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| Name | Class |
|---|---|
| University of Kentucky | OTHER |
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To assess the overall safety and efficacy of intra-arterial (IA) bevacizumab for the treatment of radiation necrosis. A single 2.5 mg/kg dose of bevacizumab will be given intra-arterially after osmotic blood-brain-barrier disruption.
BACKGROUND Radiation Necrosis: Stereotactic radiosurgery has become integral in treatment of brain tumors and arteriovenous malformations (AVM). In up to 10% of cases, this can lead to radiation necrosis (RN) with significant surrounding vasogenic edema and mass effect. Medical treatment for RN includes steroids, vitamin E, pentoxiphylline, and hyperbaric oxygen. Up to 20% of cases however, are medically refractory and experience progressive neurological decline and disabling headaches.
Surgical resection and laser interstitial thermal therapy (LITT) are sometimes used for treatment of medically refractory radiation necrosis. These invasive options carry risks of serious complications such as infection, seizures, neurological deficits, and hemorrhage, and may have a failure rate as high as 39% in patients with radiation necrosis of the brain.
Bevacizumab: Bevacizumab (Avastin, Genentech BioOncology, South San Francisco, CA) is a recombinant humanized version of a murine anti-human vascular endothelial growth factor (VEGF) monoclonal antibody. Recently, bevacizumab was shown in a small randomized controlled trial (n=14) to be effective in treatment of refractory radiation necrosis after radiation therapy in brain tumors1. Patients received 7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles. All patients receiving Bevacizumab and none of the patients receiving placebo had significant clinical and radiographic improvement.
PRE-CLINICAL DATA Role of vascular endothelial growth factor (VEGF) in radiation necrosis VEGF has been implicated in the pathophysiology of radiation necrosis. Reactive astrocytes immediately surrounding the necrotic core in RN are strongly VEGF-positive by immunohistochemistry. It is postulated that radiation causes microvascular injury leading to hypoxia. Hypoxia-induced VEGF up-regulation then drives an increase in vascular permeability, leading to the extensive vasogenic edema seen in RN. Bevacizumab binds circulating VEGF receptors with high specificity, blocking the down-stream signaling cascade.
CLINICAL DATA:
Bevacizumab was originally developed and tested as an anti-angiogenic treatment for various solid tumors. More recently, IV-Bevacizumab was shown in a small, randomized controlled trial (n=14) to be very effective in treatment of refractory radiation necrosis after radiation therapy in brain tumors1. Patients received 7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles. All patients receiving Bevacizumab and none of the patients receiving placebo had significant clinical and radiographic improvement. This improvement was durable at 10 months in 8 of 11 patients (4 patients crossed over from the control group). There was however, a very high rate of adverse events (60%), and major adverse events (30%). Major adverse events included venous sinus thrombosis, pulmonary embolus, and aspiration pneumonia.
The investigators of the present study recently published a case series of two pediatric patients with highly symptomatic steroid refractory radiation necrosis in the brain after stereotactic radiosurgery for treatment of cerebral arteriovenous malformations3. Both patients were refractory to all accepted medical therapies. Both were steroid dependent for a prolonged period and severely cushingoid. Both had suffered a significant decline in quality of life with severe headache and needed to withdraw from school. In both instances, the patients made a remarkable progressive clinical and radiographic improvement after receiving a single 2.5 mg/kg dose of intra-arterial bevacizumab, which was durable one-year later. To increase bevacizumab penetration into the brain, the investigators used intra-arterial Mannitol to disrupt the blood-brain barrier immediately prior to targeted intra-arterial drug administration.
RATIONALE:
RATIONALE: CURRENT IV BEVACIZUMAB REGIMEN FOR RADIATION NECROSIS AND ITS ASSOCIATED MORBIDITY:
Current IV-bevacizumab regimens use a dose of 7.5 mg/kg every 3 weeks for 4 cycles. There are significant known side effects of bevacizumab including gastrointestinal perforation, deep venous thrombosis, venous sinus thrombosis, pulmonary embolus, intracranial hemorrhage, wound dehiscence, and severe hypertension. These complications are common to the anti-angiogenic class of drugs and reflect systemic exposure to bevacizumab. In our initial clinical experience, the investigators utilized a combination of intra-arterial (IA) route of delivery and BBB disruption to reduce bevacizumab dose while maintaining efficacy. This is supported by the durable clinical and radiographic response in our patients after a single 2.5 mg/kg dose of bevacizumab. The investigators believed that this approach would reduce the incidence of serious systemic toxicities compared to the IV-bevacizumab regimens (7.5-15 mg/kg every 2-3 weeks for several weeks to months).
There are multiple recent reports of patients with radiation necrosis who improved with IV-bevacizumab, only to relapse months later. In fact 3/11 patients in the randomized controlled trial discussed above required repeat treatment with IV-bevacizumab because of RN symptom progression1. In contrast, the two patients in our series who received IA-bevacizumab continue to show progressive clinical and radiographic improvement more than one year later. The investigators believe that the increased penetration of bevacizumab into the brain because of the intra-arterial administration after blood-brain barrier disruption results in binding of virtually all VEGF molecules. The fact that the results are durable and progressively improving suggests that massive blocking of VEGF activity could have stopped a positive feedback loop of inflammation. Therefore, IA-bevacizumab may result in more effective and durable control of radiation necrosis compared to traditional IV-bevacizumab treatment.
RATIONALE: INTRA-ARTERIAL (IA) ROUTE OF BEVACIZUMAB ADMINISTRATION SIGNIFICANTLY INCREASES DRUG DELIVERY TO THE BRAIN:
IA-therapy decreases volume dilution of the drug in the circulation and reduces first-pass degradation via proteolytic catabolism, resulting in higher drug delivery to target brain tissue. Super-selective IA-injection of 99mTc-HMPAO (Ceretec®) into human cerebral arteries achieves a concentration of radiotracer in brain tissue 50 times higher than with IV injection. In clinical studies of cerebral chemotherapy, the concentration delivered to the tumor by using intra-arterial injection versus intravenous administration of chemotherapeutic agents was five times higher with hydrosoluble drugs and up to 50 times higher with liposoluble drugs. The investigators will infuse bevacizumab in the artery that supplies the territory affected by RN, such as cervical internal carotid artery and/or cervical vertebral artery.
RATIONALE: BLOOD-BRAIN-BARRIER BREAKDOWN PRIOR TO INTRA-ARTERIAL THERAPY FURTHER ENHANCES DRUG DELIVERY TO THE BRAIN:
The blood-brain-barrier is a selective permeability barrier that block entry of many drugs into the brain. Bevacizumab is a monoclonal antibody with a high molecular weight (149 kDa). There is convincing evidence in the literature that the concentration in the brain of high molecular weight molecules can be significantly increased after osmotic BBB disruption. Several tumor clinical trials have shown that localization of monoclonal antibodies to the brain is poor without BBB disruption (0.0006%-0.0043% of the injected dose/g of tumor). There is also evidence of a 20-fold increase in permeability to immunoreactive IgM Mab with BBB disruption in rats. The investigators believe that using blood-brain-barrier disruption significantly increases delivery of Bevacizumab to the affected brain. The investigators will use the protocol described by Neuwelt and colleagues, using infusion of 25% Mannitol over 30 seconds. This protocol has been shown to temporarily disrupt the blood brain barrier, peaking at 15 minutes and dissipating in 4 hours. IA-chemotherapy following BBBD has been shown to be feasible and safe across multiple centers with low incidence of complications27. The efficacy and safety profile was reproducible across multiple centers. In fact, safety of this protocol has been established in more than 6000 patients treated worldwide with BBBD for intra-arterial chemotherapy infusion. The main possible complication is seizure, which occurs in <6% of cases. It is important to note that these seizures generally occurred in patients with widespread malignant pathology such as Glioblastoma and CNS lymphoma who were treated with very toxic chemotherapy agents immediately after BBBD. Recent refinements to the osmotic BBBD protocol have incorporated the use of general anesthesia, as well as prophylaxis with an anti-epileptic agent and Valium to reduce seizure threshold and the chance of seizures.
SAFETY OF CEREBRAL INTRA-ARTERIAL BEVACIZUMAB TREATMENT:
Safety of IA-Bevacizumab treatment after hyperosmotic BBBD was recently established in a series of malignant glioma patients. This was done through super-selective injection of intracranial tumor arterial pedicles for purpose of anti-tumor effects. Dose-escalation was performed from 2 mg/kg to 15 mg/kg without reaching maximal tolerated dose. There was a significant decrease in the contrast enhancing and FLAIR signal characteristics of the tumor and surrounding brain at one month after treatment. Overall toxicity for this cohort was comparable to previous reports for IV Bevacizumab therapy. Specifically, hyperosmotic BBB-breakdown followed by IA-Bevacizumab administration did not cause any direct neurotoxicity; there were no cases of intracranial hemorrhage. Multiple other reports of BBBD followed by intra-arterial bevacizumab treatment for other pathologies such as vestibular schwannoma, ependymoma, and malignant brainstem glioma have also demonstrated good safety profile with no obvious neurotoxicity.
TREATMENT PLAN:
VASCULAR ACCESS, CEREBRAL ANGIOGRAM, AND OSMOTIC BLOOD-BRAIN-BARRIER DISRUPTION:
The investigators will use the protocol described by Neuwelt and colleagues, using infusion of 25% Mannitol over 30 seconds. The safety of this protocol has been established in more than 6000 patients treated worldwide with BBBD for intra-arterial chemotherapy infusion.
The patients are to be premedicated with 6 mg Dexamethasone and 1000 mg Keppra. General endotracheal anesthesia will be induced. The femoral artery will be accessed using the Seldinger technique. A 5-French diagnostic catheter will be used to catheterize the cervical internal carotid artery ipsilateral to the area of radiation necrosis. Baseline internal carotid angiogram will be performed.
The anesthesiologist will be instructed to maintain SBP >120 or at pre-operative baseline, whichever value is higher. This is important for efficient bulk flow of drug through the blood brain barrier opening. The catheter is positioned at C1-2 level in the cervical internal carotid artery and C6-7 for a vertebral artery infusion. Optimal rate of Mannitol infusion will be determined by performing injection of contrast at 4 ml/sec for 3 seconds into vessel. If there is no reflux of contrast into the external carotid artery, the injection rate injection will be increased by 2 ml/sec to maximum of 12 ml/sec. The lowest rate at which there is reflux into the external carotid artery will be chosen (the rate to just exceed cerebral blood flow.
Next, 5 mg IV Valium and 0.2 mg IV Atropine are to be administered. Warm (37 degrees Co) 25% Mannitol is filtered through a 5-micron filter, and then infused into the ipsilateral cervical carotid artery at the rate determined above for a total of 30 seconds.
INTRA-ARTERIAL BEVACIZUMAB ADMINISTRATION:
Test injection of contrast will be done in the artery. If there is any evidence of catheter-induced vasospasm, the catheter may be withdrawn more proximally within the artery. Repeat test injection of contrast will be done to document resolution of vasospasm. Within 5 minutes of Mannitol infusion, 2.5 mg/kg bevacizumab in a volume of 100 ml will be administered into the artery over 10 minutes. Repeat angiogram will be performed to document BBBD, as well as to rule out thromboembolic phenomenon.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low-dose Intra-arterial Bevacizumab | Experimental | A single intra-arterial targeted dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 25% Mannitol | Drug | Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | Imaging response to therapy will be quantitatively assessed on MRI using volumetric analysis. Regions of T2 and FLAIR prolongation above contralateral white matter will be calculated and quantified in cubic centimeters. Region of interest (ROI) will be created using a semi-automated, thresholding and region-growing technique. Enhancement of the lesion will be calculated using similar volumetric ROI analysis with a contrast threshold of 40% above background and measured in cubic centimeters. | Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS TOTAL SCORE is the sum of Items 1 through 5. A Total Score of 0-5 signifies little or no disability, score of 6-10 signifies mild disability, score of 11-20 signifies moderate disability, and score of 21+ signifies severe disability. The theoretical maximum score would be 450. |
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Inclusion Criteria:
Patients must have radiation necrosis based on radiographic evidence defined as:
Other inclusion criteria include:
leukocytes greater than equal to1,500/mcL platelets greater than equal to 85,000/mcL creatinine less than equal to 1.8 mg/dl
•Birth Control: The effects of Bevacizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing age will have a urine pregnancy test immediately before each IA Bevacizumab treatment.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shervin R Dashti, MD,PhD | Norton Healthcare | Principal Investigator |
| Justin Fraser, MD | University of Kentucky | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Kentucky Medical Center | Lexington | Kentucky | 40536 | United States | ||
| Norton Brownsboro Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35426830 | Result | Dashti SR, Kadner RJ, Folley BS, Sheehan JP, Han DY, Kryscio RJ, Carter MB, Shields LBE, Plato BM, La Rocca RV, Spalding AC, Yao TL, Fraser JF. Single low-dose targeted bevacizumab infusion in adult patients with steroid-refractory radiation necrosis of the brain: a phase II open-label prospective clinical trial. J Neurosurg. 2022 Apr 15;137(6):1676-1686. doi: 10.3171/2022.2.JNS212006. Print 2022 Dec 1. |
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This was a single-arm study. There was no wash out or run-in period after enrollment. There was no assignment to groups.
Adults recruited from outpatient medical clinics at 2 academic medical centers (5 subjects per center) between Nov 2016 and Jan 2018. Enrollment was closed once 10 adult subjects were enrolled.
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| ID | Title | Description |
|---|---|---|
| FG000 | Low-dose Intra-arterial Bevacizumab | A single intra-arterial dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Low-dose Intra-arterial Avastin (Bevacizumab) | A single intra-arterial dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age at enrollment, years |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | Imaging response to therapy will be quantitatively assessed on MRI using volumetric analysis. Regions of T2 and FLAIR prolongation above contralateral white matter will be calculated and quantified in cubic centimeters. Region of interest (ROI) will be created using a semi-automated, thresholding and region-growing technique. Enhancement of the lesion will be calculated using similar volumetric ROI analysis with a contrast threshold of 40% above background and measured in cubic centimeters. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All were treated with steroids prior to study enrollment. | Posted | Mean | Standard Deviation | cm^3 | Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab) |
|
1 year
Adverse Event Monitoring performed on Day 0, Day 1, Week 6, Month 3, and Month 12
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low-dose Intra-arterial Bevacizumab | A single intra-arterial dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Month 6 Pt 20 min non-responsive but appeared awake. Ambulance. Brain MRI decr edema no acute infarct or hemorrh. D/C home. Another Pt month 6 seizure activity w dizziness, chest pain, left jaw pain and left arm pain and numbness, double vision |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| 1st degree AV block | Cardiac disorders | CTCAE v3.0 Term | Systematic Assessment |
Pilot Phase 2 Single Arm Clinical Trial with small number of patients. Not powered sufficiently to provide definitive proof for change in current standard of care of medically refractory radiation necrosis of the brain.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Shervin R. Dashti, MD, PhD, Principal Investigator | Norton Neuroscience Institute | 502-394-6390 | shervin.dashti@nortonhealthcare.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 21, 2016 | Sep 1, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 8, 2018 | Sep 1, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D001165 | Arteriovenous Malformations |
| ID | Term |
|---|---|
| D054079 | Vascular Malformations |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D008353 | Mannitol |
| D000068258 | Bevacizumab |
| ID | Term |
|---|---|
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
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| Low-dose Intra-arterial Bevacizumab | Drug | Route of administration: In this study, the second step of the treatment will be administering intra-arterial targeted bevacizumab into the appropriate cervical artery. |
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| Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Change in Headache Associated Morbidity Measured With MIDAS DAYS of HEADACHE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months. | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS PAIN LEVEL is Item 7 which rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be. | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | Quantitative change in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with 36 indicating minimum headache impact and the max score of 78 indicating worst possible headache impact. | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab | Quantitative change in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100 where 0 is dead and 100 is fully alive and normal with no complaints and no evidence of disease. | Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Change in Steroid Usage After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | To assess the utility of intra-arterial (IA) bevacizumab treatment in allowing decreased steroid usage, total cumulative days of steroid usage were compared between the 12 months PRIOR TO and the 12 months IMMEDIATELY FOLLOWING IA bevacizumab. Days of steroid usage were tabulated via medical history and chart review at the baseline visit for the 12 months prior to IA bevacizumab and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12 for the 12 month total after IA bevacizumab treatment. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of any dose were included in the cumulative summation. | 12 months prior to single dose of IA bevacizumab; 12 months following single dose of IA bevacizumab |
| Post-operative Neurocognitive Change After Intra-arterial Bevacizumab | In order to investigate post-operative changes in Neurocognitive performance after intra-arterial bevacizumab, patients who consented underwent formal neuropsychological battery testing. Sixteen subtests from the Neuropsychological Assessment Battery (Stern & White, PAR Inc.) were chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). For each subtest, T-score = 50 is the normative mean with SD = 10. Thus T-scores of 40-60 are within one standard deviation of the mean and are considered generally normal. Scores increasingly below 40 indicate decreased neurocognitive performance compared to healthy demographically matched persons. Scores significantly above 60 indicate increase neurocognitive performance compared to healthy demographically matched persons. | Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab) |
| Louisville |
| Kentucky |
| 40242 |
| United States |
| Standard Deviation |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| MRI of Brain: volume of radiation necrosis | Mean | Standard Deviation | cubic centimeters, or cm^3 |
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| MRI of Brain: volume of edema | Mean | Standard Deviation | cubic centimeters, or cm^3 |
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| Headache severity via Migraine Disability Assessment (MIDAS) TOTAL SCORE | MIDAS (Migraine Disability Assessment) is a 7-item tool that measures how severely headaches prevented or interfered with normal activity over the past 3 months. For each item 1 through 5 the min score=0 days, max score=90 days. The MIDAS TOTAL SCORE sums items 1 - 5 only. TOTAL SCORE of 0-5 indicates little or no disability. Total Score of 6-10 indicates mild disability. Total Score of 11-20 indicates moderate disability. Total score of 21+ indicates severe disability. Theoretical Max Total Score is 450 days. | Mean | Standard Deviation | units on a scale from 0 to 450 |
|
| DAYS of Headache via Migraine Disability Assessment (MIDAS) | MIDAS (Migraine Disability Assessment) questionnaire is a 7-item tool that measures how severely headaches prevented or interfered with normal activity over the past 3 months. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months. | Mean | Standard Deviation | Days of headache over past 3 months |
|
| Headache PAIN LEVEL via Migraine Disability Assessment (MIDAS) | MIDAS (Migraine Disability Assessment) is a 7-item tool that measures how severely headaches prevented or interfered with normal activity over the past 3 months. Item 7 rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be. | Mean | Standard Deviation | units on a scale from 0 to 10 |
|
| Headache severity via Headache Impact Test (HIT-6) | The Headache Impact Test-6 is a tool used to measure the impact headaches have on a patient's ability to function in their normal daily life. This 6-item questionnaire was designed to help patients describe and communicate the way they feel and what they cannot do because of their headaches. For each item, patients must select one answer: never, rarely, sometimes, very often, or always. Scores range from min of 36 indicating minimum headache impact, to a max of 78 indicating worst possible headache impact. A score of 60 or more indicates headaches having a very severe impact on daily life. | Mean | Standard Deviation | units on a scale from 36 - 78 |
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| Cumulative Days of Steroid use during 12 months Pre-Bevacizumab | Total cumulative days of steroid usage were compared between the 12 months prior to and the 12 months immediately following targeted IA-bevacizumab. Days of steroid usage was tabulated via medical history and chart review at the baseline visit, and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of any dose were included in the cumulative summation. | Median | Inter-Quartile Range | Days |
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| Karnofsky Performance Status Scale | The Karnofsky Performance Status Scale allows patients to be classified as to their functional impairment. The lower the score, the worse the survival for most serious illnesses. Scores range from 0% to 100% where 100%=Normal with no complaints, no evidence of disease. 90%=Able to carry on normal activity; minor signs or symptoms of disease. 80%=Normal activity with effort; some signs or symptoms of disease. 70% = cares for self; unable to carry on normal activity or to do active work. 60%=Requires occasional assistance, but is able to care for most of his personal needs and 0%=Dead. | Mean | Standard Deviation | % on Karnofsky scale |
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| Digits Forward via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically adjusted, normalized battery of tests which measure neurocognitive function. The Digits Forward module generates T scores which indicate the degree to which immediate auditory attention is higher or lower than that of healthy demographically matched individuals in the normative sample. T-score of 50 is the mean and is considered normal. Scores significantly below 40 indicate decreased auditory attention. Scores significantly above 60 indicate better auditory attention than healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Digits Backward via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically adjusted, normalized battery of tests which measure neurocognitive function. The Digits Backward module generates T scores which indicate the degree to which auditory working memory is stronger or weaker than that of a healthy demographically matched individual in the normative sample. T-score of 50 is equal to the mean and is considered normal. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Numbers and Letters Speed via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically adjusted normalized battery of tests which measure neurocognitive function. Numbers & Letters Speed module is an excellent general indicator of speed and efficiency of information processing. T scores indicate the degree to which info processing speed differs from that of healthy demographically matched individuals. T-scores of 40-60 are within 1 SD of the mean (50) and are considered normal. Scores below 40 indicate decreased processing speed. Scores above 60 indicate more rapid processing speed. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Numbers and Letters Errors via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Numbers & Letters ERRORS module measures the extent of errorful processing. Errorful processing is considered "inefficient". T scores indicate the degree to which processing efficiency differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Numbers and Letters Efficiency via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Numbers & Letters EFFICIENCY module compares error detection to time. Greater "efficiency" defined as minimal errors during rapid processing. Slow, errorful processing is considered "inefficient". T scores indicate the degree to which processing efficiency differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores below 40 indicate decreased info processing efficiency. Scores above 60 indicate more efficient processing. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Naming via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Naming module measures language processing. Errorful naming is considered inefficient language processing. T scores indicate the degree to which language processing differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| List Learning List Immediate Recall via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The List Learning List Immediate Recall module is one measure of short term memory. T scores indicate the degree to which short term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| List Learning List Long Delayed Recall via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The List Learning List Long Delayed Recall module is one measure of long term memory. T scores indicate the degree to which long term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Shape Learning Immediate Recognition via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The Shape Learning Immediate Recognition module is another measure of short term memory. T scores indicate the degree to which short term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Shape Learning Delayed Recognition via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The Shape Learning Delayed Recognition module is another measure of long term memory. T scores indicate the degree to which long term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Story Learning Phrase Unit Immediate Recall via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The Story Learning Phrase Unit Immediate Recall module is another measure of short term memory. T scores indicate the degree to which short term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Story Learning Phrase Unit Delayed Recall via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The Story Learning Phrase Unit Delayed Recall module is another measure of long term memory. T scores indicate the degree to which long term memory differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Design Construction via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Design Construction module is one measure of visuospatial processing. T scores indicate the degree to which visuospatial processing differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Mazes via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Mazes module is one measure of executive functioning. T scores indicate the degree to which executive functioning differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Categories via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. Categories module is another measure of executive functioning. T scores indicate the degree to which executive functioning differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Word Generation via Neuropsychological Assessment Battery | The Neuropsychological Assessment Battery is a comprehensive, demographically normalized battery of tests of neurocognitive function. The Word Generation module is another measure of executive functioning. T scores indicate the degree to which executive functioning differs from that of healthy demographically matched individuals. T-score of 50 is the mean. Scores significantly below 40 indicate decreased performance. Scores significantly above 60 indicate stronger ability compared to healthy demographically matched persons. | Mean | Standard Deviation | T score with Mean=50, SD=10 |
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| Full Scale Intelligence Quotient (FSIQ) via Wechsler Test of Adult Reading | The Wechsler Test of Adult Reading is a test of cognitive ability. The full scale intelligence quotient (FSIQ) estimate was obtained at Baseline to provide an estimate of premorbid cognitive functioning and to serve as a covariate for neurocognitive analyses. FSIQ population mean =100, SD = 15. By convention scores 130- 210 are very superior; 120-129 superior; 110-119 high average. Scores 90-109 are considered to be in the "average" range. Scores 80-89 are low average; 70-79 borderline; 28-69 are classified as extremely low. | Mean | Standard Deviation | units on a scale from 28 to 210 |
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A single intra-arterial dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery. |
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| Secondary | Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS TOTAL SCORE is the sum of Items 1 through 5. A Total Score of 0-5 signifies little or no disability, score of 6-10 signifies mild disability, score of 11-20 signifies moderate disability, and score of 21+ signifies severe disability. The theoretical maximum score would be 450. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. | Posted | Mean | Standard Deviation | score on a scale | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| Secondary | Change in Headache Associated Morbidity Measured With MIDAS DAYS of HEADACHE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. | Posted | Mean | Standard Deviation | Days | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| Secondary | Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured. | We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS PAIN LEVEL is Item 7 which rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. | Posted | Mean | Standard Deviation | score on a scale | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| Secondary | Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | Quantitative change in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with 36 indicating minimum headache impact and the max score of 78 indicating worst possible headache impact. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All 10 received single treatment of low dose intra-arterial bevacizumab. | Posted | Mean | Standard Deviation | score on a scale | Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| Secondary | Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab | Quantitative change in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100 where 0 is dead and 100 is fully alive and normal with no complaints and no evidence of disease. | 10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All were treated with steroids prior to study enrollment. | Posted | Mean | Standard Deviation | units on a scale | Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| Secondary | Change in Steroid Usage After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) | To assess the utility of intra-arterial (IA) bevacizumab treatment in allowing decreased steroid usage, total cumulative days of steroid usage were compared between the 12 months PRIOR TO and the 12 months IMMEDIATELY FOLLOWING IA bevacizumab. Days of steroid usage were tabulated via medical history and chart review at the baseline visit for the 12 months prior to IA bevacizumab and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12 for the 12 month total after IA bevacizumab treatment. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of any dose were included in the cumulative summation. | 10 adult patients age 31.0 (IQR 24.3, 42.8) years, including 8 (80%) women, 2 (20%) men, 9 (90%) white, 1 (10%) black, 9 (90%) Non-Hispanic, and 1 (10%) Hispanic | Posted | Median | Inter-Quartile Range | Days | 12 months prior to single dose of IA bevacizumab; 12 months following single dose of IA bevacizumab |
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| Secondary | Post-operative Neurocognitive Change After Intra-arterial Bevacizumab | In order to investigate post-operative changes in Neurocognitive performance after intra-arterial bevacizumab, patients who consented underwent formal neuropsychological battery testing. Sixteen subtests from the Neuropsychological Assessment Battery (Stern & White, PAR Inc.) were chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). For each subtest, T-score = 50 is the normative mean with SD = 10. Thus T-scores of 40-60 are within one standard deviation of the mean and are considered generally normal. Scores increasingly below 40 indicate decreased neurocognitive performance compared to healthy demographically matched persons. Scores significantly above 60 indicate increase neurocognitive performance compared to healthy demographically matched persons. | 10 adult subjects, 2 male and 8 female, 1 black and 9 white, 1 Hispanic and 9 non-Hispanic, recruited from outpatient medical clinics at 2 academic medical centers (5 subjects per center) between Nov 2016 and Jan 2018. 2 subjects experienced progression of radiation necrosis requiring intervention at approx. month 11. Their 12-month data are not included in the Neurocognitive reporting. | Posted | Mean | Standard Deviation | T score where mean T=50, SD=10 | Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab) |
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| 0 |
| 10 |
| 6 |
| 10 |
| 9 |
| 10 |
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| Acute encephalopathy | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Pt admitted month 9 for 1-Confusion 2-Intermittent diaphoresis 3-Heat/cold intolerance 4-Mild abd Pain 5-Vomiting 6-Unsteadiness. Brain CT/MRI no sig change target area, age related ischemic changes. Workup neg. Meds held pt improved D/Ced home. |
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| Double Vision | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Double vision on Day 1 with dizziness reported after transferred into TCU per protocol. Investigator notified, patient transferred to ICU, symptoms resolved 2 hours after onset. |
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| Chest Pain | Cardiac disorders | CTCAE v3.0 Term | Systematic Assessment | Pt has history of chest pain but symptoms worsened and were associated with Month 6 episode of seizures |
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| Headache | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Month 9 Pt having recurrent worsening headaches, Brain MRI showed peri-lesion radiation necrosis with residual AVM. Pt opted for surgical resection of simple supra-tentorial AVM and Radiation necrosis in the Perisylvian and insular region. |
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| Dizziness | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Day 1 Double vision with dizziness reported after transferred into TCU per protocol. Investigator notified, patient transferred to ICU, symptoms resolved 2 hours after onset. |
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| Dysarthria | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Day 1 Pt developed acute onset Dysarthria followed by Lt. UE and LE Hemiparesis. Evaluated in ED, Brain CT/MRI and EEG revealed no sig changes, Hospitalized x 8 d started on steroids and Keppra (for poss seizure) weakness improved to LUE 5/5, LLE 3/5 |
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| Left Lower Extremity Hemiparesis | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Day 1 Pt developed acute onset Dysarthria followed by Lt. UE and LE Hemiparesis. Evaluated in ED, Brain CT/MRI and EEG revealed no sig changes, Hospitalized x 8 d started on steroids and Keppra (for poss seizure) weakness improved to LUE 5/5, LLE 3/5 |
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| Left Upper Extremity Hemiparesis | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Day 1 Pt developed acute onset Dysarthria followed by Lt. UE and LE Hemiparesis. Evaluated in ED, Brain CT/MRI and EEG revealed no sig changes, Hospitalized x 8 d started on steroids and Keppra (for poss seizure) weakness improved to LUE 5/5, LLE 3/5 |
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| Cerebral Edema | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Month 8 Pt having symptoms of cerebral edema, Brain MRI showed interval increase in edema and radiation necrosis. Pt opted for 2 cycles of IV Avastin with subsequent improvement in symptoms and MRI findings. |
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| Acne | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Acne Related to Decadron |
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| Altered Mental Status | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Amnesia | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Anxiety | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Asthma episode | Respiratory, thoracic and mediastinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Bilateral lower leg edema | Vascular disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Blurred vision | Eye disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Cervical strain | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Cervical strain due to MVA |
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| Confusion | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Decreased appetite | Gastrointestinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Dehydration | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Diplopia | Eye disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Expressive aphasia | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Fall | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Fracture Left Hand | Injury, poisoning and procedural complications | CTCAE v3.0 Term | Systematic Assessment |
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| Headache | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | 1 episode Frontal Headache from MVA; 1 episode Headache; 1 episode Right sided headache; 1 episode Headaches with vertigo; 3 episodes worsening headache |
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| Generalized Anxiety | Psychiatric disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Generalized Malaise | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| hair loss | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Hallucinations | Psychiatric disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Head Trauma | Injury, poisoning and procedural complications | CTCAE v3.0 Term | Systematic Assessment |
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| Hypercholesterolemia | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Hypersomnia | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Hypertension | Cardiac disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Hypertriglyceridemia | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Inability to focus | Eye disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Inability to focus attention | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Incomplete Spontaneous Abortion | Pregnancy, puerperium and perinatal conditions | CTCAE v3.0 Term | Systematic Assessment |
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| Dizziness | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Increased dizziness |
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| Eye twitches | Eye disorders | CTCAE v3.0 Term | Systematic Assessment | Left eye twitches |
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| Homonymous Hemianopia | Eye disorders | CTCAE v3.0 Term | Systematic Assessment | Left Homonymous Hemianopia |
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| Leg skin tear non-healing wound | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Left Leg skin tear non-healing wound |
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| Leg traumatic injury | Injury, poisoning and procedural complications | CTCAE v3.0 Term | Systematic Assessment | Left leg traumatic injury |
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| Loss of appetite | Gastrointestinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Loss of vision | Eye disorders | CTCAE v3.0 Term | Systematic Assessment | loss of vision X 30 seconds |
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| Lower Back pain | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Major Depressive Disorder | Psychiatric disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | CTCAE v3.0 Term | Systematic Assessment | Mild Abdominal Pain |
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| Nausea | Gastrointestinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Neck stiffness | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Nosebleeds | General disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Panic attacks | Psychiatric disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Personality Changes | Psychiatric disorders | CTCAE v3.0 Term | Systematic Assessment | Personality Changes including anger |
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| Pregnancy | Pregnancy, puerperium and perinatal conditions | CTCAE v3.0 Term | Systematic Assessment |
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| Numbness | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | 1 episode Intermittent Numbness in the bottom; 1 episode Whole body numbness |
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| Scalp Pain | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Left vertex scalp soreness |
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| Ankle sprain due to fall | Injury, poisoning and procedural complications | CTCAE v3.0 Term | Systematic Assessment | Right ankle sprain due to fall |
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| Hip Pain | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Right Hip Radiating Pain |
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| Inner Ear pain | Ear and labyrinth disorders | CTCAE v3.0 Term | Systematic Assessment | Right Inner Ear pain |
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| Knee pain | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment | right knee pain from MVA |
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| Cold sensation leg | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Right leg cold sensation knee to foot |
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| Leg cramps | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Leg Muscle aches | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Right Leg Muscle aches |
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| Partial toenail ingrown | Musculoskeletal and connective tissue disorders | CTCAE v3.0 Term | Systematic Assessment | Right partial toenail ingrown |
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| Calf muscle loss of tone | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment | Rt Calf muscle loss of tone |
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| Seizures | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Generalized Seizures | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Tonic/clonic Seizures | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Shot term memory problems | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Steroid Induced Hyperglycemia | Endocrine disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Vision loss in left eye | Eye disorders | CTCAE v3.0 Term | Systematic Assessment | temporary vision loss in left eye |
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| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Traumatic Fall | Injury, poisoning and procedural complications | CTCAE v3.0 Term | Systematic Assessment |
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| Trouble performing simple tasks | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Unsteadiness | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Upper Respiratory Infection | Respiratory, thoracic and mediastinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Urinary incontinence | Renal and urinary disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Visual seizure | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Weight Loss | Metabolism and nutrition disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Whole body shaking associated with seizures | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Worsening Acne on extremities | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Worsening chest pain | Cardiac disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Worsening of left sided weakness | Nervous system disorders | CTCAE v3.0 Term | Systematic Assessment |
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| Worsening of striae bilateral arms | Skin and subcutaneous tissue disorders | CTCAE v3.0 Term | Systematic Assessment |
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Not provided
Not provided
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D061067 |
| Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Title | Measurements |
|---|---|
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| MIDAS TOTAL at 6 months |
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| MIDAS TOTAL at 9 months |
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| MIDAS TOTAL at 12 months |
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| MIDAS DAYS of HEADACHE at 6 months |
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| MIDAS DAYS of HEADACHE at 9 months |
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| MIDAS DAYS of HEADACHE at 12 months |
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| Title | Measurements |
|---|---|
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| MIDAS PAIN LEVEL at 6 months |
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| MIDAS PAIN LEVEL at 9 months |
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| MIDAS PAIN LEVEL at 12 months |
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| Headache Impact Test-6, 3 months |
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| Headache Impact Test-6, 6 months |
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| Headache Impact Test-6, 9 months |
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| Headache Impact Test-6, 12 months |
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| Karnofsky at Month 3 |
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| Karnofsky at Month 12 |
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| Digits Forward at 12 months |
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| Digits Backward at Baseline |
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| Digits Backward at 3 months |
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| Digits Backward at 12 months |
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| Numbers & Letters SPEED at Baseline |
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| Numbers & Letters SPEED at 3 months |
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| Numbers & Letters SPEED at 12 months |
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| Numbers & Letters Errors at BASELINE |
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| Numbers & Letters Errors at 3 months |
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| Numbers & Letters Errors at 12 months |
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| Numbers & Letters EFFICIENCY at Baseline |
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| Numbers & Letters EFFICIENCY at 3 Months |
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| Numbers & Letters EFFICIENCY at 12 months |
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| Naming at BASELINE |
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| Naming at 3 months |
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| Naming at 12 months |
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| List Learning List Immediate Recall at BASELINE |
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| List Learning List Immediate Recall at 3 months |
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| List Learning List Immediate Recall at 12 months |
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| List Learning List Long Delayed Recall at BASELINE |
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| List Learning List Long Delayed Recall at 3 months |
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| List Learning List Long Delayed Recall at 12 months |
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| Shape Learning Immediate Recognition at BASELINE |
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| Shape Learning Immediate Recognition at 3 months |
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| Shape Learning Immediate Recognition at 12 months |
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| Shape Learning Delayed Recognition at BASELINE |
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| Shape Learning Delayed Recognition at 3 months |
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| Shape Learning Delayed Recognition at 12 months |
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| Story Learning Phrase Unit Immediate Recall at BASELINE |
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| Story Learning Phrase Unit Immediate Recall at 3 months |
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| Story Learning Phrase Unit Immediate Recall at 12 months |
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| Story Learning Phrase Unit Delayed Recall at BASELINE |
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| Story Learning Phrase Unit Delayed Recall at 3 months |
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| Story Learning Phrase Unit Delayed Recall at 12 months |
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| Design Construction at BASELINE |
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| Design Construction at 3 months |
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| Design Construction at 12 months |
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| Mazes at BASELINE |
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| Mazes at 3 months |
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| Mazes at 12 months |
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| Categories at BASELINE |
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| Categories at 3 months |
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| Categories at 12 months |
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| Word Generation at BASELINE |
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| Word Generation at 3 months |
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| Word Generation at 12 months |
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| DIGITS BACKWARD: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the DIGITS BACKWARD variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 3.78 | 0.100 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.602 | 2-Sided | Other |
| NUMBERS & LETTERS SPEED: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS SPEED variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 2.847 | 0.149 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.532 | 2-Sided | Other |
| NUMBERS & LETTERS ERRORS: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS ERRORS variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 6.470 | 0.041 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.721 | 2-Sided | Other |
| NUMBERS & LETTERS EFFICIENCY: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS EFFICIENCY variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F (2,5) = 3.256 | 0.124 | partial eta^2 | 0.566 | 2-Sided | Other |
| NAMING: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NAMING variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.110 | 0.898 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.042 | 2-Sided | Other |
| LIST LEARNING LIST IMMEDIATE RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the LIST LEARNING LIST IMMEDIATE RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.299 | 0.754 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.107 | 2-Sided | Other |
| LIST LEARNING LIST LONG DELAYED RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the LIST LEARNING LIST LONG DELAYED RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 7.556 | 0.031 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.751 | 2-Sided | Other |
| SHAPE LEARNING IMMEDIATE RECOGNITION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the SHAPE LEARNING IMMEDIATE RECOGNITION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 1.018 | 0.426 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.289 | 2-Sided | Other |
| SHAPE LEARNING DELAYED RECOGNITION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the SHAPE LEARNING DELAYED RECOGNITION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 1.412 | 0.326 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.361 | 2-Sided | Other |
| STORY LEARNING PHRASE UNIT IMMEDIATE RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the STORY LEARNING PHRASE UNIT IMMEDIATE RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.247 | 0.790 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.090 | 2-Sided | Other |
| STORY LEARNING PHRASE UNIT DELAYED RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the STORY LEARNING PHRASE UNIT DELAYED RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.786 | 0.505 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.239 | 2-Sided | Other |
| DESIGN CONSTRUCTION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the DESIGN CONSTRUCTION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 4.362 | 0.080 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.636 | 2-Sided | Other |
| MAZES: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the MAZES variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 5.654 | 0.052 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.693 | 2-Sided | Other |
| CATEGORIES: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the CATEGORIES variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.033 | 0.968 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.013 | 2-Sided | Other |
| WORD GENERATION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the WORD GENERATION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate. | One way Repeat Meas ANOVA | F(2,5) = 0.884 | 0.469 | The threshold for statistical significance was p < 0.05. | partial eta^2 | 0.261 | 2-Sided | Other |