Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinasesALK,ROS1,NTRKandMET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harborRAS/MAPKpathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. JapicCTI-173646.

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

OBJECTIVE. To study the expression and function of L-type amino acid transporter 1 (LAT1), a major catalytic subunit of system L that is responsible for

This single-arm, open-label, Phase II study evaluated the efficacy and safety of single-agent bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in Japanese patients with recurrent malignant glioma. Patients with histologically confirmed, measurable glioblastoma or World Health Organization Grade III glioma, previously treated with temozolomide plus radiotherapy, received 10 mg/kg bevacizumab intravenous infusion every 2 weeks. The primary endpoint was 6-month progression-free survival in the patients with recurrent glioblastoma. Of the 31 patients enrolled, 29 (93.5%) had glioblastoma and 2 (6.5%) had Grade III glioma. Eleven (35.5%) patients were receiving corticosteroids at baseline; 17 (54.8%) and 14 (45.2%) patients had experienced one or two relapses, respectively. The 6-month progression-free survival rate in the 29 patients with recurrent glioblastoma was 33.9% (90% confidence interval, 19.2–48.5) and the median progression-free survival was 3.3 months. The 1-year survival rate was 34.5% with a median overall survival of 10.5 months. There were eight responders (all partial responses) giving an objective response rate of 27.6%. The disease control rate was 79.3%. Eight of the 11 patients taking corticosteroids at baseline reduced their dose or discontinued corticosteroids during the study. Bevacizumab was well-tolerated and Grade ≥3 adverse events of special interest to bevacizumab were as follows: hypertension [3 (9.7%) patients], congestive heart failure [1 (3.2%) patient] and venous thromboembolism [1 (3.2%) patient]. One asymptomatic Grade 1 cerebral hemorrhage was observed, which resolved without treatment. Single-agent bevacizumab provides clinical benefit for Japanese patients with recurrent glioblastoma.

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II–IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II–III astrocytoma, IDH-mutant, n = 9; and grade II–III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the “neoantigen expression ratio,” decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for “high-affinity,” “clonal,” and “passenger gene–derived” neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.