Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood–brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood–brain barrier under image guidance by using an MRI-guided focused ultrasound blood–brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

Aims: Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor‐κB (NF‐κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF‐κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.Methods: We conducted the systematic sequencing of 21 genes relevant to the NF‐κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.Results: The results showed that 68 out of 71 PCNSLs had mutations in the NF‐κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.Conclusions: The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B‐cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

Purpose: Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods: Patients age 20 to 79 years old with performance status scores of 0 to 2—and 3 if caused only by neurologic deficits—and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results: Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion: Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.