Inclusion Criteria:
1. Adult male/female patients ≥ 20 years of age
2. Patients with histologically confirmed glioblastoma, recurrent after prior radiotherapy and temozolomide chemotherapy.
3. Patient may have been operated for recurrence. If operated: with measurable residual tumor
4. Minimum interval since completion of radiation treatment is 12 weeks
5. Patients if already on the steroids then should be on a stable dose of steroids for at least 7 days prior to study treatment
6. Body mass index (BMI) ≥17 kg / m2
7. Minimum interval since last drug therapy:
* 1 week for non-cytotoxic agents (e.g., interferon, tamoxifen), daily chemotherapy (e.g., metronomic temozolomide, cytoxan) or targeted therapies administered daily (e.g., gleevec, tarceva)
* 4 weeks since last cytotoxic therapy
* 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen (e.g., carmustine (BCNU))
8. Patients with life expectancy ≥ 3 months
9. The Karnofsky performance status (KPS) in the patient must be \> 60
10. Eastern Cooperative Oncology Group (ECOG) Score ≤ 2
11. Adequate hepatic, renal, coagulation, and hematopoietic function
* Hemoglobin ≥ 8 g/dL
* Platelets ≥ 100,000/mm3
* Neutrophils ≥ 1,500/mm3
* Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
* Urine protein creatinine (UPC) ratio \< 1 or urine dipstick for proteinuria ≤ 2+
* Alanine transaminase (ALT) \< 3 ULN
* Aspartate transaminase (AST) \< 3 x ULN
* Prothrombin time ≤ 1.2 x ULN
* International Normalized Ratio (INR) \< 1.5
* Bilirubin \< 2 x ULN
12. Patients with the region of interest (ROI) for FUS exposure are located close to the cortex with at least 20 mm distance beneath the skull bone and the ROI is not in the deep center brain with crucial brain functions, such as in the region of brain stem, or motor or speech regions
13. Patients with the potential for pregnancy and their partner must agree to use adequate contraception or be surgically sterile, or abstain from heterosexual activity starting with the first dose of treatment through at least 6 months after the last dose of BEV to avoid conception. Female patients of child-bearing potential must have a negative pregnancy test. Male patients must agree to use an adequate method of contraception starting with the first dose of treatment through 6 months after the last dose of BEV.
14. Able to give informed consent for the participation in the trial
Exclusion Criteria:
1. Patients who have had previous treatment with an inhibitor of vascular endothelial growth factor (VEGF) or VEGFR (including bevacizumab)
2. New York Heart Association (NYHA) Grade II or greater congestive heart failure requiring hospitalization within 12 months prior to screening
3. Severe hypertension at screening (diastolic blood pressure \> 100 mmHg on medication)
4. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, severe cerebral or myocardial infarction, cardiac shunt, heart attack within the previous 12 months, stroke (except for transient ischemic attack; TIA) within the previous 6 months, or psychiatric illness/social situations that would limit compliance with study requirements
5. Unstable pulmonary disease or Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of screening
6. Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain or documented clinically significant arrhythmias
7. Major surgery such as intra-thoracic, intra-abdominal or intra-pelvic (with the exception of craniotomy), open biopsy or significant traumatic injury ≤ 4 weeks prior to screening, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to screening, or who have not recovered from side effects of such procedure or injury
8. Known HIV positive patients, however, that HIV testing is not required for entry into this study
9. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of screening
10. Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within one week prior to beginning treatment
11. Pregnant or breast-feeding women
12. Known sensitivity/allergy to PET tracers, Magnetic Resonance Imaging (MRI) contrast agents, Computer Tomography (CT) contrast agents, SonoVue®, bevacizumab, or any of their components
13. Abnormal baseline findings considered by the investigator to indicate conditions that might affect study endpoints
14. Patients who have hemorrhage or cyst within the ROI
15. The receipt of an investigational drug within a period of 4 weeks prior to the first FUS exposure
16. Use of any recreational drugs or history of drug addiction
17. Any other condition that, in the investigator's judgment, might increase the risk to the patients or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study
