Alejandro Santillan

Weill Cornell Medical College, New York City, New York, United States

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Publications (40)68.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.
    Journal of controlled release : official journal of the Controlled Release Society. 09/2014;
  • Andres R Plasencia, Alejandro Santillan
    Journal of vascular surgery. 07/2014; 60(1):233.
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    ABSTRACT: Object The therapeutic potential for cerebral angiography (CA) in young children is expanding. However, its use in this patient population is limited by presumed higher complication rates among children. Therefore, to improve the accuracy of counseling of the parents/guardians of these patients and to identify modifiable risk factors, the authors evaluated complications after CA in young children. Methods The authors reviewed data for 309 consecutive cerebral angiograms obtained in 87 children younger than 36 months of age from 2004 to 2010 at a single institution. They analyzed demographics, diagnosis, angiographic findings, and complications. Results The patient population comprised 40 boys and 47 girls; mean age was 14.36 months (range 1-36 months) and mean weight was 10.8 kg (range 3.7-21.0 kg). For 292 of the 309 procedures, intraarterial chemotherapy was administered; the remaining 17 procedures were for vascular malformations, stroke, tumor embolization, and intracranial hemorrhage. The rate of neurological complications was 0.0%. The rate of nonneurological complications was 2.9%: 7 cases of contrast allergy or bronchospasm, 1 groin hematoma (body weight 7 kg), and 1 transient femoral artery occlusion (body weight 10.8 kg). The rate of radiographic complications was 1.3%: 1 case of transient asymptomatic intraarterial dissection and 3 cases of asymptomatic vasospasm. Postprocedural MRI was performed for 33.3% of patients with no evidence of ischemia. There were no delayed complications. Mean follow-up time was 16.6 months. No association was found between complications and age, duration of anesthesia, number of vessels catheterized, size of the sheath, or diagnostic versus interventional procedures. Despite a trend toward a higher rate of complications for patients who weighed less than 15 kg, this finding was not significant (p = 0.35). Conclusions The rate of complications for CA in young children is comparable to rates reported for older children and lower than rates reported for adults. When appropriately indicated, CA should not be omitted from the therapeutic strategy of children younger than 36 months of age.
    Journal of Neurosurgery Pediatrics 01/2014; · 1.63 Impact Factor
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    ABSTRACT: We have developed a novel minimally invasive technique for the intra-arterial delivery of therapeutics to the mouse brain. CD-1 mice were anesthetized and placed in a lateral decubitus position. A 10mm midline longitudinal incision was made over the thyroid bone. The omohyoid and sternomastoid muscles were retracted to expose the common carotid artery and external carotid artery (ECA). To maximize delivery of administered agents, the superior thyroid artery was ligated or coagulated, and the occipital artery and the pterygopalatine artery (PPA) were temporarily occluded with 6-0 prolene suture. The ECA was carefully dissected and a permanent ligature was placed on its distal segment while a temporary 6-0 prolene ligature was placed on the proximal segment in order to obtain a flow-free segment of vessel. A sterilized 169μm outer diameter polyimide microcatheter was introduced into the ECA and advanced in retrograde fashion towards the carotid bifurcation. The catheter was then secured and manually rotated so that the microcatheter tip was oriented cephalad in the internal carotid artery (ICA). We were able to achieve reproducible results for selective ipsilateral hemispheric carotid injections of mannitol mediated therapeutics and/or gadolinium-based MRI contrast agent. Survival rates were dependent on the administered agent and ranged from 78-90%. This technique allows for reproducible delivery of agents to the ipsilateral cerebral hemisphere by utilizing anterograde catheter placement and temporary ligation of the PPA. This method is cost-effective and associated with a low rate of morbimortality.
    Journal of neuroscience methods 11/2013; · 2.30 Impact Factor
  • JAMA neurology. 06/2013; 70(6):796.
  • Molecular Genetics and Metabolism 02/2013; 108(2):S41. · 2.83 Impact Factor
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    ABSTRACT: Dural arteriovenous fistulas (DAVFs) are rare pathological entities presenting with a diverse clinical course, ranging from benign to life-threatening. Digital subtraction angiography remains the gold standard in the diagnosis of clinically suspected DAVFs. This article reviews the ethiopathogenesis, natural history, classification systems, clinical and angiographic features, and the current treatment strategies for these complex lesions. The management of DAVFs may include conservative treatment, endovascular intervention, microsurgery, and stereotactic radiosurgery. A multidisciplinary approach involving a neurosurgeon, interventional neuroradiologist, and neurologist is required before considering any type of treatment modality. The indication for the best therapeutic alternative must be individualized for each patient.
    Clinical neurology and neurosurgery 12/2012; · 1.30 Impact Factor
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    ABSTRACT: Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival.
    Journal of Clinical Neuroscience 09/2012; 19(11):1568-72. · 1.25 Impact Factor
  • Archives of neurology 09/2012; 69(9):1204-5. · 7.58 Impact Factor
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    ABSTRACT: BACKGROUND: The balloon-assisted coil embolization (BACE) technique represents an effective tool for the treatment of complex wide-necked intracranial aneurysms; however, its safety is a matter of debate. This study presents the authors' institutional experience regarding the safety of the BACE technique. METHODS: 428 consecutive patients with 491 intracranial aneurysms (274 acutely ruptured and 217 unruptured) treated with conventional coil embolization (CCE) or with BACE were retrospectively reviewed. All procedure-related adverse events were reported, regardless of clinical outcome. Thromboembolic events, intraprocedural aneurysm ruptures, device-related complications, morbidity and mortality were compared between the CCE and BACE groups. RESULTS: The total rate of procedural and periprocedural adverse events was 9.6% (47/491 embolizations). Thromboembolic events, intraprocedural aneurysmal rupture and device-related complications occurred in 2.4%, 3.9% and 3.3% of procedures, respectively. The risk of thromboembolic events and device-related problems was similar between the CCE and BACE groups. A trend towards a higher risk of intraprocedural aneurysm rupture was observed in the BACE group (not statistically significant). The total cumulative morbidity and mortality for both groups was 2.6% (11/428 patients) and there was no statistically significant difference in the morbidity, mortality and cumulative morbidity and mortality rates between the two groups. CONCLUSION: In this series of patients with acutely ruptured and unruptured aneurysms, the BACE technique allowed treatment of aneurysms with unfavorable anatomic characteristics without increasing the incidence of procedural complications.
    Journal of Neurointerventional Surgery 06/2012; · 2.50 Impact Factor
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    ABSTRACT: Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome with a prevalence of approximately 1 in 30,000. NF 2 is characterized by bilateral vestibular schwannomas, as well as meningiomas, ependymomas and gliomas. Currently, surgical resection and radiotherapy represent the mainstay of treatment, although new studies suggest a role for certain chemotherapeutic agents. Intravenous administration of Bevacizumab (Avastin, Genetech Pharmaceuticals) has been shown to be active in the treatment of vestibular schwannomas. The IV route of administration, however, carries a risk of known systemic side-effects such as bowel perforation, wound dehiscence and pulmonary embolism. In addition, the percentage of drug that reaches the tumor site may be restricted by the blood tumor barrier. This report describes the super-selective intra-arterial infusion of Bevacizumab following blood brain barrier disruption for the treatment of vestibular schwannomas in three patients with Neurofibromatosis type 2. It represents the first time such a technique has been performed for this disease. Additionally, this method of drug delivery may have important implications in the treatment of patients with vestibular schwannomas associated with Neurofibromatosis type 2.
    Interventional Neuroradiology 06/2012; 18(2):127-32. · 0.77 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE:Intraprocedural aneurysmal rupture is a feared complication of coil embolization of intracranial aneurysms and is associated with high rates of morbidity and mortality. We report the incidence, endovascular management, and clinical outcome of patients with IAR, with emphasis on the role of the balloon-assisted technique.MATERIALS AND METHODS:We conducted a retrospective analysis of all intracranial aneurysms treated by coil embolization between September 2001 and June 2011. All patients with IAR were studied. Comparison of immediate clinical outcomes was performed by using univariate analysis (Fisher exact test).RESULTS:Of 652 intracranial aneurysms treated with coil embolization, an IAR occurred in 22 (3.4%). Rupture occurred during placement of coils in 18 cases, microcatheters in 2 cases, and a guidewire in 1 case, and during induction of anesthesia in 1 case. Before treatment, 15 of 22 (68%) patients were in good clinical condition (WFNS grade I). There were fewer patients with worsening of the WFNS grade following an IAR when the balloon-assisted technique was used (7.7%) compared with when it was not (55.5%) (P = .023). Death occurred in 2 (9.1%) patients.CONCLUSIONS:IAR is a potentially serious complication of coil embolization. If IAR occurs, balloon-assistance is helpful in obtaining rapid hemostasis resulting in better short-term outcomes.
    American Journal of Neuroradiology 05/2012; · 3.17 Impact Factor
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    ABSTRACT: In this article, a detailed description of the normal arterial supply and venous drainage of the spinal cord is provided, and the role of catheter angiography and MR angiography in depicting the vascular anatomy of the spinal cord is discussed.
    Journal of Neurointerventional Surgery 01/2012; 4(1):67-74. · 2.50 Impact Factor
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    ABSTRACT: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.
    Journal of Experimental Therapeutics and Oncology 01/2012; 10(1):31-7.
  • Andres R Plasencia, Alejandro Santillan
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    ABSTRACT: The treatment of arteriovenous malformations (AVMs) requires a multidisciplinary management including microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). This article reviews the recent advancements in the multimodality treatment of patients with AVMs using endovascular neurosurgery and SRS. We describe the natural history of AVMs and the role of endovascular and radiosurgical treatment as well as their interplay in the management of these complex vascular lesions. Also, we present some representative cases treated at our institution.
    Surgical Neurology International 01/2012; 3(Suppl 2):S90-S104. · 1.18 Impact Factor
  • 2012 Annual Meeting of the Congress of Neurological Surgeons; 01/2012
  • 2012 Annual Meeting of the Congress of Neurological Surgeons; 01/2012
  • Andres R Plasencia, Alejandro Santillan
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    ABSTRACT: Endovascular embolization represents the method of choice for the treatment of carotid-cavernous fistulas (CCFs). We report our experience using the endovascular technique in 24 patients harboring 25 CCFs treated between October 1994 and April 2010, with an emphasis on the role of detachable balloons for the treatment of direct CCFs. Of the 16 patients who presented with direct CCFs (Barrow Type A CCFs) (age range, 7-62 years; mean age, 34.3 years), 14 were caused by traumatic injury and 2 by a ruptured internal carotid artery (ICA) aneurysm. Eight patients (age range, 32-71 years; mean age, 46.5 years) presented with nine indirect CCFs (Barrow Types B, C, and D). The clinical follow-up after endovascular treatment ranged from 2 to 108 months (mean, 35.2 months). In two cases (8%), the endovascular approach failed. Symptomatic complications related to the procedure occurred in three patients (12.5%): transient cranial nerve palsy in two patients and a permanent neurological deficit in one patient. Detachable balloons were used in 13 out of 16 (81.3%) direct CCFs and were associated with a cure rate of 92.3%. Overall, the angiographic cure rate was obtained in 22 out of 25 (88%) fistulas. Patients presenting with III nerve palsy improved gradually between 1 day and 6 months after treatment. Good clinical outcomes [modified Rankin scale (mRS) ≤ 2] were observed in 22 out of 24 (91.6%) patients at last follow-up. Endovascular treatment using detachable balloons still constitutes a safe and effective method to treat direct carotid-cavernous fistulas.
    Surgical Neurology International 01/2012; 3:5. · 1.18 Impact Factor
  • 2012 Annual Meeting of the Congress of Neurological Surgeons; 01/2012
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    ABSTRACT: Neuroform stent-assisted coil embolization facilitates the endovascular treatment of wide-necked intracranial aneurysms. However, the safety and efficacy of its long-term use have not been fully elucidated. To retrospectively examine the long-term results of Neuroform stent usage in conjunction with coil embolization in wide-necked intracranial aneurysms. Between November 2002 and December 2010, 79 patients harboring wide-necked intracranial aneurysms were treated with use of the Neuroform stent. The stenting procedure failed in 2 patients. Therefore, 77 patients harboring 79 intracranial aneurysms were included for analysis. Patient and aneurysm characteristics, progression of aneurysm occlusion, and occurrence of complications were analyzed. Follow-up imaging included digital subtraction angiography (DSA) or magnetic resonance angiography (MRA). Kaplan-Meier analysis, as well as univariate analysis were performed to determine the progression of aneurysm occlusion and to examine the predictive factors for complete aneurysm occlusion, respectively. Overall, complete aneurysm occlusion was observed in 42.4% of the cases immediately after treatment and progressed to 96.5% at 7-year follow-up. The mean angiographic follow-up time was 25.8 months (range, 0-84 months). Eleven aneurysms (14%) were re-treated. Sixty-eight patients (88.3%) had favorable clinical outcome with a modified Rankin Scale (mRS) ≤ 1, 3 patients (3.9%) had an mRS of 2, and 5 patients (6.5%) did not have a clinical follow-up. The mean clinical follow-up time was 45.4 months (range, 3-92 months). One patient (1.3%) died of a procedure-related hemorrhage. Neuroform stent-assisted coil embolization of wide-necked intracranial aneurysms prevents hemorrhage and provides a high rate of aneurysm occlusion at long-term follow-up.
    Neurosurgery 11/2011; 70(5):1232-7; discussion 1237. · 2.53 Impact Factor

Publication Stats

89 Citations
68.20 Total Impact Points

Institutions

  • 2011–2014
    • Weill Cornell Medical College
      • Department of Neurological Surgery
      New York City, New York, United States
  • 2009–2014
    • New York Presbyterian Hospital
      • • Department of Neurological Surgery
      • • Department of Radiology
      New York City, New York, United States
  • 2012
    • Congress of Neurological Surgeons
      Schaumburg, Illinois, United States
  • 2009–2010
    • University of Miami Miller School of Medicine
      • Department of Surgery
      Miami, FL, United States