Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

PURPOSE: The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy. METHODS: This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ. RESULTS: The highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009). CONCLUSION: Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM. CLINICALTRIALS: gov Identifier: NCT03344250.

Disease Assessments in Patients with Glioblastoma.

PURPOSE OF REVIEW: The neuro-oncology team faces a unique challenge when assessing treatment response in patients diagnosed with glioblastoma. Magnetic resonance imaging (MRI) remains the standard imaging modality for measuring therapeutic response in both clinical practice and clinical trials. However, even for the neuroradiologist, MRI interpretations are not straightforward because of tumor heterogeneity, as evidenced by varying degrees of enhancement, infiltrating tumor patterns, cellular densities, and vasogenic edema. The situation is even more perplexing following therapy since treatment-related changes can mimic viable tumor. Additionally, antiangiogenic therapies can dramatically decrease contrast enhancement giving the false impression of decreasing tumor burden. Over the past few decades, several approaches have emerged to augment and improve visual interpretation of glioblastoma response to therapeutics. Herein, we summarize the state of the art for evaluating the response of glioblastoma to standard therapies and investigational agents as well as challenges and future directions for assessing treatment response in neuro-oncology. RECENT FINDINGS: Monitoring glioblastoma responses to standard therapy and novel agents has been fraught with many challenges and limitations over the past decade. Excitingly, new promising methods are emerging to help address these challenges. Recently, the Response Assessment in Neuro-Oncology (RANO) working group proposed an updated response criteria (RANO 2.0) for the evaluation of all grades of glial tumors regardless of IDH status or therapies being evaluated. In addition, advanced neuroimaging techniques, such as histogram analysis, parametric response maps, morphometric segmentation, radio pharmacodynamics approaches, and the integrating of amino acid radiotracers in the tumor evaluation algorithm may help resolve equivocal lesion interpretations without operative intervention. Moreover, the introduction of other techniques, such as liquid biopsy and artificial intelligence could complement conventional visual assessment of glioblastoma response to therapies. Neuro-oncology has evolved over the past decade and has achieved significant milestones, including the establishment of new standards of care, emerging therapeutic options, and novel clinical, translational, and basic research. More recently, the integration of histopathology with molecular features for tumor classification has marked an important paradigm shift in brain tumor diagnosis. In a similar manner, treatment response monitoring in neuro-oncology has made considerable progress. While most techniques are still in their inception, there is an emerging body of evidence for clinical application. Further research will be critically important for the development of impactful breakthroughs in this area of the field.

MRI features predict tumor grade in isocitrate dehydrogenase (IDH)-mutant astrocytoma and oligodendroglioma.

PURPOSE: Nearly all literature for predicting tumor grade in astrocytoma and oligodendroglioma pre-dates the molecular classification system. We investigated the association between contrast enhancement, ADC, and rCBV with tumor grade separately for IDH-mutant astrocytomas and molecularly-defined oligodendrogliomas. METHODS: For this retrospective study, 44 patients with IDH-mutant astrocytomas (WHO grades II, III, or IV) and 39 patients with oligodendrogliomas (IDH-mutant and 1p/19q codeleted) (WHO grade II or III) were enrolled. Two readers independently assessed preoperative MRI for contrast enhancement, ADC, and rCBV. Inter-reader agreement was calculated, and statistical associations between MRI metrics and WHO grade were determined per reader. RESULTS: For IDH-mutant astrocytomas, both readers found a stepwise positive association between contrast enhancement and WHO grade (Reader A: OR 7.79 [1.97, 30.80], p = 0.003; Reader B: OR 6.62 [1.70, 25.82], p = 0.006); both readers found that ADC was negatively associated with WHO grade (Reader A: OR 0.74 [0.61, 0.90], p = 0.002); Reader B: OR 0.80 [0.66, 0.96], p = 0.017), and both readers found that rCBV was positively associated with WHO grade (Reader A: OR 2.33 [1.35, 4.00], p = 0.002; Reader B: OR 2.13 [1.30, 3.57], p = 0.003). For oligodendrogliomas, both readers found a positive association between contrast enhancement and WHO grade (Reader A: OR 15.33 [2.56, 91.95], p = 0.003; Reader B: OR 20.00 [2.19, 182.45], p = 0.008), but neither reader found an association between ADC or rCBV and WHO grade. CONCLUSIONS: Contrast enhancement predicts WHO grade for IDH-mutant astrocytomas and oligodendrogliomas. ADC and rCBV predict WHO grade for IDH-mutant astrocytomas, but not for oligodendrogliomas.

Vascular complications in patients with brain tumors.

PURPOSE OF REVIEW: Venous thromboembolism (VTE) and other vascular events are common in patients with brain tumors, but their optimal management is not firmly established, in large part due to the competing risk of intracranial hemorrhage (ICH) in this population. RECENT FINDINGS: There is conflicting evidence on whether therapeutic anticoagulation increases the risk of ICH in patients with brain tumors, with several metanalysis and retrospective cohort studies showing an increased risk and others showing no differences. Current guidelines recommend anticoagulating brain tumors patients with VTE with either low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), and several retrospective studies have shown the risk of ICH with DOACs is similar or smaller than with LMWH. SUMMARY: An increased risk of VTE exists in a variety of brain tumor types. Most patients with brain tumors and VTE should receive therapeutic anticoagulation, and recent retrospective evidence supports the use of both LMWH and DOACs as effective and relatively safe in this setting. Patients with brain tumors are also at increased risk of other vascular tumor- or treatment-related complications whose optimal management is unclear.

The landscape of brain tumor mimics in neuro-oncology practice.

BACKGROUND AND OBJECTIVE: Differentiating neoplastic and non-neoplastic brain lesions is essential to make management recommendations and convey prognosis, but the distinction between brain tumors and their mimics in practice may prove challenging. The aim of this study is to provide the incidence of brain tumor mimics in the neuro-oncology setting and describe this patient subset. METHODS: Retrospective study of adult patients referred to the Division of Neuro-oncology for a presumed diagnosis of brain tumor from January 1, 2005 through December 31, 2017, who later satisfied the diagnosis of a non-neoplastic entity based on neuroimaging, clinical course, and/or histopathology evaluation. We classified tumor mimic entities according to clinical, radiologic, and laboratory characteristics that correlated with the diagnosis. RESULTS: The incidence of brain tumor mimics was 3.4% (132/3897). The etiologies of the non-neoplastic entities were vascular (35%), inflammatory non-demyelinating (26%), demyelinating (15%), cysts (10%), infectious (9%), and miscellaneous (5%). In our study, 38% of patients underwent biopsy to determine diagnosis, but in 26%, the biopsy was inconclusive. DISCUSSION: Brain tumor mimics represent a small but important subset of the neuro-oncology referrals. Vascular, inflammatory, and demyelinating etiologies represent two-thirds of cases. Recognizing the clinical, radiologic and laboratory characteristics of such entities may improve resource utilization and prevent unnecessary as well as potentially harmful diagnostic and therapeutic interventions.

Current Considerations in the Treatment of Grade 3 Gliomas.

OPINION STATEMENT: Treatment recommendations for grade 3 gliomas are guided by their histopathologic and molecular phenotype. In the 2021 WHO classification, these tumors are categorized into two types, grade 3 IDH mutant (IDHmt), 1p/19q codeleted oligodendroglioma and IDH mutant astrocytoma. Treatment consists of maximal safe surgery, followed by radiation therapy (RT) and alkylating agent-based chemotherapy. Based on the updated CATNON result, RT followed by temozolomide improves outcome in patients with non-codeleted grade 3 IDHmt astrocytoma. In patients with IDHmt, codeleted oligodendroglioma, the addition of procarbazine, CCNU, and vincristine regimen is the recommended treatment, based on large randomized controlled trials. These current treatments prolong the overall survival to up to 10 years in patients with grade 3 IDHmt astrocytoma and 14 years in grade 3 IDHmt codeleted oligodendroglioma. Treatment options at recurrence include re-resection, re-irradiation, and other cytotoxic chemotherapy; however, these are of limited benefit. Novel agents targeting IDH mutation and its metabolic effects are currently under investigation to improve the outcome of these patients.

Development and validation of a liquid chromatography coupled with tandem mass spectrometry method for determining total and unbound pamiparib in human plasma and brain tumors.

Pamiparib (BGB-290) is an orally bioavailable, small molecule inhibitor of poly (ADP-ribose) polymerase 1 (PARP1) and PARP2. A reversed-phase LC with tandem mass spectrometry method was developed and fully validated for determining total and unbound pamiparib concentrations in human plasma and brain tumor tissue. Plasma and tissue homogenate samples were prepared by methanol protein precipitation. Pamiparib and the internal standard [13 C2 ,15 N2 ]pamiparib were separated on a Waters BEH C18 (50 × 2.1 mm, 1.7 µm) column, with a gradient elution consisting of mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) at a flow rate of 0.25 mL/min. The analytes were monitored with multiple reaction monitoring mode under positive electrospray ionization. The method was fully validated for specificity, linearity, accuracy and precision, matrix effect and recovery, and short- and long-term stability. The lower limit of quantitation was 0.5 nM of pamiparib in plasma or tissue homogenate. The calibration curve was linear over the pamiparib concentration range of 0.5-1000 nM in plasma. The intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. Pamiparib was stable in plasma at -80°C for at least 6 months. The method was successfully applied to assess the plasma and tumor pharmacokinetics of total and unbound pamiparib in patients with glioma.

Incidence, risk factors and management of venous thromboembolism in patients with primary CNS lymphoma.

INTRODUCTION: Venous thromboembolism (VTE) is a known complication of malignancy. While brain tumors in general predispose to VTE, the incidence in primary central nervous system lymphoma (PCNSL) is poorly characterized. We sought to characterize incidence, risk factors, management, and outcome of VTE in PCNSL METHOD: Retrospective study of 78 PCNSL patients from 2/1/2002 to 4/1/2020 at the University of Virginia RESULTS: 31% (24/78) of patients developed VTE. 12.8% (10/78) had deep venous thrombosis (DVT) alone, 11.5% (9/78) isolated pulmonary embolism (PE) and 6.4% (5/78) both. The median time from PCNSL diagnosis to VTE was 3 months. In a univariate competing risks analysis, previous VTE (p < 0.001), impaired ambulation (p = 0.035), baseline hemoglobin < 10 g/dL (p = 0.025) and history of diabetes mellitus (type 1 or 2) (p = 0.007) were associated with increased VTE risk. 34.8% were anticoagulated acutely with heparin (8/23) or 65.2% LMWH (15/23), and 25.0% (6/24) received warfarin, 41.7% (10/24) LMWH, and 33.3% (8/24) DOACs long-term. One adverse event was attributable to anticoagulation (arm hematoma with hemoglobin decrease). Five patients received IVC filters with concomitant oral anticoagulation; one experienced IVC thrombosis after anticoagulation discontinuation. Six of the 24 patients experienced recurrent VTE, four while anticoagulated. CONCLUSION: Patients with PCNSL are at high risk of VTE, most of which accrues in the first few months. History of VTE, diabetes mellitus (type 1 or 2), impaired ambulatory status, or hemoglobin < 10 g/dL may predispose patients to this complication. While optimal management is uncertain, anticoagulation prevented recurrent VTE in most patients without intracranial bleeding.

Fluid attenuation in non-contrast-enhancing tumor (nCET): an MRI Marker for Isocitrate Dehydrogenase (IDH) mutation in Glioblastoma.

PURPOSE: The WHO 2016 update classifies glioblastomas (WHO grade IV) according to isocitrate dehydrogenase (IDH) gene mutation status. We aimed to determine MRI-based metrics for predicting IDH mutation in glioblastoma. METHODS: This retrospective study included glioblastoma cases (n = 199) with known IDH mutation status and pre-operative MRI (T1WI, T2WI, FLAIR, contrast-enhanced T1W1 at minimum). Two neuroradiologists determined the following MRI metrics: (1) primary lobe of involvement (frontal or non-frontal); (2) presence/absence of contrast-enhancement; (3) presence/absence of necrosis; (4) presence/absence of fluid attenuation in the non-contrast-enhancing tumor (nCET); (5) maximum width of peritumoral edema (cm); (6) presence/absence of multifocal disease. Inter-reader agreement was determined. After resolving discordant measurements, multivariate association between consensus MRI metrics/patient age and IDH mutation status was determined. RESULTS: Among 199 glioblastomas, 16 were IDH-mutant. Inter-reader agreement was calculated for contrast-enhancement (ĸ = 0.49 [- 0.11-1.00]), necrosis (ĸ = 0.55 [0.34-0.76]), fluid attenuation in nCET (ĸ = 0.83 [0.68-0.99]), multifocal disease (ĸ = 0.55 [0.39-0.70]), and primary lobe (ĸ = 0.85 [0.80-0.91]). Mean difference for peritumoral edema width between readers was 0.3 cm [0.2-0.5], p < 0.001. Multivariate analysis uncovered significant associations between IDH-mutation and fluid attenuation in nCET (OR 82.9 [19.22, ∞], p < 0.001), younger age (OR 0.93 [0.86, 0.98], p = 0.009), frontal lobe location (OR 11.08 [1.14, 352.97], p = 0.037), and less peritumoral edema (OR 0.15 [0, 0.65], p = 0.044). CONCLUSIONS: Conventional MRI metrics and patient age predict IDH-mutation status in glioblastoma. Among MRI markers, fluid attenuation in nCET represents a novel marker with high inter-reader agreement that is strongly associated with Glioblastoma, IDH-mutant.

MRI and CT Identify Isocitrate Dehydrogenase (IDH)-Mutant Lower-Grade Gliomas Misclassified to 1p/19q Codeletion Status with Fluorescence in Situ Hybridization.

Background Fluorescence in situ hybridization (FISH) is a standard method for 1p/19q codeletion testing in diffuse gliomas but occasionally renders erroneous results. Purpose To determine whether MRI/CT analysis identifies isocitrate dehydrogenase (IDH)-mutant gliomas misassigned to 1p/19q codeletion status with FISH. Materials and Methods Data in patients with IDH-mutant lower-grade gliomas (World Health Organization grade II/III) and 1p/19q codeletion status determined with FISH that were accrued from January 1, 2010 to October 1, 2017, were included in this retrospective study. Two neuroradiologist readers analyzed the pre-resection MRI findings (and CT findings, when available) to predict 1p/19q status (codeleted or noncodeleted) and provided a prediction confidence score (1 = low, 2 = moderate, 3 = high). Percentage concordance between the consensus neuroradiologist 1p/19q prediction and the FISH result was calculated. For gliomas where (a) consensus neuroradiologist 1p/19q prediction differed from the FISH result and (b) consensus neuroradiologist confidence score was 2 or greater, further 1p/19q testing was performed with chromosomal microarray analysis (CMA). Nine control specimens were randomly chosen from the remaining study sample for CMA. Percentage concordance between FISH and CMA among the CMA-tested cases was calculated. Results A total of 112 patients (median age, 38 years [interquartile range, 31-51 years]; 57 men) were evaluated (112 gliomas). Percentage concordance between the consensus neuroradiologist 1p/19q prediction and the FISH result was 84.8% (95 of 112; 95% confidence interval: 76.8%, 90.9%). Among the 17 neuroradiologist-FISH discordances, there were nine gliomas associated with a consensus neuroradiologist confidence score of 2 or greater. In six (66.7%) of these nine gliomas, the 1p/19q codeletion status as determined with CMA disagreed with the FISH result and agreed with the consensus neuroradiologist prediction. For the nine control specimens, there was 100% agreement between CMA and FISH for 1p/19q determination. Conclusion MRI and CT analysis can identify diffuse gliomas misassigned to 1p/19q codeletion status with fluorescence in situ hybridization (FISH). Further molecular testing should be considered for gliomas with discordant neuroimaging and FISH results. © RSNA, 2019 Online supplemental material is available for this article.

Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma.

The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

Automated apparent diffusion coefficient analysis for genotype prediction in lower grade glioma: association with the T2-FLAIR mismatch sign.

PURPOSE: The prognosis of lower grade glioma (LGG) patients depends (in large part) on both isocitrate dehydrogenase (IDH) gene mutation and chromosome 1p/19q codeletion status. IDH-mutant LGG without 1p/19q codeletion (IDHmut-Noncodel) often exhibit a unique imaging appearance that includes high apparent diffusion coefficient (ADC) values not observed in other subtypes. The purpose of this study was to develop an ADC analysis-based approach that can automatically identify IDHmut-Noncodel LGG. METHODS: Whole-tumor ADC metrics, including fractional tumor volume with ADC > 1.5 × 10-3mm2/s (VADC>1.5), were used to identify IDHmut-Noncodel LGG in a cohort of N = 134 patients. Optimal threshold values determined in this dataset were then validated using an external dataset containing N = 93 cases collected from The Cancer Imaging Archive. Classifications were also compared with radiologist-identified T2-FLAIR mismatch sign and evaluated concurrently to identify added value from a combined approach. RESULTS: VADC>1.5 classified IDHmut-Noncodel LGG in the internal cohort with an area under the curve (AUC) of 0.80. An optimal threshold value of 0.35 led to sensitivity/specificity = 0.57/0.93. Classification performance was similar in the validation cohort, with VADC>1.5 ≥ 0.35 achieving sensitivity/specificity = 0.57/0.91 (AUC = 0.81). Across both groups, 37 cases exhibited positive T2-FLAIR mismatch sign-all of which were IDHmut-Noncodel. Of these, 32/37 (86%) also exhibited VADC>1.5 ≥ 0.35, as did 23 additional IDHmut-Noncodel cases which were negative for T2-FLAIR mismatch sign. CONCLUSION: Tumor subregions with high ADC were a robust indicator of IDHmut-Noncodel LGG, with VADC>1.5 achieving > 90% classification specificity in both internal and validation cohorts. VADC>1.5 exhibited strong concordance with the T2-FLAIR mismatch sign and the combination of both parameters improved sensitivity in detecting IDHmut-Noncodel LGG.

Correction to: Neurological and Medical Complications in Brain Tumor Patients.

The order of the authors was inadvertently inverted; Dr. Alyahya is the intended first author.

Neurological and Medical Complications in Brain Tumor Patients.

PURPOSE OF REVIEW: Patients with brain tumors are susceptible to multiple complications that can affect their survival or quality of life. The scope of these complications is widening due to prolonged overall survival and improved therapies. In this review, we discuss the most common complications in this patient population focusing on the recent literature. We specifically concentrated on tumor-related epilepsy, vasogenic edema, infectious, vascular, chemotherapeutic, radiation, endocrine, and cognitive complications. RECENT FINDINGS: Molecular biomarkers play a role in epileptogenicity in brain tumor patients, and anti-epileptic drugs may cause neuro-cognitive side effects independent of other factors. The pathophysiology of vasogenic edema remains complex and poorly understood. Limited data suggest that newer oral anticoagulants appear to be safe and effective in venous and arterial thromboembolic complications. Brain tumor patients are prone to a wide variety of complications, including some related to new therapies. Optimal management of these complications improves quality of life, and in some cases overall survival.

A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872.

BACKGROUND: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. METHODS: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). RESULTS: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. CONCLUSIONS: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

Increased intratumoral infiltration in IDH wild-type lower-grade gliomas observed with diffusion tensor imaging.

PURPOSE: Diffuse lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) gene mutations (IDHMUT) have a distinct survival advantage compared with IDH wild-type (IDHWT) cases but the mechanism underlying this disparity is not well understood. Diffusion Tensor Imaging (DTI) has identified infiltrated non-enhancing tumor regions that are characterized by low isotropic (p) and high anisotropic (q) diffusion tensor components that associate with poor survival in glioblastoma. We hypothesized that similar regions are more prevalent in IDHWT (vs. IDHMUT) LGG. METHODS: p and q maps were reconstructed from preoperative DTI scans in N = 41 LGG patients with known IDH mutation and 1p/19q codeletion status. Enhancing and non-enhancing tumor volumes were autosegmented from standard (non-DTI) MRI scans. Percentage non-enhancing tumor volumes exhibiting low p and high q (Vinf) were then determined using threshold values (p = 2 × 10-3mm2/s, q = 3 × 10-4 mm2/s) and compared between IDHWT and IDHMUT LGG, and between IDHMUT LGG with and without 1p/19q codeletion. RESULTS: Vinf volumes were significantly larger in IDHWT LGG than in IDHMUT LGG (35.4 ± 18.3% vs. 15.9 ± 7.6%, P < 0.001). Vinf volumes did not significantly differ between IDHMUT LGG with and without 1p/19q codeletion (17.1 ± 9.5% vs. 14.8 ± 5.8%, P = 1.0). CONCLUSION: IDHWT LGG exhibited larger volumes with suppressed isotropic diffusion (p) and high anisotropic diffusion (q) which reflects regions with increased cell density but non-disrupted neuronal structures. This may indicate a greater prevalence of infiltrative tumor in IDHWT LGG.

Oligodendroglioma confers higher risk of radiation necrosis.

BACKGROUND: Radiation therapy (RT) remains a mainstay for the treatment of lower grade gliomas. Radiation neurotoxicity is a serious complication, carrying high morbidity in the absence of tumor progression. The incidence remains poorly categorized and known risk factors identified are related to the radiation modality. We hypothesized that patients with oligodendroglioma have a higher risk of radiation necrosis (RN) as compared to patients with astrocytoma. METHODS: We conducted a retrospective review of adults with lower grade diffuse gliomas over a 10-year span. The primary outcome was RN, either pathologically confirmed or clinically diagnosed. Cases without pathological confirmation must have been symptomatic, requiring administration of bevacizumab or high-dose steroids. Cox proportional hazard ratios were used for multivariate analyses. RESULTS: In 319 patients, we identified RN in 41 patients (12.9%): 28 patients (21.3%) with oligodendroglioma and 13 (6.9%) with astrocytoma (HR 3.42, p < 0.001). Patients with oligodendroglioma who received > 54 Gy had a higher incidence (31.2%) than those receiving ≤ 54 Gy (14.3%, HR 6.9, p = 0.002). There was no similar correlation among patients with astrocytoma. There was no difference in incidence based on use of concomitant temozolomide. Radiation necrosis appeared within 24 months from radiation in 80.5% of patients. CONCLUSION: Our study suggests that patients with oligodendroglioma are at higher risk of developing RN. The incidence increases with increasing radiation dose in patients with oligodendroglioma but not with astrocytoma. RN usually appears within 24 months from RT. Patients with oligodendroglioma receiving > 54 Gy are at highest risk.

Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma.

INTRODUCTION: We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM). METHODS: Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured in samples of tumor tissue, plasma, and cerebrospinal fluid (CSF). We analyzed tumor specimens obtained from the first (initial/pre-study) and second (recurrent/on-study) surgery by immunohistochemistry for Rb status and downstream signaling of CDK4/6 inhibition. Participants with Rb-positive recurrent tumors continued ribociclib treatment on a 21-day-on, 7-day-off schedule after surgery, and were monitored for toxicity and disease progression. RESULTS: Three participants with recurrent Rb-positive GBM participated in this study. Mean unbound (pharmacologically active) ribociclib concentrations in plasma, CSF, MRI-enhancing, MRI-non-enhancing, and tumor core regions were 0.337 µM, 0.632 µM, 1.242 nmol/g, 0.484 nmol/g, and 1.526 nmol/g, respectively, which exceeded the in vitro IC50 (0.04 µM) for inhibition of CDK4/6 in cell-free assay. Modulation of pharmacodynamic markers of ribociclib CDK 4/6 inhibition in tumor tissues were inconsistent between study participants. No participants experienced serious adverse events, but all experienced early disease progression. CONCLUSIONS: This study suggests that ribociclib penetrated recurrent GBM tissue at concentrations predicted to be therapeutically beneficial. Our study was unable to demonstrate tumor pharmacodynamic correlates of drug activity. Although well tolerated, ribociclib monotherapy seemed ineffective for the treatment of recurrent GBM.

FDG PET/MRI Coregistration Helps Predict Response to Gamma Knife Radiosurgery in Patients With Brain Metastases.

OBJECTIVE: The purpose of this study was to determine whether relative standardized uptake value (SUV) measurements at FDG PET/MRI coregistration are predictive of local tumor control in patients with brain metastases treated with stereotactic radiosurgery (SRS). MATERIALS AND METHODS: A retrospective review was conducted of the images and clinical characteristics of a cohort of patients with brain metastases from non-CNS neoplasms treated with gamma knife radiosurgery (GKRS) who underwent posttherapy FDG PET because of MRI findings concerning for progression. The PET and contrast-enhanced MR images were fused. Relative SUV measurements were calculated from ROIs placed in the area of highest FDG uptake within the enhancing lesion and in the contralateral normal-appearing white matter. Relative SUV was defined as the ratio of maximum SUV in the tumor to maximum SUV in healthy white matter. Two independent readers evaluated response to GKRS using serial posttherapy MRI performed at least 3 months after GKRS completion. The relation between relative SUV and local tumor progression was evaluated with respect to treatment effect. RESULTS: Eighty-five patients (48 [56.5%] women, 37 [43.5%] men; mean age at diagnosis, 60.5 ± 11.3 years) met the inclusion criteria. Thirty-three (38.8%) lesions progressed after SRS. There was a significant association between relative SUV and local tumor control (p = 0.035). Relative SUV provided a diagnostic ROC AUC of 0.67 (95% CI, 0.55-0.79). CONCLUSION: Quantitative relative SUV at posttherapy FDG PET serves as a biomarker of response to SRS in patients with brain metastases in cases in which lesion growth is identified at follow-up MRI. This prognostic data may affect management, supporting the need for further therapeutic actions for selected patients.