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.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan-Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases.

Systematic review of the management of brain metastases from hormone receptor positive breast cancer.

INTRODUCTION: Brain metastases are a common cause of morbidity and mortality in patients with breast cancer. Local central nervous system (CNS) directed therapies are usually the first line treatment for breast cancer brain metastases (BCBM), but those must be followed by systemic therapies to achieve long-term benefit. Systemic therapy for hormone receptor (HR+) breast cancer has evolved in the last 10 years, but their role when brain metastases occur is uncertain. METHODS: We performed a systematic review of the literature focused on management of HR+ BCBM by searching Medline/PubMed, EBSCO, and Cochrane databases. The PRISMA guidelines were used for systematic review. RESULTS: Out of 807 articles identified, 98 fulfilled the inclusion criteria in their relevance to the management of HR+ BCBM. CONCLUSIONS: Similar to brain metastases from other neoplasms, local CNS directed therapies are the first line treatment for HR+ BCBM. Although the quality of evidence is low, after local therapies, our review supports the combination of targeted and endocrine therapies for both CNS and systemic management. Upon exhaustion of targeted/endocrine therapies, case series and retrospective reports suggest that certain chemotherapy agents are active against HR+ BCBM. Early phase clinical trials for HR+ BCBM are ongoing, but there is a need for prospective randomized trials to guide management and improve patients' outcome.

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.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

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.

Melanoma brain metastasis mimicking cortical laminar necrosis.

Background: Metastatic lesions to the brain are common in patients with melanoma. Imaging characteristics can support the diagnosis of metastatic melanoma, but alternative diagnoses should be considered. Case Description: Here, we present a case of a 57-year-old man in whom a metastatic melanoma initially mimicked the imaging characteristics of cortical laminar necrosis. Conclusion: This comprises the first report of melanoma brain metastasis presenting with these imaging characteristics and emphasizes the importance of maintaining a high index of suspicion for metastatic lesions in patients with known cancer.

Proliferating CD8+ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma.

BACKGROUND: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. METHODS: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. RESULTS: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). CONCLUSIONS: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Systemic coagulation is activated in patients with meningioma and glioblastoma.

PURPOSE: Up to 30% of patients with glioblastoma (GBM) develop venous thromboembolism (VTE) over the course of the disease. Although not as high, the risk for VTE is also increased in patients with meningioma. Direct measurement of peak thrombin generation (TG) allows quantitative assessment of systemic coagulation activation in patients with GBM and meningioma. Our aim was to determine the extent of systemic coagulation activation induced by brain tumors, to measure the shift between pre- and post-operative peak TG in patients with GBM, and to assess the relationship between pre-surgical peak TG and pre-operative brain tumor volume on imaging. METHODS: Pre- and post-surgical plasma samples were obtained from successive patients with GBM and once from patients with meningioma and healthy age- and sex-matched blood donor controls. TG was measured using the calibrated automated thrombogram (CAT) assay, and tumor volumes were measured in pre-surgical MRI scans. RESULTS: Pre-surgical peak TG was higher in patients with GBM than in controls (288.6 ± 54.1 nM vs 187.1 ± 41.7 nM, respectively, P < 0.001), and, in the nine patients with GBM and paired data available, peak TG was significantly reduced after surgery (323 ± 38 nM vs 265 ± 52 nM, respectively, P = 0.007). Similarly, subjects with meningioma demonstrated higher peak TG compared to controls (242.2 ± 54.9 nM vs 177.7 ± 57.0 nM, respectively, P < 0.001). There was no association between peak TG and pre-operative tumor volume or overall survival. CONCLUSION: Our results indicate that systemic coagulation activation occurs with both meningioma and GBM, but to a greater degree in the latter. Preoperative peak TG did not correlate with tumor volume, but removal of GBM caused a significant decrease in coagulation activation.

Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS). METHODS: This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations. RESULTS: Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment. DISCUSSION: Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 + T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS.

Imaging Mimics of Brain Tumors.

Nonneoplastic entities may closely resemble the imaging findings of primary or metastatic intracranial neoplasia, posing diagnostic challenges for the referring provider and radiologist. Prospective identification of brain tumor mimics is an opportunity for the radiologist to add value to patient care by decreasing time to diagnosis and avoiding unnecessary surgical procedures and medical therapies, but requires familiarity with mimic entities and a high degree of suspicion on the part of the interpreting radiologist. This article provides a framework for the radiologist to identify "brain tumor mimics," highlighting imaging and laboratory pearls and pitfalls, and illustrating unique and frequently encountered lesions.

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.

Genesis of Quality Measurements to Improve the Care Delivered to Patients With Brain Metastases.

PURPOSE: High-value and high-quality health care requires outcome measurements to inform treatment decisions, but, to our knowledge, no standardized measurements exist to evaluate brain metastases (BMs) care. We propose a set of measurements and report on their implementation in the care of patients with BMs. METHODS: On the basis of a stakeholders' needs assessment and review of the literature, we identified outcome and process measurements to assess the care of patients with BMs according to treatment modality. Retrospectively, we applied these indicators of care to all patients diagnosed and treated at our institution over 2 years. RESULTS: We ascertained 5 outcome and 6 process measurements of relevance in the care of BMs. When applied to 209 patients (89.7%) who received cancer treatment, 77% were alive > 90 days after diagnosis. The proportion alive at 90 days after surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS) was 82%, 59%, and 81%, respectively. Other performance measurements included 30-day postoperative readmission rate (6%), SRS within 30 days of surgery (79%), use of memantine with WBRT (41%), advance directives within 6 months of diagnosis (53%), and palliative care consultation for patients with poor prognosis or receiving WBRT (45%). Measurements for the 24 patients (10.3%) receiving best supportive care were advance directives documentation (67%) and referral to palliative or hospice care (83%). CONCLUSION: We propose a set of measurements to apprise quality improvement efforts, inform treatment decision-making, and to use in evaluation of the performance of interdisciplinary BMs programs. Their refinement can potentially enhance the quality and value of care delivered to patients with BMs.

Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases.

PURPOSE/OBJECTIVE(S): Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor burden and outcomes in patients with brain metastases treated with TKIs. MATERIALS/METHODS: We identified and retrospectively reviewed cases of EGFR-mutant or ALK-rearranged lung cancer with brain metastases at any time during their cancer course. Clinical characteristics and treatment information were abstracted from the medical records. Brain metastases were contoured to calculate total volume of disease at diagnosis and after initial therapy. High intracranial burden was defined as either > 10 brain metastases, volume of brain metastases > 15 cc, or largest lesion > 3 cm. Intracranial response was determined according to Response Assessment in Neuro-Oncology (RANO) criteria on the patient level. We determined the correlation between clinical and imaging characteristics and intracranial progression free survival (IC-PFS) and overall survival (OS). RESULTS: Fifty-seven patients with EGFR (n = 49) and ALK (n = 8) alterations were identified. Median follow-up from initial brain metastasis diagnosis was 17 months. Neurological symptoms were present in 54% at brain metastasis diagnosis. For those receiving TKIs alone or TKIs with radiation, at least a partial intracranial response (≥ 65% volume reduction) at 3 months from starting therapy was achieved in 94% and 58%. Progressive intracranial disease at 3 months occurred in 6.3% and 8.3%. Patients with high intracranial burden (n = 21) had a median 17 brain metastases, 6.5 cc volume, and 1.9 cm maximal tumor diameter. Median IC-PFS and OS for patients with high intracranial burden was 13.9 and 35.4 months. Patients with high intracranial burden and neurological symptoms at diagnosis had similar IC-PFS and OS compared to those with low burden and absence of neurological symptoms (p > 0.05 for each). CONCLUSION: Most patients receiving TKIs as part of their initial therapy achieve an early and durable volumetric intracranial response, irrespective of presenting disease burden or neurologic symptoms.

Diffuse large B-cell lymphoma relapse presenting as extensive neurolymphomatosis.

A 56-year-old woman with a history of diffuse large B-cell non-Hodgkin lymphoma (DLBCL-NHL) in remission for two years presented with weight loss and multifocal sensory/motor symptoms. Magnetic resonance imaging (MRI) of the neuraxis and whole-body FDG PET/CT led to a diagnosis of secondary neurolymphomatosis (NL). MRI demonstrated extensive thickening and enhancement of multiple cranial nerves and peripheral nerve plexuses with corresponding elevated metabolism on FDG PET/CT. Treatment with chemotherapy resulted in complete response on FDG PET/CT and subsequently she underwent autologous stem cell transplantation. NL is a rare manifestation of lymphoma affecting the peripheral nervous system. Nonspecific neuropathic symptoms make clinical diagnosis difficult. Though nerve biopsy is considered the gold standard, MRI and FDG PET/CT are accepted alternatives for making the diagnosis. We review imaging findings in NL, describe the differential diagnosis, and discuss the limitations of the imaging modalities.

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.

Adaptive dose-finding based on safety and feasibility in early-phase clinical trials of adoptive cell immunotherapy.

BACKGROUND/AIMS: Dose feasibility is a challenge that may arise in the development of adoptive T cell therapies for cancer. In early-phase clinical trials, dose is quantified either by a fixed or per unit body weight number of cells infused. It may not be feasible, however, to administer a patient's assigned dose due to an insufficient number of cells harvested or functional heterogeneity of the product. The study objective becomes to identify the maximum tolerated dose with high feasibility of being administered. This article describes a new dose-finding method that adaptively accounts for safety and feasibility endpoints in guiding dose allocation. METHODS: We propose an adaptive dose-finding method that integrates accumulating feasibility and safety data to select doses for participant cohorts in early-phase trials examining adoptive cell immunotherapy. We sequentially model the probability of dose-limiting toxicity and the probability of feasibility using independent beta-binomial models. The probability model for toxicity borrows information across all dose levels using isotonic regression, allowing participants infused at a lower dose than his or her planned dose to contribute safety data to the dose-finding algorithm. We applied the proposed methodology in a single simulated trial and evaluated its operating characteristics through extensive simulation studies. RESULTS: In simulations conducted for a phase I study of adoptive immunotherapy for newly diagnosed glioblastoma, the proposed method demonstrates the ability to identify accurately the feasible maximum tolerated doses and to treat participants at and around these doses. Over 10 hypothesized scenarios studied, the percentage of correctly selecting the true feasible and maximum tolerated dose ranged from 50% to 90% with sample sizes averaging between 21 and 24 participants. A comparison to the only known existing method accounting for safety and feasibility yields competitive performance. CONCLUSION: We have developed a new practical adaptive dose-finding method to assess feasibility in early-phase adoptive cell therapy trials. A design that incorporates feasibility, as a function of the quantity and quality of the product manufactured, in addition to safety will have an impact on the recommended phase II doses in studies that evaluate patient outcomes.

Checkpoint inhibitor failure in hypermutated and mismatch repair-mutated recurrent high-grade gliomas.

BACKGROUND: Recurrent high-grade gliomas in adults remain a deadly cancer with median survival of less than 1 year. In the absence of effective agents, immunotherapy with checkpoint inhibitors has been adopted as a potentially beneficial next step for recurrences with hypermutated or mismatch repair-mutated phenotypes. The rationale for their use, however, is based on case reports and studies with other types of cancer. METHODS: We reviewed 4 cases of hypermutated or mismatch repair-mutated recurrent high-grade gliomas treated with checkpoint inhibitors. RESULTS: All cases had recurrent high-grade glioma that harbored either a hypermutated phenotype and/or a mismatch repair mutation. Treatment with checkpoint inhibitor therapy resulted in no significant response. CONCLUSIONS: In our experience, hypermutated or mismatch repair-mutated high-grade gliomas in adults do not respond to checkpoint inhibitors alone. This lack of efficacy is in agreement with underwhelming results of clinical trials examining checkpoint inhibitors in high-grade gliomas. The case reports of responders have been in pediatric patients with glioma and are likely a different subtype altogether.