Three-column osteotomy in long constructs has lower rates of proximal junctional kyphosis and better restoration of lumbar lordosis than anterior column realignment.

PURPOSE: Three-column osteotomies (TCOs) and minimally invasive techniques such as anterior column realignment (ACR) are powerful tools used to restore lumbar lordosis and sagittal alignment. We aimed to appraise the differences in construct and global spinal stability between TCOs and ACRs in long constructs. METHODS: We identified consecutive patients who underwent a long construct lumbar or thoracolumbar fusion between January 2016 and November 2021. "Long construct" was any construct where the uppermost instrumented vertebra (UIV) was L2 or higher and the lowermost instrumented vertebra (LIV) was in the sacrum or ileum. RESULTS: We identified 69 patients; 14 (20.3%) developed PJK throughout follow-up (mean 838 days). Female patients were less likely to suffer PJK (p = 0.009). TCO was more associated with open (versus minimally invasive) screw/rod placement, greater number of levels, higher UIV, greater rate of instrumentation to the ilium, and posterior (versus anterior) L5-S1 interbody placement versus the ACR cohort (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.005, respectively). Patients who developed PJK were more likely to have undergone ACR (12 (32.4%) versus 2 (6.3%, p = 0.007)). The TCO cohort had better improvement of lumbar lordosis despite similar preoperative measurements (ACR: 16.8 ± 3.78°, TCO: 23.0 ± 5.02°, p = 0.046). Pelvic incidence-lumbar lordosis mismatch had greater improvement after TCO (ACR: 14.8 ± 4.02°, TCO: 21.5 ± 5.10°, p = 0.042). By multivariate analysis, ACR increased odds of PJK by 6.1-times (95% confidence interval: 1.20-31.2, p = 0.29). CONCLUSION: In patients with long constructs who undergo ACR or TCO, we experienced a 20% rate of PJK. TCO decreased PJK 6.1-times compared to ACR. TCO demonstrated greater improvement of some spinopelvic parameters.

Reducing drain use with paraspinal muscle flaps for spinal closures: A retrospective cohort study.

BACKGROUND: Paraspinal muscle (PSM) flaps can be mobilized with superficial undermining and lateral release from the thoracolumbar fascia and/or deep undermining and medial release from the transverse processes and ribs. The objective of the study was to compare the effect of the PSM flap technique on drain use, retention, and complication rates. METHODS: A retrospective chart review was performed for patients who underwent spinal coverage with PSM flaps at a single institution from April 2020 to June 2021. Patient demographics, preoperative comorbidities, surgical technique, drain usage, and postoperative complications were analyzed to compare the effects of different PSM flap surgical techniques on postoperative drain use and complications. RESULTS: Sixty patients were included. Both superficial and deep releases were performed in half (47%) of the cases, while the remainder was split between superficial (25%) and deep (28%) releases. Drains were used less frequently for the deep release (35%) than the superficial (93%) or both releases (96%, p < 0.01). The deep release had shorter mean drain retention time (5.8 days) than the superficial (30.3 days) or both releases (24.8 days, p < 0.01). There were no significant differences between the techniques in terms of complications. For the deep release, the use of drains was not associated with a reduction in complications (odds ratio 0.91 [0.84 - 0.98], p = 0.97). CONCLUSIONS: In a selected patient population, a "deep release only" PSM flap technique may allow for drainless spinal closure without an increased risk of seroma or other complications.

Risk Factors for Adjacent Segment Disease in Short Segment Lumbar Interbody Fusion-A Case Series.

BACKGROUND: Adjacent segment disease (ASD) is a common problem after lumbar spinal fusions. Ways to reduce the rates of ASD are highly sought after to reduce the need for reoperation. OBJECTIVE: To find predisposing factors of ASD after lumbar interbody fusions, especially in mismatch of pelvic incidence and lumbar lordosis (PI-LL). METHODS: We conducted a retrospective cohort study of all patients undergoing lumbar interbody fusions of less than 4 levels from June 2015 to July 2020 with at least 1 year of follow-up and in those who had obtained postoperative standing X-rays. RESULTS: We found 243 patients who fit inclusion and exclusion criteria. Fourteen patients (5.8%) developed ASD, at a median of 24 months. Postoperative lumbar lordosis was significantly higher in the non-ASD cohort (median 46.4° ± 1.4° vs 36.9° ± 3.6°, P < .001), pelvic tilt was significantly lower in the non-ASD cohort (16.0° ± 0.66° vs 20.3° ± 2.4°, P = .002), PI-LL mismatch was significantly lower in the non-ASD cohort (5.28° ± 1.0° vs 17.1° ± 2.0°, P < .001), and age-appropriate PI-LL mismatch was less common in the non-ASD cohort (34 patients [14.8%] vs 13 [92.9%] of patients with high mismatch, P < .001). Using multivariate analysis, greater PI-LL mismatch was predictive of ASD (95% odds ratio CI = 1.393-2.458, P < .001) and age-appropriate PI-LL mismatch was predictive of ASD (95% odds ratio CI = 10.8-970.4, P < .001). CONCLUSION: Higher PI-LL mismatch, both age-independent and when adjusted for age, after lumbar interbody fusion was predictive for developing ASD. In lumbar degenerative disease, correction of spinopelvic parameters should be a main goal of surgical correction.

Cervical Spine Research Society-Cervical Stiffness Disability Index (CSRS-CSDI): Validation of a Novel Scoring System Quantifying the Effect of Postarthrodesis Cervical Stiffness on Patient Quality of Life.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: The aim was to create and validate a novel patient-reported outcome measure (PROM) focusing on stiffness-related patient functional limitations after cervical spine fusion. SUMMARY OF BACKGROUND DATA: Cervical arthrodesis is a common treatment for myelopathy/radiculopathy, however, results in increased neck stiffness as a collateral outcome. No current PROM exists quantifying the impact of postoperative stiffness on patient function. METHODS: The Cervical Spine Research Society-Cervical Stiffness Disability Index (CSRS-CSDI) was created through a modified Delphi process. The resultant 10-item questionnaire yields a score out of 100 with higher scores indicating increased functional difficulty related to neck stiffness. Cross-sectional study of control and postoperative patients was completed for CSRS-CSDI validation. Retest reliability (intraclass correlation coefficient), internal consistency (Cronbach alpha), responsiveness (levels fused vs. CSRS-CSDI scores), and discriminatory validation (CSRS-CSDI vs. neck disability index) scores) were completed. RESULTS: Fifty-seven surgical and 24 control patients completed the questionnaire. Surgical patients underwent a variety of procedures: 11 (19%) motion preserving operations, nine (16%) subaxial 1-2 level fusions, seven (12%) subaxial 3-5 level fusions, five (9%) C1-subaxial cervical spine fusions, 20 (35%) C2-upper thoracic spine fusions, five (9%) occiput-subaxial or thoracic spine fusions. The questionnaire demonstrated high internal consistency (Cronbach alpha=0.92) and retest reliability (intraclass correlation coefficient=0.95, P <0.001). Good responsiveness validity with a significant difference between fusion cohorts was found ( P <0.001, rs =0.63). Patient CSRS-CSDI scores also correlated with neck disability index scores recorded ( P <0.001, r =0.70). CONCLUSION: This is the first study to create a PROM addressing the functional impact of cervical stiffness following surgical arthrodesis. The CSRS-CSDI was a reliable and valid measure of postoperative stiffness impact on patient function. This may prove useful in counseling patients regarding their expected outcomes with further investigation demonstrating its value in a prospective fashion.

Anterior longitudinal ligament release from a posterior approach: an alternative to three-column osteotomy.

PURPOSE: Expansion of the anterior column and compression of the posterior column restores lordosis and sagittal imbalance. Anterior longitudinal ligament (ALL) release has been described from lateral and anterior approaches as a technique to improve lumbar lordosis; however, posterior approach to release the ALL has not been adequately assessed. METHODS: We demonstrate a case series of ALL release using a posterior approach performed in conjunction with posterior column osteotomy (PCO), with or without transforaminal lumbar interbody fusion (TLIF) for spinal deformity. Eleven cases were identified from billing records between 2010 and 2019. Retrospective review was conducted for perioperative complications and revision surgery. Overall and segmental lumbar lordosis (LL) correction was measured from pre- and postoperative imaging. RESULTS: Eleven patients underwent ALL release with a PCO. Kyphosis, scoliosis, and flat back syndrome were the most common spinal deformities. On average, patients had 9 ± 3 levels fused and a single level ALL release. ALL release was most commonly performed at L1-L2 and L2-L3 levels. An overall LL correction of 28.6° ± 19.8o was achieved; ALL release introduced 16.7° ± 11.9° of lordotic correction and accounted for 49.2 ± 30.4% of the overall lordotic correction. Average blood loss was 1030 ± 573 mL. CONCLUSIONS: ALL release as an adjunct to PCO and TLIF is a viable technique for providing increased deformity correction without subjecting the patient to a more invasive three-column osteotomy. While this approach may not be appropriate for all patients, it represents a useful option in spinal deformity correction while limiting blood loss and additional anterior surgery. LEVEL OF EVIDENCE: IV.

Iliac Screw Fixation Revisited: Improved Clinical and Radiologic Outcomes Using a Modified Iliac Screw Fixation Technique.

STUDY DESIGN: A retrospective study. OBJECTIVE: To describe the modified iliac screw (mILS) technique and compare it to other spinopelvic fixation techniques in terms of wound healing complications, hardware prominence, and failure. SUMMARY OF BACKGROUND DATA: The traditional entry point of an iliac screw often causes postoperative gluteal pain from the prominent screw head. The use of an offset connector also adds a point of weakness to the construct. By choosing a different screw entry point offset connectors can be avoided, and the screw head itself is less prominent, thereby reducing postoperative discomfort. MATERIALS AND METHODS: A retrospective analysis was performed of adult patients undergoing lumbopelvic fixation (LPF) between January 2014 and June 2019. Patients were grouped into 1 of 3 groups based on the technique of pelvic fixation: S2 alar-iliac (S2AI) screw, traditional iliac screw (tILS), and mILS. The primary outcome parameter was the minimal distance from screw head to skin. Secondary outcome parameters were instrumentation loosening/failure, adjacent level fractures, pseudoarthrosis, and medial or lateral iliac screw perforation. RESULTS: A total of 190 patients undergoing LPF were included in the following 3 groups: mILS group (n=113), tILS group (n=40), and S2AI group (n=37). The mean minimal distance from screw head to skin in the mILS group was 31.3 mm compared with 23.7 mm in the tILS group (P<0.00199). No statistically significant differences were found when comparing the 3 groups with respect to complications. The mILS group did not show any cases of prominent instrumentation and had the lowest rate of instrumentation failure. CONCLUSIONS: The mILS technique is an acceptable alternative for LPF, offering the benefits of iliac screw fixation while avoiding offset connectors and screw prominence complications associated with tILS. LEVEL OF EVIDENCE: Level III.

Surgical Treatment of Ossifications of the Cervical Anterior Longitudinal Ligament: A Retrospective Cohort Study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: The study aims to evaluate anterior cervical discectomy and fusion (ACDF) in the treatment of patients with ossification of the anterior longitudinal ligament (OALL). METHODS: We retrospectively reviewed cases performed at our institution between January 2015 and December 2018; adult (age ≥18 years) patients who underwent anterior cervical decompression and fusion in the presence of dysphagia and OALL. Ten patients (9 male, 1 female, mean age 64.4 years) with OALL who underwent ACDF were included. Charts were reviewed for demographics and comorbidities. Primary outcomes assessed were intra- and postoperative complications. Secondary outcomes were fusion rates, instrumentation failure, postsurgical instability/deformity, and readmission rates. RESULTS: The average duration of symptoms prior to surgery was 12.3 months. All patients presented with dysphagia (mean Bazaz score 2.0). The average number of levels with OALL was 4.7 (±1.67). All patients underwent ACDF and 3 patients underwent additional posterior cervical fusion for kyphotic deformity correction or when extensive laminectomy was required. We did not encounter any intraoperative complications. Eight patients (72%) had solid fusion demonstrated on the lateral x-rays and no evidence of progressive kyphotic deformity. We did not encounter any instrumentation failure or loosening. Two patients developed recurrence of dysphagia (Bazaz scores 2 and 3 respectively). CONCLUSION: ACDF for OALL with dysphagia and concomitant myelopathy in our small series of 10 patients demonstrate good fusion and clinical outcomes. Larger studies will be necessary to determine the optimal treatment for patients with dysphagia due to OALL.

Extreme Lateral Interbody Fusion for Thoracic and Thoracolumbar Disease: The Diaphragm Dilemma.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Complication profiles for lateral approaches to the spine are well established. However, the influence of level of surgery on complication rates and subtypes are less well established. To determine risk factors for complications as determined by level and surgery type in patients undergoing a lateral (retroperitoneal or retropleural approach) to the thoracolumbar spine. METHODS: All adult patients undergoing a lateral thoracolumbar fusion with or without posterior instrumentation performed at a single institution were identified. Primary outcomes assessed were presence of complication, complication subtype, and need for reoperation. The primary independent variables were spinal level (thoracic, thoracolumbar, or lumbar) and type of surgery (discectomy or corpectomy). Categorical outcomes were compared using chi-square test. Unadjusted and adjusted odds ratios for corpectomy status were calculated to determine risk of complication by level. P < .05 was considered statistically significant. RESULTS: A total of 165 patients aged 18 to 75 years were identified as having undergone a lateral fusion. Complication rates were 28.6%, 36.4%, and 11% for thoracic, thoracolumbar, and lumbar lateral approach fusions, respectively. Under univariate analysis, patients undergoing lateral approach in the thoracic spine group had significantly higher rates of postoperative complications than those in the lumbar group (P = .005). After adjusting for corpectomy status, there was no difference in complication rates. CONCLUSIONS: Lateral (retroperitoneal or retropleural) approaches to the thoracic and thoracolumbar spine may be used with complication rates comparable to well-established lumbar approaches. Extent of surgery (corpectomy vs discectomy) rather than level of surgery may represent the primary driver of complications.

The Modified Iliac Screw: An Anatomic Comparison and Technical Guide.

BACKGROUND: Iliac screws are a widely used sacropelvic fixation technique, which is often criticized for its impaired wound healing owing to hardware prominence. The aim of this study was to present a modified iliac screw (MIS) fixation technique that uses a different entry point more medially and caudally to the posterior superior iliac spine next to the rudimentary S1-S2 joint. Soft tissue coverage and midline distance in an MIS and a traditional iliac screw were compared. METHODS: Two different variations of iliac screws were placed into 12 fresh frozen adult cadavers (9 male, 3 female, mean age at death 77.08 years, mean body mass index 23.4). The distance between the midline and the center of the screw head was measured. We also compared the angulation of the trajectories. After wound closure, we measured the distance between the iliac screw head and the skin. RESULTS: The mean distance from the screw tulip head to the skin was 2.43 cm (range, 1.2-4.2 cm) with the traditional iliac screw and 3.16 cm (range, 1.7-4.3 cm) with the MIS. The mean distance to the midline with the MIS was 3.1 cm (range, 2.4-4.5 cm) lateral to the midline compared with the traditional iliac screw, of which the mean was 4.2 cm lateral to the midline (range, 3.7-4.9 cm). Mean angulation was 10°. CONCLUSIONS: The MIS avoids the use of connectors and provides less prominent pelvic fixation. Clinically, this might help prevent prominent hardware and related wound healing impairment.

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted.

Selective Vulnerability of the Foramen Magnum in a Rat Blast Traumatic Brain Injury Model.

Primary blast traumatic brain injury (bTBI) accounts for a significant proportion of wartime trauma. Previous studies have demonstrated direct brain injury by blast waves, but the effect of the location of the blast epicenter on the skull with regard to brain injury remains poorly characterized. In order to investigate the role of the blast epicenter location, we modified a previously established rodent model of cranium-only bTBI to evaluate two specific blast foci: a rostrally focused blast centered on bregma (B-bTBI), which excluded the foramen magnum region, and a caudally focused blast centered on the occipital crest, which included the foramen magnum region (FM-bTBI). At all blast overpressures studied (668-1880 kPa), rats subjected to FM-bTBI demonstrated strikingly higher mortality, increased durations of both apnea and hypoxia, and increased severity of convexity subdural hematomas, than rats subjected to B-bTBI. Together, these data suggest a unique role for the foramen magnum region in mortality and brain injury following blast exposure, and emphasize the importance of the choice of blast focus location in experimental models of bTBI.

Cerebral Edema After Cardiopulmonary Resuscitation: A Therapeutic Target Following Cardiac Arrest?

We sought to review the role that cerebral edema plays in neurologic outcome following cardiac arrest, to understand whether cerebral edema might be an appropriate therapeutic target for neuroprotection in patients who survive cardiopulmonary resuscitation. Articles indexed in PubMed and written in English. Following cardiac arrest, cerebral edema is a cardinal feature of brain injury and is a powerful prognosticator of neurologic outcome. Like other conditions characterized by cerebral ischemia/reperfusion, neuroprotection after cardiac arrest has proven to be difficult to achieve. Neuroprotection after cardiac arrest generally has focused on protecting neurons, not the microvascular endothelium or blood-brain barrier. Limited preclinical data suggest that strategies to reduce cerebral edema may improve neurologic outcome. Ongoing research will be necessary to determine whether targeting cerebral edema will improve patient outcomes after cardiac arrest.

Glibenclamide pretreatment protects against chronic memory dysfunction and glial activation in rat cranial blast traumatic brain injury.

Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc-bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre-treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations.

Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease.

Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage brain injury. Previous work suggests that heparin, due to the multimodal nature of its actions, reduces the incidence of clinical vasospasm and delayed cerebral ischemia that accompany the disease. This narrative review examines how heparin may mitigate the non-vasospastic pathological aspects of aSAH, particularly those related to neuroinflammation. Following a brief review of early brain injury in aSAH and heparin's general pharmacology, we discuss potential mechanistic roles of heparin therapy in treating post-aSAH inflammatory injury. These roles include reducing ischemia-reperfusion injury, preventing leukocyte extravasation, modulating phagocyte activation, countering oxidative stress, and correcting blood-brain barrier dysfunction. Following a discussion of evidence to support these mechanistic roles, we provide a brief discussion of potential complications of heparin usage in aSAH. Our review suggests that heparin's use in aSAH is not only safe, but effectively addresses a number of pathologies initiated by aSAH.

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage.

A growing body of clinical literature emphasizes the impact of cerebral edema in early brain injury following aneurysmal subarachnoid hemorrhage (aSAH). Aneurysm rupture itself initiates global cerebral edema in up to two thirds of cases. Although cerebral edema is not a universal feature of aSAH, it portends a poor clinical course, with quantitative analysis revealing a direct correlation between cerebral edema and poor outcome, including mortality and cognitive deficits. Mechanistically, global cerebral edema has been linked to global ischemia at the time of aneurysm rupture, dysfunction of autoregulation, blood breakdown products, neuroinflammation, and hyponatremia/endocrine abnormalities. At a molecular level, several culprits have been identified, including aquaporin-4, matrix metalloproteinase-9, SUR1-TRPM4 cation channels, vascular endothelial growth factor, bradykinin, and others. Here, we review these cellular and molecular mechanisms of global cerebral edema formation in aSAH. Given the importance of edema to the outcome of patients with aSAH and its status as a highly modifiable pathological process, a better understanding of cerebral edema in aSAH promises to hasten the development of medical therapies to improve outcomes in this frequently devastating disease.

Decompressive Craniectomy in Neurocritical Care.

Neurosurgeons increasingly use decompressive craniectomy (DC) in neurocritical care. In this review, the authors summarize the topic of DC for the neurointensivist. Following a brief overview of the procedure, the major indications for the procedure are described. This includes a review of the literature regarding well-established indications, such as infarction and traumatic brain injury, as well as lesser known indications, including intracerebral hemorrhage, ruptured cerebrovascular malformations, sinus thrombosis, and infection. Complications unique to DC, specifically syndrome of the trephined, hygroma, and hydrocephalus, also are reviewed with a discussion of their management, both in the immediate and the postoperative period.

Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications.

Aneurysmal subarachnoid hemorrhage (SAH) typically carries a poor prognosis. Growing evidence indicates that overabundant production of nitric oxide (NO) may be responsible for a large part of the secondary injury that follows SAH. Although SAH modulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform, NOS-2, accounts for a majority of NO-mediated secondary injuries after SAH. Here, we review the indispensable physiological roles of NO that must be preserved, even while attempting to downmodulate the pathophysiologic effects of NO that are induced by SAH. We examine the effects of SAH on the function of the various NOS isoforms, with a particular focus on the pathological effects of NOS-2 and on the mechanisms responsible for its transcriptional upregulation. Finally, we review interventions to block NOS-2 upregulation or to counteract its effects, with an emphasis on the potential therapeutic strategies to improve outcomes in patients afflicted with SAH. There is still much to be learned regarding the apparently maladaptive response of NOS-2 and its harmful product NO in SAH. However, the available evidence points to crucial effects that, on balance, are adverse, making the NOS-2/NO/peroxynitrite axis an attractive therapeutic target in SAH.

Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning.

Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4(+) and CD8(+) T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR(+) T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.

In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy.

Human T cells genetically modified to express chimeric antigen receptors (CAR) specific to the B cell tumor antigen CD19 can successfully eradicate systemic human CD19(+) tumors in immunocompromised SCID (severe combined immunodeficient)-Beige mice. However, in the clinical setting, CD4(+) CD25(hi) T regulatory cells (Treg) present within the tumor microenvironment may be potent suppressors of tumor-targeted effector T cells. In order to assess the impact of Tregs on CAR-modified T cells in the SCID-Beige xenotransplant model, we isolated, genetically targeted and expanded natural T regulatory cells (nTreg). In vitro nTregs modified to express CD19-targeted CARs efficiently inhibited the proliferation of activated human T cells, as well as the capacity of CD19-targeted 19-28z(+) effector T cells to lyse CD19(+) Raji tumor cells. Intravenous infusion of CD19-targeted nTregs into SCID-Beige mice with systemic Raji tumors traffic to sites of tumor and recapitulate a clinically relevant hostile tumor microenvironment. Antitumor efficacy of subsequently infused 19-28z(+) effector T cells was fully abrogated as assessed by long-term survival of treated mice. Optimal suppression by genetically targeted nTregs was dependent on nTreg to effector T-cell ratios and in vivo nTreg activation. Prior infusion of cyclophosphamide in the setting of this nTreg-mediated hostile microenvironment was able to restore the antitumor activity of subsequently infused 19-28z(+) effector T cells through the eradication of tumor-targeted nTregs. These findings have significant implications for the design of future clinical trials utilizing CAR-based adoptive T-cell therapies of cancer.