Inclusion Criteria:
1. Subject is 18 years or older and has signed and dated the trial informed consent form (ICF)
2. Life expectancy ≥ 12 weeks
3. Subject is willing and able to comply with the trial testing, procedures, and follow-up schedule
4. History of a histologically confirmed diagnosis of glioblastoma per 2021 WHO criteria
5. Have radiographic evidence of tumor progression/recurrence with measurable disease (≥ 1 cm to ≤ 5cm bidirectional diameters) by contrast-enhancement on MRI, according to RANO criteria
6. Prior surgery and treatment with combination of radiotherapy and chemotherapy ± Tumor Treating Fields (Optune®)
7. Prior cranial radiation dose \< 66 Gy
8. WHO performance status ≤ 2
9. The interval since completion of cranial radiotherapy must be \> 6 months, unless there is tissue confirmation of tumor recurrence/progression outside the previous radiation treatment field, in which case the interval since completion of cranial radiation must be at least 12 weeks
10. Interval since last systemic therapy until presumed date of intervention ≥ 1 cycle or ≥ 2 biological half-lives, i.e.
1. ≥ 4 weeks since last dose of temozolomide
2. ≥ 6 weeks since last dose of lomustine or other nitrosourea
3. ≥ 2 weeks since last dose of a small molecule targeted agent (Tyrosine Kinase Inhibitor or similar)
4. ≥ 6 weeks from last dose of last intravenous bevacizumab infusion, or other antibody-based VEGF therapy
11. If receiving steroids, patient should be on a stable or decreasing dose equivalent to dexamethasone ≤ 6 mg/d, for at least 7 days prior to registration
12. Have adequate organ and bone marrow function within 14 days prior to registration, as defined below:
1. INR ≤ 1.2 (in absence of anticoagulation)
2. Platelets ≥ 100,000/L
3. Creatinine ≤1.5 mg/dL
4. Absolute Neutrophil Count ≥1.5 x 10\^9/L
5. Hemoglobin ≥9.0 g/dL
13. Have a negative pregnancy test within 14 days prior to registration on study (for FOCBP, female of child-bearing potential)
14. Subject is a male or non-pregnant female. If female of child-bearing potential, and if sexually active must be using, or agree to use, a medically acceptable method of birth control as confirmed by the investigator
15. Angiographic Mapping Inclusion Criteria:
1. Accessible neurovascular anatomy that allows for safe microcatheter placement (up to two locations) to infuse TheraSphere GBM to treat all of the T1 enhancing component of target lesion confirmed by neuro-interventional team.
2. Total treatment volume is ≤ 150cc as determined by multidisciplinary team.
16. Additional Inclusion Criteria:
1. Group A: perfused volume encompasses the non-dominant hemisphere and non-eloquent regions of the brain
2. Group B: perfused volume encompasses the non-dominant hemisphere and eloquent regions of the brain
3. Group C: perfused volume encompasses the dominant hemisphere and non-eloquent regions of the brain
4. Group D: perfused volume encompasses the dominant hemisphere and eloquent regions of the brain
Exclusion Criteria:
1. Have bilateral gadolinium enhancing disease, tumor located in the posterior fossa, tumor involving critical subcortical structures (thalamus/hypothalamus, midbrain, brainstem, corticospinal tract, internal capsule, cerebral peduncle), tumor approximating or invading the brainstem and/or optic chiasma, leptomeningeal disease, or extracranial metastatic disease
2. Have received more than 1 course of prior cranial radiotherapy (EBRT)
3. Have received radiosurgery, brachytherapy, or hypofractionated radiotherapy
4. Have received more than 2 systemic treatment protocols (lines of treatment), not including maintenance temozolomide
5. Have received prior intra-arterial cerebral infusion therapy
6. Have received more than 2 surgical GBM-related procedures
7. Have received prior thoracic radiation therapy
8. Are at increased risk of wound dehiscence by the discretion of the investigators (e.g. brain surgery within the last 3 months, poor skin condition, and/or previously infected surgical field or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)
9. Have uncontrolled epilepsy
10. Have severe and/or insufficiently controlled intercurrent illness; patients with the following are not eligible:
1. Hypertension grade 3 or higher without adequate control on medications
2. Symptomatic or unstable cardiac disease, known to have right-to-left shunts, or severe pulmonary hypertension (pulmonary artery pressure \> 90 mmHg)
3. Pulmonary insufficiency (arterial oxygen pressure (Pa,O2) of \< 60 mmHg, or oxygen saturation (Sa,O2) of \< 90%) as measured by fingertip pulse oximeter
4. Ongoing or active bacterial or viral infection requiring systemic treatment (including HIV)
5. Pneumonitis
6. Psychiatric illness/social situations that would limit compliance with study requirements
7. Peripheral Neuropathy ≥ grade 1
8. Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety, study endpoints or longevity
11. Are currently pregnant or breast feeding (unless patient agrees to stop breastfeeding)
12. Patients with a history of an active other malignancy within 1 year prior to registration. NOTE: Exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease, or recurrent glioblastoma
13. Patients with a history of ischemic cerebral disease and/or at risk of cerebral herniation
14. Medical contraindication to undergo contrast-enhanced magnetic resonance imaging (MRI)
15. Known history of hypersensitivity reactions to iodinated and/or gadolinium-based contrast
16. Subject has received any other investigational agents within 4 weeks of treatment, or is currently participating, or plans to participate in, another investigational trial that may confound the results of this trial (unless written approval is received from the Boston Scientific study team)
17. Angiographic Mapping Exclusion Criteria: Patients with significant vascular disease, significant AV shunting, or anatomic tortuosity on MR/CT Angiogram precluding safe or feasible vascular access
