Long-Acting Opioid Analgesics for Acute Pain: Pharmacokinetic Evidence Reviewed.

Long-acting injectable (LAI) opioid formulations mitigate the harm profiles and management challenges associated with providing effective analgesia for animals. A single dose of a long-acting opioid analgesic can provide up to 72 h of clinically relevant pain management. Yet, few of these new drugs have been translated to products for veterinary clinics. Regulatory pathways allow accelerated drug approvals for generic and biosimilar drugs. These pathways depend on rigorous evidence for drug safety and pharmacokinetic evidence demonstrating bioequivalence between the new and the legacy drug. This report reviews the animal PK data associated with lipid and polymer-bound buprenorphine LAI formulations. Buprenorphine is a widely used veterinary opioid analgesic. Because of its safety profile and regulatory status, buprenorphine is more accessible than morphine, methadone, and fentanyl. This review of PK studies coupled with the well-established safety profile of buprenorphine suggests that the accelerated approval pathways may be available for this new family of LAI veterinary pharmaceuticals.

Dendrimer Technology in Glioma: Functional Design and Potential Applications.

Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, and especially glioblastoma, remains dire. One of the greatest obstacles to improving treatment efficacy and destroying cancer cells is the safe delivery of chemotherapeutic drugs and biologics to the tumor site at a high enough dose to be effective. Over the past few decades, a burst of research has leveraged nanotechnology to overcome this obstacle. There has been a renewed interest in adapting previously understudied dendrimer nanocarriers for this task. Dendrimers are small, highly modifiable, branched structures featuring binding sites for a variety of drugs and ligands. Recent studies have demonstrated the potential for dendrimers and dendrimer conjugates to effectively shuttle therapeutic cargo to the correct tumor location, permeate the tumor, and promote apoptosis of tumor cells while minimizing systemic toxicity and damage to surrounding healthy brain tissue. This review provides a primer on the properties of dendrimers; outlines the mechanisms by which they can target delivery of substances to the site of brain pathology; and delves into current trends in the application of dendrimers to drug and gene delivery, and diagnostic imaging, in glioma. Finally, future directions for translating these in vitro and in vivo findings to the clinic are discussed.

Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier.

Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood-brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects.

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy.

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches.

Translation of novel therapies for brain cancer into clinical practice is of the utmost importance as primary brain tumors are responsible for more than 200,000 deaths worldwide each year. While many research efforts have been aimed at improving survival rates over the years, prognosis for patients with glioblastoma and other primary brain tumors remains poor. Safely delivering chemotherapeutic drugs and other anti-cancer compounds across the blood-brain barrier and directly to tumor cells is perhaps the greatest challenge in treating brain cancer. Polymeric nanoparticles (NPs) are powerful, highly tunable carrier systems that may be able to overcome those obstacles. Several studies have shown appropriately-constructed polymeric NPs cross the blood-brain barrier, increase drug bioavailability, reduce systemic toxicity, and selectively target central nervous system cancer cells. While no studies relating to their use in treating brain cancer are in clinical trials, there is mounting preclinical evidence that polymeric NPs could be beneficial for brain tumor therapy. This review includes a variety of polymeric NPs and how their associated composition, surface modifications, and method of delivery impact their capacity to improve brain tumor therapy.

Metformin and Cancer, an Ambiguanidous Relationship.

The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.

Ultrasound monitoring of microcirculation: An original study from the laboratory bench to the clinic.

OBJECTIVE: Monitoring microcirculation and visualizing microvasculature are critical for providing diagnosis to medical professionals and guiding clinical interventions. Ultrasound provides a medium for monitoring and visualization; however, there are challenges due to the complex microscale geometry of the vasculature and difficulties associated with quantifying perfusion. Here, we studied established and state-of-the-art ultrasonic modalities (using six probes) to compare their detection of slow flow in small microvasculature. METHODS: Five ultrasonic modalities were studied: grayscale, color Doppler, power Doppler, superb microvascular imaging (SMI), and microflow imaging (MFI), using six linear probes across two ultrasound scanners. Image readability was blindly scored by radiologists and quantified for evaluation. Vasculature visualization was investigated both in vitro (resolution and flow characterization) and in vivo (fingertip microvasculature detection). RESULTS: Superb Microvascular Imaging (SMI) and Micro Flow Imaging (MFI) modalities provided superior images when compared with conventional ultrasound imaging modalities both in vitro and in vivo. The choice of probe played a significant difference in detectability. The slowest flow detected (in the lab) was 0.1885 ml/s and small microvasculature of the fingertip were visualized. CONCLUSIONS: Our data demonstrated that SMI and MFI used with vascular probes operating at higher frequencies provided resolutions acceptable for microvasculature visualization, paving the path for future development of ultrasound devices for microcirculation monitoring.

Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology.

The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

OBJECTIVE: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma. METHODS: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. RESULTS: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004). CONCLUSIONS: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.

Intraoperative Laser Speckle Contrast Imaging For Real-Time Visualization of Cerebral Blood Flow in Cerebrovascular Surgery: Results From Pre-Clinical Studies.

Cerebrovascular surgery can benefit from an intraoperative system that conducts continuous monitoring of cerebral blood flow (CBF). Such a system must be handy, non-invasive, and directly integrated into the surgical workflow. None of the currently available techniques, considered alone, meets all these criteria. Here, we introduce the SurgeON™ system: a newly developed non-invasive modular tool which transmits high-resolution Laser Speckle Contrast Imaging (LSCI) directly onto the eyepiece of the surgical microscope. In preclinical rodent and rabbit models, we show that this system enabled the detection of acute perfusion changes as well as the recording of temporal response patterns and degrees of flow changes in various microvascular settings, such as middle cerebral artery occlusion, femoral artery clipping, and complete or incomplete cortical vessel cautery. During these procedures, a real-time visualization of vasculature and CBF was available in high spatial resolution through the eyepiece as a direct overlay on the live morphological view of the surgical field. Upon comparison with indocyanine green angiography videoangiography (ICG-VA) imaging, also operable via SurgeON, we found that direct-LSCI can produce greater information than ICG-VA and that continuous display of data is advantageous for performing immediate LSCI-guided adjustments in real time.

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste.

PURPOSE: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood-brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. EXPERIMENTAL DESIGN: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel. RESULTS: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. CONCLUSIONS: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.

A miniature multi-contrast microscope for functional imaging in freely behaving animals.

Neurovascular coupling, cerebrovascular remodeling and hemodynamic changes are critical to brain function, and dysregulated in neuropathologies such as brain tumors. Interrogating these phenomena in freely behaving animals requires a portable microscope with multiple optical contrast mechanisms. Therefore, we developed a miniaturized microscope with: a fluorescence (FL) channel for imaging neural activity (e.g., GCaMP) or fluorescent cancer cells (e.g., 9L-GFP); an intrinsic optical signal (IOS) channel for imaging hemoglobin absorption (i.e., cerebral blood volume); and a laser speckle contrast (LSC) channel for imaging perfusion (i.e., cerebral blood flow). Following extensive validation, we demonstrate the microscope's capabilities via experiments in unanesthetized murine brains that include: (i) multi-contrast imaging of neurovascular changes following auditory stimulation; (ii) wide-area tonotopic mapping; (iii) EEG-synchronized imaging during anesthesia recovery; and (iv) microvascular connectivity mapping over the life-cycle of a brain tumor. This affordable, flexible, plug-and-play microscope heralds a new era in functional imaging of freely behaving animals.

A Long-Term Study of a Lipid-Buprenorphine Implant in Rats.

Animal models to study opiates are of growing interest. We have examined the short-term safety of buprenorphine implants in Fischer F344/NTac rats treated with excess doses of a cholesterol-triglyceride suspension of buprenorphine. A single injection of 0.65 mg/kg afforded clinically significant blood levels of analgesia for 3 days. Chemistry, hematology, coagulation, and urinalysis values with 2- to 10-fold excess doses of the drug-lipid suspension were within normal limits. Histopathology findings were unremarkable. The skin and underlying tissue surrounding the drug injection were unremarkable. Here we report the results of a long-term follow-up study of female rats injected with 0.65 and 1.3 mg/kg. The 14-month evaluation showed no abnormal findings that could be attributed to the drug or lipid suspension. These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery in laboratory animals and suggest that this model may be used to study long-term effects of opiate therapy.

Targeted Local Therapy for Management of Intracranial High-Grade Gliomas.

Systemic chemotherapy of malignant brain tumors has failed to achieve sufficient drug concentrations at the neoplasm site and frequently results in severe toxicities. Therefore, the local application of several anticancer agents, oncolytic viruses and vectors for gene therapy, immune-modifying preparations, and angiogenesis inhibitors has been investigated widely. Various modes of their administration were introduced, including intratumoral injections, implantation of reservoirs or pumps, convection-enhanced delivery, and use of nanocarriers, thermoreversible gels, microchips, and drug-loaded polymers. Many of these therapeutic approaches have shown promising results in management of high-grade gliomas.

Suspected Lonely Mouse Syndrome as a Cage Effect in a Drug Safety Study.

Studies have demonstrated that buprenorphine, a front line drug for veterinary analgesia, may alleviate symptoms of chronic pain. A cage side observation protocol was used to record behavioral signs in a mouse clinical trial of extended release buprenorphine. A retrospective review of the observations for signs of pain and stress revealed that mice given a fivefold overdose of buprenorphine (16.25 mg/kg) showed lethargy and facial signs associated with stress. However, similar signs were observed in the drug-free control mice as early as Day 3 of single-cage housing. This appears to be the first report of cage effects in a clinical trial for a veterinary drug.

Developing Therapies for Brain Tumors: The Impact of the Johns Hopkins Hunterian Neurosurgical Research Laboratory.

The Johns Hopkins Hunterian Neurosurgical Laboratory at the Johns Hopkins University School of Medicine was created in 1904 by Harvey Cushing and William Halsted and has had a long history of fostering surgical training, encouraging basis science research, and facilitating translational application. Over the past 30 years, the laboratory has addressed the paucity of brain tumor therapies. Pre-clinical work from the laboratory led to the development of carmustine wafers with initial US Food and Drug Administration (FDA) approval in 1996. Combining carmustine wafers, radiation, and temozolomide led to a significant increase in the median survival of patients with glioblastoma. The laboratory has also developed microchips and immunotherapy to further extend survival in this heretofore underserved population. These achievements were made possible by the dedication, commitment, and creativity of more than 300 trainees of the Hunterian Neurosurgical Laboratory. The laboratory demonstrates the beneficial influence of research experience as well its substantial impact on the field of biomedical research.

The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma.

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas.

PURPOSE: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. EXPERIMENTAL DESIGN: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. RESULTS: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. CONCLUSIONS: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124-36. ©2016 AACR.

The Johns Hopkins Hunterian Laboratory Philosophy: Mentoring Students in a Scientific Neurosurgical Research Laboratory.

After over 50 years of scientific contribution under the leadership of Harvey Cushing and later Walter Dandy, the Johns Hopkins Hunterian Laboratory entered a period of dormancy between the 1960s and early 1980s. In 1984, Henry Brem reinstituted the Hunterian Neurosurgical Laboratory, with a new focus on localized delivery of therapies for brain tumors, leading to several discoveries such as new antiangiogenic agents and Gliadel chemotherapy wafers for the treatment of malignant gliomas. Since that time, it has been the training ground for 310 trainees who have dedicated their time to scientific exploration in the lab, resulting in numerous discoveries in the area of neurosurgical research. The Hunterian Neurosurgical Laboratory has been a unique example of successful mentoring in a translational research environment. The laboratory's philosophy emphasizes mentorship, independence, self-directed learning, creativity, and people-centered collaboration, while maintaining productivity with a focus on improving clinical outcomes. This focus has been served by the diverse backgrounds of its trainees, both in regard to educational status as well as culturally. Through this philosophy and strong legacy of scientific contribution, the Hunterian Laboratory has maintained a positive and productive research environment that supports highly motivated students and trainees. In this article, the authors discuss the laboratory's training philosophy, linked to the principles of adult learning (andragogy), as well as the successes and the limitations of including a wide educational range of students in a neurosurgical translational laboratory and the phenomenon of combining clinical expertise with rigorous scientific training.

Inhibition of Corneal Neovascularization by Subconjunctival Injection of Fc-Endostatin, a Novel Inhibitor of Angiogenesis.

We assessed the antiangiogenic effects of subconjunctival injection of Fc-endostatin (FcE) using a human vascular endothelial growth factor-induced rabbit corneal neovascularization model. Angiogenesis was induced in rabbit corneas through intrastromal implantations of VEGF polymer implanted 2 mm from the limbus. NZW rabbits were separated into groups receiving twice weekly subconjunctival injections of either saline; 25 mg/mL bevacizumab; 2 mg/mL FcE; or 20 mg/mL FcE. Corneas were digitally imaged at 5 time points. An angiogenesis index (AI) was calculated (vessel length (mm) × vessel number score) for each observation. All treatment groups showed a significant decrease in the vessel length and AI compared to saline on all observation days (P < 0.001). By day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (P < 0.01). There was no significant difference between FcE 2 and BV, although the values trended towards significantly increased inhibition by BV. BV was a significantly better inhibitor than FcE 20 by day 8 (P < 0.01). FcE was safe and significantly inhibited new vessel growth in a rabbit corneal neovascularization model. Lower concentration FcE 2 exhibited better inhibition than FcE 20, consistent with previous FcE studies referencing a biphasic dose-response curve. Additional studies are necessary to further elucidate the efficacy and clinical potential of this novel angiogenesis inhibitor.