A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas.

PURPOSE: This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6 weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) PATIENTS & METHODS: Children and young adults < 22 years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54-59.4 Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116 mg/m2/day × 21 days of a 28-day cycle. RESULTS: Twenty-nine patients (age range 4-19 years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116 mg/m2/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. CONCLUSION: The RP2D of lenalidomide administered daily during radiation therapy is 116 mg/m2/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer.

Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

The role of intense athletic activity on structural lumbar abnormalities in adolescent patients with symptomatic low back pain.

PURPOSE: To determine if adolescent athletics increases the risk of structural abnormalities in the lumbar spine. METHODS: A retrospective review of patients (ages 10-18) between 2004 and 2012 was performed. Pediatric patients with symptomatic low back pain, a lumbar spine MRI, and reported weekly athletic activity were included. Patients were stratified to an "athlete" and "non-athlete" group. Lumbar magnetic resonance and plain radiographic imaging was randomized, blinded, and evaluated by two authors for a Pfirrmann grade, herniated disc, and/or pars fracture. RESULTS: A total of 114 patients met the inclusion criteria and were stratified into 66 athletes and 48 non-athletes. Athletes were more likely to have abnormal findings compared to non-athletes (67 vs. 40 %, respectively, p = 0.01). Specifically, the prevalence of a spondylolysis with or without a slip was higher in athletes vs. non-athletes (32 vs. 2 %, respectively, p = 0.0003); however, there was no difference in the average Pfirrmann grade (1.19 vs. 1.14, p = 0.41), percentage of patients with at least one degenerative disc (39 vs. 31 %, p = 0.41), or disc herniation (27 vs. 33 %, p = 0.43). Body mass index, smoking history, and pelvic incidence (51.5° vs. 48.7°, respectively, p = 0.41) were similar between the groups. CONCLUSION: Adolescents with low back pain have a higher-than-expected prevalence of structural pathology regardless of athletic activity. Independent of pelvic incidence, adolescent athletes with low back pain had a higher prevalence of spondylolysis compared to adolescent non-athletes with back pain, but there was no difference in associated disc degenerative changes or herniation.

A population-based review of bone morphogenetic protein: associated complication and reoperation rates after lumbar spinal fusion.

OBJECT The authors compared the rates of postoperative adverse events and reoperation of patients who underwent lumbar spinal fusion with bone morphogenetic protein (BMP) to those of patients who underwent lumbar spinal fusion without BMP. METHODS The authors retrospectively analyzed the PearlDiver Technologies, Inc., database, which contains the Medicare Standard Analytical Files, the Medicare Carrier Files, the PearlDiver Private Payer Database (UnitedHealthcare), and select state all-payer data sets, from 2005 to 2010. They identified patients who underwent lumbar spinal fusion with and without BMP. The ICD-9-CM code 84.52 was used to identify patients who underwent spinal fusion with BMP. ICD-9-CM diagnosis codes identified complications that occurred during the initial hospital stay. ICD-9-CM procedural codes were used to identify reoperations within 90 days of the index procedure. The relative risks (and 95% CIs) of BMP use compared with no BMP use (control) were calculated for the association of any complication with BMP use compared with the control. RESULTS Between 2005 and 2010, 460,773 patients who underwent lumbar spinal fusion were identified. BMP was used in 30.7% of these patients. The overall complication rate in the BMP group was 18.2% compared with 18.7% in the control group. The relative risk of BMP use compared with no BMP use was 0.976 (95% CI 0.963-0.989), which indicates a significantly lower overall complication rate in the BMP group (p < 0.001). In both treatment groups, patients older than 65 years had a statistically significant higher rate of postoperative complications than younger patients (p < 0.001). CONCLUSIONS In this large-scale institutionalized database study, BMP use did not seem to increase the overall risk of developing a postoperative complication after lumbar spinal fusion surgery.

Surgical Site Infections in Spinal Surgery.

Surgical site infections (SSIs) are a potentially devastating complication of spine surgery. SSIs are defined by the Centers for Disease Control and Prevention as occurring within 30 days of surgery or within 12 months of placement of foreign bodies, such as spinal instrumentation. SSIs are commonly categorized by the depth of surgical tissue involvement (ie, superficial, deep incisional, or organ and surrounding space). Postoperative infections result in increased costs and postoperative morbidity. Because continued research has improved the evaluation and management of spinal infections, spine surgeons must be aware of these modalities. The controversies in evaluation and management of SSIs in spine surgery will be reviewed.

The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster.

Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17~92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17~92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC.

Evaluation and treatment of spinal metastatic disease.

With the increased survival of oncologic patients, evaluation and management of patients with spinal metastasis is crucial to reducing morbidity and maximizing function. In this chapter, we present some guidelines for the initial systematic evaluation of patients with spinal lesions, as well as the risks, benefits, and alternatives to nonoperative and operative management of metastatic spinal disease, and the overall survival of these patients.

Low-Density Lipoprotein Cholesterol and Statin Usage Are Associated With Rates of Pseudarthrosis Following Single-Level Posterior Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the relationships of low-density lipoprotein cholesterol and statin usage with pseudarthrosis following single-level posterior or transforaminal lumbar interbody fusion (PLIF/TLIF). SUMMARY OF BACKGROUND DATA: Hypercholesterolemia can lead to atherosclerosis of the segmental arteries, which branch into vertebral bone through intervertebral foramina. According to the vascular hypothesis of disc disease, this can lead to ischemia of the lumbar discs and contribute to lumbar degenerative disease. Yet, little has been reported regarding the effects of cholesterol and statins on the outcomes of lumbar fusion surgery. MATERIALS AND METHODS: TriNetX, a global federated research network, was retrospectively queried to identify 52,140 PLIF/TLIF patients between 2002 and 2021. Of these patients, 2137 had high cholesterol (≥130 mg/dL) and 906 had low cholesterol (≤55 mg/dL). Perioperatively, 18,275 patients used statins, while 33,415 patients did not. One-to-one propensity score matching for age, sex, race, and comorbidities was conducted to balance the analyzed cohorts. The incidence of pseudarthrosis was then assessed in the matched cohorts within the six-month, one-year, and two-year postoperative periods. RESULTS: After propensity score matching, high-cholesterol patients had greater odds of developing pseudarthrosis six months [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.28-2.33], one year (OR: 1.59, 95% confidence interval (CI): 1.20-2.10), and two years (OR: 1.57, 95% CI: 1.20-2.05) following a PLIF/TLIF procedure. Patients with statin usage had significantly lower odds of developing pseudarthrosis six months (OR: 0.74, 95% CI: 0.69-0.79), one year (OR: 0.76, 95% CI: 0.71-0.81), and two years (OR: 0.77, 95% CI: 0.72-0.81) following single-level PLIF/TLIF. CONCLUSIONS: The findings suggest that patients with hypercholesterolemia have an increased risk of developing pseudarthrosis following PLIF/TLIF while statin use is associated with a decreased risk. The data presented may underscore an overlooked opportunity for perioperative optimization in lumbar fusion patients, warranting further investigation in this area.

Radiographic Alignment Parameters for Lumbosacral Reconstruction in Patients With Altered S1 Morphology.

STUDY DESIGN: Retrospective quantitative analysis study. OBJECTIVES: Pelvic incidence has been established as central radiographic marker which determines patient-specific correction goals during surgery for adult spinal deformity. In cases with sacral doming or sacral osteotomy where the PI cannot be calculated, reliable radiographic parameters need to be established to determine surgical goals. We aim to determine multiple radiographic parameters and formulas that can be utilized when the S1 superior endplate is obscured. METHODS: Retrospective analysis was performed on 68 healthy volunteers without prior spine surgery with full-length radiographs. Pelvic incidence, sacral slope, and pelvic tilt were calculated for each patient. Additional measurements such as L4, L5, and S2 incidence, tilt, and slope were collected. A new radiographic parameter defined as the L4-Sciatic notch angle was measured. Regression analysis was performed on each value to determine its relationship with S1 based incidence, tilt, and slope. RESULTS: Mean values for L5 incidence, L4 incidence, and L4 sciatic notch angle were 21.8° ± 8.9, 4.4° ± 8.1, and 44.4° ± 12, respectively. The linear regression analysis produced the following formulas which can be utilized to determine deformity correction goals when pelvic incidence can be calculated pre-operatively: L5i = .65*S1i-11.4, L4i = .44*S1i-18.6, and L4SNA = -.34*S1i + 66.5. In settings where pelvic incidence cannot be calculated, the following formulas can be utilized: L5i = .66*S2i-32.3 and L4SNA = -.02*S2i2 + 1.1*S2i + 63.5. P-values for all regression analyses were <.001. CONCLUSION: This study provides target radiographic alignment values that can be utilized for patients with either pre-operative altered S1 endplates or in cases with intraoperative alteration of S1 (sacral osteotomy).

Opioid and Sedative NarxCare Scores Greater Than 300 Are Associated With Adverse Outcomes After Nonemergent Spine Surgery.

STUDY DESIGN: This was a prospectively captured cohort study. OBJECTIVE: To explore associations between the preoperative opioid-specific NarxCare Scores (NCS) (NCS-opioids) as well as sedative-specific NCS (NCS-sedatives) as measures of patients' prescription drug use and (1) 90-day postoperative readmission; (2) ED visits; (3) reoperation; (4) prolonged (>2 d) hospital length of stay (LOS); and (5) nonhome discharge. In addition, we sought to evaluate the previously suggested 300+ threshold as a cutoff for moderate/high-risk designation. BACKGROUND: The association between preoperative opioids and sedative use and healthcare utilization after nonemergent spine surgery is not well quantified. The NCS is a weighted scalar measure of opioids and sedatives that accounts for the number of prescribing providers, dispensing pharmacies, milligram equivalence doses, and overlapping prescription days. METHODS: A total of 4680 nonemergent spine surgery cases were included. Preoperative NCS-opioids/sedatives were captured. Bivariate and multivariable regression models were constructed to analyze associations between NCS-opioids/sedatives ranges and outcomes while accounting for baseline differences. Spline regression and propensity score matching (PSM) analyses were also implemented. RESULTS: For NCS-opioid, multivariable regression demonstrated higher odds of prolonged LOS starting in the 400 to 499 NCS-opioids category [odds ratio (OR): 1.44; 95% confidence interval (CI): 1.05-1.97; P =0.026] going into the 500+ category (OR: 1.94; 95% CI: 1.29-2.93; P =0.002]. The 500+ categories exhibited higher odds of 90-day readmission (OR: 1.77; 95% CI: 1.01-3.09; P =0.045). PSM comparison demonstrated that patients within the 300+ category had higher incidence of prolonged LOS [n=455 (44%) vs . n=537 (52%); P <0.001], 90-day readmission [n=118 (11%) vs . n=155 (15%); P =0.019] and 90-day reoperation [n=51 (4.9%) vs . n=74 (7.2%); P =0.042]. For NCS-sedative; there was higher odds of prolonged LOS (OR: 1.73; 95% CI: 1.14-2.63; P =0.010) and nonhome discharge(OR: 2.09; 95%CI: 1.22-3.63; P =0.008) within the 400 to 499 NCS-sedatives category. PSM comparison demonstrated significantly higher rates of prolonged LOS within the 300+ NCS-sedative cohort ( vs . scores <300), [n=277 (44%) vs. 319 (50%); P =0.021]. CONCLUSION: Spine surgery continues to advance toward patient-specific care. Higher NCS-opioids/sedatives values may predict up to a twofold increase in postoperative healthcare utilization. High values should prompt an interdisciplinary approach to mitigate deleterious prescription drug use.

Perioperative outcomes of cervical disc arthroplasty: no difference between orthopaedic and neurologic surgeons.

Background: Given differences in residency training background, there has been increasing interest in characterizing differential outcomes between orthopaedic surgeons (OS) and neurosurgeons (NS) with regards to outcomes after cervical disc arthroplasty (CDA). This study aimed to assess if there were differences in perioperative outcomes of CDA between OS and NS. Methods: Patients who underwent a single-level CDA between 2012 and 2019 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database using current procedural terminology codes. The patients were subsequently stratified into those who underwent CDA with OS versus NS, and propensity score-matched to adjust for differences in patient characteristics. Differences were assessed in medical and surgical complications, as well as operative time and healthcare utilization parameters [reoperations, readmissions, and lengths-of-stay (LOS)]. Results: A total of 2,148 patients were identified (NS: n=1,395; OS: n=753). After 1:1 propensity score matching (n=741 each), there were no differences in characteristics between patients who underwent CDA by OS versus NS (P>0.05). There were no significant differences in any of the medical or surgical complications between the two groups (P>0.05 for each). There was a significant difference in the operative time between NS and OS (103.7±36.18 vs. 98.75±36.69 minutes; P=0.009). There were no significant differences in readmissions, reoperations, or LOS between the two groups (P>0.05 for each). Conclusions: There were no differences in medical or surgical complications, as well as in reoperations, readmissions, and LOS in patients who underwent a single-level CDA between OS and NS. There was a statistically significant shorter operative time of four minutes for OS as compared to NS, which is unlikely to have clinical relevance.

New Imaging Modalities for Degenerative Cervical Myelopathy.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is defined as dysfunction of the spinal cord as a result of compression from degenerative changes to surrounding joints, intervertebral disks, or ligaments. Symptoms can include upper extremity numbness and diminished dexterity, difficulty with fine manipulation of objects, gait imbalance, and incoordination, and compromised bowel and bladder function. Accurate diagnosis and evaluation of the degree of impairment due to degenerative cervical myelopathy remain a challenging clinical endeavor requiring a thorough and accurate history, physical examination, and assessment of imaging findings. METHODS: A narrative review is presented summarizing the current landscape of imaging modalities utilized in DCM diagnostics and the future direction of research for spinal cord imaging. RESULTS AND DISCUSSION: Current imaging modalities, particularly magnetic resonance imaging and, to a lesser extent, radiographs/CT, offer important information to aid in decision making but are not ideal as stand-alone tools. Newer imaging modalities currently being studied in the literature include diffusion tensor imaging, MR spectroscopy, functional magnetic resonance imaging, perfusion imaging, and positron emission tomography. These newer imaging modalities attempt to more accurately evaluate the physical structure, intrinsic connectivity, biochemical and metabolic function, and perfusion of the spinal cord in DCM. Although there are still substantial limitations to implementation, future clinical practice will likely be revolutionized by these new imaging modalities to diagnose, localize, surgically plan and manage, and follow patients with DCM.

Transforming Standard of Care for Spine Surgery: Integration of an Online Single-Session Behavioral Pain Management Class for Perioperative Optimization.

Estimates suggest that 10-40% of lumbar spine surgery patients experience persistent post-surgical pain (PPSP). PPSP is associated with 50% greater healthcare costs, along with risks of emotional distress and impaired quality of life. In 2019, U.S. Health and Human Services identified brief and digital behavioral treatments as important for pain management after surgery. Indeed, brief behavioral pain treatments delivered in the perioperative period may offer patients a low burden opportunity to acquire essential pain coping strategies for enhanced surgical recovery. Additionally, the COVID-19 pandemic has diminished in-person pain treatment access during extended perioperative time frames, thus underscoring the need for on-line options and home based care. This report describes the integration of an online, live-instructor delivered single-session pain self-management intervention (Empowered Relief) into the standard of care for lumbar spine surgery. Here, we apply the RE-AIM framework; describe systems implementation of the Empowered Relief intervention in a large, academic medical center during the COVID-19 pandemic; describe operational challenges and financial considerations; and present patient engagement data. Finally, we discuss the scalable potential of Empowered Relief and other single-session interventions in surgical populations, their importance during extended perioperative periods, practical and scientific limitations, and new directions for future research on this topic.

A Retrospective Analysis of the L3-L4 Disc and Spinopelvic Parameters on Outcomes in Thoracolumbar Fusion: Was Art Steffee Right?

OBJECTIVE: To determine whether the L3-L4 disc angle may be a surrogate marker for global lumbar alignment in thoracolumbar fusion surgery and to explore the relationship between radiographic and patient-reported outcomes after thoracolumbar fusion surgery. METHODS: Retrospective chart review was conducted on patients who had undergone a lumbar fusion involving levels from T9 to pelvis. EuroQol-Five Dimension (EQ-5D-3L) scores and adverse events including adjacent-segment disease and degeneration, pseudoarthrosis, proximal junctional kyphosis, stenosis, and reoperation were collected. Pre- and postoperative spinopelvic parameters were measured on weight-bearing radiographs, with the L3-L4 disc angle of novel interest. Univariate logistic and linear regression were performed to assess the associations of radiographic parameters with adverse event incidence and improvement in EQ-5D-3L, respectively. RESULTS: In total, 182 patients met inclusion criteria. Univariable analysis revealed that increased magnitude of L3-L4 disc angle, anterior pelvic tilt, and pelvic incidence measures are associated with increased likelihood of developing postoperative adverse events. Conversely, increased lumbar lordosis demonstrated a decreased incidence of developing a postoperative adverse event. Linear regression showed that radiographic parameters did not significantly correlate with postoperative EQ-5D-3L scores, although scores were significantly improved postfusion in all dimensions except Self-Care (P = 0.51). CONCLUSIONS: L3-L4 disc angle magnitude may serve as a surrogate marker of global lumbar alignment. The degree of spinopelvic alignment did not correlate to improvement in EQ-5D-3L score in the present study, suggesting that quality of life metric change may not be a sensitive or specific marker of postfusion alignment.

MPAPASS software enables stitched multiplex, multidimensional EV repertoire analysis and a standard framework for reporting bead-based assays.

Extracellular vesicles (EVs) of various types are released or shed from all cells. EVs carry proteins and contain additional protein and nucleic acid cargo that relates to their biogenesis and cell of origin. EV cargo in liquid biopsies is of widespread interest owing to its ability to provide a retrospective snapshot of cell state at the time of EV release. For the purposes of EV cargo analysis and repertoire profiling, multiplex assays are an essential tool in multiparametric analyte studies but are still being developed for high-parameter EV protein detection. Although bead-based EV multiplex analyses offer EV profiling capabilities with conventional flow cytometers, the utilization of EV multiplex assays has been limited by the lack of software analysis tools for such assays. To facilitate robust EV repertoire studies, we developed multiplex analysis post-acquisition analysis (MPAPASS) open-source software for stitched multiplex analysis, EV database-compatible reporting, and visualization of EV repertoires.

Predicting Reciprocal Thoracic Change, Proximal Junctional Kyphosis, and Revision Surgery in Adult Spinal Deformity.

BACKGROUND: Compensatory mechanisms in patients with adult spinal deformity (ASD) that lead to poor quality of life include positive sagittal balance and pelvic retroversion. The objective of this retrospective review was to identify demographic and radiographic parameters of sagittal alignment that are correlated with thoracic kyphosis (TK), PJK, and reoperation in patients undergoing surgical correction for ASD. METHODS: A single-center database of 155 patients with ASD undergoing surgery from 2008 to 2015 was reviewed. Patients >18 years old who underwent multilevel thoracolumbar fusion or fusion of thoracic vertebrae to the pelvis were included. Demographics and radiographic measurements of sagittal alignment were collected preoperatively, 6 weeks postoperatively, and 1 year postoperatively. Statistical analysis was performed to compare groups that did or did not develop change in thoracic kyphosis or PJK at early or late follow-up. Additionally, patients requiring reoperation were evaluated. RESULTS: Increased thoracic kyphosis was associated with older age, hypolordosis, and comorbid PJK. Early PJK was associated with older age, hypolordosis, and increased T1 pelvic angle. Reoperation was associated with older age, higher positive sagittal balance, hypolordosis, and pelvic retroversion; PJK and thoracic kyphosis did not increase risk for reoperation. CONCLUSIONS: Thoracic reciprocal change following surgical correction of ASD is highly associated with PJK, although neither increased risk of reoperation. PJK may be predicted by older age, hypolordosis, and increased T1 pelvic angle. Reoperation in patients with ASD is more likely in older patients with positive sagittal balance, a compensatory flat lower back, and compensatory pelvic retroversion.

Longer operative time associated with prolonged length of stay, non-home discharge and transfusion requirement after anterior cervical discectomy and fusion: an analysis of 24,593 cases.

BACKGROUND: Prolonged operative time of single-level ACDF has been associated with adverse postoperative outcomes. The current literature does not contain a comprehensive quantitative description of these associations PURPOSE: This study characterized the associations between single-level anterior cervical discectomy and fusion(ACDF) operative time and (1)30-day postoperative healthcare utilization, and (2)the incidence of local wound complications, need for transfusion and mechanical ventilation. DESIGN/SETTING: Retrospective database analysis PATIENT SAMPLE: The American College of Surgeons National Surgical Quality Improvement Program(ACS-NSQIP) database was queried for single-level ACDF cases(2012-2018) using current procedural terminology codes. A total of 24,593 cases were included. OUTCOME MEASURES: Primary outcomes included healthcare utilization(lengths of stay[LOS], discharge dispositions, 30-day readmissions, and reoperations) per operative time category. The secondary outcome was the incidence of wound complications, blood transfusion and need for ventilation per operative time category. METHODS: Multivariate regression determined operative time categories associated with increased risk while adjusting for patient demographics and comorbidities. Predictive spline regression models visualized the associations. RESULTS: Compared to the reference operative time of 81-100-minutes, the 101-120-minute category was associated with higher odds of LOS >2 days(OR:1.36,95%CI(1.18-1.568);p<.001) and non-home discharge(OR:1.341,95%CI(1.081-1.664);p=.008). Three-times greater odds of LOS >2 days(OR:3.367,95%CI(2.719-4.169); p<.001) and twice the odds of non-home discharge(OR:2.174,95%CI(1.563-3.022);p<.001) were detected at 181-200-minutes. The highest operative time category(≥221 minutes) was associated with the highest odds of LOS>2 days(OR:4.838,95%CI(4.032-5.804);p<.001), non-home discharge(OR:2.687,95%CI(2.045-3.531);p<.001) and reoperation(OR:1.794,95%CI(1.094-2.943);p=.021). Patients within the 201-220 and the ≥221-minute categories exhibited a significant association with greater odds of transfusion(OR:8.57,95%CI(2.321-31.639);p<.001, and OR:11.699, 95%CI(4.179-32.749);p=.001, respectively). Spline regression demonstrated that the odds of LOS >2 days, non-home discharge disposition, reoperation and bleeding requiring transfusion events began to rise, starting at 94, 91.6, 91.6, and 93.3 minutes of operative time, respectively. CONCLUSION: This study demonstrated that prolonged operative time is associated with increased odds of healthcare utilization and transfusion after single-level ACDF. Operative times greater than 91 minutes may carry higher odds of postoperative complications.

Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells.

Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8+ tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4+ CD25+Foxp3+ Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control-treated mice. In addition, PD-1 expression on CD3+CD8+ T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rß, and TGF-ß2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone.

A simple, high-throughput method of protein and label removal from extracellular vesicle samples.

Evidence continues to increase of the clinical utility extracellular vesicles (EVs) as translational biomarkers. While a wide variety of EV isolation and purification methods have been implemented, few techniques are high-throughput and scalable for removing excess fluorescent reagents (e.g. dyes, antibodies). EVs are too small to be recovered from routine cell-processing procedures, such as filtration or centrifugation. The lack of suitable methods for removing unbound labels, especially in optical assays, is a major roadblock to accurate EV phenotyping and utilization of EV assays in a translational or clinical setting. Therefore, we developed a method for using a multi-modal resin, referred to as EV-Clean, to remove unbound labels from EV samples, and we demonstrate improvement in flow cytometric EV analysis with the use of this EV-Clean method.

Late-week surgery and discharge to specialty care associated with higher costs and longer lengths of stay after elective lumbar laminectomy.

OBJECTIVE: In a healthcare landscape in which costs increasingly matter, the authors sought to distinguish among the clinical and nonclinical drivers of patient length of stay (LOS) in the hospital following elective lumbar laminectomy-a common spinal surgery that may be reimbursed using bundled payments-and to understand their relationships with patient outcomes and costs. METHODS: Patients ≥ 18 years of age undergoing laminectomy surgery for degenerative lumbar spinal stenosis within the Cleveland Clinic health system between March 1, 2016, and February 1, 2019, were included in this analysis. Generalized linear modeling was used to assess the relationships between the day of surgery, patient discharge disposition, and hospital LOS, while adjusting for underlying patient health risks and other nonclinical factors, including the hospital surgery site and health insurance. RESULTS: A total of 1359 eligible patients were included in the authors' analysis. The mean LOS ranged between 2.01 and 2.47 days for Monday and Friday cases, respectively. The LOS was also notably longer for patients who were ultimately discharged to a skilled nursing facility (SNF) or rehabilitation center. A prolonged LOS occurring later in the week was not associated with greater underlying health risks, yet it nevertheless resulted in greater costs of care: the average total surgical costs for lumbar laminectomy were 20% greater for Friday cases than for Monday cases, and 24% greater for late-week cases than for early-week cases ultimately transferred to SNFs or rehabilitation centers. A Poisson generalized linear model fit the data best and showed that the comorbidity burden, surgery at a tertiary care center versus a community hospital, and the incidence of any postoperative complication were associated with significantly longer hospital stays. Discharge to home healthcare, SNFs, or rehabilitation centers, and late-week surgery were significant nonclinical predictors of LOS prolongation, even after adjusting for underlying patient health risks and insurance, with LOSs that were, for instance, 1.55 and 1.61 times longer for patients undergoing their procedure on Thursday and Friday compared to Monday, respectively. CONCLUSIONS: Late-week surgeries are associated with a prolonged LOS, particularly when discharge is to an SNF or rehabilitation center. These findings point to opportunities to lower costs and improve outcomes associated with elective surgical care. Interventions to optimize surgical scheduling and perioperative care coordination could help reduce prolonged LOSs, lower costs, and, ultimately, give service line management personnel greater flexibility over how to use existing resources as they remain ahead of healthcare reforms.