PKU-UM Joint Institute
Subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke with the highest immediate mortality of all strokes (exceeding 30%) and leading to severe disability for those who survive. This leads to a significant number of potential life years lost, creating a financial and intellectual loss to society. In addition to the initial insult, delayed cerebral ischemia (DCI) secondary to arterial vasospasm and chronic hydrocephalus requiring permanent CSF diversion are other complicating factors of subarachnoid hemorrhage. To date, aside from nimodipine, there are no preventative options for DCI or chronic hydrocephalus in SAH patients. With such strong data involving DFO use in SAH animal models and recent human data with DFO use in intracranial hemorrhage (ICH), a multicenter, randomized Phase I/II trial to determine the safety and futility of deferoxamine treatment in the human SAH population is expected provide data that changes the current treatment methodology of subarachnoid hemorrhage and improves patient functional outcomes. This proposed trial will evaluate the safety and futility of clinical deferoxamine use in SAH and could lead to changes in the current SAH treatment algorithm. If this trial is successful, it will generate crucial preliminary data that will support further clinical trial grant applications for a Phase III trial with a much larger sample size through the NIH/NINDS (USA) and National Science Foundation (China).
Xu Z, Pandey AS
NIH R01 EB028309
8/1/2019 – 4/30/2023
The goal of this proposal is to develop the first integrated tcMRgHt system for treatment of brain tumors. Approximately 256,000 new patients are diagnosed with primary brain tumor annually worldwide, and many more patients are diagnosed with brain metastases. The current clinical treatment for brain tumors is a highly invasive surgery. The five-year survival rate is only 33% with many surviving patients suffering from cognitive deficits. Transcranial magnetic resonance guided focused ultrasound (tcMRgFUS) has been investigated as a noninvasive ablation method in the brain. However, due to the overheating of the skull, tcMRgFUS cannot treat a target volume >1 cm diameter in the brain or locations within 2 cm from the skull surface, rendering inoperable up to ~90% of the cortex regions where brain tumors often reside. We hypothesize that transcranial MR guided histotripsy (tcMRgHt) can overcome the treatment location and volume limitations of tcMRgFUS and provide a non-invasive ablation technique to improve the treatment of brain tumors. Using microsecond-length, high-amplitude ultrasound pulses applied from outside the skull, cavitation can be precisely generated to disrupt cells within the targeted brain region. The heating to the skull and surrounding tissue can be avoided by using a very low duty cycle (<0.1%). Our preliminary data show that histotripsy applied through excised human skulls was used to ablate a wide range of locations and brain volumes inside the skull, while keeping the temperature increase in the skull under 4°C. Although the feasibility of transcranial histotripsy and MRI guidance has been shown separately, developing and building an integrated tcMRgHt system is a substantial technical challenge. We propose the following three specific aims. 1) Design and construct an integrated tcMRgHt system. 2) Develop and optimize specialized RF pulse sequences for MRI guidance of tcMRgHt. 3) Validate the performance of the tcMRgHt system in ex vivo brain phantom and human cadaver. An integrated tcMRgHt system that can noninvasively treat a wide range of locations and volumes in the brain and validated in human cadavers would be a critical milestone to advance this promising technology for future clinical translation for treatment of brain tumors.
Pandey AS, Xi G, Chaudhary N, Daou J
NIH R01 NS 10804203
9/30/2018 – 7/31/2023
Intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke with 4 million annual cases worldwide. Evacuation of the ICH leads to reduction in intracranial pressure (ICP) as well as prevention of secondary cerebral injuries. Current strategy for removing ICH requires an invasive craniotomy and the need for traversing normal brain. Minimally invasive methods include: 1) craniopuncture/tPA method which requires days for evacuation of ICH and risk of rehemorrhage; 2) endoscopic ultrasonic aspiration has the force to injure cerebral tissue as well as the need for learning endoscopic techniques. There is a clear unmet clinical need for a minimally invasive method that can safely, effectively, and rapidly reduce the ICH volume without using thrombolytic drugs and be applied with the simplest methodology. We propose histotripsy as a novel ultrasonic technique that can fully address this unmet clinical need. Histotripsy uses microsecond duration, high-pressure ultrasound pulses applied from outside the skull and focused inside the ICH to produce cavitation to liquefy the ICH without causing brain injury. The liquefied ICH can be immediately drained via a small bore catheter. We have used histotripsy with electronic focal steering to achieve rapid transcranial ICH liquefaction (~40 mL in 10 min) and drainage through excised human skulls. We have developed a miniature hydrophone integrated within the catheter to precisely focus the ultrasound through excised human skulls and the catheter can also be used for drainage of the liquefied ICH. We have also demonstrated the in vivo feasibility and safety in a porcine ICH model. We propose three specific aims toward developing histotripsy as a novel technique for safely evacuating ICH and improving outcomes. 1) Design and construct a portable histotripsy ICH system with real-time 3D feedback that can transcranially liquefy and drain ICH with high precision and efficacy. 2) Validate the targeting precision, treatment location profile, and efficacy of the transcranial histotripsy ICH system in human ICH phantom and fresh human cadaver. 3) Validate the safety and efficacy of the transcranial histotripsy ICH system in an established in vivo porcine ICH model. If these aims are successfully completed, we will establish a portable histotripsy ICH system suitable for clinical use and proceed towards a clinical trial.
Pandey AS, Chaudhary N, Xi G, Keep R
NIH R21 NS 10466302
9/30/2018 – 8/31/2022
Intracerebral hemorrhage is a subtype of hemorrhagic stroke that has devastating consequences when it occurs in humans. Broadly there are two mechanisms of neuronal damage that occurs in the event of an ICH. The early brain injury is secondary to the hematoma itself and early erythrolysis within 24 hours of the injury. Delayed brain injury is mediated by various pathways related to the scavenging of the hematoma by the macrophage system. There is reasonable animal model data that validates pathomechanisms of delayed neurotoxicity following an ICH. Ultra-early erythrolysis is a novel phenomenon that has been observed in a recent animal ICH model study by the authors. In this rat model there is good correlation of early erythrolysis with hypo or isointensity on T2* sequences within the hematoma within first 24 hours after an ICH and increased tissue iron levels in the perihematomal brain tissue on histology. There is no such correlative phenomenon that has been documented in the human population. The proposed study will attempt to confirm or refute the presence of the phenomenon of ultra-early erythrolysis and mediated neuronal injury due to increased iron levels in the periphery of the hematoma based on MRI. Various MRI parameters like volume of T2* iso/non-hypointensity within the hematoma, R2* value in the periphery of the hematoma and volume of edema on FLAIR sequence will be measured on day 1, day 14 and day 30 to evaluate the presence of the phenomenon of ultra-early erythrolysis in ICH in human subjects, not only in the first 24 hrs but also up to 30 days following the hematoma.
Anticoagulation in ICH survivors for prevention and recovery (ASPIRE)
University of Cincinnati
7/1/2019 - 4/30/2024
Risk factors for surgical site infection in MRSA-colonized patients: A 5-year review of all surgical cases at Michigan Medicine
Pandey A, Adapa A
Blue Cross Blue Shield of Michigan Foundation
9/8/2020 - 9/7/2021
Statins use in intracerebral hemorrhage patients (SATURN)
University of Cincinnati
9/1/2019 - 5/31/2026
The role of carbonic anhydrase in hydrocephalus formation post-intraventricular hemorrhage in a murine model
Pandey A, Koduri S, Xi G
12/1/2020 - 11/30/2021