Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2͞ 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. brain tumor ͉ microbubble A dvances in tumor cell biology have led to the availability of new types of anticancer chemotherapeutic agents that are superior to the conventional agents in that they can precisely target the signal-transduction system unique to malignant tumor cells, thereby lowering the toxic effects of anticancer agents on normal cells. Herceptin (trastuzumab; Genentech) is a humanized mAb that targets human epidermal growth factor receptor 2 (HER2͞c-erbB2) expressed in breast cancer cells. It has been used to treat breast cancer patients, and it has succeeded remarkably in controlling local and distal breast cancer lesions (1). Although breast cancer often metastasizes to the brain (2), Herceptin could only be used to treat extracranial lesions because there is currently no efficient method to deliver it to the CNS. The increased use of Herceptin to treat breast cancer patients has resulted in a higher incidence of brain metastasis from primary lesions (3, 4). When Herceptin was used as a first-line therapy in breast cancer patients, metastatic extracranial lesions responded to the agent in 71% of the patients who continued to develop metastatic lesions in the brain (3).The CNS is protected from the entry of foreign substances by the almost impenetrable blood-brain barrier (BBB) (5, 6), which hampers the delivery of potentially effective diagnostic or therapeutic agents and complicates the treatment of CNS diseases, including malignant brain diseases such as metastatic brain tumors. Because antibody-based agents with a molecular size of Ϸ150 kDa are easily blocked by the BBB, their delivery to the CNS requires the temporary suspension of the physiological role of the BBB to bar larger molecules from the CNS.Current advances in acoustic technology have made ultrasound a modality with therapeutic as well as diagnostic applicability. Focused ultrasound techniques facilitate the concentration of acoustic energy o...

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0351-2) contains supplementary material, which is available to authorized users.