Rupen Desai

Risk Assessment And Characterization of 30-Day Perioperative Myocardial Infarction Following Spine Surgery: A Retrospective Analysis of 1346 Consecutive Adult Patients.

Study Design. A retrospective review. Objective. The aim of the study was to perform a risk assessment of 30-day perioperative myocardial infarction (MI) for spine surgery patients. Summary of Background Data. There is an increased emphasis to reduce complications and improve outcomes after spinal surgery. One of the more devastating perioperative complications of spinal surgery is MI. Methods. We evaluated all medical records of 1346 consecutive patients who underwent spinal surgery at a single institution from 2008 to 2010 for incidence of MI within 30 days of surgery and documented all demographic, preoperative, and operative variables. Associations between postoperative MI and individual risk factors were determined using logistic regression analysis. Patients were stratified into emergent and elective groups and a similar analysis was performed. Results. Overall, 22 patients (1.6%) had 30-day perioperative MI, 14 patients (1.2%) undergoing elective surgery, and 8 patients (4.2%) after emergent surgery (P = 0.047). Three (13.6%) patients experienced 30-day mortality and an additional 3 (13.6%) patients experienced mortality within 1 year. Multivariate logistic regression determined that age more than 65 years, atrial fibrillation, hypertension, prior MI, anticoagulant use, low albumin, length of stay more than 7 days, intraoperative transfusion, trauma etiology, baseline creatinine more than 1 mg/dL, and at least 2 levels of spinal fusion were predictive of postoperative MI. For patients undergoing emergent surgery, age more than 65 years was associated with an increased risk of postoperative MI. When stratified by elective surgery, we found that age more than 65, postoperative stay more than 7 days, intraoperative blood transfusion, baseline creatinine more than 1 mg/dL, and fusion of more than 1 level were associated with an increased risk of MI. Conclusion. The present study demonstrates a low incidence of MI after elective surgery with a higher incidence after emergent spine surgery and identifies patient factors predictive of postoperative MI. Level of Evidence: 3

Emerging immunotherapies for glioblastoma.

ABSTRACT Introduction: Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA’s approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM. Areas covered: Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy. Expert opinion: Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.

Prospect of rindopepimut in the treatment of glioblastoma

ABSTRACT Introduction: Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain – glioblastoma (GBM). Areas covered: The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut’s clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion: Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut’s future role in GBM therapy.

315 Race as a Predictor of Postoperative Hospital Readmission After Spine Surgery.

INTRODUCTION Hospital readmission after surgery results in a substantial economic burden, and several recent studies have investigated the impact of race and ethnicity on hospital readmission rates, with the goal to identify hospitals and patients with high readmission risk. METHODS This single-institution, retrospective cohort study assesses the impact of race, along with preoperative and intraoperative risk factors, on 30-day readmission rates following spinal surgery. A total of 1346 consecutive adult patients who underwent anterior and/or posterior spinal surgery from 2008 to 2010 for degenerative and deformity causes, as well as for higher-risk causes, including traumatic and neoplastic etiologies, were included in the study. Clinical variables included age, demographics, surgical etiology, intraoperative technique, and other comorbidities known to be associated with postoperative complication. RESULTS A total of 1346 patients (654 male, 692 female) were included in the study. With the use of multivariate logistic regression, black patients were found to have over twice the odds of readmission (odds ratio [OR], 2.20; 95% confidence interval [CI],: 1.04-4.64), and patients with total length of stay of 7 or more days had nearly 5 times the odds of readmission (OR, 4.73; 95% CI, 1.72-12.98). Conversely, patients who underwent cervical surgery were found to have lower odds of readmission (OR, 0.27; 95% CI, 0.08-0.91). CONCLUSION Within the context of the ongoing national goal of reducing hospital readmission, our study demonstrated that race and length of hospital stay influence the incidence of 30-day readmission rates after spinal surgery. Studies such as ours will aid in identifying patients with postoperative readmission risk and help elucidate the underlying factors that may be contributing to disparities in readmission after surgery.

C-arm Positioning Is a Significant Source of Radiation in Spine Surgery.

Study Design. Prospective chart review. Objective. It is well-known that radiation exposure during minimally invasive spine procedures can be substantial. Less interest has focused on setup radiation exposure before incision, including preoperative images used for surgical approach. The present study seeks to better quantify the significance of setup radiation in the total radiation exposure of minimally invasive spine surgery. Summary of Background Data. Radiographic localization is necessary in minimally invasive spine procedures to visualize anatomy, but increased radiation exposure is associated with health risks. Preoperative imaging for anatomical localization has not been previously analyzed as an appreciable source of radiation. Methods. From an institutional review board–approved database of more than 1100 procedures, the minimally invasive spine cases with recorded set-up radiation were extracted. The total radiation, set-up radiation, and procedure type data were evaluated. Statistics were generated using a chi-squared analysis. Results. Set-up and total radiation data were collected for 270 spine surgeries performed by four surgeons at two locations. There were 30 thoracic and 240 thoracolumbar/lumbar cases; 78 anterior and 192 posterior cases. Average total radiation (set-up and intraoperative) was 8.04 rad, and average setup radiation was 1.90 rad (28%, std 2.97 rad) across all cases. On average for the thoracolumbar/lumbar cases, set-up radiation accounted for almost 25% of total radiation with 1.76 rad from setup out of 8.16 rad total. Thoracic-only cases often necessitated even more images for localization, generating an average set-up/total percentage of 52%. Across all procedures, set-up radiation significantly increased the total radiation exposure because it accounted for more than 25% of the total procedure. Conclusion. Radiation exposure during preoperative localization can be substantial. Operating room personnel should recognize the high percentage of radiation that occurs during set-up, and merit should be given to techniques and technologies that can limit unnecessary radiation exposure during this portion of the procedure. Level of Evidence: 2

369 Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts.

INTRODUCTION Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for hematological cancers but requires a rethinking for clinical efficacy against solid tumors, where CARs have largely failed. Lymphodepletive preconditioning regimens can enhance CAR activity in vivo by promoting T-cell expansion and depleting immunoinhibitory cells that counteract cellular immunity. These nonspecific regimens, however, can be exceedingly toxic and contribute to poor quality of life. Novel strategies are needed to bypass the intratumoral inhibition of CARs. CD4+FoxP3+ regulatory T cells (Tregs) play a critical role in treatment failure, and, importantly, CARs have been shown to inadvertently potentiate Tregs by providing a local source of interleukin-2 (IL-2) for Treg consumption. We explored whether specific disruption of this axis would confer efficacy against solid tumors. METHODS We developed second (CD28z) and third (CD28-4-1BBz) generation CARs targeting the tumor-specific mutation, EGFRvIII. To eliminate secretion of IL-2, 2 amino acid substitutions were introduced in the PYAP Lck binding motif of the CD28 domain (xCD28) of CAR transgenes. We evaluated these modified second- and third-generation CARs against established B16 melanomas expressing EGFRvIII. RESULTS Second-generation CD28z CARs fail to expand in vivo. Addition of 4-1BB in third-generation CARs improves expansion, but this modification alone was insufficient for CD28-4-1BBz CARs to treat tumors without prior host lymphodepletion. CARs deficient in Lck signaling, however, significantly retarded tumor growth in immune-intact mice without prior lymphodepletion, and this was dependent on inclusion of 4-1BB in CAR design. To determine if deficient Lck signaling altered CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs ± Tregs. Cotransfer was sufficient to abrogate the efficacy of CD28-4-1BBz CARs, whereas the efficacy of xCD28-4-1BBz CARs remained unperturbed. CONCLUSION xCD28-4-1BBz CARs may be an effective immunotherapy for solid tumors infiltrated with Treg and may mitigate the need for toxic lymphodepletive preconditioning.INTRODUCTION: Von Hippel-Lindau (VHL) disease is an autosomal dominant neoplastic disorder leading to formation of multiple central nervous system hemangioblastomas (HBs). (1) Although most VHL-associatedHBs remain quiescent (Q-HB), some ( 50%) progress to symptomatic tumor growth or cyst formation (S-HB). (2) We recently reported increased erythropoietin (EPO) transcription, focal activation of EPO receptors, and resultant JAK-STAT signaling cascade activation in S-HB (when compared with paired Q-HB). Although, polycythemia is rarely reported in VHL, an autocrine/paracrine EPO-EPOR loop in HB may be similar to ones reported in malignant tumors. (3) Here, we investigated the locality (distant vs autocrine/apocrine) of EPO in VHL and report focal production of EPO that supports an autocrine/paracrine mechanism for activation of EPO-R cascade.

Do obese patients have worse outcomes after direct lateral interbody fusion compared to non-obese patients?

Obese patients undergoing lumbar spinal fusion surgery are a challenge to the operating surgeon. Direct lateral interbody fusion (DLIF) has been performed for degenerative disease of the lumbar spine with good outcomes; nevertheless, how obese patients fare compared to non-obese patients after DLIF remains unknown. The primary aim of this study is to compare rates of postoperative complications and long-term outcomes between obese and non-obese patients undergoing DLIF. Sixty-three patients (obese: 29, non-obese: 34) undergoing index DLIF for degenerative disease of the spine between 2010 and 2012 at our institution were retrospectively enrolled. We analyzed data on demographics, postoperative complications, back and leg pain, and functional disability over 2 years. Patients completed the Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) back and leg pain numerical rating scores before surgery, then at 12 and 24 months after surgery. Outcomes and complication rates were compared between the cohorts. The cohorts were similar at baseline. Postoperative complications rates were similar between obese and non-obese patients. There was no statistically significant difference in the incidence of durotomy (p=0.91), anterior thigh numbness (p=0.60), cerebrospinal fluid leak (p=0.91), postoperative infection (p=0.37), or bleeding requiring transfusion (p=0.16). No patient experienced a nerve injury or psoas hematoma. Both cohorts had similar 2 year improvement in VAS for back pain, leg pain, and ODI. Our study demonstrates that obese and non-obese patients undergoing DLIF have similar complication profiles; hence, a patients weight should not be a contraindication to DLIF.

Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma

ABSTRACT Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363).

Race as a predictor of postoperative hospital readmission after spine surgery

Hospital readmission after surgery results in a substantial economic burden, and several recent studies have investigated the impact of race and ethnicity on hospital readmission rates, with the goal to identify hospitals and patients with high readmission risk. This single-institution, retrospective cohort study assesses the impact of race, along with other risk factors, on 30-day readmission rates following spinal surgery. This study is a single-institution retrospective cohort study with accrual from January 1, 2008, to December 31, 2010. Inclusion criteria included adult patients who underwent anterior and/or posterior spinal surgery. The primary aim of this study was to assess the impact of patient race and other risk factors for postoperative hospital readmission within 30days following spine surgery. A total of 1346 patients (654 male, 692 female) were included in the study. Overall, 159 patients (11.8%) were readmitted in the 30days following their surgery. Multivariate logistic regression found significant risk factors for 30-day readmission, including Black race (OR: 2.20, C.I. 95% (1.04, 4.64)) and total length of stay greater than 7days (OR: 4.73, C.I. 95% (1.72, 12.98)). Cervical surgery was associated with decreased odds of readmission (OR: 0.27, C.I. 95% (0.08, 0.91)). Our study demonstrates that race and length of hospital stay influence the incidence of 30-day readmission rates after spinal surgery. Studies such as ours will aid in identifying patients with postoperative readmission risk and help elucidate the underlying factors that may be contributing to disparities in readmission after surgery.

Independent predictors of mortality following spine surgery.

We investigated the effect of preoperative patient demographics and operative factors on mortality in the 30day postoperative period after spine surgery. Postoperative mortality from surgical interventions has significantly decreased with progressive improvement in surgical techniques and patient selection. Well-studied preoperative risk factors include age, obesity, emphysema, clotting disorders, renal failure, and cardiovascular disease. However, the prognostic implications of such risk factors after spine surgery specifically remain unknown. The medical records of all consecutive patients undergoing spine surgery from 2008-2010 at our institution were reviewed. Patient demographics, comorbidities, indication for operation, surgical details, postoperative complications, and mortalities were collected. The association between preoperative demographics or surgical details and postoperative mortality was assessed via logistic regression analysis. All 1344 consecutive patients (1153 elective, 191 emergency) met inclusion criteria for the study; 19 (1.4%) patients died in the 30days following surgery. Multivariable logistic regression found several predictive factors of mortality for all spine surgery patients: operation in the cervical area (odds ratio [OR]: 7.279, 95% confidence interval [CI]: 1.37-42.83, p=0.02), postoperative sepsis (OR: 5.75, 95% CI: 1.16-26.38, p=0.03), operation for neoplastic (OR: 7.68, 95% CI: 1.53-42.71, p=0.01) or traumatic (OR: 13.76, 95% CI: 2.40-88.68, p=0.03) etiology, and age as defined as a continuous variable (OR: 1.05, 95% CI: 1.01-1.10, p=0.03). This study demonstrates predictive factors to help identify and evaluate patients who are at higher risk for mortality from spinal surgery, and potentially devise methods to reduce this risk.