tissue samples obtained from contrast-enhancing lesions, elevated relative cerebral blood volume (rCBV) was significantly associated with the presence of recurrent tumor (p< 0.03), while increases in normalized choline (nCho) and choline-to-NAA index (CNI) were significantly associated with the presence of recurrent tumor in non-enhancing tissue samples (p< 0.008). Cutoff values of 1.6(rCBV), 2.7(CNI), and 2.1(nCho) had the highest performance. CONCLUSION Our results confirm the utility of rCBV in distinguishing the effects of treatment from recurrent tumor within the contrast enhancing lesion. We report a novel finding that metabolic parameters can differentiate recurrent tumor from treatment-related changes in the non-enhancing lesion of high-grade gliomas. These results will help improve future management of patients with suspected recurrence.

Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy. Experimental Design: We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data. Results: H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients. Conclusions: Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.

Medulloblastoma recurrence has historically been diagnosed based on identification of new contrast-enhancing lesions on surveillance imaging. We propose reduced diffusion is a more sensitive imaging marker than contrast-enhancement in identifying recurrent metastatic medulloblastoma. We identified 46 pediatric patients with medulloblastoma at our institution. Seventeen patients went on to develop definitive disease recurrence within the brain. In these patients, MR imaging at the time of diagnosis of recurrence and for 6 months prior to diagnosis was evaluated for presence of contrast enhanced lesions, size of contrast enhanced lesions, presence of lesions with reduced diffusion, and quantitative measurement of ADC within the recurrent lesions. All patients with recurrent medulloblastoma demonstrated reduced diffusion within recurrent lesions. ADC measurements were 0.658 ± 0.072 for recurrent lesions as compared to 0.923 ± 0.146 for contralateral normal white matter region of interest (ROI) measurements (p = 0.00001). Eleven patients (65%) with disease recurrence demonstrated contrast enhancement within the recurrent lesions. All six patients with non-enhancing recurrence demonstrated reduced diffusion with mean ADC of 0.680 ± 0.097, which was statistically significantly lower compared to contralateral normal brain with ADC values 0.894 ± 0.089 (p = 0.003). Non-enhancing recurrent disease was found equally within the tumor resection bed and mixed distal and tumor resection bed. In our cohort of patients with recurrent medulloblastoma, recurrent lesions did not uniformly demonstrate contrast enhancement on MR imaging but all recurrent lesions demonstrated reduced diffusion. Our findings support diffusion weighted imaging (DWI) is more sensitive than contrast enhancement for detection of medulloblastoma recurrence. As such, DWI should be considered part of standard of care imaging for medulloblastoma surveillance.

PURPOSE: Post-radiation changes in the brain can mimic tumor recurrence on MRI, requiring multiple short term follow-ups to differentiate tumor progression from radiation necrosis. We propose combining functional and anatomic imaging with FDOPA PET tracer in hybrid PET-MRI to improve detection of tumor recurrence. MATERIALS AND METHODS: Seventeen adult patients treated with radiation therapy were identified - four with metastatic disease from breast and lung cancer and thirteen with primary brain glioma (11 IDH wildtype glioblastoma and 2 astrocytoma). Patients were scanned on hybrid PET-MRI (GE Healthcare) with clinical MRI brain sequences and dynamic FDOPA uptake. Dynamic FDOPA uptake within these tumors over 45 minutes after tracer injection was analyzed and compared to ADC histogram analysis. RESULTS: For each of the patients, clinical multi sequence gadolinium enhanced MRI and dynamic PET imaging for up to 45 minutes with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in groups was 51.4% ($28,321), as opposed to the cost of individual radiosynthesis performed for each study. Quantitative analysis of tracer uptake in striatum, internal carotid artery, and superior sagittal sinus were performed with appropriate accumulation and subsequent washout of tracer respectively. Successful dynamic FDOPA uptake within the tumor was seen in all patients and ratio of tumor to contralateral ROI were found to range from 1.8–4.5. While raw SUV values did not differentiate between recurrent tumor and radiation changes, T/C SUVmax ratios were elevated to 4.5 in recurrent glioblastoma, 2.5 in hypoxic treated glioblastoma, and 1.8 in non-recurrent metastatic breast cancer after gamma knife treatment. CONCLUSION: Batch imaging of patients with [18F]FDOPA PET-MRI is feasible and cost effective. Understanding radionuclide synthesis process is critical for increasing accessibility of novel PET tracers to patients and results in significant cost savings.

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

We present our initial experience in using single modality fluoromisonidazole (FMISO) PET/MR imaging to noninvasively evaluate the biological effects induced by bevacizumab therapy in a patient treated for recurrent high grade glioma. In this index patient, bevacizumab therapy resulted in the development of nonenhancing tumor characterized by reduced diffusion and markedly decreased FMISO uptake in the setting of maintained CBF and CBV. These observations suggest that the dynamic biological interplay between tissue hypoxia and vascular normalization occurring within treated recurrent high grade glioma can be captured utilizing FMISO PET/MR imaging.

Tumor-to-tumor metastasis of breast carcinoma to meningioma is a rare phenomenon. It is likely underdiagnosed given the relatively high prevalence and comorbidity of these two primary tumor types, the lack of standardized methodologies for its diagnosis, and the tendency to obfuscate this lesion with simple meningioma or cerebral metastasis of breast carcinoma. Careful histopathologic study of the resected meningioma is the cornerstone of diagnosis of these lesions, although certain conventional radiological features along with specialized modalities may clue the diagnosis. Vigilance for this lesion is appropriate in selected patients with known breast cancer or meningioma, as the two are often coexistent in the same patient, permitting tumor-to-tumor metastasis. Detection of this rare disease process may alter the treatment plan and prognosis. Here, we report a case of breast carcinoma-to-meningioma metastasis in a patient who developed subacute neurological decline while undergoing long-term treatment of her primary, late-stage breast cancer.

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 9 10-6mm2/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L\1,209 and LCP[0.71 versus ADC-L[1,209 and LCP \0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multicenter (BRAIN) study. © 2012 Springer Science+Business Media, LLC.

Recent studies have indicated that a significant survival advantage is conferred to patients with gliomas whose lesions harbor mutations in the genes isocitrate dehydrogenase 1 and 2 (IDH1/2). IDH1/2 mutations result in aberrant enzymatic production of the potential oncometabolite D-2-hydroxyglutarate (2HG). Here, we report on the ex vivo detection of 2HG in IDH1-mutated tissue samples from patients with recurrent low-grade gliomas using the nuclear magnetic resonance technique of proton high-resolution magic angle spinning spectroscopy. Relative 2HG levels from pathologically confirmed mutant IDH1 tissues correlated with levels of other ex vivo metabolites and histopathology parameters associated with increases in mitotic activity, relative tumor content, and cellularity. Ex vivo spectroscopic measurements of choline-containing species and in vivo magnetic resonance measurements of diffusion parameters were also correlated with 2HG levels. These data provide extensive characterization of mutant IDH1 lesions while confirming the potential diagnostic value of 2HG as a surrogate marker of patient survival. Such information may augment the ability of clinicians to monitor therapeutic response and provide criteria for stratifying patients to specific treatment regimens.

Purpose: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen. Experimental Design: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADCmin of contrast-enhancing lesions. Results: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADCmin less than 384 × 10–6 mm2/s was significantly associated with shorter progression-free and overall survival. Conclusions: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADCmin derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. Clin Cancer Res; 18(4); 1146–55. ©2012 AACR.

The objective of this study was to test the predictive value of serial MRI data in relation to clinical outcome for patients with glioblastoma multiforme (GBM). Sixty-four patients with newly diagnosed GBM underwent conventional MRI and diffusion-weighted and perfusion-weighted imaging postsurgery and prior to radiation/chemotherapy (pre-RT), immediately after RT (post-RT), and every 1-2 months thereafter until tumor progression, up to a maximum of 1 year. Tumor volumes and perfusion and diffusion parameters were calculated and subject to time-independent and time-dependent Cox proportional hazards models that were adjusted for age and MR scanner field strength. Larger volumes of the T2 hyperintensity lesion (T2ALL) and nonenhancing lesion (NEL) at pre-RT, as well as increased anatomic volumes at post-RT, were associated with worse overall survival (OS). Higher normalized cerebral blood volumes (nCBVs), normalized peak height (nPH) and normalized recirculation factors (nRF) at pre-RT, and nCBV at post-RT, in the T2ALL and NEL, were associated with shorter progression-free survival (PFS). From pre- to post-RT, there was a reduction in nCBV and nPH and an increase in apparent diffusion coefficient (ADC). Patients with lower nRF values at pre-RT, or a larger increase in nRF from pre-RT to post-RT, had significantly longer PFS. Time-dependent analysis showed that patterns of changes in ADC and anatomic volumes were associated with OS, while changes in nCBV, nPH, and the contrast-enhancing volume were associated with PFS. Our studies suggest that quantitative MRI variables derived from anatomic and physiological MRI provide useful information for predicting outcome in patients with GBM.

Voltage-gated potassium channels are widely expressed throughout the entire nervous system. These channels play a critical role in establishing the resting membrane potential and generation of neuronal action potentials. There is mounting evidence that autoantibodies reactive to neuronal cell surface antigens, such as voltage-gated potassium channels, play a pathogenic role in a wide spectrum of central and peripheral nervous system disorders. We report a case of new-onset drug-refractory seizure disorder associated with the presence of high levels of serum anti-voltage-gated potassium channel antibodies that responded only to immunotherapy. As demonstrated by this case report, anti-voltage-gated potassium channel antibody associated drug-refractory seizure disorder, although rare, should be considered in patients with unexplained adult-onset seizure activity. Once the diagnosis has been established the initiation of immunotherapy should be undertaken without delay.

Purpose To integrate standard anatomic magnetic resonance imaging in conjunction with uniformly acquired physiologic imaging biomarkers of untreated glioma with different histological grades with the goal of generating an algorithm that can be applied for patient management. Methods A total of 143 patients with previously untreated glioma were scanned immediately before surgical resection using conventional anatomical MR imaging, and with uniform acquisition of perfusion-weighted imaging, diffusion-weighted imaging, and proton MR spectroscopic imaging. Regions of interest corresponding to anatomic and metabolic lesions were identified to assess tumor burden. MR parameters that had been found to be predictive of survival in patients with grade IV glioma were evaluated as a function of tumor grade and histological sub-type. Based on these finding both anatomic and physiologic imaging parameters were then integrated to generate an algorithm for management of patients with newly diagnosed presumed glioma. Results Histological analysis indicated that the population comprised 56 patients with grade II, 31 with grade III, and 56 with grade IV glioma. Based on standard anatomic imaging, the presence of hypointense necrotic regions in post-Gadolinium T1-weighted images and the percentage of the T2 hyperintense lesion that was either enhancing or necrotic were effective in identifying patients with grade IV glioma. The individual parameters of diffusion and perfusion parameters were significantly different for patients with grade II astrocytoma versus oligodendroglioma sub-types. All tumors had regions with elevated choline to N-acetylasparate index (CNI). Lactate was higher for grade III and grade IV glioma and lipid was significantly elevated for grade IV glioma. These results were integrated into a proposed management algorithm for newly diagnosed glioma that will need to be prospectively tested in future studies. Conclusion Metabolic and physiologic imaging characteristics provide information about tumor heterogeneity that may be important for assisting the surgeon to ensure acquisition of representative histology. Correlation of these integrated MR parameters with clinical features will need to be assessed with respect to their role in predicting outcome and stratifying patients into risk groups for clinical trials. Future studies will use image directed tissue sampling to confirm the biological interpretation of these parameters and to assess how they change in response to therapy.

Purpose Glioblastoma Multiforme (GBM) is the most common and lethal primary brain tumor in adults. The goal of this study was to test the predictive value of MR parameters in relation to the survival of patients with newly diagnosed GBM who were scanned prior to receiving adjuvant radiation and chemotherapy. Methods The study population comprised 68 patients who had surgical resection and were to be treated with fractionated external beam radiation therapy and chemotherapy. Imaging scans included anatomical MRI, diffusion and perfusion weighted imaging and 1H MRSI. The MR data were acquired 3–5 weeks after surgery and approximately 1 week before treatment with radiation therapy. The diffusion, perfusion and spectroscopic parameter values were quantified and subjected to proportional hazards analysis that was adjusted for age and scanner field strength. Results The patients with larger lesion burden based upon volumes of anatomic lesions, volume of CNI2 (number of voxels within the T2 lesion having choline to NAA index >2), volume of CBV3 (number of pixels within the T2 lesion having relative cerebral blood volume >3), and volume of nADC1.5 (number of pixels within the T2 lesion having normalized apparent diffusion coefficient