Citations

AbstractNeurolymphomatosis (NL) is a rare manifestation of lymphoma, with limited evidence for optimal management. The largest patient series, 50 cases of lymphoma and leukemia, was published in 2010 with limited rituximab exposure. This study aims to evaluate the clinical presentation, diagnostic testing, and outcomes of NL in the rituximab era. Forty biopsy-proven cases of NL, in association with non-Hodgkin lymphoma (NHL), at the Mayo Clinic were retrospectively evaluated. B-cell NHL was associated with 97% of NL cases, of which diffuse large B-cell lymphoma (DLBCL) was the most common (68%). Primary NL, defined as neural involvement present at the time of diagnosis of lymphoma, was noted in 52% cases. Seventy percent of patients presented with sensorimotor weakness and neuropathic pain. Magnetic resonance imaging (MRI) was positive in 100% patients. Overall survival (OS) was significantly better for primary NL and NL associated with indolent lymphomas. Relapses were seen in 60% (24/40) of patients; 75% involved the peripheral or central nervous system at relapse. The use of rituximab in the frontline setting significantly impacted progression-free survival (PFS). Transplant consolidation was noted to be associated with improved OS. This study adds to the available literature on NL in the rituximab era. The overall outcomes have improved in recent years. In our experience, MRI and positron emission tomography/computed tomography may be required for accurate assessment of the extent of disease involvement and identification of an optimal biopsy site. The use of rituximab was associated with improvement in PFS, and autologous stem cell transplant was associated with OS.

Abstract Introduction Tumefactive multiple sclerosis (MS) and glioblastoma (GBM) can be difficult to differentiate. Clinical presentations are nonspecific and may occur in patients with both diseases. Magnetic resonance imaging (MRI) scans are routinely used to generate an initial differential diagnosis. Although imaging features can help distinguish these entities, there are no pathognomonic signs, neither on traditional nor advanced MRI. Moreover, the ability to differentiate these entities depends on the radiologists’ experience. Ensuring the correct diagnosis has important therapeutic and prognostic implications, as the management of these diseases is very different. To date, a brain biopsy often represents the only option to obtain a diagnosis, but it may be inconclusive and could add unnecessary morbidity. We hypothesize that a machine-learning tool based on routinely performed MRI scans could guarantee a more reliable, fast, and reproducible diagnosis. Methods Only patients with a histological diagnosis were included in the study. Patients that underwent any form of radiation therapy before the surgery were excluded to avoid confounding factors due to treatment-related effects. A total of 99 MS and 257 GBMs were included, and preoperative T2-weighted images were collected. For each patient, the lesions' segmentation was performed, including both the contrast-enhancing and non-enhancing areas of the lesions. The segmentation masks were used to extract radiomic features from the T2-weighted sequences. All MRI images were standardized to the same mean and standard deviation before feature extraction and resampled to a voxel size of 1.0 × 1.0 × 1.0 mm. Features extraction was performed using Pyradiomics (v. 3.0.1) and included first order, shape, and texture features, totaling 100 features. The classifier consisted of a support vector machine (SVM) model. Patients were randomly assigned to the training and test sets with an 80-20% proportion for each class. To select the best hyperparameters for the SVM classifier, a grid-search analysis was performed on the training set using a nested cross-validation scheme (k=5). All experiments were performed using Python (v. 3.5) and the Scikit-learn library (v. 0.23.1). Results The mean accuracy and area under the ROC curve for the best set of hyperparameters on the validation set were 0.83 and 0.86, respectively. The weighted-average precision, recall, and F1 scores on the test set were 0.78, 0.76, and 0.77, respectively. Conclusions Radiomic features extracted from a routinely acquired MRI sequence showed promising results in differentiating tumefactive multiple sclerosis from glioblastoma, opening the possibility to obtain a reliable diagnosis without the need for a brain biopsy. Future experiments Future experiments will focus on using post-contrast T1-weighted images for the radiomic features extractions, testing multiple machine learning models and features selection algorithms, and including more diagnostic classes (i.e., metastasis, lymphomas). Citation Format: Gian Marco Conte, Jeanette E. Eckel-Passow, W. Oliver Tobin, Paul Decker, Daniel H. Lachance, Robert B. Jenkins, Bradley J. Erickson. Differentiation of tumefactive multiple sclerosis and glioblastoma using radiomics features extracted from magnetic resonance imaging and machine learning [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-023.

Abstract BACKGROUND Molecular parameters have been incorporated into the 2016 WHO Classification of CNS Tumors and subsequent cIMPACT-NOW updates to facilitate clinical management of glioma patients. However, there have been few reports of the overall clinical utility of comprehensive genetic testing in adult glioma patients. We report the results of sequencing and chromosomal microarray analysis of adult gliomas seen at the Mayo Clinic and through the Mayo Clinic Laboratories (MCL) reference practice. METHODS A consecutive series of 379 Mayo Clinic adult glioma patients were consented to receive targeted next generation sequencing and chromosomal microarray analysis, regardless of standard clinical ordering practices. Known diagnostic, prognostic, and predictive alterations were annotated for each case. These results were compared to the larger MCL reference practice of 2400 adult glioma samples that received one or both tests clinically. RESULTS Of the consecutive Mayo Clinic cases, 67% had alterations that fell into at least one of the diagnostic, prognostic, and/or predictive categories. Molecular testing generated diagnostic, prognostic, and predictive information in 44%, 34%, and 36% of cases, respectively. Diagnostically, molecular testing mainly aided in arriving at a final integrated diagnosis, and only a small number of cases (n= 5; 1%) had a change in diagnosis. The consecutive cases represent the typical distribution of adult glioma types (47% IDH-wildtype glioblastoma/astrocytoma, 22% IDH-mutant astrocytoma/glioblastoma, 13% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 18% other tumor types). The MCL practice is enriched in tumors with atypical molecular patterns (37% IDH-wildtype glioblastoma/astrocytoma, 17% IDH-mutant astrocytoma/glioblastoma, 18% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 29% other tumor types). CONCLUSIONS Molecular testing provides useful diagnostic, prognostic, and predictive information for the clinical management of adult glioma patients. While the current guidelines for ordering molecular testing are effective for diagnostic purposes, additional prognostic and predictive information can be gleaned from comprehensive molecular testing of adult gliomas.

Abstract Background: Genome-wide association studies (GWAS) revealed that 25 regions in 24 genes are associated with adult diffuse glioma development. These regions were identified by performing GWAS of glioma overall and by pathology (GBM and nonGBM). The 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly-classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. We hypothesized that germline variants may increase susceptibility to, or interact with, these somatic alterations to accelerate the development of specific molecular subtypes of glioma. We further hypothesize that germline variants associated with IDH-mutated glioma might be associated with other IDH-mutated tumors, namely, cholangiocarcinoma, acute myeloid leukemia (AML) and melanoma. Methods: We performed a GWAS by glioma molecular subtype - as defined by presence or absence of IDH somatic mutation and 1p/19q codeletion. A total of 1320 glioma cases and 1889 controls were used in the discovery set, and 799 glioma cases and 808 controls in the validation set. A meta-analysis was performed with a genome-wide p-value threshold of 5 × 10−8. GTEx data were used to perform an expression quantitative trait loci (eQTL) analysis. For germline variants that were significantly associated with IDH-mutated glioma, we evaluated pleiotropy with cholangiocarcinoma, AML and melanoma using TCGA and Mayo Biobank controls. Results: Variants in or near D2HGDH on chromosome 2 were genome-wide significant in IDH-mutated glioma (meta p-value = 2.82 × 10−10). TCGA reported that the D2HGDH region was commonly deleted in IDH-mutated gliomas that do not have 1p/19q codeletion. In TCGA data for IDH-mutated, non-codeleted glioma, we observed that the D2HGDH variant was inversely associated with tumor deletions of D2HGDH (odds ratio=0.57, p-value=0.015). The eQTL analyses demonstrated significant associations between D2HGDH germline variant and expression of D2HGDH (p=2.2 × 10−11). Further stratifying IDH-mutated glioma by 1p/19q codeletion status, one variant near FAM20C on chromosome 7 was genome-wide significant in gliomas that have IDH mutation and 1p/19q codeletion (meta p-value=9.56 × 10−9). Analyses are currently underway to evaluate pleiotropy of these IDH-mutated glioma germline variants with other IDH-mutated tumors including cholangiocarcinoma, AML and melanoma. Variants in or near GMEB2 on chromosome 20 were genome-wide significant in IDH wild-type glioma (meta p-value=2.60 × 10−10). The most significant variant in the GMEB2 region remained significant after adjustment for the known RTEL1 glioma risk variant nearby on chromosome 20 (p=0.029). Conclusions: We identified and validated novel germline variants in two genes that are associated with etiology of IDH-mutated and one gene that is associated with IDH wild-type adult diffuse glioma. Citation Format: Jeanette E. Eckel-Passow, Kristen L. Drucker, Thomas M. Kollmeyer, Matthew L. Kosel, Paul A. Decker, Annette M. Molinaro, Terri Rice, Corrine E. Praska, Lauren E. Clark, Alissa A. Caron, Alexej Abyzov, Anthony Batzler, Jun S. Song, Melike Pekmezci, Helen M. Hansen, Lucie S. McCoy, Paige M. Bracci, Joseph Wiemels, John K. Wiencke, Stephen Francis, Terence C. Burns, Caterina Giannini, Daniel H. Lachance, Margaret Wrensch, Robert B. Jenkins. Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH, FAM20C and GMEB2 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1193.

AbstractBackgroundOligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a “false-positive” result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result.MethodsFISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015–2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible.ResultsThe overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations.ConclusionSelective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

e13020 Background: Seizures are common in patients with glioma. Phenytoin, traditionally used for these patients, can be associated with intolerable side effects and potentially alters the metabolism of chemotherapeutic agents. Levetiracetam has more favorable pharmacokinetics facilitating ease of use with fewer side effects and is nonenzyme inducing. We compare seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. Methods: Retrospective analysis of consecutive patients with glioma. Subjects had at least one clinical seizure and had to be followed for 6 months. Seizure outcomes and side effects were compared between cohorts treated with phenytoin or levetiracetam. Seizure outcomes were measured by time to second seizure and seizure frequency. Results: 76 patients (34 female) with pathologically proven glioma and seizures were identified, 25 treated with phenytoin and 51 with levetiracetam. 64% had grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p = 0.584), second seizure rates (p = 0.462), and average seizures per month (p = 0.776). When adjusting for age, gender, type of seizure, type of glioma, and dosage using univariate and multivariate models there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values >0.05). The incidence of side effects in the levetiracetam group was 5.9% versus 20% in the phenytoin group (p = 0.106). Additionally, 36.0% of the patients in the phenytoin group had dose adjustments not related to breakthrough seizures compared to only 9.8% in the levetiracetam group (p = 0.010). Conclusions: In this study, glioma patients treated with levetiracetam had similar seizure control as patients treated with phenytoin. Patients treated with levetiracetam experienced fewer side effects and required fewer non seizure related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma. No significant financial relationships to disclose.

Abstract Background Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. Methods A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10−8. Results Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10−10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10−8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10−9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10−10). Conclusions Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

9075 Background: Chemotherapy-induced peripheral neuropathy (CIPN), a common dose-limiting side effect of chemotherapy, remains without known effective interventions. Preliminary data support that Scrambler therapy, a device which treats pain via non-invasive cutaneous electrostimulation, is beneficial for the treatment of CIPN. This pilot trial was performed to investigate the effect of Scrambler therapy for the treatment of CIPN. Methods: Eligible patients included those age ≥18 years, ECOG PS ≤2, life expectancy ≥3 months, with pain or CIPN symptoms of ≥1 month duration and tingling or pain ≥4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area for up to 10 daily 30 minute sessions. Symptoms were monitored daily during therapy using a questionnaire to measure symptoms of neuropathy with a numerical analogue scale. Results: We report on the first 11 CIPN patients, enrolled between 7/18/2011 and 12/12/2011, 3 men and 8 women; mean age 57 years. Patients had history of exposure to various chemotherapeutic agents and the majority had symptoms >2 years. The table portrays data at baseline, at the end of the 10 planned days of therapy, and the percent changes from baseline to the end of treatment, regarding patient reported pain, tingling, and numbness over the preceding 24 hours. There were no adverse events. Persistent benefit out to 5 weeks was seen in some patients; maturing data will be available by May 2012. Descriptive summary statistics formed the basis of data analysis. Further patients are being entered on this trial. Conclusions: Scrambler therapy appears to be beneficial in the treatment of CIPN. A prospective placebo-controlled clinical trial should be performed to confirm these preliminary findings. [Table: see text]