Aladine A. Elsamadicy

Preoperative Nutritional Status is an Independent Predictor of 30-day Hospital Readmission After Elective Spine Surgery.

Study Design. A retrospective cohort review. Objective. The aim of this study is to investigate whether preoperative malnutrition is an independent risk factor for unplanned 30-day readmission after elective spine surgery. Summary of Background Data. Thirty-day hospital readmission rate is being used as a proxy for quality of care. Accordingly, hospitals and health systems are investing considerable resources into the identification of patients at risk of hospital readmission and designing interventions to reduce the rate of hospital readmissions. Methods. The medical records of 145 patients undergoing elective spine surgery at a major academic medical center were reviewed. Preoperative serum albumin level was assessed on all patients and used to quantify nutritional status. Albumin less than 3.5 g/dL was recognized malnourished. Patient demographics, comorbidities, and postoperative complication rates were collected. The association between preoperative serum albumin level and 30-day readmission rate was assessed via multivariate logistic regression analysis. Results. Baseline characteristics were similar between both groups. Low albumin was found in 28% of patients in this study. Malnourished patients were more likely to experience a postoperative complication and a prolonged duration of hospital stay (3.80 vs. 8.67 days), P = 0.03. Overall, 14.48% of patients were readmitted within 30 days of discharge, with malnourished patients experiencing a three-fold increase in 30-day readmission rates (malnourished: 27.50% vs. nourished: 9.52%, P = 0.02). Binary logistic regression with and without propensity score adjustment for risk factors demonstrated that preoperative malnutrition (low serum albumin level) is an independent predictor of 30-day readmission after elective spine surgery (P = 0.01). Conclusion. Pre-operative malnutrition is an independent risk factor for readmission within 30 days of discharge after elective spine surgery. Laboratory markers of nutrition can identify patients at risk of unplanned hospital readmission. This risk determination identifies a potentially modifiable risk factor for early readmission. Level of Evidence: 3

Do measures of surgical effectiveness at 1 year after lumbar spine surgery accurately predict 2-year outcomes?

OBJECTIVE With the recent passage of the Patient Protection and Affordable Care Act, there has been a dramatic shift toward critical analyses of quality and longitudinal assessment of subjective and objective outcomes after lumbar spine surgery. Accordingly, the emergence and routine use of real-world institutional registries have been vital to the longitudinal assessment of quality. However, prospectively obtaining longitudinal outcomes for patients at 24 months after spine surgery remains a challenge. The aim of this study was to assess if 12-month measures of treatment effectiveness accurately predict long-term outcomes (24 months). METHODS A nationwide, multiinstitutional, prospective spine outcomes registry was used for this study. Enrollment criteria included available demographic, surgical, and clinical outcomes data. All patients had prospectively collected outcomes measures and a minimum 2-year follow-up. Patient-reported outcomes instruments (Oswestry Disability Index [ODI], SF-36, and visual analog scale [VAS]-back pain/leg pain) were completed before surgery and then at 3, 6, 12, and 24 months after surgery. The Health Transition Index of the SF-36 was used to determine the 1- and 2-year minimum clinically important difference (MCID), and logistic regression modeling was performed to determine if achieving MCID at 1 year adequately predicted improvement and achievement of MCID at 24 months. RESULTS The study group included 969 patients: 300 patients underwent anterior lumbar interbody fusion (ALIF), 606 patients underwent transforaminal lumbar interbody fusion (TLIF), and 63 patients underwent lateral interbody fusion (LLIF). There was a significant correlation between the 12- and 24-month ODI (r = 0.82; p < 0.0001), SF-36 Physical Component Summary score (r = 0.89; p < 0.0001), VAS-back pain (r = 0.90; p < 0.0001), and VAS-leg pain (r = 0.85; p < 0.0001). For the ALIF cohort, patients achieving MCID thresholds for ODI at 12 months were 13-fold (p < 0.0001) more likely to achieve MCID at 24 months. Similarly, for the TLIF and LLIF cohorts, patients achieving MCID thresholds for ODI at 12 months were 13-fold and 14-fold (p < 0.0001) more likely to achieve MCID at 24 months. Outcome measures obtained at 12 months postoperatively are highly predictive of 24-month outcomes, independent of the surgical procedure. CONCLUSIONS In a multiinstitutional prospective study, patient-centered measures of surgical effectiveness obtained at 12 months adequately predict long-term (24-month) outcomes after lumbar spine surgery. Patients achieving MCID at 1 year were more likely to report meaningful and durable improvement at 24 months, suggesting that the 12-month time point is sufficient to identify effective versus ineffective patient care.

Radiation-Induced Malignant Gliomas: A Current Review

OBJECTIVE Radiation-induced malignant gliomas (RIMGs) are known uncommon risks of brain irradiation. We describe 4 cases of RIMG that occurred at our institution and conduct the largest comprehensive review of the literature to characterize RIMGs better. METHODS Patients were identified through the PubMed database. Pearson R linear correlation test was used to evaluate the correlation between radiotherapy (RT) dose and age and latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A normalized biologic equivalent dose analysis was performed to indicate the minimum and maximum radiation threshold for neoplasia. A Kaplan-Meier analysis was used to illustrate the overall survival curves. RESULTS The analysis included 172 cases from the PubMed database and 4 cases occurring at our institution. The median RT dose administered was 35.6 Gy, with the most common dosage ranges being 21-30 Gy (31%) and 41-50 Gy (21.5%). Median latency period was 9 years until diagnosis of RIMG, and RIMG occurred within 15 years in 82% of the patients. There was no correlation between the age of the patient at the time RT was administered (R(2) = 0.00081) or amount of RT (R(2) = 0.00005) and latency period for RIMG. The mean biologic equivalent dose for neoplasia of a RIMG was 63.3 Gy. The median survival of patients with RIMG improved over time (P = 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007. CONCLUSIONS The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. Although the risk is low, patients should be aware of RIMG as a possible complication of brain irradiation.

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.

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM. Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers. Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations. Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175–86. ©2018 AACR. See related commentary by Jackson and Lim, p. 4059

Association of Intraoperative Blood Transfusions on Postoperative Complications, 30-Day Readmission Rates, and 1-Year Patient-Reported Outcomes.

Study Design. Ambispective cohort review. Objective. The aim of this study was to determine the effect of allogeneic red blood cell (RBC) transfusion on postoperative patient complications profiles and 30-day readmission rates following elective spine surgery. Summary of Background Data. Thirty-day hospital readmission rates are being used as a proxy for quality of care. Intra- or perioperative allogeneic RBC transfusions are associated with deleterious effects. Whether allogeneic RBC transfusions are associated with higher perioperative complications and 30-day readmission rates after elective spine surgery remains unknown. Methods. The medical records of 160 patients undergoing elective spine surgery at a major academic medical center were reviewed. Patient demographics, comorbidities, and postoperative complication rates were collected. All patients completed patient-reported outcomes instruments (Oswestry Disability Index, SF-36, and VAS-NP/BP/LP) before surgery, then at 3, 6, and 12 months after surgery. The association between intra- or perioperative allogeneic RBC transfusions and 30-day readmission rate was assessed via multivariate logistic regression analysis. Results. Baseline characteristics were similar in both cohorts. The mean pre- and postoperative hemoglobin levels were lower for the transfusion than nontransfusion cohorts. Postoperative complication rates were 44.67% and 23.00% in the transfusion and nontransfusion cohorts, respectively. Overall, 9.38% of patients were re-admitted within 30 days of hospital discharge, with a three-fold higher increase in 30-day readmission rate in the transfusion cohort compared to the nontransfusion cohort (no transfusion: 5% vs. transfusion: 16.67%, P = 0.01). In a multivariate logistic regression model, intra- or perioperative allogeneic RBC transfusion was an independent predictor of 30-day readmission after elective spine surgery (P = 0.005). Conclusion. Our study suggests that allogeneic RBC transfusions may be associated with increased postoperative complications, length of hospital stay, and 30-day readmission rates. Level of Evidence: 3

Racial Disparities in 30-Day Readmission Rates After Elective Spine Surgery: A Single Institutional Experience.

Study Design. Retrospective cohort review. Objective. The aim of this study is to investigate whether patient race is an independent predictor of unplanned 30-day hospital readmission after elective spine surgery. Summary of Background Data. Racial disparities are known to exist for many aspects of surgical care. However, it is unknown if disparities exist in 30-day readmissions after elective spine surgery, an area that is becoming a prime focus for clinical leaders and policymakers. Methods. Records of 600 patients undergoing elective spine surgery at a major academic medical center were reviewed. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. Patients records were reviewed to determine the cause of readmission and the length of hospital stay. The main outcome measure was risk-adjusted odds of all-cause 30-day readmission. We used multivariate logistic regression to determine if Black patients had an increased likelihood of 30-day readmission compared with White patients. Results. Baseline characteristics were similar between both groups. Black patients had higher readmission rates than White patients (10.56% vs. 7.86%, P = 0.04). In a univariate analysis, race, body mass index, sex, patient age, smoking, diabetes, and fusion levels were associated with increased 30-day readmission rates. However, in a multivariate logistic regression model, race was an independent predictor of 30-day readmission after elective spine surgery. In addition, no significant differences in baseline, 1-year and 2-year patient reported outcomes measures were observed between both groups. Conclusion. This study suggests that Black patients are more likely to be readmitted within 30-days of discharge after elective spine surgery. Efforts at reducing disparities should focus not only on race-based measures but also effective post discharge care. Level of Evidence: 3

30-day Readmission After Spine Surgery: An Analysis of 1400 Consecutive Spine Surgery Patients

Study Design. Retrospective cohort review. Objective. To identify the rates, causes, and risk factors for 30-day unplanned readmissions in after elective spine surgery at our institution. Summary of Background Data. Early readmission after spine surgery is being used as a proxy for quality of care. One-fifth of patients are rehospitalized within 30 days after spine surgery. Nearly 60% of these readmissions are unplanned, which translates into billions of dollars in healthcare costs. Methods. A total of 1400 patients undergoing elective spine surgery at Duke University Hospital between 2008 and 2010 were included in the study. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. Patient records were reviewed to determine the cause of readmission and the length of hospital stay. Results. A total of 132 (9.4%) unplanned early readmissions were identified. The mean ± SD age was 58.6 ± 15.1 years. Lumbar decompression and fusion was the most common procedure The most common causes for readmission were infection or a concern for infection (34.8%) and pain (19.7%), and 26.5% of readmissions required a return to the operating room. The majority of patients that were readmitted presented to the emergency department from home (58.0%) whereas 25.2% were readmitted from a skilled nursing facility. The mean ± SD number of days from discharge to readmission was 9.8 ± 7.9 days and the average length of hospital stay for the readmissions was 7.5 days. Conclusion. This study suggests that infection and refractory pain were the most common primary reasons for unplanned readmission. Efforts at reducing unplanned early readmission after elective spine surgery should be focused on more effective post discharge care. Level of Evidence: 3

Pretreatment of Depression Before Cervical Spine Surgery Improves Patients' Perception of Postoperative Health Status: A Retrospective, Single Institutional Experience

BACKGROUND Previous research has indicated that postoperative pain and functional outcomes are influenced by affective disorders, especially depression. The aim of this retrospective analysis is to assess whether pretreatment of depression before surgery improved patient-reported outcomes measures and overall satisfaction with care. METHODS A total of 140 adult patients (pretreated patients: 25; control patients: 115) underwent anterior cervical discectomy and fusion at Duke University Medical Center were included in this study. Of the 140 patients, 25 patients had a known history of depression diagnosed and treated by a board-certified psychiatrist with an antidepressant at least 6 months before surgery. Enrollment criteria included available demographic, surgical, medication, and clinical outcome data. Patients completed the Neck Disability Index (NDI), Short Form-12 (SF-12), and visual analog scale (VAS) before surgery, then at 3, 6, 12, and 24 months after surgery. Clinical outcomes were compared between both patient cohorts. RESULTS Baseline characteristics were similar between both cohorts. At baseline there were no significant differences in NDI (P = 0.11), SF-12 physical component score (PCS; P = 0.63), and neck pain VAS (P = 0.80). There were no significant differences in the incidence of nerve root injury (P = 0.00) or durotomy (P = 0.31) between the treatment and control cohorts. At 1 year postoperatively, both cohorts demonstrated similar improvement in neck pain VAS (P = 0.92), NDI (P = 0.32), SF-12 PCS (P = 0.15), and SF-12 mental component score (P = 0.38). These results were durable through 2 years. At 2 years, both the demonstrated similar improvement from baseline in neck pain VAS (P = 0.88), NDI (P = 0.43), SF-12 PCS (P = 0.28), and SF-12 mental component score (P = 0.40). CONCLUSION Our study suggests that in patients with depression, pretreatment with antidepressants before surgery significantly improves their perception and pain and functional disability.

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell–deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell–activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.Patients with glioblastoma experience lymphopenia and sequestration of T cells in the bone marrow, which is recapitulated in mice with brain tumors, where the reversible nature of this effect is demonstrated by an approach that enables the efficacy of other immunotherapeutics.