Are Clinical or Surgical Outcomes Different Based on Whether the Same Surgeon or Hospital System Performs the Spine Revision?

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the effects of discontinuity in care by changing surgeons, health systems, or increased time to revision surgery on revision spine fusion surgical outcomes and patient-reported outcomes. SUMMARY OF BACKGROUND INFORMATION: Patients undergoing revision spine fusion experience worse outcomes than those undergoing primary lumbar surgery. Those requiring complex revisions are often transferred to tertiary or quaternary referral centers under the assumption that those institutions may be more accustomed at performing those procedures. However, there remains a paucity of literature assessing the impact of discontinuity of care in revision spinal fusions. METHODS: Patients who underwent revision 1-3 level lumbar spine fusion 2011-2021 were grouped based on (1) revision performed by the index surgeon versus a different surgeon, (2) revision performed within the same versus different hospital system as the index procedure, and (3) length of time from index procedure. Multivariate regression for outcomes controlled for confounding differences. RESULTS: A total of 776 revision surgeries were included. An increased time interval between the index procedure and the revision surgery was predictive of a lower risk for subsequent revision procedure (odds ratio: 0.57, P =0.022). Revision surgeries performed by the same surgeon predicted a reduced length of hospital stay (ß: -0.14, P =0.001). Neither time to revision nor undergoing by the same surgeon or same practice predicted 90-day readmission rates. Patients are less likely to report meaningful improvement in Mental Component Score-12 or Physical Component Score-12 if revision surgery was performed at a different hospital system. CONCLUSIONS: Patients who have revision lumbar fusions have similar clinical outcomes regardless of whether their surgeon performed the index procedure. However, continuity of care with the same surgeon may reduce hospital length of stay and associated health care costs. The length of time between primary and revision surgery does not significantly impact patient-reported outcomes. LEVEL OF EVIDENCE: Level III.

Interactions of Nanoscale Self-Assembled Peptide-Based Assemblies with Glioblastoma Cell Models and Spheroids.

Peptide nanoassemblies have garnered remarkable importance in the development of novel nanoscale biomaterials for drug delivery into tumor cells. Taking advantage of receptor mediated recognition of two known peptides, angiopep-2 (TFFYGGSRGKRNNFKTEEY) and A-COOP-K (ACGLSGLC10 VAK) that bind to the over-expressed receptors low density lipoprotein (LRP-1) and fatty acid binding protein (FABP3) respectively, we have developed new peptide conjugates by combining the anti-inflammatory, antitumor compound azelaic acid with angiopep-2, which efficiently self-assembled into nanofibers. Those nanofibers were then functionalized with the A-COOP-K sequence and formed supramolecular hierarchical structures that were found to entrap the chemotherapeutic drug doxorubicin efficaciously. Furthermore, the nanoassemblies were found to release the drug in a dose-dependent manner and showed a stepwise increase over a period of 2 weeks under acidic conditions. Two cell lines (U-87-MG and U-138-MG) were utilized as models for glioblastoma cells grown in the presence of serum and under serum-free conditions to mimic the growth conditions of natural tumors. The drug entrapped assemblies were found to inhibit the cell proliferation of both U-87 and U-138MG glioblastoma cells. Three dimensional spheroids of different sizes were grown to mimic the tumors and evaluate the efficacy of drug release and internalization. Our results indicated that the nanoassemblies were found to have higher internalization of DOX and were well-spread throughout the spheroids grown, particularly under serum-free conditions. The nanoassemblies also displayed blood-brain barrier penetration when tested with a multicellular in vitro model. Such self-assembled nanostructures with targeting ability may provide a suitable platform for the development of new peptide-based biomaterials that can provide more insights about the mechanistic approach for drug delivery for not only 2D cell cultures but also 3D tumoroids that mimic the tumor microenvironments.

An investigation of binding interactions of tumor-targeted peptide conjugated polyphenols with the kinase domain of ephrin B4 and B2 receptors.

Recent studies have shown that Ephrin receptors may be upregulated in several types of cancers including breast, ovarian and endometrial cancers, making them a target for drug design. In this work, we have utilized a target-hopping approach to design new natural product-peptide conjugates and examined their interactions with the kinase-binding domain of EphB4 and EphB2 receptors. The peptide sequences were generated through point mutations of the known EphB4 antagonist peptide TNYLFSPNGPIA. Their anticancer properties and secondary structures were analyzed computationally. Conjugates of most optimum of peptides were then designed by binding the N-terminal of the peptides with the free carboxyl group of the polyphenols sinapate, gallate and coumarate, which are known for their inherent anticancer properties. To investigate if these conjugates have a potential to bind to the kinase domain, we carried out docking studies and MMGBSA free energy calculations of the trajectories based on the molecular dynamics simulations, with both the apo and the ATP bound kinase domains of both receptors. In most cases binding interactions occurred within the catalytic loop region, while in some cases the conjugates were found to spread out across the N-lobe and the DFG motif region. The conjugates were further tested for prediction of pharmacokinetic properties using ADME studies. Our results indicated that the conjugates were lipophilic and MDCK permeable with no CYP interactions. These findings provide an insight into the molecular interactions of these peptides and conjugates with the kinase domain of the EphB4 and EphB2 receptor. As a proof of concept, we synthesized and carried out SPR analysis with two of the conjugates (gallate-TNYLFSPNGPIA and sinapate-TNYLFSPNGPIA). Results indicated that the conjugates showed higher binding with the EphB4 receptor and minimal binding to EphB2 receptor. Sinapate-TNYLFSPNGPIA showed inhibitory activity against EphB4. These studies reveal that some of the conjugates may be developed for further investigation into in vitro and in vivo studies and potential development as therapeutics.

Evaluating Outcomes of Spinopelvic Fixation for Patients Undergoing Long Segment Thoracolumbar Fusion with a Prior Total Hip Arthroplasty.

INTRODUCTION: Understanding the relationship between spinal fusion and its effects on relative spinopelvic alignment in patients with prior total hip arthroplasty (THA) is critical. However, limited data exist on the effects of long spinal fusions on hip alignment in patients with a prior THA. Our objective was to compare clinical outcomes and changes in hip alignment between patients undergoing long fusion to the sacrum versus to the pelvis in the setting of prior THA. METHODS: Patients with a prior THA who underwent elective thoracolumbar spinal fusion starting at L2 or above were retrospectively identified. Patients were placed into one of two groups: fusion to the sacrum or pelvis. Preoperative, six-month postoperative, one-year postoperative, and delta spinopelvic and acetabular measurements were measured from standing lumbar radiographs. RESULTS: A total of 112 patients (55 sacral fusions, 57 pelvic fusions) were included. Patients who underwent fusion to the pelvis experienced longer length of stay (LOS) (8.31 vs. 4.21, P < 0.001) and less frequent home discharges (30.8% vs. 61.9%, P = 0.010), but fewer spinal revisions (12.3% vs. 30.9%, P = 0.030). No difference was observed in hip dislocation rates (3.51% vs. 1.82%, P = 1.000) or hip revisions (5.26% vs. 3.64%, P = 1.000) based on fusion construct. Fusion to the sacrum alone was an independent predictor of an increased spine revision rate (odds ratio: 3.56, P = 0.023). Patients in the pelvic fusion group had lower baseline lumbar lordosis (LL) (29.2 vs. 42.9, P < 0.001), six-month postoperative LL (38.7 vs. 47.3, P = 0.038), and greater 1-year ∆ pelvic incidence-lumbar lordosis (-7.98 vs. 0.21, P = 0.032). CONCLUSION: Patients with prior THA undergoing long fusion to the pelvis experienced longer LOS, more surgical complications, and lower rate of spinal revisions. Patients with instrumentation to the pelvis had lower LL preoperatively with greater changes in LL and pelvic incidence-lumbar lordosis postoperatively. No differences were observed in acetabular positioning, hip dislocations, or THA revision rates between groups.

Impact of Prolonged Operative Duration on Postoperative Symptomatic Venous Thromboembolic Events After Thoracolumbar Spine Surgery.

OBJECTIVE: To determine the effect of operative duration on the rate of postoperative symptomatic venous thromboembolic (VTE) events in patients undergoing thoracolumbar spine fusion. METHODS: We identified all thoracolumbar spine fusion patients between 2012 and 2021. Operative duration was defined as time from skin incision to skin closure. A 1:1 propensity match was conducted incorporating patient and surgical characteristics. Logistic regression was performed to assess predictors of postoperative symptomatic VTE events. A receiver operating characteristic curve was created to determine a cutoff time for increased likelihood of VTE. RESULTS: We identified 101 patients with VTE and 1108 patients without VTE. Seventy-five patients with VTE were matched to 75 patients without VTE. Operative duration (339 vs. 262 minutes, P = 0.010) and length of stay (5.00 vs. 3.54 days, P = 0.008) were significantly longer in patients with a VTE event. Operative duration was an independent predictor of VTE on multivariate regression (odds ratio: 1.003, 95% confidence interval: 1.001-1.01, P = 0.021). For each additional hour of operative duration, the risk of VTE increased by 18%. A cutoff time of 218 minutes was identified (area under the curve [95% confidence interval] = 0.622 [0.533-0.712]) as an optimal predictor of increased risk for a VTE event. CONCLUSIONS: Operative duration significantly predicted symptomatic VTE, especially after surgical time cutoff of 218 minutes. Each additional hour of operative duration was found to increase VTE risk by 18%. We also identify the impact of VTE on 90-day readmission rates, suggesting significantly higher costs and opportunity for hospital acquired conditions, in line with prior literature.

Molecular dynamics, MMGBSA, and docking studies of natural products conjugated to tumor-targeted peptide for targeting BRAF V600E and MERTK receptors.

Recent studies have revealed that MERTK and BRAF V600E receptors have been found to be over-expressed in several types of cancers including melanoma, making these receptors targets for drug design. In this study, we have designed novel peptide conjugates with the natural products vanillic acid, thiazole-2-carboxylic acid, cinnamic acid, theanine, and protocatechuic acid. Each of these compounds was conjugated with the tumor targeting peptide sequence TAASGVRSMH, known to bind to NG2 and target tumor neovasculature. We examined their binding affinities and stability with MERTK and BRAF V600E receptors using molecular docking and molecular dynamics studies. Compared to the neat compounds, the peptide conjugates displayed higher binding affinity toward both receptors. In the case of MERTK, the most stable complexes were formed with di-theaninate-peptide, vanillate-peptide, and thiazole-2-amido peptide conjugates and binding occurred in the hinge region. Additionally, it was discovered that the peptide alone also had high binding ability and stability with the MERTK receptor. In the case of BRAF V600E, the peptide conjugates of protocatechuate, vanillate and thiazole-2-amido peptide conjugates showed the formation of the most stable complexes and binding occurred in the ATP binding cleft. Further analysis revealed that the number of hydrogen bonds and hydrophobic interactions played a critical role in enhanced stability of the complexes. Docking studies also revealed that binding affinities for NG2 were similar to MERTK and higher for BRAF V600E. MMGBSA studies of the trajectories revealed that the protocatechuate-peptide conjugate showed the highest binding energy with BRAF V600E while the peptide-TAASGVRSMH showed the highest binding energy with MERTK. ADME studies revealed that each of the compounds showed medium to high permeability toward MDCK cells and were not hERG blockers. Furthermore, the conjugates were not CYP inhibitors or substrates, but they were found to be Pgp substrates. Our results indicated that the protocatechuate-TAASGVRSMH, thiazole-2-amido-TAASGVRSMH, and vanillate-TAASGVRSMH conjugates may be furthered developed for in vitro and in vivo studies as novel tumor targeting compounds for tumor cells over-expressing BRAF V600E, while di-theaninate-amido-TAASGVRSMH and thiazole-2-amido-TAASGVRSMH conjugates may be developed for targeting MERTK receptors. These studies provide insight into the molecular interactions of natural product-peptide conjugates and their potential for binding to and targeting MERTK and BRAF V600E receptors in developing new therapeutics for targeting cancer.

Sagittal alignment differences on the operating room table compared to preoperative and postoperative imaging in anterior cervical discectomy and fusion.

Study Design: The study design used was a retrospective cohort. Objective: The objective of this study is to determine if intraoperative improvements in sagittal alignment on the operating table persisted on postoperative standing radiographs. Summary of Background Data: Cervical sagittal alignment may be correlated to postoperative outcomes. Since anterior cervical discectomy and fusions (ACDFs) can restore some cervical lordosis through intervertebral grafts/cages, it is important to understand if intraoperative radiographic measurements correlate with persistent postoperative radiographic changes. Materials and Methods: Patients undergoing elective primary ACDF were screened for the presence of lateral cervical radiographs preoperatively, intraoperatively, and postoperatively. Patients were excluded if their first postoperative radiograph was more than 3 months following the procedure or if cervical lordosis was not able to be measured at each time point. Paired t-tests were utilized to compare differences in measurements between time points. Statistical significance was set at P < 0.05. Results: Of 46 included patients, 26 (56.5%) were female, and the mean age was 55.2 ± 11.6 years. C0-C2 lordosis significantly increased from the preoperative to intraoperative time point (delta [Δ] = 4.49, P = 0.029) and significantly decreased from the intraoperative to postoperative time period (Δ = -6.57, P < 0.001), but this resulted in no significant preoperative to postoperative change (Δ = -2.08, P = 0.096). C2 slope decreased from the preoperative to the intraoperative time point (Δ = -3.84, P = 0.043) and significantly increased from the intraoperative to the postoperative time point (Δ = 3.68, P = 0.047), which also resulted in no net change in alignment between the preoperative and postoperative periods (Δ = -0.16, P = 0.848). There was no significant difference in the C2-C7 SVA from the preoperative to intraoperative (Δ = 0.85, P = 0.724) or intraoperative to postoperative periods (Δ = 2.04, P = 0.401); however, the C2-C7 SVA significantly increased from the preoperative to postoperative period (Δ = 2.88, P = 0.006). Conclusions: Intraoperative positioning predominantly affects the mobile upper cervical spine, particularly C0-C2 lordosis and C2 slope, but these changes do not persist postoperatively.