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Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo. Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

Supplementary Figures 1-6

Upon discovery of Michelangelo's concealed neuroanatomical images in "Separation of Light from Darkness," by Suk and Tamargo in 2010, there remained a compelling need to investigate in greater detail the reasoning behind Michelangelo's depiction of imagery of the brain, brainstem, spinal cord, eyeballs and optic nerves in the Sistine Chapel. At cursory glance, "Separation of Light from Darkness" depicts God's first act of Genesis 1:3-5 (King James Bible), in which he creates light and separates it from the darkness, enveloping the world he has just created. It is a seemingly simple, conspicuous act, but careful analysis reveals that Michelangelo used his artistic, academic, and poetic genius to embed layers of symbolic meanings. The authors believe that the great artist infused a visual metaphor of a scene from Plato's "Allegory of the Cave" in Book VII of The Republik (~380BC) to represent his key ideologies in Neoplatonism and pious convictions Michelangelo painted the Sistine Chapel during the flourishing period of High Renaissance (~1475-1527). High Renaissance art followed and reflected the period of 'rebirth' in which philosophy, literature, art, and sciences drew on ancient knowledge from Classical Antiquity, principally the ancient Greeks. The Renaissance was a period of rapid growth where people applied new found knowledge to the Classical Greek studies of Socrates, Plato, and Aristotle (from about the 4th to 3rd century BC). One of the most influential ancient philosophers was Plato (~428-348 BC) whose teachings propagated throughout Athens for about two centuries around his lifetime, through his established school, the Academy. His philosophy of Neoplatonism was resurrected by an Italian baron, Cosimo I de Medici who employed Marsilio Ficino (1433-99) to lead the Florentine Platonic Academy (of which Michelangelo was a student) and translate all of Plato's writings into Latin Through analysis of Michelangelo's paintings, his preliminary sketches, poems, written letters, and the political and religious context of his time, the authors attempt to provide key evidence to reveal the meaning and symbolism behind Michelangelo's concealed anatomic representations.

Traumatic spinal cord injury (SCI) is a common and devastating condition. In the absence of effective validated therapies, there is an urgent need for novel methods to achieve injury stabilization, regeneration, and functional restoration in SCI patients. Ultrasound is a versatile platform technology that can provide a foundation for viable diagnostic and therapeutic interventions in SCI. In particular, real-time perfusion and inflammatory biomarker monitoring, focal pharmaceutical delivery, and neuromodulation are capabilities that can be harnessed to advance our knowledge of SCI pathophysiology and to develop novel management and treatment options. Our review suggests that studies that evaluate the benefits and risks of ultrasound in SCI are severely lacking and our understanding of the technology's potential impact remains poorly understood. Although the complex anatomy and physiology of the spine and the spinal cord remain significant challenges, continued technological advances will help the field overcome the current barriers and bring ultrasound to the forefront of SCI research and development.

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.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).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.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.

Cotton balls are used in neurosurgical procedures to assist with hemostasis and improve vision within the operative field. Although the surgeon can reshape pieces of cotton for multiple intraoperative uses, this customizability and scale also places them at perpetual risk of being lost, as blood-soaked cotton balls are visually similar to raw brain tissue. Retained surgical cotton can induce potentially life-threatening immunologic responses, impair postoperative imaging, lead to a textiloma or misdiagnosis, and/or require reoperation. This study investigated three imaging modalities (optical, acoustic, and radiographic) to find the most effective method of identifying foreign bodies during neurosurgery. First, we examined the use of dyes to increase contrast between cotton and surrounding parenchyma (optical approach). Second, we explored the ability to distinguish surgical cotton on or below the tissue surface from brain parenchyma using ultrasound imaging (acoustic approach). Lastly, we analyzed the ability of radiography to differentiate between brain parenchyma and cotton. Our preliminary testing demonstrated that dark-colored cotton is significantly more identifiable than white cotton on the surface level. Additional testing revealed that cotton has noticeable different acoustic characteristics (eg, speed of sound, absorption) from neural tissue, allowing for enhanced contrast in applied ultrasound imaging. Radiography, however, did not present sufficient contrast, demanding further examination. These solutions have the potential to significantly reduce the possibility of intraoperative cotton retention both on and below the surface of the brain, while still providing surgeons with traditional cotton material properties without affecting the surgical workflow.

Background Hydrocephalus is managed by surgically implanting flow-diversion technologies such as differential pressure valves and antisiphoning devices; however, such hardware is prone to failure. Extensive research has tested them in flow-controlled settings using saline or de-aerated water, yet little has been done to validate their performance in a setting recreating physiologically relevant parameters, including intracranial pressures, cerebrospinal fluid (CSF) protein content, and body position. Objective To more accurately chart the episodic drainage characteristics of flow-diversion technology. A gravity-driven benchtop model of flow was designed and tested continuously during weeks-long trials. Methods Using a hydrostatic pressure gradient as the sole driving force, interval flow rates of 6 valves were examined in parallel with various fluids. Daily trials in the upright and supine positions were run with fluid output collected from distal catheters placed at alternating heights for extended intervals. Results Significant variability in flow rates was observed, both within specific individual valves across different trials and among multiple valves of the same type. These intervalve and intravalve variabilities were greatest during supine trials and with increased protein. None of the valves showed evidence of overt obstruction during 30 d of exposure to CSF containing 5 g/L protein. Conclusion Day-to-day variability of ball-in-cone differential pressure shunt valves may increase overdrainage risk. Narrow-lumen high-resistance flow control devices as tested here under similar conditions appear to achieve more consistent flow rates, suggesting their use may be advantageous, and did not demonstrate any blockage or trend of decreasing flow over the 3 wk of chronic use.

Spinal cord injury (SCI) is a devastating condition that affects about 17,000 individuals every year in the United States, with approximately 294,000 people living with the ramifications of the initial injury. After the initial primary injury, SCI has a secondary phase during which the spinal cord sustains further injury due to ischemia, excitotoxicity, immune-mediated damage, mitochondrial dysfunction, apoptosis, and oxidative stress. The multifaceted injury progression process requires a sophisticated injury-monitoring technique for an accurate assessment of SCI patients. In this narrative review, we discuss SCI monitoring modalities, including pressure probes and catheters, micro dialysis, electrophysiologic measures, biomarkers, and imaging studies. The optimal next-generation injury monitoring setup should include multiple modalities and should integrate the data to produce a final simplified assessment of the injury and determine markers of intervention to improve patient outcomes.

High Intensity Focused Ultrasound (HIFU) is an emerging and increasingly useful modality in the treatment of cancer and other diseases. Although traditional use of ultrasound at lower frequencies has primarily been for diagnostic imaging purposes, the development of HIFU has allowed this particular modality to expand into therapeutic use. This non-invasive and acoustic method involves the use of a piezoelectric transducer to deliver high-energy pulses in a spatially coordinated manner, while minimizing damage to tissue outside the target area. This review describes the history of the development of diagnostic and therapeutic ultrasound and explores the biomedical applications utilizing HIFU technology including thermally ablative treatment, therapeutic delivery mechanisms, and neuromodulatory phenomena. The application of HIFU across various tumor types in multiple organ systems is explored in depth, with particular attention to successful models of HIFU in the treatment of various medical conditions. Basic mechanisms, preclinical models, previous clinical use, and ongoing clinical trials are comparatively discussed. Recent advances in HIFU across multiple medical fields reveal the growing importance of this biomedical technology for the care of patients and for the development of possible pathways for the future use of HIFU as a commonplace treatment modality.

Background and importance En bloc resection of sacral tumors is the most effective treatment to help prevent recurrence. Sacrectomy, however, can be destabilizing, depending on the extent of resection. Various surgical techniques for improving stability and enabling early ambulation have been proposed. Clinical presentation Here, we report a case in which we use PMMA (poly[methyl methacrylate]) to augment pelvic instrumentation to improve mechanical stability after sacrectomy for en bloc resection of a solitary fibrous tumor. Conclusion We highlight the use of sacroplasty augmentation of pelvic ring reconstruction to provide biomechanical stability without the need for fusion of any mobile spine segments, which allowed for early patient ambulation and no appreciable loss of range of motion or mobility.

BACKGROUND: We have previously reported a method and device capable of manipulating ICP pulsatility while minimally effecting mean ICP. OBJECTIVE: To test the hypothesis that different modulations of the intracranial pressure (ICP) pulse waveform will have a differential effect on cerebral blood flow (CBF). METHODS: Using an epidural balloon catheter attached to a cardiac-gated oscillating pump, 13 canine subjects underwent ICP waveform manipulation comparing different sequences of oscillation in successive animals. The epidural balloon was implanted unilaterally superior to the Sylvian sulcus. Subjects underwent ICP pulse augmentation, reduction and inversion protocols, directly comparing time segments of system activation and deactivation. ICP and CBF were measured bilaterally along with systemic pressure and heart rate. CBF was measured using both thermal diffusion, and laser doppler probes. RESULTS: The activation of the cardiac-gate balloon implant resulted in an ipsilateral/contralateral ICP pulse amplitude increase with augmentation (217%/202% respectively, P

Neurosurgical operations are long and intensive medical procedures, during which the surgeon must constantly have an unobscured view of the brain in order to be able to properly operate, and thus must use a variety of tools to clear obstructions (like blood and fluid) from the operating area. Currently, cotton balls are the most versatile and effective option to accomplish this as they absorb fluids, are soft enough to safely manipulate the brain, act as a barrier between other tools and the brain, and function as a spacer to keep anatomies of the brain open and visible during the operation. While cotton balls allow neurosurgeons to effectively improve visibility of the operating area, they may also be accidentally left in the brain upon completion of the surgery. This can lead to a wide range of post-operative risks including dangerous immune responses, additional medical care or surgical operations, and even death. This project seeks to develop a unique medical device that utilizes ultrasound technology in order to minimize cotton retention after neurosurgical procedures in order to reduce undesired post-operative risks, and maximize visibility.

Spinal cord injury (SCI) affects approximately 2.5 million people worldwide. The primary phase of SCI is initiated by mechanical trauma to the spinal cord, while the secondary phase involves the ensuing tissue swelling and ischemia that worsen tissue damage and functional outcome. Optimizing blood flow to the spinal cord after SCI can mitigate injury progression and improve outcome. Accurate, sensitive, real-time monitoring is critical to assessing the spinal cord perfusion status and optimizing management, particularly in those with injuries severe enough to require surgery. However, the complex anatomy of the spinal cord vasculature and surrounding structures present significant challenges to such a monitoring strategy. In this study, Doppler ultrasound was hypothesized to be a potential solution to detect and monitor spinal cord tissue perfusion in SCI patients who required spinal decompression and/or stabilization surgeries. This approach could provide real-time visual blood flow information and pulsatility of the spinal cord as biomarkers of tissue perfusion. Importantly, Doppler ultrasound could be readily integrated into the surgical workflow, because the spinal cord was exposed during surgery, thereby allowing easy access for Doppler deployment, while keeping the dura intact. Doppler ultrasound successfully measured blood flow in single and bifurcated microfluidic channels at physiologically relevant flow rates and dimensions in both in-vitro and in-vivo porcine SCI models. Furthermore, perfusion was quantified from the obtained images. Our results provide a promising and viable solution to intraoperatively assess and monitor blood flow at the SCI site to optimize tissue perfusion and improve functional recovery in SCI patients.

Background Surgical treatment of severe cervicothoracic kyphotic deformity may require the use of 3-column osteotomies such as the pedicle subtraction osteotomy and vertebral column resection (VCR), or VCR with anterior longitudinal ligament resection. Such procedures are extensive and are associated with high intra- and perioperative morbidity, in part, due to the need for risky reduction maneuvers. Objective To describe a novel technique utilizing a laterally placed articulating hinge to facilitate kyphotic deformity correction of the cervicothoracic spine. Methods A patient with severe chin-on-chest deformity of the cervicothoracic spine presented for evaluation and a 2-stage VCR with anterior longitudinal ligament resection was planned. To reduce the risk of intraoperative neurological injury and for increased control during reduction maneuvers, lateral instrumentation was placed through the chest wall resection above and below the level of VCR, which was adjoined with an articulating hinge rod apparatus. Results Satisfactory reduction of the kyphosis was achieved utilizing the hinge rod apparatus for controlled deformity correction. The patient remained neurologically intact following this procedure with improvement in their spinal alignment. Conclusion We present a novel technique utilizing a lateral hinge rod apparatus for efficient, controlled correction of severe kyphotic deformity.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo. Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.

The spinal column is the most common site for skeletal metastases but involves the cervical spine in only 8–20% of cases. Metastatic disease is more common than primary spinal tumors, and surgery for metastatic spine disease is generally palliative. Due to its junctional location, metastatic disease from the occiput to C2 is more likely to cause instability, compared to the mobile subaxial spine. As such, patients most commonly present with refractory neck pain from mechanical instability. In the setting of cervical spine or craniovertebral junction tumors, the treatment goals for patients undergoing occipital-cervical stabilization are to decompress neural elements, realign the cervical spine, and stabilize the spinal column.

Experimental study. The objective of this study was to establish a non-invasive model to produce pressure ulcers of varying severity in animals with spinal cord injury (SCI). The study was conducted at the Johns Hopkins Hospital in Baltimore, Maryland, USA. A mid-thoracic (T7–T9) left hemisection was performed on Sprague-Dawley rats. At 7 days post SCI, rats received varying degrees of pressure on the left posterior thigh region. Laser Doppler Flowmetry was used to record blood flow. Animals were killed 12 days after SCI. A cardiac puncture was performed for blood chemistry, and full-thickness tissue was harvested for histology. Doppler blood flow after SCI prior to pressure application was 237.808±16.175 PFUs at day 7. Following pressure application, there was a statistically significant decrease in blood flow in all pressure-applied groups in comparison with controls with a mean perfusion of 118.361±18.223 (P

BACKGROUND AND IMPORTANCE Occurrence of spinal epithelioid sarcomas is rare, with few cases reported in the literature. Although wide local resection is the recommended treatment, this technique is challenging in the spine. CLINICAL PRESENTATION The case of a 17-year-old male with a recurrent epithelioid sarcoma with intradural extension in the cervical spine is presented. Because of nerve root involvement, the patient presented with right upper extremity weakness. The patient underwent a posterior C1-C4 spondylectomy to achieve an en bloc resection, followed by reconstruction from the occiput to T4. The right vertebral artery and C1-C4 nerve roots were sacrificed because of tumor involvement. After 3 years of follow-up the patient is disease-free but has persistent right deltoid weakness. CONCLUSION Cervical spondylectomy via a single-staged posterior approach is a challenging yet feasible procedure for the treatment of epithelioid sarcomas. To the best of the authors' knowledge, this is the first report of complete resection of an epithelioid sarcoma with intradural extension in the cervical spine. Although neurovascular structures may warrant sacrifice, this procedure may provide improved long-term prognosis.

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a propensity for metastasis, leading many patients to fail available treatments and/or present with advanced-stage disease. There is currently a scarcity of targeted therapies for NPC, despite working knowledge of several proteins with key roles in NPC cancer biology. These include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor patient prognosis. These proteins are known to be targeted by ribavirin, a well-characterized anti-viral drug that has recently been repurposed as an anti-cancer agent in several solid and hematologic malignancies. In the present study, we investigated the potential of ribavirin as a targeted therapy and radiosensitizing agent in five human NPC cell lines. We show in vitro, using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, and mTOR were observed in western blots and enzymatic activity assays in response to ribavirin treatment. In vivo, monotherapy with ribavirin reduced flank tumor growth in multiple NPC xenograft models. Given that radiation therapy is a mainstay of NPC treatment, we next investigated the effects of combining ribavirin with radiation. Using clonogenic assays and flow cytometry, we demonstrate that ribavirin enhanced the cytotoxic effects of radiation on NPC cells in vitro. Most importantly, using a flank tumor xenograft model, we show that pre-treatment with ribavirin potentiated the effects of radiation therapy in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR modulation and positions ribavirin for clinical evaluation as a targeted therapy and radiosensitizing agent in this cancer. Citation Format: Sakibul Huq, Joshua Casaos, Riccardo Serra, Michael Peters, Yuanxuan Xia, Andy Ding, Jeffrey Ehresman, Jayanidhi Kedda, Manuel Morales, Noah Gorelick, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler. Use of the anti-viral drug ribavirin as a radiosensitizing agent in nasopharyngeal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6268.

Purpose: Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma that is often diagnosed at an advanced stage, leading to poor disease-free and overall survival. Accumulating literature suggests that elevated protein expression of enhancer of zeste homolog 2 (EZH2), eukaryotic initiation factor 4E (eIF4E), and inosine-5’-monophosphate dehydrogenase (IMPDH)—proteins implicated in myriad cancers—correlates with poor prognosis in NPC. These three proteins are modulated by the Food and Drug Administration-approved antiviral drug ribavirin, which has recently been repositioned by our laboratory and others as a promising anticancer agent. Based on this intersection of molecular signature and drug targets, we investigated the potential of ribavirin as a therapeutic agent for NPC. Experimental Design: We assessed antineoplastic efficacy of ribavirin on six human NPC cell lines in vitro using cellular growth assays, flow cytometry, and scratch wound assays. Mechanistic pathways involved were investigated using genomic expression datasets, Western blots, and enzymatic activity assays. The effects of combining ribavirin with radiation were assessed using clonogenic assays and flow cytometry. Finally, we evaluated the effects of ribavirin on tumor growth in vivo using two human cell line-derived xenograft models. Results: Ribavirin significantly decreased NPC cellular proliferation and migratory capacity in addition to promoting cell cycle arrest and cell death. Modulation of the EZH2, Snail, eIF4E, and IMPDH pathways was observed in response to ribavirin treatment. Ribavirin significantly enhanced the cytotoxic effects of radiation therapy in NPC. Most importantly, ribavirin significantly reduced flank tumor growth in two NPC xenograft models. Conclusions: Our work suggests that ribavirin has potent anticancer effects in NPC and could represent a safe and promising addition to current NPC treatment regimens. Citation Format: Sakibul Huq, Joshua Casaos, Michael Peters, Yuanxuan Xia, Andy Ding, Manuel Morales, Noah Gorelick, Riccardo Serra, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler. Repositioning the FDA-approved antiviral drug ribavirin as targeted therapy for nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B06.

The growing cost of medical care worldwide, particularly in oncology, has incentivized researchers and physicians to repurpose clinically used drugs to alleviate the financial burden of drug development and offer potential new therapeutics. Recent works have demonstrated anticancer properties of the FDA-approved drug ribavirin, a synthetic guanosine analogue and antiviral molecule used over the past four decades for the treatment of hepatitis C. The efficacy of ribavirin in cancer has been explored through several preclinical models and ongoing clinical trials in multiple cancers, including acute myeloid leukemia, oropharyngeal squamous cell carcinoma, and metastatic breast cancer. In this review, we summarize the role of ribavirin as an antiviral medication and focus our attention on its recent use as an antitumoral agent. We highlight current knowledge of the potential use and mechanisms of action of ribavirin in cancer. Because current therapeutics for patients with cancer still fail to cure, introducing new forms of treatment is essential. Converging evidence suggests that ribavirin represents a promising addition to a generation of newly repurposed safe and effective anticancer agents.

Upon discovery of Michelangelo’s concealed neuroanatomical images in “Separation of Light from Darkness,” by Suk and Tamargo in 2010, there remained a compelling need to investigate in greater detail the reasoning behind Michelangelo’s depiction of imagery of the brain, brainstem, spinal cord, eyeballs and optic nerves in the Sistine Chapel. At cursory glance, “Separation of Light from Darkness” depicts God’s first act of Genesis 1:3-5 (King James Bible), in which he creates light and separates it from the darkness, enveloping the world he has just created. It is a seemingly simple, conspicuous act, but careful analysis reveals that Michelangelo used his artistic, academic, and poetic genius to embed layers of symbolic meanings. The authors believe that the great artist infused a visual metaphor of a scene from Plato’s “Allegory of the Cave” in Book VII of The Republik (~380BC) to represent his key ideologies in Neoplatonism and pious convictions. Michelangelo painted the Sistine Chapel during the flourishing period of High Renaissance (~1475–1527). High Renaissance art followed and reflected the period of ‘rebirth’ in which philosophy, literature, art, and sciences drew on ancient knowledge from Classical Antiquity, principally the ancient Greeks. The Renaissance was a period of rapid growth where people applied new found knowledge to the Classical Greek studies of Socrates, Plato, and Aristotle (from about the 4th to 3rd century BC). One of the most influential ancient philosophers was Plato (~428-348 BC) whose teachings propagated throughout Athens for about two centuries around his lifetime, through his established school, the Academy. His philosophy of Neoplatonism was resurrected by an Italian baron, Cosimo I de Medici who employed Marsilio Ficino (1433-99) to lead the Florentine Platonic Academy (of which Michelangelo was a student) and translate all of Plato’s writings into Latin. Through analysis of Michelangelo’s paintings, his preliminary sketches, poems, written letters, and the political and religious context of his time, the authors attempt to provide key evidence to reveal the meaning and symbolism behind Michelangelo’s concealed anatomic representations.

Chordomas and chondrosarcomas are rare primary malignant spine tumors. In spite of recent advancements in chemotherapy, targeted therapy, and radiation therapy, surgery remains the gold standard for treatment of these lesions. Specifically, en bloc resection with wide tumor-free margins has better outcomes in terms of duration of disease-free and overall survival than does intralesional resection. Nonetheless, en bloc resections in the spine are technically demanding and highly morbid procedures, particularly in the lumbar spine because of the proximity of the lumbar plexus, great vessels, iliopsoas muscle, bowel, and others. This chapter reviews the operative management of lumbar chordomas and chondrosarcomas, emphasizing the surgical technique to achieve an en bloc resection via spondylectomy.

Giant cell tumors (GCTs) are rare primary bone neoplasms. The best long-term prognosis is achieved via complete tumor excision, but this feat is challenging in the spine due to proximity of blood vessels and nervous tissue. When occurring in the sacrum, GCTs have been removed in an en bloc fashion via combined anterior/posterior approaches, oftentimes with nerve root sacrifice. The purpose of this article is to present a case of a single-staged, posterior-only approach for en bloc resection of a sacral GCT without nerve root sacrifice.A 45-year-old female presented with intractable lower back and leg pain, saddle anesthesia, and lower extremity weakness. She underwent imaging studies, which revealed a lesion involving the S1 and S2 vertebral bodies. Computed tomography guided biopsy revealed the lesion to be a GCT. The patient underwent a posterior-only approach without nerve root sacrifice to achieve an en bloc resection, followed by lumbopelvic reconstruction.Sacrectomy via a single-staged posterior approach with nerve root preservation is a challenging yet feasible procedure for the treatment of giant cell tumors in carefully selected patients.

Background and Purpose— Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy. Methods— An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E–deficient (ApoE −/− ) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE −/− on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE −/− on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology. Results— Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE −/− mice on HFD. ApoE −/− mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice ( P −/− mice on HFD ( P −/− on HFD). The findings were confirmed with OCT imaging after perfusion and histology. Conclusions— OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE −/− mouse on HFD.

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti–programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti–PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti–PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

BACKGROUND: Pedicle screws are used to stabilize all 3 columns of the spine, but can be technically demanding to place. Although intraoperative fluoroscopy and stereotactic-guided techniques slightly increase placement accuracy, they are also associated with increased radiation exposure to patient and surgeon as well as increased operative time. OBJECTIVE: To describe and critically evaluate our 7-year institutional experience with placement of pedicle screws in the thoracic and lumbar spine using a free-hand technique. METHODS: We retrospectively reviewed records of all patients undergoing free-hand pedicle screw placement without fluoroscopy in the thoracic or lumbar spine between June 2002 and June 2009. Incidence and extent of cortical breach by misplaced pedicle screw was determined by review of postoperative computed tomography scans. We defined breach as more than 25% of the screw diameter residing outside of the pedicle or vertebral body cortex. RESULTS: A total of 964 patients received 6816 free-hand placed pedicle screws in the thoracic or lumbar spine. Indications for hardware placement were degenerative/deformity disease (51.2%), spondylolisthesis (23.7%), tumor (22.7%), trauma (11.3%), infection (7.6%), and congenital (0.9%). A total of 115 screws (1.7%) were identified as breaching the pedicle in 87 patients (9.0%). Breach occurred more frequently in the thoracic than the lumbar spine (2.5% and 0.9%, respectively; P < .0001) and was more often lateral (61.3%) than medial (32.8%) or superior (2.5%). T4 (4.1%) and T6 (4.0%) experienced the highest breach rate, whereas L5 and 51 had the lowest breach rate. Eight patients (0.8%) underwent revision surgery to correct malpositioned screws. CONCLUSION: Free-hand pedicle screw placement based on external anatomy alone can be performed with acceptable safety and accuracy and allows avoidance of radiation exposure encountered in fluoroscopic techniques. Image-guided assistance may be most valuable when placing screws between T4 and T6, where breach rates are highest.

BACKGROUND: Primary sacral neoplasms that extend superiorly to involve the distal lumbar spine represent complex surgical problems. Treatment options for these patients are often limited to hemicorporectomy. OBJECTIVE: To detail our surgical technique for en bloc resection of a sarcoma involving the L5 vertebral segment and sacrum and the reconstruction of the lumbopelvic junction. METHODS: A 52-year-old woman presented with intractable pain secondary to a sarcoma involving the L5 vertebral segment and sacrum. She underwent a combined L5 spondylectomy and total sacrectomy for en bloc resection of her neoplasm. A novel lumbopelvic reconstruction technique was used to establish a liaison between the lumbar spine and pelvis. RESULTS: Operative complications included a venous vascular injury and a nonviable myocutaneous flap. Post-operatively, the patient had complete resolution of her pain. Unfortunately, the patient developed metastatic disease and died 5 months after her initial surgical procedure. CONCLUSION: We describe a patient who underwent a combined L5 spondylectomy and total sacrectomy for en bloc resection of a lumbosacral sarcoma. Additionally, we report a novel technique to reconstruct the lumbopelvic junction. The operative procedures are detailed with the aid of radiographs, intraoperative photographs, and illustrations.

Study design This illustrative case report is designed to provide technical data regarding the use of a posterior approach to resect a retropharyngeal chordoma involving the craniovertebral junction. Objective The objective of this report is to emphasize the utility of the posterior approach when treating anterior tumors of the craniovertebral junction. Summary of background data Traditionally, a transoral transpharyngeal or extended anterior approach was used to resect anterior tumors of the craniovertebral junction. These approaches have several limitations unique to these exposures, limitations not applicable to a posterior midline cervical approach. Methods A case report is provided that illustrates the use of a posterior cervical approach used to resect a retropharyngeal craniovertebral junction chordoma. Results Gross total resection of a retropharyngeal chordoma was achieved using a posterior cervical approach. Although local tumor recurrence did occur, this was resected and adjuvant radiotherapy prescribed. This resulted in an ongoing 4-year recurrence free survival. Conclusions The posterior cervical midline exposure could be used to dissect and remove anterior retropharyngeal tumors, with minimal morbidity.

Michelangelo Buonarroti (1475-1564) was a master anatomist as well as an artistic genius. He dissected cadavers numerous times and developed a profound understanding of human anatomy. From 1508 to 1512, Michelangelo painted the ceiling of the Sistine Chapel in Rome. His Sistine Chapel frescoes are considered one of the monumental achievements of Renaissance art. In the winter of 1511, Michelangelo entered the final stages of the Sistine Chapel project and painted 4 frescoes along the longitudinal apex of the vault, which completed a series of 9 central panels depicting scenes from the Book of Genesis. It is reported that Michelangelo concealed an image of the brain in the first of these last 4 panels, namely, the Creation of Adam. Here we present evidence that he concealed another neuronanatomic structure in the final panel of this series, the Separation of Light From Darkness, specifically a ventral view of the brainstem. The Separation of Light From Darkness is an important panel in the Sistine Chapel iconography because it depicts the beginning of Creation and is located directly above the altar. We propose that Michelangelo, a deeply religious man and an accomplished anatomist, intended to enhance the meaning of this iconographically critical panel and possibly document his anatomic accomplishments by concealing this sophisticated neuroanatomic rendering within the image of God.

Background En bloc resection, with adequate surgical margins, of primary malignant bone tumors of the sacrum is associated with long term disease control and potential cure. Resection of sacral tumors is difficult due to the proximity of neurovascular and visceral structures, and complete, or even partial, sacrectomy often results in functional loss for the patient. Objective We describe the technique for en bloc resection of a sacral chordoma through a mid-sacral amputation. Results We demonstrate successful removal of a large sacral tumor with wide surgical margins while preserving neurologic function. Conclusion This technique for midsacral amputation to remove a sacral tumor en bloc minimizes local recurrence and maximizes neurovascular function.

OBJECTIVE Spinal cord compression secondary to a subluxation of one vertebral body over another can be achieved with reduction of the translational deformity. Intraoperative reduction of C1-C2 subluxations can be technically challenging when one uses traditional techniques (e.g., wiring and transarticular screw fixation). The popularization of C1 lateral mass and C2 pedicle screws has allowed surgeons to achieve a more complex realignment at this region of the spine. Control of both C1 and C2 with independent fixation can be used to obtain reduction. In certain instances, placement of C2 pedicle screws is not possible. The use of C2 translaminar screws (if the C2 lamina is present and suitable) is an alternative method of fixation in C2 and can be used for intraoperative reduction. CLINICAL PRESENTATION A 15-year-old boy with juvenile rheumatoid arthritis presented with spinal cord compression secondary to a C1-C2 subluxation. The C2 pedicle anatomy precluded safe placement of C2 pedicle screws. An alternative method of fixation with the use of C2 translaminar screws and reduction was performed to obtain proper alignment and decompress the spinal cord. TECHNIQUE C1 lateral mass screws and C2 translaminar screws are inserted in the usual fashion. Two contoured rods, two rod holders, and two distractors, combined with C1 lateral mass screws and C2 translaminar screws, were used to achieve reduction. Concomitant distraction between the C2 translaminar screw head and the rod holder resulted in ventral translation of C2 on C1, decompressing the spinal cord. The reduction was maintained by tightening the C2 locking nut onto the rod. CONCLUSION The use of C2 translaminar screws (if the C2 lamina is present and suitable) is an alternative method of fixation in C2. C1 lateral mass and C2 translaminar screw fixation provide a powerful means of reducing C1-C2 subluxations and maintaining alignment, achieving indirect decompression of the spinal cord.

OBJECTIVE Total sacrectomies are performed for extensive en bloc tumor resections. Exposure traditionally combines a posterior approach with a laparotomy to facilitate vascular control. We present a case of a total en bloc sacrectomy performed entirely through the posterior approach, thereby avoiding the need for a laparotomy. CLINICAL PRESENTATION A 57-year-old man presented with sacral pain and loss of bowel and bladder function. A large sacral mass was identified and submitted to biopsy. Results were consistent with an osteoblastoma, although osteosarcoma could not be excluded on pathological examination. The patient was taken to the operating room for a total sacrectomy and en bloc resection of the mass. TECHNIQUE Lateral iliac osteotomies were performed, followed by an L5-S1 discectomy and resection of the annulus, thus mobilizing the sacrum. Gradual distraction of the interspace coupled with upward traction of the sacrum provided an anterior exposure through which the internal iliac vessels were controlled, dissected, and divided. A combined transperineal approach completed the posterior dissection and the tumor was delivered en bloc. Lumbopelvic reconstruction was performed simultaneously. CONCLUSION With the use of interspace distraction and sacral elevation to facilitate vascular control, a total sacrectomy was performed without the need for the anterior exposure of a laparotomy.

✓The authors describe a technique for total L-5 spondylectomy and reconstruction of the lumbosacral junction. The technique, which involves separately staged posterior and anterior procedures, is reported in two patients harboring neoplasms that involved the L-5 level. The first stage consisted of a posterior approach with removal of all posterior bone elements of L-5 and radical L4–5 and L5–S1 discectomies. Lumbosacral and lumbopelvic instrumentation included pedicle screws as well as iliac screws or a transiliac rod. The second stage consisted of an anterior approach with mobilization of vascular structures, completion of L4–5 and L5–S1 discectomies, and removal of the L-5 vertebral body. Anterior lumbosacral reconstruction included placement of a distractable cage and tension band between L-4 and S-1. Allograft bone was used for fusion in both stages. No significant complications were encountered. At more than 1 year of follow-up, both patients were independently ambulatory, without evidence of recurrent or metastatic disease, and adequate lumbosacral alignment was maintained. The authors conclude that this technique can be safely performed in appropriately selected patients with neoplasms involving L-5.

The histology of the primary tumor in metastatic spine disease plays an important role in its treatment and prognosis. However, there is paucity in the literature of histology-specific analysis of spinal metastases. In this study, prognostic variables were reviewed for patients who underwent surgery for breast metastases to the spinal column. Respective chart review was done to first identify all patients with breast cancer over an 8-year period at a major cancer center and then to select all those with symptomatic metastatic disease to the spine who underwent spinal surgery. Univariate and multivariate analyses were used to assess several prognostic variables. Presence of visceral metastases, multiplicity of bony lesions, presence of estrogen receptors (ER), and segment of spine (cervical, thoracic, lumbar, sacral) in which metastases arose were compared with patient survival. Eighty-seven patients underwent 125 spinal surgeries. Those with estrogen receptor (ER) positivity had a longer median survival after surgery compared to those with estrogen receptor negativity. Patients with cervical location of metastasis had a shorter median survival compared with those having metastases in other areas of the spine. The presence of visceral metastases or a multiplicity of bony lesions did not have prognostic value. In patients with spinal metastases from breast cancer, aggressive surgical management may be an option for providing significant pain relief and preservation/improvement of neurological function. Interestingly, in patients undergoing such surgery, cervical location of metastasis is a negative prognostic variable, and ER-positivity is associated with better survival, while presence of visceral or multiple bony lesions does not significantly alter survival.

✓Symptomatic irreducible basilar invagination has traditionally been approached through a transoral–transpharyngeal route with resection of the anterior portion of C-1 and the odontoid. Modification of this exposure with either a Le Fort osteotomy or a transmandibular osteotomy and circumglossal approach has increased the access to pathological conditions in this region. These traditional routes all require traversing the oral cavity and accepting the associated potential complications. The authors have developed a novel surgical approach, an endoscopic transcervical odontoidectomy, which allows access for resection of the odontoid and for brainstem and spinal cord decompression without traversing the oral cavity. In this paper they describe the technique and its advantages and present three cases in which patients underwent the endoscopic transcervical odontoidectomy for basilar invagination.Three consecutive patients (age range 42–74 years) who had irreducible basilar invagination underwent the endoscopic transcervical odontoidectomy. All were symptomatic and had neck pain and myelopathy. All were evaluated preoperatively and postoperatively with computed tomography and magnetic resonance imaging. In all cases the procedure resulted in complete decompression. There were no serious complications. No patient required prolonged intubation, tracheostomy, or enteral tube feeding. One patient had an intraoperative cerebrospinal fluid leak, which had no postoperative sequelae.The authors present an alternative surgical approach for treating ventral compression of the brainstem and spinal cord. The technique is safe and effective for decompression and provides a surgical route that can be added to the armamentarium of treatments for pathological conditions in this region.

✓ Although radical resection prolongs the disease-free survival period, surgical management of primary sacral tumors is challenging because of their location and often large size. Moreover, in cases of lesions for which a radical resection necessitates total sacrectomy, reconstruction is required. The authors have previously described a modified Galveston technique in which a liaison between the spine and pelvis is achieved using lumbar pedicle screws and Galveston rods embedded into the ilia; additionally, a transiliac bar reestablishes the pelvic ring. Although this reconstruction technique achieves stabilization, several biomechanical limitations exist. In the present report the authors present the case of a patient who underwent spinal pelvic reconstruction after a total sacrectomy was performed to remove a giant sacral chordoma. They describe a novel spinal pelvic reconstruction technique that addresses some of the biomechanical limitations.

OBJECTIVE Several authors have noted increased neurological deficits and worsening dysesthesia in the postoperative period in patients with spinal cord ependymoma. We describe the neurological progression and pain evolution of these patients over the 1-year period after surgery. In addition, our favored method of en bloc tumor resection is illustrated, and the rate of complications, recurrence, and survival in this group of patients is addressed. METHODS We operated on 26 patients (12 male and 14 female) with low-grade spinal cord ependymomas between 1975 and 2001. The median age at diagnosis was 42 years. Tumors extended into the cervical cord in 13 patients, the thoracic cord in 7 patients, and the conus medullaris in 6 patients. Eleven patients had previous surgery and/or radiation therapy. RESULTS We achieved a gross total resection in 88% of patients, whereas 8% had a subtotal resection and 4% had a biopsy. Only 1 patient developed a recurrence over a mean follow-up period of 31 months. CONCLUSION We conclude that radical surgical resection of spinal cord ependymomas can be safely achieved in the majority of patients. A trend toward neurological improvement from a postoperative deficit can be expected between 1 and 3 months after surgery and continues up to 1 year. Postoperative dysesthesias begin to improve within 1 month of surgery and are significantly better by 1 year after surgery. The best predictor of outcome is the preoperative neurological status.

Extensive clival tumors that involve both the midline and lateral skull base compartments, or those that extend inferiorly to the anterior cervical spine, are difficult to expose in a wide fashion using any of the transmaxillary, transoral, or transcervical routes. In the transmandibular, circumglossal, retropharyngeal (TCR) approach wide access of this region can be obtained, thus allowing for a more complete resection of tumor and infiltrated bone. It also provides for an improved ability to perform dural reconstruction, should it be necessary. Over the past 4 years four patients with extensive clival chordomas underwent resection via the TCR approach. Gross-total resection was achieved in two patients, a greater than 98% resection in one patient, and a greater than 95% resection in the fourth patient. The surgical technique, all approach-related complications and morbidity, and patient outcome are discussed. If an expanded exposure of the clivus is necessary, the TCR approach is a good choice as well as a useful surgical technique to have available.

Malignant brain tumors are typically characterized by high rates of invasiveness and resistance to many forms of treatment. The main treatment modalities for malignant brain tumors consist of maximum safe surgical resection, chemotherapy, radiosurgery, or combination of these. Locally delivered chemotherapy is particularly suitable for brain tumor therapy following surgical resection since it bypasses the blood–brain barrier, maintains a higher stable drug concentration for longer periods of time, and has a more extensive distribution in the peritumoral areas than systemically administered chemotherapy with subsequent tumoricidal effects. The development of Gliadel, a BCNU-loaded polymer, approved in 1996 and successfully evaluated in clinical trials, has opened the door for a new arsenal of drugs for treatment of malignant primary brain tumors. New chemotherapeutic agents such as platinum-derived drugs, antiangiogenic compounds, and immunomodulatory molecules, among others, have undergone successful preclinical testing and await further clinical evaluation. A new generation of drug delivery microchips, gene-targeted drugs, and nanocarriers will enable simultaneous treatment with multiple agents based on the histological phenotype and genotype profile, which should result in highly individualized and more effective treatments for patients with this devastating disease.