Novel Standalone Motion-Sparing Pelvic Fixation Prevents Short-Term Insufficiency Fractures After Midsacrectomies Without Sacrificing Normal, Mobile Lumbar Segments Traditionally Used for Stabilization.

BACKGROUND AND OBJECTIVES: Sacrectomy is often the treatment of choice to provide the greatest chance of progression-free and overall survival for patients with primary malignant bone tumors of the sacrum. After midsacrectomy, the stability of the sacropelvic interface is diminished, resulting in insufficiency fractures. Traditional stabilization involves lumbopelvic fixation but subjects normal mobile segments to fusion. The purpose of this study was to determine whether standalone intrapelvic fixation is a safe adjunct to midsacrectomy, avoiding both sacral insufficiency fractures and the morbidity of instrumenting into the mobile spine. METHODS: A retrospective study identified all patients who underwent resection of sacral tumors at 2 comprehensive cancer centers between June 2020 and July 2022. Demographic, tumor-specific, operative characteristics and outcome data were collected. The primary outcome was presence of sacral insufficiency fractures. A retrospective data set of patients undergoing midsacrectomy without hardware placement was collected as a control. RESULTS: Nine patients (5 male, 4 female), median age 59 years, underwent midsacrectomy with concomitant placement of standalone pelvic fixation. No patients developed insufficiency fractures during the 216 days of clinical and 207 days of radiographic follow-up. There were no adverse events attributable to the addition of standalone pelvic fixation. In our historical cohort of partial sacrectomies without stabilization, there were 4/25 patients (16%) with sacral insufficiency fractures. These fractures appeared between 0 and 5 months postoperatively. CONCLUSION: A novel standalone intrapelvic fixation after partial sacrectomy is a safe adjunct to prevent postoperative sacral insufficiency fractures in patients undergoing midsacrectomy for tumor. Such a technique may allow for long-term sacropelvic stability without sacrificing mobile lumbar segments.

Low-Intensity Pulsed Ultrasound Neuromodulation of a Rodent's Spinal Cord Suppresses Motor Evoked Potentials.

OBJECTIVE: Here we investigate the ability of low-intensity ultrasound (LIUS) applied to the spinal cord to modulate the transmission of motor signals. METHODS: Male adult Sprague-Dawley rats (n = 10, 250-300 g, 15 weeks old) were used in this study. Anesthesia was initially induced with 2% isoflurane carried by oxygen at 4 L/min via a nose cone. Cranial, upper extremity, and lower extremity electrodes were placed. A thoracic laminectomy was performed to expose the spinal cord at the T11 and T12 vertebral levels. A LIUS transducer was coupled to the exposed spinal cord, and motor evoked potentials (MEPs) were acquired each minute for either 5- or 10-minutes of sonication. Following the sonication period, the ultrasound was turned off and post-sonication MEPs were acquired for an additional 5 minutes. RESULTS: Hindlimb MEP amplitude significantly decreased during sonication in both the 5- (p < 0.001) and 10-min (p = 0.004) cohorts with a corresponding gradual recovery to baseline. Forelimb MEP amplitude did not demonstrate any statistically significant changes during sonication in either the 5- (p = 0.46) or 10-min (p = 0.80) trials. CONCLUSION: LIUS applied to the spinal cord suppresses MEP signals caudal to the site of sonication, with recovery of MEPs to baseline after sonication. SIGNIFICANCE: LIUS can suppress motor signals in the spinal cord and may be useful in treating movement disorders driven by excessive excitation of spinal neurons.

Novel Approach of Femur Shortening With Insertion of Expandable Rod to Achieve End-to-End Repair of Sciatic Nerve Laceration.

BACKGROUND: Sciatic nerve injuries are challenging for diagnosis and treatment. Particularly in proximally located high-grade injuries, neurorrhaphy often has poor outcomes. Most advocate autologous grafting and some more recently have suggested the value of knee flexion braces to facilitate end-to-end repair. OBJECTIVE: To describe a case of femur shortening to facilitate tension-free, end-to-end sciatic nerve neurorrhaphy. METHODS: The patient was a 17-year-old man who was injured by the propeller of a motor boat and suffered a series of lacerations to both lower extremities including transection of his right sciatic nerve in the proximal thigh. After extensive mobilization of the nerve, a greater than 7-cm gap was still present. The patient was treated with femur shortening to facilitate end-to-end coaptation. He subsequently had an expandable rod placed which was lengthened 1 mm per day until his leg length was symmetric. RESULTS: Within 7 months postoperatively, the patient had an advancing Tinel sign and paresthesias to the dorsum of his foot. Nine months postoperatively, he had early mobility in his plantarflexion. CONCLUSION: We present a novel method of femur shortening with insertion of an expandable rod to facilitate direct end-to-end and tension-free sciatic nerve neurorrhaphy in a proximally located injury. Furthermore, larger scale and comparative studies are warranted to further explore this and other techniques.

First Experience With Postoperative Transcranial Ultrasound Through Sonolucent Burr Hole Covers in Adult Hydrocephalus Patients.

BACKGROUND: Managing patients with hydrocephalus and cerebrospinal fluid (CSF) disorders requires repeated head imaging. In adults, it is typically computed tomography (CT) or less commonly magnetic resonance imaging (MRI). However, CT poses cumulative radiation risks and MRI is costly. Ultrasound is a radiation-free, relatively inexpensive, and optionally point-of-care alternative, but is prohibited by very limited windows through an intact skull. OBJECTIVE: To describe our initial experience with transcutaneous transcranial ultrasound through sonolucent burr hole covers in postoperative hydrocephalus and CSF disorder patients. METHODS: Using cohort study design, infection and revision rates were compared between patients who underwent sonolucent burr hole cover placement during new ventriculoperitoneal shunt placement and endoscopic third ventriculostomy over the 1-year study time period and controls from the period 1 year before. Postoperatively, trans-burr hole ultrasound was performed in the clinic, at bedside inpatient, and in the radiology suite to assess ventricular anatomy. RESULTS: Thirty-seven patients with sonolucent burr hole cover were compared with 57 historical control patients. There was no statistically significant difference in infection rates between the sonolucent burr hole cover group (1/37, 2.7%) and the control group (0/57, P = .394). Revision rates were 13.5% vs 15.8% (P = 1.000), but no revisions were related to the burr hole or cranial hardware. CONCLUSION: Trans-burr hole ultrasound is feasible for gross evaluation of ventricular caliber postoperatively in patients with sonolucent burr hole covers. There was no increase in infection rate or revision rate. This imaging technique may serve as an alternative to CT and MRI in the management of select patients with hydrocephalus and CSF disorders.

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.

Advances in monitoring for acute spinal cord injury: a narrative review of current literature.

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.

Nerve Root Sparing En Bloc Resection of Sacral Chondrosarcoma: Technical Note and Review of the Literature.

BACKGROUND: Total en bloc sacrectomy provides the best long-term local control for large primary bony sacral tumors, but often requires lumbosacral nerve root sacrifice leading to loss of ambulation and/or bowel, bladder, and/or sexual dysfunction. Nerve-sparing techniques may be an option for some patients that avoid these outcomes and accordingly improve postoperative quality of life. OBJECTIVE: To describe the technique for a posterior-only en bloc hemisacrectomy with maximal nerve root preservation and to summarize the available literature. METHODS: A 38-yr-old woman with a 7.7 × 5.4 × 4.5 cm biopsy-proven grade 2 chondrosarcoma involving the left L5-S2 posterior elements underwent a posterior-only left hemisacrectomy tri-rod L3-pelvis fusion. A systematic review of the English literature was also conducted to identify other descriptions of high sacrectomy with distal sacral nerve root preservation. RESULTS: Computer-aided navigation facilitated an extracapsular resection that allowed preservation of the left-sided L5 and S3-Co roots. Negative margins were achieved and postoperatively the patient retained ambulation and good bowel/bladder function. Imaging at 9-mo follow-up showed no evidence of recurrence. The systematic review identified 4 prior publications describing 6 total patients who underwent nerve-sparing sacral resection. Enneking-appropriate resection was only obtained in 1 case though. CONCLUSION: Here we describe a technique for distal sacral nerve root preservation during en bloc hemisacrectomy for a primary sacral tumor. Few prior descriptions exist, and the present technique may help to reduce the neurological morbidity of sacral tumor surgery.

High-Intensity Focused Ultrasound: A Review of Mechanisms and Clinical Applications.

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.

Ultrasound in Traumatic Spinal Cord Injury: A Wide-Open Field.

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.

Sacroplasty Augmentation of Instrumented Pelvic Reconstruction After High Sacrectomy: A Technical Case Report.

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.

Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.

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.

Evaluating the Effects of Cerebrospinal Fluid Protein Content on the Performance of Differential Pressure Valves and Antisiphon Devices Using a Novel Benchtop Shunting Model.

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.

Epidural Oscillating Cardiac-Gated Intracranial Implant Modulates Cerebral Blood Flow.

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 < .0005) and inversion (139%/120%, P < .0005). The observed changes associated with the ICP mean values were smaller, increasing with augmentation (23%/31%, P < .0001) while decreasing with inversion (7%/11%, P = .006/.0003) and reduction (4%/5%, P < .0005). CBF increase was observed for both inversion and reduction protocols (28%/7.4%, P < .0001/P = .006 and 2.4%/1.3%, P < .0001/P = .003), but not the augmentation protocol. The change in CBF was correlated with ICP pulse amplitude and systolic peak changes and not with change in mean ICP or systemic variables (heart rate, arterial blood pressure). CONCLUSION: Cardiac-gated manipulation of ICP pulsatility allows the study of intracranial pulsatile dynamics and provides a potential means of altering CBF.

Minimizing cotton ball retention in neurological procedures.

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.

Minimizing cotton retention in neurosurgical procedures: which imaging modality can help?

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.

The Use of Ribavirin as an Anticancer Therapeutic: Will It Go Viral?

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.

Use of an Articulating Hinge to Facilitate Cervicothoracic Deformity Correction During Vertebral Column Resection.

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.

Neoplatonic Symbolism by Michelangelo in Sistine Chapel's Separation of Light from Darkness.

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.

Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM.

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.