Jeffrey J. Barry

Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

Cancer immunoresistance and immune escape may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.

The relationship between tear severity, fatty infiltration, and muscle atrophy in the supraspinatus.

BACKGROUND Fatty infiltration and muscle atrophy have been described as interrelated characteristic changes that occur within the muscles of the rotator cuff after cuff tears, and both are independently associated with poor outcomes after surgical repair. We hypothesize that fatty infiltration and muscle atrophy are two distinct processes independently associated with supraspinatus tears. MATERIALS AND METHODS A retrospective review of 377 patients who underwent shoulder magnetic resonance imaging at one institution was performed. Multivariate analysis was performed based on parameters including age, sex, rotator cuff tear severity, fatty infiltration grade, and muscle atrophy. RESULTS A total of 116 patients (30.8%) had full-thickness tears of the supraspinatus, 153 (40.6%) had partial thickness tears, and 108 (28.7%) had no evidence of tear. With increasing tear severity, the prevalence of substantial fatty infiltration (grade ≥2) increased: 6.5% of patients with no tears vs 41.4% for complete tears (P < .001). Similarly, the prevalence of supraspinatus atrophy increased with worsening tear severity: 36.1% of no tears vs 77.6% of complete tears (P < .001). Multivariate analysis demonstrated a significant independent association between fatty infiltration and muscle atrophy when taking into account sex, age, and tear severity. CONCLUSIONS Fatty infiltration and muscle atrophy are independently associated processes. Fatty infiltration is also related to increasing age, muscle tear severity, and sex, whereas muscle atrophy is related to increasing age but not tear severity. In patients without rotator cuff tears, fatty infiltration and atrophy prevalence increased independently with increasing age.

Perioperative Outcomes and Complications of Pedicle Subtraction Osteotomy in Cases With Single Versus Two Attending Surgeons.

STUDY DESIGN Retrospective case series. OBJECTIVE To assess the perioperative morbidity of pedicle subtraction osteotomy (PSO) based on the presence of 1 versus 2 attending surgeons. BACKGROUND SUMMARY Pedicle subtraction osteotomies are challenging cases with high complication rates and substantial physiological burden on patients. The literature supports the benefits of 2-surgeon strategies in complex cases in other specialties. METHODS We reviewed a single institution database of all pedicle subtraction osteotomies (78 cases) from 2005-2010 and divided the cohort into single versus 2-surgeon groups (42 vs. 36 cases, respectively). We performed subset analysis after excluding cases before 2007 and excluding patients with staged anterior and posterior procedures. We analyzed cases for estimated blood loss, length of surgery, length of stay, radiographic analysis, rate of return to the operating room within 30 days, and medical and neurological complications. RESULTS The groups were similar when comparing mean number of posterior levels fused, levels decompressed and revision rates, however, the average age of the single surgeon and 2 surgeon groups was 57.6 and 64.3 years, respectively (p = .02). The 2 groups had comparable correction of radiographic parameters. Mean percent estimated blood loss for single versus 2 surgeons was 109% versus 35% (p < .001) and estimated blood loss was 5,278 versus 2,003 mL (p < .001). Average surgical time for single versus 2 surgeons was 7.6 versus 5.0 hours (p < .001). A total of 45% of single-surgeon patients compared with 25% of 2-surgeon patients experienced at least 1 major complication within 30 days. In the single-surgeon group, 19% had unplanned surgery within 30 days, versus 8% in the 2-surgeon group. CONCLUSIONS The use of 2 surgeons at an experienced spine deformity center decreases the operative time and estimated blood loss, and may be a key factor in witnessed decreased major complication prevalence. This approach also may decrease the rate of premature case termination and return to operating room in 30 days.

The next step: innovative molecular targeted therapies for treatment of intracranial chordoma patients.

BACKGROUND:Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Patients who relapse or cannot undergo a complete en bloc resection generally have a poor prognosis. New agents for postoperative adjuvant treatment of chordomas are needed. OBJECTIVE:To highlight potential clinical trials that could evolve from new insights into the molecular biology of chordoma. METHODS:We performed a review of recent studies published in the literature that have begun to characterize the molecular features of chordoma, and with this knowledge, several targets for potential clinical therapies have been determined. RESULTS:Several receptor tyrosine kinases and their downstream signaling cascades show dysregulation in chordoma and represent attractive targets for future therapeutic interventions. The pathways shown to be of particular importance in chordoma involve the platelet-derived growth factor receptor, epidermal growth factor receptor, hepatocyte growth factor receptor, and common downstream cascade of phosphoinositide 3-kinases, Akt, and mammalian target of rapamycin. CONCLUSION:Recent findings characterizing the molecular biology of chordoma have illuminated multiple possible targets for future clinical trials. The availability of inhibitors against these aberrant pathways makes clinical trials with chordoma both feasible and immediately realizable. Additionally, we emphasize the rationale for combination therapy when implementing molecular therapy in chordoma and other cancers.

Prior Lumbar Spinal Arthrodesis Increases Risk of Prosthetic-Related Complication in Total Hip Arthroplasty.

BACKGROUND Degenerative hip disorders often coexist with degenerative changes of the lumbar spine. Limited data on this patient population suggest inferior functional improvement and pain relief after surgical management. The purpose of this study is to compare the rates of prosthetic-related complication after primary total hip arthroplasty (THA) in patients with and without prior lumbar spine arthrodesis (SA). METHODS Medicare patients (n = 811,601) undergoing primary THA were identified and grouped by length of prior SA (no fusion, 1-2 levels fused [S-SAHA], and ≥3 levels fused [L-SAHA]). RESULTS Compared with controls, patients with prior SA had significantly higher rates of complications including dislocation (control: 2.36%; S-SAHA: 4.26%; and L-SAHA: 7.51%), revision (control: 3.43%, S-SAHA: 5.55%, and L-SAHA: 7.77%), loosening (control: 1.33%, S-SAHA: 2.10%, and L-SAHA: 3.04%), and any prosthetic-related complication (control: 7.33%, S-SAHA: 11.15% [relative risk: 1.52], and L-SAHA: 14.16% [relative risk: 1.93]) within 24 months (P < .001). CONCLUSION The interplay of coexisting degenerative hip and spine disease deserves further attention of both arthroplasty and spine surgeons.

Spinal Realignment for Adult Deformity: Three-column Osteotomies Alter Total Hip Acetabular Component Positioning.

Introduction: A goal of adult spinal deformity surgery is correction of sagittal imbalance by increasing lumbar lordosis (LL), allowing a previously retroverted pelvis to normalize as evidenced by decreases in pelvic tilt (PT). Realignment of pelvic orientation may alter the position of preexisting total hip arthroplasties (THAs). Methods: Twenty-seven patients with unilateral THA who underwent thoracolumbar fusions for adult spinal deformity from the pelvis to L1 or above were retrospectively reviewed (levels fused, 10.3 [range, 6 to 17]; age, 70 ± 9 years). Comparisons of preoperative and postoperative spinal deformity parameters, acetabular tilt (AT), and acetabular cup abduction angle (CAA) were performed, with subgroup analysis for those who had undergone three-column osteotomy and those who had not. Results: Preoperative deformity was severe, with findings of a sagittal vertical axis >9 cm, PT >25°, and pelvic incidence-LL >20°. Postoperatively, AT decreased significantly (−7° ± 10°; P < 0.001), signifying relative acetabular retroversion. Comparing patients with three-column osteotomy versus those without, AT changes were greater in those with three-column osteotomy (11° ± 7° and −2 ± 10°, respectively; P = 0.024). AT was significantly correlated with changes of PT (r = 0.704; P < 0.001) and LL (r = −0.481; P = 0.011). AT decreased (ie, retroverted) 1° for every 3.23° of LL or 1.13° of PT correction. The coronal plane CAA did not change substantially. Discussion: Spinal deformity correction, with techniques such as three-column osteotomy, result in significant THA acetabular component repositioning in the sagittal plane. Resultant decreased AT (ie, retroversion) theoretically may affect tribology, wear, and joint stability and warrants further investigation.

Length of Endoprosthetic Reconstruction in Revision Knee Arthroplasty Is Associated With Complications and Reoperations

BackgroundComplex revision total knee arthroplasty (TKA) often calls for endoprosthetic reconstruction to address bone loss, poor bone quality, and soft tissue insufficiency. Larger amounts of segmental bone loss in the setting of joint replacement may be associated with greater areas of devascularized tissue, which could increase the risk of complications and worsen functional results.Questions/purposesAre longer endoprosthetic reconstructions associated with (1) higher risk of deep infection; (2) increased risk of reoperation and decreased implant survivorship; or (3) poorer ambulatory status?MethodsThis is a single-institution retrospective case series of nononcologic femoral endoprosthetic reconstructions for revision TKA from 1995 to 2013 (n = 32). Cases were categorized as distal (n = 17) or diaphyseal (n = 15) femoral reconstructions based on extension to or above the supracondylar metaphyseal-diaphyseal junction, respectively. Five patients from each group were lost to followup before 2 years (distal mean 4 years [range, 2–8 years]; diaphyseal mean = 6 years [range, 2–16 years]), and one of the 12 distal reconstructions and two of the 10 diaphyseal reconstructions had not been evaluated within the past 5 years. Clinical outcomes and ambulatory status (able to walk or not) were assessed through chart review by authors not involved in any cases. Prior incidence of periprosthetic joint infection was high in both groups (distal = seven of 12 versus diaphyseal = four of 10; p = 0.670).ResultsPatients with diaphyseal femoral replacements were more likely to develop postoperative deep infections than patients with distal femoral replacements (distal = three of 12 versus diaphyseal = nine of 10; p = 0.004). Implant survivorship (revision-free) for diaphyseal reconstructions was worse at 2 years (distal = 100%, 95% confidence interval [CI], 100%–100% versus diaphyseal = 40%, 95% CI, 19%–86%; p = 0.001) and 5 years (distal = 90%, 95% CI, 75%–100% versus diaphyseal = 30%, 95% CI, 12%–73%; p = 0.001). Infection-free, revision-free survival (retention AND no infection) was worse for diaphyseal femoral replacing reconstructions than for distal femoral replacements at 2 years (distal = 70%, 95% CI, 48%–100% versus diaphyseal = 20%, 95% CI, 6%–69%; p = 0.037) and 5 years (distal = 70%, 95% CI, 48%–100% versus diaphyseal = 10%, 95% CI, 2%–64%; p = 0.012). There was no difference with the small numbers available in proportion of patients able to walk (distal reconstruction = eight of 11 versus diaphyseal = seven of 10; p = 1.000), although all but one patient in each group required walking aids.ConclusionsEndoprosthetic femoral reconstruction is a viable salvage alternative to amputation for treatment of failed TKA with segmental distal femoral bone loss. In our small series even with substantial loss to followup and likely best-case estimates of success, extension proximal to the supracondylar metaphyseal-diaphyseal junction results in higher infection and revision risk. In infection, limb salvage remains possible with chronic antibiotic suppression, which we now use routinely for all femoral replacement extending into the diaphysis.Level of EvidenceLevel III, therapeutic study.

Effects of Prior Cervical Fusion on Patient Outcomes After Shoulder Arthroplasty

Background The coexistence of cervical disease and shoulder pathology is not uncommon. The purpose of this study is to evaluate the early complication rates and outcomes after shoulder arthroplasty in patients with prior cervical arthrodesis. Methods A retrospective analysis was performed on a prospectively collected cohort at a single institution. Shoulder arthroplasty (TSA or RTSA) patients with prior cervical fusion (cervical arthrodesis-shoulder arthroplasty [CASA]) were identified and age-matched to controls without cervical fusion from 2012 to 2015. Early (<90-day) complications, visual analog scale (VAS) pain scores, and hospital length of stays were analyzed. Active shoulder range of motion (ROM) and American Shoulder and Elbow Surgeon (ASES) scores preoperatively, 6-week, 6-month, and 1-year postoperatively were compared. Results Seventeen CASA patients were matched to 34 controls. Patients were similar in gender, American Society of Anesthesiologist score, body mass index, opioid use, and arthroplasty procedure (TSA vs RTSA). CASA patients had similar postoperative VAS pain scores (4.6 vs 4.0), hospital length of stay (2.3 vs 2.5), and 90-day complications (3/17 vs 3/34) when compared to controls. Active shoulder ROM and ASES preoperatively and postoperatively at 6-week, 6-month, and 1-year were similar between the 2 groups. CASA patients had similar improvements in ASES scores at 1-year from preoperative scores when compared to controls (25.8 ± 24.3 vs 35.8 ± 21.4, P = .25). Conclusion Prior cervical fusion does not appear to be a risk factor for increased perioperative complications or poorer patient reported outcomes in patients undergoing shoulder arthroplasty.