Antibody-Suppressor CXCR5+CD8+ T Cells Are More Potent Regulators of Humoral Alloimmunity after Kidney Transplant in Mice Compared to CD4+ Regulatory T Cells.

Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.

CXCR5 + CD8 + T Cell-mediated Suppression of Humoral Alloimmunity and AMR in Mice Is Optimized With mTOR and Impaired With Calcineurin Inhibition.

BACKGROUND: Adoptive cellular therapy (ACT) with antibody-suppressor CXCR5 + CD8 + T cells (CD8 + T Ab-supp ) inhibits alloantibody production, antibody-mediated rejection (AMR), and prolongs graft survival in multiple transplant mouse models. However, it is not known how conventional immunosuppressive agents impact the efficacy of CD8 + T Ab-supp ACT. METHODS: We investigated the efficacy of CD8 + T Ab-supp cell ACT when combined with calcineurin inhibitor (CNi) or mammalian target of rapamycin inhibitor (mTORi) in a murine model of kidney transplant. RESULTS: ACT-mediated decrease in germinal center B cells, posttransplant alloantibody titer, and amelioration of AMR in high alloantibody-producing CCR5 knockout kidney transplant recipients were impaired when ACT was combined with CNi and enhanced when combined with mTORi. CNi (but not mTORi) reduced ACT-mediated in vivo cytotoxicity of IgG + B cells and was associated with increased quantity of germinal center B cells. Neither CNi nor mTORi treatment impacted the expression of cytotoxic effector molecules (FasL, Lamp1, perforin, granzyme B) by CD8 + T Ab-supp after ACT. Concurrent treatment with CNi (but not mTORi) reduced in vivo proliferation of CD8 + T Ab-supp after ACT. The increase in quantity of splenic CD44 + CXCR5 + CD8 + T cells that occurs after ACT was reduced by concurrent treatment with CNi but not by concurrent treatment with mTORi (dose-dependent). CONCLUSIONS: Impaired efficacy of ACT by CNi is attributed to reduced persistence and/or expansion of CD8 + T Ab-supp cells after ACT. In contrast, concurrent immunosuppression with mTORi preserves CD8 + T Ab-supp cells quantity, in vivo proliferation, and in vivo cytotoxic effector function after ACT and enhances suppression of humoral alloimmunity and AMR.

Textbook Outcome as a Quality Metric in Living and Deceased Donor Kidney Transplantation.

BACKGROUND: Quality in kidney transplantation is measured using 1-year patient and graft survival. Because 1-year patient and graft survival exceed 95%, this metric fails to measure a spectrum of quality. Textbook outcomes (TO) are a composite quality metric offering greater depth and resolution. We studied TO after living donor (LD) and deceased donor (DD) kidney transplantation. STUDY DESIGN: United Network for Organ Sharing data for 69,165 transplant recipients between 2013 and 2017 were analyzed. TO was defined as patient and graft survival of 1 year or greater, 1-year glomerular filtration rate of greater than 40 mL/min, absence of delayed graft function, length of stay of 5 days or less, no readmissions during the first 6 months, and no episodes of rejection during the first year after transplantation. Bivariate analysis identified characteristics associated with TO, and covariates were incorporated into multivariable models. Five-year conditional survival was measured, and center TO rates were corrected for case complexity to allow center-level comparisons. RESULTS: The national average TO rates were 54.1% and 31.7% for LD and DD transplant recipients. The hazard ratio for death at 5 years for recipients who did not experience TO was 1.92 (95% CI 1.68 to 2.18, p ≤ 0.0001) for LD transplant recipients and 2.08 (95% CI 1.93 to 2.24, p ≤ 0.0001) for DD transplant recipients. Center-level comparisons identify 18% and 24% of centers under-performing in LD and DD transplantation. High rates of TO do not correlate with transplantation center volume. CONCLUSION: Kidney transplant recipients who experience TO have superior long-term survival. Textbook outcomes add value to the current standards of 1-year patient and graft survival.

Textbook Outcome as a Quality Metric in Liver Transplantation.

Quality in liver transplantation (LT) is currently measured using 1-y patient and graft survival. Because patient and graft survival rates now exceed 90%, more informative metrics are needed. Textbook outcomes (TOs) describe ideal patient outcomes after surgery. This study critically evaluates TO as a quality metric in LT. Methods: United Network for Organ Sharing data for 25 887 adult LT recipients were used to define TO as patient and graft survival >1 y, length of stay ≤10 d, 0 readmissions within 6 mo, absence of rejection, and bilirubin <3 mg/dL between months 2 and 12 post-LT. Univariate analysis identified donor and recipient characteristics associated with TO. Covariates were analyzed using purposeful selection to construct a multivariable model, and impactful variables were incorporated as linear predictors into a nomogram. Five-year conditional survival was tested, and center TO rates were corrected for case complexity to allow for center-level comparisons. Results: The national average TO rate is 37.4% (95% confidence interval, 36.8%-38.0%). The hazard ratio for death at 5 y for patients who do not experience TO is 1.22 (95% confidence interval, 1.11-1.34; P ≤ 0.0001). Our nomogram predicts TO with a C-statistic of 0.68. Center-level comparisons identify 31% of centers as high performing and 21% of centers as below average. High rates of TO correlate only weakly with center volume. Conclusions: The composite quality metric of TO after LT incorporates holistic outcome measures and is an important measure of quality in addition to 1-y patient and graft survival.

Antibody-suppressor CXCR5+ CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice.

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.

CXCR5+CD8+ T cells: A Review of their Antibody Regulatory Functions and Clinical Correlations.

CD8+ T cells have conventionally been studied in relationship to pathogen or tumor clearance. Recent reports have identified novel functions of CXCR5+CD8+ T cells that can home to lymphoid follicles, a key site of antibody production. In this review we provide an in-depth analysis of conflicting reports regarding the impact of CXCR5+CD8+ T cells on antibody production and examine the data supporting a role for antibody-enhancement (B cell "helper") and antibody-downregulation (antibody-suppressor) by CXCR5+CD8+ T cell subsets. CXCR5+CD8+ T cell molecular phenotypes are associated with CD8-mediated effector functions including distinct subsets that regulate antibody responses. Co-inhibitory molecule PD-1, among others, distinguish CXCR5+CD8+ T cell subsets. We also provide the first in-depth review of human CXCR5+CD8+ T cells in the context of clinical outcomes and discuss the potential utility of monitoring the quantity of peripheral blood or tissue infiltrating CXCR5+CD8+ T cells as a prognostic tool in multiple disease states.

Spinal Cord Stimulation for Restless Legs Syndrome: Case Series and Mechanistic Hypothesis.

BACKGROUND: Spinal cord stimulation (SCS) is a well-established therapy for chronic pain syndromes, with growing applicability to other conditions. Restless legs syndrome (RLS) is a widespread, chronic movement disorder managed primarily and incompletely by medication, and its etiology can be classified as idiopathic or secondary. METHODS: Three patients underwent SCS implantation for chronic back and/or leg pain with concomitant targeting of RLS: (1) a 34-year-old man with sporadic RLS symptoms that strongly intensified after military-related spinal fractures, (2) a 54-year-old man with RLS likely secondary to meralgia paresthetica, and (3) a 42-year-old man with low back and right lower extremity pain after a military motor vehicle accident. RESULTS: Continuing through 40-month, 2-month, and 28-month follow-ups, respectively, the patients experienced exemplary relief of their RLS symptoms. Notably in the case of patient 1, this benefit appears separate from his pain relief, as during the 5-month period directly after surgery but before adjusted targeting, he only experienced pain alleviation. CONCLUSIONS: To our knowledge, this is the first reported case of using SCS as a potentially long-lasting, safe, and highly effective therapy for RLS of mixed etiology. Additionally, 2 patients with RLS possibly secondary to chronic pain also benefited from the therapy. This success may be due to increased inhibition from hypothalamic cells controlling dopaminergic input to the spine.

Combined liver-lung transplantation: Indications, outcomes, current experience and ethical Issues.

Combined liver-lung transplantation (CLLT) is a rare, life-saving procedure to treat concomitant lung and liver disease. There have been 93 combined lung and liver transplantations performed in the United States since 1994. Techniques include both lung first and liver first sequential transplants with selective extracorporeal circulation of either thoracic or abdominal portions, with either end-to-end or Roux-en-Y choledochojejunostomy for biliary reconstruction. This review evaluates the existing literature regarding combined lung and liver transplantation (CLLT), describing the candidates, operation, perioperative complications, associated management strategies, and recommendations for immunosuppressive therapy and follow up.

A Review of Empathy, Its Importance, and Its Teaching in Surgical Training.

BACKGROUND: There has been much discussion in the medical literature about the importance of empathy and physician communication style in medical practice. Empathy has been shown to have a very real positive effect on patient outcomes. Most of the existing literature speaks to its role in medical education, with relatively little empiric study about empathy in the surgical setting. OBJECTIVE: Review of empathy and its importance as it pertains to the surgeon-patient relationship and improving patient outcomes, and the need for increased education in empathy during surgical training. METHODS: The published, peer-reviewed literature on patient-physician and patient-surgeon communication, medical student and resident education in empathy, and empathy research was reviewed. PubMed was queried for MESH terms including "empathy," "training," "education," "surgery," "resident," and "communication." RESULTS: There is evidence of a decline in empathy that begins during the clinical years of medical school, which continues throughout residency training. Surgeons are particularly susceptible to this decline as by-product of the nature of their work, and the current lack of formalised training in empathic patient communication poses a unique problem to surgical residents. CONCLUSIONS: The literature suggests that empathy training is warranted and should be incorporated into surgical residencies through didactics, role-playing and simulations, and apprenticeship to empathic attending role models.

Long-term Cost Utility of Spinal Cord Stimulation in Patients with Failed Back Surgery Syndrome.

BACKGROUND: Failed back surgery syndrome (FBSS) is a cause of significant morbidity for up to 40% of patients following spine surgery, and is estimated to cost almost $20 billion. Treatment options for these patients currently include conventional medical management (CMM), repeat operation, or spinal cord stimulation (SCS). Much of the published data regarding cost effectiveness of SCS comprise smaller scale randomized controlled trials (RCTs) rather than large databases capturing practices throughout the US. SCS has been shown to have superior outcomes to CMM or repeat spinal operation in several landmark studies, yet there are few large studies examining its long-term economic impact. OBJECTIVES: This study compares health care utilization for SCS compared to other management in patients with FBSS. STUDY DESIGN: Retrospective. SETTING: Inpatient and outpatient sample. METHODS: Patients with a history of FBSS from 2000 to 2012 were selected. We compared those who received SCS to those who underwent conventional management. A longitudinal analysis was used to model the value of log(cost) in each one year interval using a generalized estimating equations (GEE) model to account for the correlation of the same patient's cost in multiple years. Similarly, a Poisson GEE model with the log link was applied to correlated count outcomes. RESULTS: We identified 122,827 FBSS patients. Of these, 5,328 underwent SCS implantation (4.34%) and 117,499 underwent conventional management. Total annual costs decreased over time following implantation of the SCS system, with follow-up analysis at 1, 3, 6, and 9 years. The longitudinal GEE model demonstrated that placement of an SCS system was associated with an initial increase in total costs at the time of implantation (cost ratio [CR]: 1.74; 95% confidence interval [CI]: 1.41, 2.15, P < 0.001), however there was a significant and sustained 68% decrease in cost in the year following SCS placement (CR: 0.32; 95% CI: 0.24, 0.42, P < 0.001) compared to CMM. There was also an aggregate time trend that for each additional year after SCS, cost decreased on average 40% percent annually (CR: 0.60; 95% CI: 0.55, 0.65, P < 0.001), with follow-up up to 1, 3, 6, and 9 years post-procedure. LIMITATIONS: Costs are not correlated with patient outcomes, patients are not stratified in terms of complexity of prior back surgery, as well as inherent limitations of a retrospective analysis. CONCLUSIONS: We found that from 2000 to 2012, only 4.3% of patients across the United States with FBSS were treated with SCS. Long-term total annual costs for these patients were significantly reduced compared to patients with conventional management. Although implantation of an SCS system results in a short-term increase in costs at one year, the subsequent annual cumulative costs were significantly decreased long-term in the following 9 years after implantation. This study combines the largest group of FBSS patients studied to date along with the longest follow-up interval ever analyzed. Since SCS has repeatedly been shown to have superior efficacy to CMM in randomized clinical trials, the current study demonstrating improved long-term health economics at 1, 3, 6, and 9 years supports the long-term cost utility of SCS in the treatment of FBSS patients. Key words: Failed back surgery syndrome, spinal cord stimulation, back pain, leg pain, neuromodulation, FBSS, SCS.

Increasing Rates of Imaging in Failed Back Surgery Syndrome Patients: Implications for Spinal Cord Stimulation.

BACKGROUND: Failed back surgery syndrome (FBSS) has a high incidence following spinal surgery, is notoriously refractory to treatment, and results in high health care utilization. Spinal cord stimulation (SCS) is a well-accepted modality for pain relief in this population; however, until recently magnetic resonance imaging (MRI) was prohibited due to risk of heat conduction through the device. OBJECTIVES: We examined trends in imaging use over the past decade in patients with FBSS to determine its impact on health care utilization and implications for patients receiving SCS. STUDY DESIGN: Retrospective. SETTING: Inpatient and outpatient sample. METHODS: We identified patients from 2000 to 2012 using the Truven MarketScan database. Annual imaging rates (episodes per 1000 patient months) were determined for MRI, computed tomography (CT) scan, x-ray, and ultrasound. A multivariate Poisson regression model was used to determine imaging trends over time, and to compare imaging in SCS and non-SCS populations. RESULTS: A total of 311,730 patients with FBSS were identified, of which 5.17% underwent SCS implantation (n = 16,118). The median (IQR) age was 58.0 (49.0 - 67.0) years. Significant increases in imaging rate ratios were found in all years for each of the modalities. Increases were seen in the use of CT scans (rate ratio [RR] = 3.03; 95% confidence interval [CI]: 2.79 - 3.29; P < 0.0001), MRI (RR = 1.73; 95% CI: 1.61 - 1.85; P < 0.0001), ultrasound (RR = 2.00; 95% CI: 1.84 - 2.18; P < 0.0001), and x-ray (RR = 1.10; 95% CI: 1.05 - 1.15; P < 0.0001). Despite rates of MRI in SCS patients being half that in the non-SCS group, these patients underwent 19% more imaging procedures overall (P < 0.0001). SCS patients had increased rates of x-ray (RR = 1.27; 95% CI: 1.25 - 1.29), CT scans (RR = 1.32; 95% CI: 1.30 - 1.35), and ultrasound (RR = 1.10; 95% CI: 1.07 - 1.13) (all P < 0.0001). LIMITATIONS: This study is limited by a lack of clinical and historical variables including the complexity of prior surgeries and pain symptomatology. Miscoding cannot be precluded, as this sample is taken from a large nationwide database. CONCLUSIONS: We found a significant trend for increased use of advanced imaging modalities between the years 2000 and 2012 in FBSS patients. Those patients treated with SCS were 50% less likely to receive an MRI (as expected, given prior incompatibility of neuromodulation devices), yet 32% and 27% more likely to receive CT and x-ray, respectively. Despite the decrease in the use of MRI in those patients treated with SCS, their overall imaging rate increased by 19% compared to patients without SCS. This underscores the utility of MR-conditional SCS systems. These findings demonstrate that imaging plays a significant role in driving health care expenditures. This is the largest analysis examining the role of imaging in the FBSS population and the impact of SCS procedures. Further studies are needed to assess the impact of MRI-conditional SCS systems on future trends in imaging in FBSS patients receiving neuromodulation therapies. Key words: Failed back surgery syndrome, spinal cord stimulation, imaging, health care utilization, MRI, chronic pain, back pain, neuromodulation.

Specialty-Based Variations in Spinal Cord Stimulation Success Rates for Treatment of Chronic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) has emerged as an appropriate modality of treatment for intractable chronic pain. The present study examines variations in SCS trial-to-permanent conversion rates based on provider types performing the procedure. MATERIALS AND METHODS: We designed a large, retrospective analysis using the Truven MarketScan data base analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007-2012. Patients were categorized based on provider type performing the implantation including anesthesiologists, neurosurgeons, orthopedic surgeons, and physical medicine and rehabilitation (PM&R). Univariate and multivariate models identified factors associated with successful conversion. RESULTS: A total of 7667 unique instances of SCS implants were identified across five providers. Overall, 4842 (63.2%) of those receiving trials underwent permanent SCS system implantation. Anesthesiology performed the majority of implants (62.8%), followed by neurosurgery (22.0%), orthopedic surgery (10.2%), and PM&R (5.3%). Compared to anesthesiologists, both neurosurgeons (OR 10.99, 95% CI [9.11, 13.25]; p < 0.001) and orthopedic surgeons (OR 4.64, 95% CI [3.81, 5.65]; p < 0.001) had significantly higher conversion rates, while PM&R (OR 0.71, 95% CI [0.58, 0.87]; p = 0.001) had significantly lower. Percutaneous implants comprised 5473 (71.4%) of all implants. Neurosurgeons and orthopedic surgeons performed a significantly greater number of paddle implants among the different providers (p < 0.0001). Explant rates were similar across all cohorts analyzed (average 11.6%; p = 0.546). CONCLUSIONS: In this nationwide analysis, our results suggest that over a recent five-year period, conversion rates are highest when SCS trials are performed by neurosurgeons and orthopedic surgeons. The study has important implications for establishing uniform guidelines for training, patient selection, and education of physicians across multiple disciplines.

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 ±â€ŠSD age was 58.6 ±â€Š15.1 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 ±â€ŠSD number of days from discharge to readmission was 9.8 ±â€Š7.9 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.

Prevalence of Specific Types of Pain Diagnoses in a Sample of United States Adults.

BACKGROUND: Patients with pain conditions place significant demands on health care services globally. Health economists have reported the annual economic cost of pain in the United States as high as $635 billion. A common challenge in treating patients suffering from chronic pain conditions is accurate diagnosis and treatment. OBJECTIVE: The aim of this study was to determine the modern-day prevalence of individual types of pain diagnoses in adults. STUDY DESIGN: Retrospective analysis of Truven MarketScan® Commercial and Medicare Supplemental database. SETTING: United States patient population with a pain diagnoses from 2000 to 2012. METHODS: Multivariate analysis was used to determine the individual prevalence of specific types of pain diagnoses over a 13-year period. PATIENTS: We grouped the 6,575,999 patients with ICD-9 pain diagnoses into pain groupings. RESULTS: We determined the prevalence of pain groupings as back pain (74.7%), chronic pain (10.4%), complex regional pain syndrome (1.2%), degenerative spine disease (63.6%), limb pain (50.0%), neuritis/radiculitis (52.8%), and post-laminectomy syndrome (14.8%). LIMITATIONS: Retrospective and non-randomized study, with a patient cohort that is weighted towards recent years and commercial insurance. Coding discrepancies that are recorded and collected for patients. CONCLUSIONS: The demographic differences and similarities within the subgroups highlighted the concept that pain diagnoses should be considered as separate, but related entities. The present study helps us to better understand the frequency of specific pain diagnoses, and directs future studies to appropriately focus on pain diagnoses based on prevalence. This will allow increased understanding of the variation in pain diagnoses and prevent over-generalization in studies examining pain patients to more accurately reflect the varied subtypes and their economic impact.Duke University Institutional Review Board Protocol: 00053624Key words: Pain diagnoses, CRPS, neuritis, radiculitis, limb pain, degenerative spine disease, back pain, chronic pain, post-laminectomy pain, prevalence, MarketScan.

Explantation Rates and Healthcare Resource Utilization in Spinal Cord Stimulation.

OBJECTIVES: Certain patients ultimately undergo explantation of their spinal cord stimulation (SCS) devices. Understanding the predictors and rates of SCS explantation has important implications for healthcare resource utilization (HCRU) and pain management. The present study identifies explant predictors and discerns differences in HCRU for at-risk populations. METHODS: We designed a large, retrospective analysis using the Truven MarketScan Database. We included all adult patients who underwent a SCS trial from 2007 to 2012. Patients were grouped into cohorts that remained explant-free or underwent explantation over a three-year period, and multivariate models evaluated differences in healthcare resource utilization. RESULTS: A total of 8727 unique instances of trial implants between 2007 and 2012 were identified. Overall, 805 (9.2%) patients underwent device explantation. One year prior to SCS implantation, the explant cohort had significantly higher median baseline costs ($42,140.3 explant vs. $27,821.7 in non-explant groups; p < 0.0001), total number of pain encounters (180 vs. 103 p < 0.0001), and associated costs ($15,446.9 vs. $9,227.9; p < 0.0001). The explant cohort demonstrated increased use of procedures (19.0 vs. 9.0; p < 0.0001) compared to non-explanted patients. For each month after initial SCS implantation, explanted patients had a slower decrease in total costs (4% vs. 6% in non-explant; p < 0.01). At the month of explant, explant patients were expected to have incurred 2.65 times the total cost compared to the non-explant cohort (CR 2.65, 95% CI [1.83, 3.84]; p < 0.001). Medium volume providers had lower rates of explantation at one-year and three-years compared to low volume providers (p = 0.042). Increased age and Charlson index were independent predictors of explantation during the same periods. CONCLUSIONS: In this nationwide analysis, we identified that SCS device explantation is correlated with patients who have higher baseline costs, higher total cost post-SCS implantation, and increased use of procedures to control pain. The higher rates of explantation at three-years postimplant among low volume providers suggest that variations in provider experience and approach also contributes to differences in explantation rates.

The Volume-Outcome Effect: Impact on Trial-to-Permanent Conversion Rates in Spinal Cord Stimulation.

OBJECTIVES: Conversion rates from trial leads to permanent spinal cord stimulation (SCS) systems have important implications for healthcare resource utilization (HCRU) and pain management. We hypothesized that there is a volume-outcome effect, with chronic pain patients who visit high volume SCS implanters will have higher trial-to-permanent conversion rates. MATERIALS AND METHODS: We designed a large, retrospective analysis using the Truven MarketScan database analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007 to 2012 was designed. Patients were divided into three provider-based groups: high (>25), medium (9-24), and low (3-8) volume providers. Univariate and multivariate models identified factors associated with successful conversion. RESULTS: A total of 17,850 unique trial implants were performed by 3028 providers. Of 13,879 patients with baseline data available, 8981 (64.7%) progressed to permanent SCS. Higher volume providers were associated with slightly higher conversion rates (65.9% vs. 63.3% low volume, p = 0.029), explant rates (9.2% vs. 7.7% medium volume, p = 0.026), younger age (52.0 ± 13.4 years vs. 53.0 ± 13.4 years, p = 0.0026), Medicare/Medicaid (47.8% vs. 35.0% low volume, p < 0.0001), Southern region (53.5% vs. 38.9% low volume, p < 0.0001), and higher Charlson comorbidity scores (1.0 [SD = 1.4], p = 0.0002). Multivariate regression results showed female gender (1.13 [95% CI: 1.05-1.22], p < 0.001) and high volume providers associated with higher odds of successful trial conversion (1.12 [95% CI: 1.02-1.22], p = 0.014). CONCLUSIONS: In this nationwide analysis, high volume providers achieved higher trial-to-permanent SCS conversion rates than lower volume providers. The study has implications for both training requirements and referral patterns to delineate minimum implant experience necessary for provider proficiency. Future studies may be useful to understand HCRU differences.

Thoracic Nerve Root Entrapment by Intrathecal Catheter Coiling: Case Report and Review of the Literature.

BACKGROUND: Intrathecal catheter placement has long-term therapeutic benefits in the management of chronic, intractable pain. Despite the diverse clinical applicability and rising prevalence of implantable drug delivery systems in pain medicine, the spectrum of complications associated with intrathecal catheterization remains largely understudied and underreported in the literature. OBJECTIVE: To report a case of thoracic nerve root entrapment resulting from intrathecal catheter migration. STUDY DESIGN: Case report. SETTING: Inpatient hospital service. RESULTS/ CASE REPORT: A 60-year-old man status post implanted intrathecal (IT) catheter for intractable low back pain secondary to failed back surgery syndrome returned to the operating room for removal of IT pump trial catheter after experiencing relapse of preoperative pain and pump occlusion. Initial attempt at ambulatory removal of the catheter was aborted after the patient reported acute onset of lower extremity radiculopathic pain during the extraction. Noncontrast computed tomography (CT) subsequently revealed that the catheter had ascended and coiled around the T10 nerve root. The patient was taken back to the operating room for removal of the catheter under fluoroscopic guidance, with possible laminectomy for direct visualization. Removal was ultimately achieved with slow continuous tension, with complete resolution of the patient's new radicular symptoms. LIMITATIONS: This report describes a single case report. CONCLUSION: This case demonstrates that any existing loops in the intrathecal catheter during initial implantation should be immediately re-addressed, as they can precipitate nerve root entrapment and irritation. Reduction of the loop or extrication of the catheter should be attempted under continuous fluoroscopic guidance to prevent further neurosurgical morbidity.

Implantable Neurostimulation for Headache Disorders: Effect on Healthcare Utilization and Expenditures.

OBJECTIVES: Chronic daily headache is a considerable source of morbidity for patients and also carries an enormous economic burden. Patients who fail standard medication regimens lack well-defined therapies, and neurostimulation is an emerging option for these patients. The purpose of this study was to analyze the cost utility of implantable neurostimulation for treatment of headache. METHODS: We utilized the Thompson Reuters Marketscan Data base to identify individuals diagnosed with headache disorders who underwent percutaneous neurostimulation. Healthcare expenditures for individuals who subsequently received permanent, surgically implanted neurostimulatory devices were compared to those who did not. Only individuals who sought implantable neurostimulation were included to account for headache severity. The cohorts were adjusted for comorbidity and prior headache-related expenses. Costs were modeled longitudinally using a generalized estimating equation. RESULTS: A total of 579 patients who underwent percutaneous trial of neurostimulation were included, of which 324 (55.96%) converted to permanent neurostimulation within one year. Unadjusted expenditures were greater for patients who underwent conversion to the permanent neurostimulation device, as expected. Costs grew at a lower rate for patients who converted to permanent device implantation. Cost neutrality for patients receiving the permanent device was reached in less than five years after the enrollment date. The mean cost of conversion to a permanent implantation was $18,607.53 (SD $26,441.34). CONCLUSIONS: Our study suggests that implantable neurostimulation reduces healthcare expenditures within a relatively short time period in patients with severe refractory headache.

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.

Comparison of Bilateral vs. Staged Unilateral Deep Brain Stimulation (DBS) in Parkinson's Disease in Patients Under 70 Years of Age.

OBJECTIVE: The most popular surgical method for deep brain stimulation (DBS) in Parkinson's disease (PD) is simultaneous bilateral DBS. However, some centers conduct a staged unilateral approach advocating that reduced continuous intraoperative time reduces postoperative complications, thus justifying the cost of a second operative session. To test these assumptions, we performed a retrospective analysis of the Truven Health MarketScan® Database. METHODS: Using the MarketScan Database, we retrospectively analyzed patients that underwent simultaneous bilateral or staged unilateral DBS between 2000 and 2009. The main outcome measures were 90-day postoperative complication rates, number of reprogramming hours one year following procedure, and annualized healthcare cost. The outcome measures were compared between cohorts using multivariate regressions controlling for appropriate covariates. RESULTS: A total of 713 patients that underwent DBS between 2000 and 2009 met inclusion criteria for the study. Of these patients, 556 underwent simultaneous bilateral DBS and 157 received staged unilateral DBS. No statistically significant differences were found between groups in the rate of infection (simultaneous: 4.3% vs. staged: 7.0%; p = 0.178), pneumonia (3.1% vs. 5.7%; p = 0.283), hemorrhage (2.9% vs. 2.5%; p = 0.844), pulmonary embolism (0.5% vs. 1.3%), and device-related complications (0.5% vs. 0.0%). Patients in the staged cohort had a higher rate of lead revision in 90 days (3.2% vs. 12.7%; RR = 3.07; p < 0.001). The staged cohort had a higher mean (SD) number of reprogramming hours within one year of procedure (6.0 ± 5.7 vs. 7.8 ± 8.1; RR = 1.17; p < 0.001). No significant difference was found between the mean (SD) annualized payments between the cohorts ($86,100 ± $94,700 vs. $102,100 ± $121,500; p = 0.148). CONCLUSION: Our study did not find a significant difference between 90-day postoperative complication rates or annualized cost between the staged and simultaneous cohorts. Thus, we believe that it is important to consider other factors when deciding between the staged and simultaneous DBS. Such factors include patient convenience and the laterality of symptoms.