Effect of Antibiotic Spacer Dosing on Treatment Success in Two-Stage Exchange for Periprosthetic Joint Infection.

INTRODUCTION: In two-stage exchange for periprosthetic joint infection (PJI), adding antibiotics to cement spacers is the standard of care; however, little is known about optimal dosage. There is emphasis on using >3.6 g of total antibiotic, including ≥2.0 g of vancomycin, per 40 g of cement, but these recommendations lack clinical evidence. We examined whether recommended antibiotic spacer doses affect treatment success. METHODS: This was a retrospective review of 202 patients who underwent two-stage exchange for PJI from 2004 to 2020 with at least 1-year follow-up. Patients were separated into high (>3.6 g of total antibiotic per 40 g of cement) and low-dose spacer groups. Primary outcomes were overall and infectious failure. RESULTS: High-dose spacers were used in 80% (162/202) of patients. High-dose spacers had a reduced risk of overall (OR, 0.37; P = 0.024) and infectious (OR, 0.35; P = 0.020) failure for infected primary arthroplasties, but not revisions. In multivariate analysis, vancomycin dose ≥2.0 g decreased the risk of infectious failure (OR, 0.31; P = 0.016), although not overall failure (OR, 0.51; P = 0.147). CONCLUSION: During two-stage exchange for PJI, spacers with greater than 3.6 g of total antibiotic may reduce overall and infectious failure for infected primary arthroplasties. Furthermore, using at least 2.0 g of vancomycin could independently decrease the risk of infectious failure.

Early Clinical Outcomes of "Lemon-Dropped" Complex Primary Total Joint Arthroplasty Patients to a Tertiary Care Center.

BACKGROUND: In the era of value-based care, pressures lead to cherry-picking healthier patients and lemon-dropping riskier patients to higher levels-of-care. This study examined whether "lemon-dropped" primary total joint arthroplasty (pTJA) patients require increased health care resources and experience worse outcomes. METHODS: This was a retrospective cohort study of all pTJAs at one tertiary care center in 2022, excluding bilaterals, acute fractures, oncologic cases, and conversion hips. Patients were classified via referral pattern as simple or complex (referred for medical or surgical complexity). Primary outcomes were implant costs and any emergency department visit, readmission, reoperation, or complication within 90 days. Secondary outcomes were distance traveled to the hospital, anesthesia type, estimated blood loss, case duration, time in the recovery unit, length of stay, and discharge disposition. Outcomes were assessed via electronic medical record review and analyzed via Fisher's exact and unpaired Welch's t-tests. RESULTS: In total 641 pTJAs (322 hips, 319 knees) met inclusion criteria; 10.3% were complex referrals. Complex patients were younger (59 versus 66 years, P < .05) and more often non-White (41 versus 31%, P < .001), non-English speaking (11 versus 7%, P < .001), and had nonprimary osteoarthritis as a surgical indication (59 versus 12%, P < .001), but had similar Charlson Comorbidity Index and American Society of Anesthesiologists scores. Complex patients had increased odds of 90-day emergency department visits (OR [odds ratio] = 2.11, P = .04), 90-day complications (OR = 2.63, P < .001), and non-home discharge (OR = 2.60, P = .006); higher mean relative implant costs (1.31x, P < .001); longer time in the operating room (181 versus 158 minutes P < .001), time in surgery (125 versus 105 minutes, P < .001), and length of stay (3.2 versus 1.7 days, P = .005). CONCLUSIONS: "Lemon-dropped" pTJAs had worse early clinical outcomes and higher health care utilization, despite a control group with patients ill enough to utilize a tertiary care center as their medical home. Reimbursement models and evaluation metrics must account for these differences.

Comparison of Static and Articulating Spacers After Periprosthetic Joint Infection.

INTRODUCTION: There is no consensus on whether articulating or static spacers are superior during two-stage exchange arthroplasty for periprosthetic joint infection. We aimed to compare surgical time, need for extensile exposure, surgical costs, and treatment success for articulating and static spacers. METHODS: This was a retrospective review of 229 periprosthetic joint infections treated with two-stage exchange with a minimum of one-year follow-up. For articulating and static spacers, we compared the need for extensile exposure during reimplantation and treatment failure based on an updated definition. Surgical time and costs at both stages were also compared. Subgroup analysis was performed for total knee and hip arthroplasties. RESULTS: There was no difference in the surgical time for spacer insertion; however, articulating spacers demonstrated reduced surgical time during reimplantation (181 vs. 234 minutes, P < 0.001). In multivariate analysis, there was no difference in extensile exposures (odds ratio 2.20, P = 0.081), but treatment failure was more likely for static spacers (odds ratio 2.17, P = 0.009). Overall surgical costs for two-stage exchange were similar between groups (23,782 vs. 23,766, P = 0.495). CONCLUSION: Articulating spacers demonstrated shorter surgical times and a trend toward decreased extensile exposures during reimplantation. They also had higher treatment success rates and similar surgical costs for overall two-stage exchange.

Virtual Reality as a Learning Tool for Trainees in Unicompartmental Knee Arthroplasty: A Randomized Controlled Trial.

INTRODUCTION: The efficacy of virtual reality (VR) as a teaching augment for arthroplasty has not been well examined for unfamiliar multistep procedures such as unicompartmental knee arthroplasty (UKA). This study sought to determine whether VR improves surgical competence over traditional procedural preparation when performing a UKA. METHODS: Twenty-two orthopaedic surgery trainees were randomized to two surgical preparation cohorts: (1) "Guide" group (control) with access to manufacture's technique guide and surgical video and (2) "VR" group with access to an immersive commercially available VR learning module. Surgical performance of UKA on a SawBone model was assessed through time and the Objective Structured Assessment of Technical Skills (OSATS) validated rating system. RESULTS: Participants were equally distributed among all training levels and previous exposure to UKA. No difference in mean surgical times was observed between Guide and VR groups (Guide = 42.4 minutes versus VR = 43.0 minutes; P = 0.9) or mean total OSATS (Guide = 15.7 versus VR = 14.2; P = 0.59). Most trainees felt VR would be a useful tool for resident education (77%) and would use VR for case preparation if available (86.4%). CONCLUSION: In a randomized controlled trial of trainees at a single, large academic center performing a complex, multistep, unfamiliar procedure (UKA), VR training demonstrated equivalent surgical competence compared with the use of traditional technique guides, as measured by surgical time and OSATS scores. Most of the trainees found the VR technology beneficial. This study suggests that VR technology may be considered as an adjunct to traditional surgical preparation/training methods.

Irrigation and Debridement with Chronic Antibiotic Suppression Is as Effective as 2-Stage Exchange in Revision Total Knee Arthroplasty with Extensive Instrumentation.

BACKGROUND: Extraction of implants because of periprosthetic infection (PJI) following complex revision total knee arthroplasty (rTKA) with extensive instrumentation is a daunting undertaking for surgeon and patient alike. The purpose of the present study was to evaluate whether infections following complex rTKA are better treated with 2-stage exchange or irrigation and debridement (I&D) with modular component exchange and antibiotic suppression in terms of infection control, reoperation, and function. METHODS: We reviewed rTKAs that had been performed for the treatment of PJI from 2005 to 2016. Extensive instrumentation was defined as the presence ≥1 of the following: metaphyseal cones/sleeves, distal femoral replacement, periprosthetic fracture instrumentation, or fully cemented stems measuring >75 mm. Cases were categorized according to the initial treatment (I&D with antibiotic suppression or initiation of 2-stage exchange). RESULTS: Eighty-seven patients with PJI and extensive instrumentation were identified: 56 patients who were managed with I&D with suppression and 31 who were managed with the initiation of 2-stage exchange. The rate of success (defined as no reoperation for infection) was similar for the 2 groups (62.5% the I&D group compared with 67.7% for the 2-stage group; p = 0.62). The rate of mortality was also similar (39.3% for the I&D group compared with 38.7% for the 2-stage group; p = 0.96). Of the 31 patients in the 2-stage group, 18 (58.1%) underwent reimplantation with a revision replacement. Of those 18 patients, 13 were still infection-free at the time of the most recent follow-up; however, when the analysis was expanded to all 31 patients in the 2-stage group, only 13 (41.9%) both had a successful reimplantation and did not require additional surgery for infection. Nine (29.0%) of the 31 patients in the 2-stage group never underwent the second stage, and 4 (12.9%) of the 31 required arthrodesis at the second stage. In contrast, 35 (62.5%) of the 56 patients in the I&D group were successfully managed, without additional surgery for the treatment of infection. At the time of the latest follow-up (mean, 3.2 years; range, 2 to 13 years), more patients in the I&D group were ambulatory (76.8% in the I&D group compared with 54.8% in the 2-stage group; p = 0.05) and maintained a functional bending knee joint (85.7% in the I&D group compared with 45.2% in the 2-stage group; p < 0.001). CONCLUSIONS: In the treatment of periprosthetic infection of rTKA with extensive instrumentation, I&D with chronic antibiotic suppression was as effective as 2-stage exchange in terms of preventing reoperation for infection and was more effective in terms of maintaining function. These data apply to rTKA with extensive periarticular instrumentation and should not be extrapolated to primary or simple revision implants. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Antibiotic-Laden Bone Cement Use and Revision Risk After Primary Total Knee Arthroplasty in U.S. Veterans.

BACKGROUND: It is controversial whether the use of antibiotic-laden bone cement (ALBC) in primary total knee arthroplasty (TKA) affects periprosthetic joint infection (PJI) or revision rates. The impact of ALBC on outcomes of primary TKA have not been previously investigated in U.S. veterans, to our knowledge. The purposes of this study were to quantify utilization of ALBC among U.S. veterans undergoing primary TKA and to determine if ALBC usage is associated with differences in revision TKA rates. METHODS: Patients who had TKA with cement from 2007 to 2015 at U.S. Veterans Health Administration (VHA) hospitals with at least 2 years of follow-up were retrospectively identified. Patients who received high-viscosity Palacos bone cement with or without gentamicin were selected as the final study cohort. Patient demographic and comorbidity data were collected. Revision TKA was the primary outcome. All-cause revisions and revisions for PJI were identified from both VHA and non-VHA hospitals. Unadjusted and adjusted regression analyses were performed to identify variables that were associated with increased revision rates. RESULTS: The study included 15,972 patients who had primary TKA with Palacos bone cement at VHA hospitals from 2007 to 2015. Plain bone cement was used for 4,741 patients and ALBC was used for 11,231 patients. Utilization of ALBC increased from 50.6% in 2007 to 69.4% in 2015. At a mean follow-up of 5 years, TKAs with ALBC had a lower all-cause revision rate than those with plain bone cement (5.3% versus 6.7%; p = 0.0009) and a lower rate of revision for PJI (1.9% versus 2.6%; p = 0.005). On multivariable regression, ALBC use was associated with a lower risk of all-cause revision compared with plain bone cement (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92; p = 0.0019). Seventy-one primary TKAs needed to be implanted with ALBC to avoid 1 revision TKA. CONCLUSIONS: The utilization of ALBC for primary TKAs performed at VHA hospitals has increased over time and was associated with a lower all-cause revision rate and a lower rate of revision for PJI. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Wearable activity sensors and early pain after total joint arthroplasty.

A prospective observational cohort of 20 primary total hip arthroplasty (n = 12) and total knee arthroplasty (n = 8) patients (mean age: 63 ± 6 years) was passively monitored with a consumer-level wearable activity sensor before and 6 weeks after surgery. Patients were clustered by minimal change or decreased activity using sensor data. Decreased postoperative activity was associated with greater pain reduction (-5.5 vs -2.0, P = .03). All patients surpassed minimal clinical benefit thresholds of total joint arthroplasty (TJA) (Hip Disability and Osteoarthritis Score Junior 30.5 vs 20.8, P = .23; Knee Injury and Osteoarthritis Outcome Score Junior 23.3 vs 18.2, P = .77) within 6 weeks. Patients who objectively "take it easy" after TJA may experience less pain with no difference in early subjective outcome. Remote, passive analysis of outpatient wearable sensor data may permit real-time detection of early problems after TJA.

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

BACKGROUND: Complex 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/PURPOSES: Are 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? METHODS: This 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). RESULTS: Patients 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. CONCLUSIONS: Endoprosthetic 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 EVIDENCE: Level III, therapeutic study.

Early Outcomes of Primary Total Hip Arthroplasty After Prior Lumbar Spinal Fusion.

BACKGROUND: The coexistence of degenerative hip disease and spinal pathology is not uncommon with the number of surgical treatments performed for each condition increasing annually. The limited research available suggests spinal pathology portends less pain relief and worse outcomes after total hip arthroplasty (THA). We hypothesize that primary THA patients with preexisting lumbar spinal fusions (LSF) experience worse early postoperative outcomes. METHODS: This study is a retrospective matched cohort study. Primary THA patients at 1 institution who had undergone prior LSF (spine arthrodesis-hip arthroplasty [SAHA]) were identified and matched to controls of primary THA without LSF. Early outcomes (<90 days) were compared. RESULTS: From 2012 to 2014, 35 SAHA patients were compared to 70 matched controls. Patients were similar in age, sex, American Society of Anesthesiologist score, body mass index, and Charlson Comorbidity Index. SAHA patients had higher rates of complications (31.4% vs 8.6%, P = .008), reoperation (14.3% vs 2.9%, P = .040), and general anesthesia (54.3% vs 5.7%, P = .0001). Bivariate analysis demonstrated SAHA to predict reoperation (odds ratio, 5.67; P = .045) and complications (odds ratio, 4.89; P = .005). With the numbers available, dislocations (0% vs 2.8%), infections (0% vs 8.6%), readmissions, postoperative walking distance, and disposition only trended to favor controls (P > .05). Comparing controls to SAHA patients with <3 or ≥3 levels fused, longer fusions had increased cumulative postoperative narcotic consumption (mean morphine equivalents, 44.3 vs 46.9 vs 169.4; P = .001). CONCLUSION: Patients with preexisting LSF experience worse early outcomes after primary THA including higher rates of complications and reoperation. Lower rates of neuraxial anesthesia and increased narcotic usage represent potential contributors. The complex interplay between the lumbar spine and hip warrants attention and further investigation.

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.

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.

Long-Acting Opioid Use Independently Predicts Perioperative Complication in Total Joint Arthroplasty.

BACKGROUND: Opioid therapy is an increasingly used modality for treatment of musculoskeletal pain despite multiple associated risks. The purpose of this study was to evaluate how preoperative opioid use affects early outcomes after total joint arthroplasty. METHODS: A total of 174 patients undergoing total joint arthroplasty were matched by age, gender, and procedure into 3 groups stratified by preoperative opioid use (nonuser, short acting [eg, Vicodin], long acting [eg, Oxycontin]). RESULTS: Compared to nonusers, preoperative long-acting use was associated with increased postoperative mean opioid consumption (46 mg vs 366 mg mean morphine equivalents, P < .001) and independently predicted complications within 90 days (odds ratio: 6.15, confidence interval: [1.46, 25.95], P = .013). CONCLUSION: Preoperative opioid use should be disclosed as a risk factor for complication to patients and taken into consideration by physicians before initiating opioid management.

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 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.

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.

Early surgical intervention in adult patients with ganglioglioma is associated with improved clinical seizure outcomes.

Gangliogliomas are rare central nervous system tumors, most commonly affecting children and young adults. Chronic seizure and epilepsy are the most frequent presentation of patients with gangliogliomas. In this report, we review the modern literature regarding the effects of early surgical intervention on the clinical outcome of patients with ganglioglioma. A boolean search of PubMed using key words "ganglioglioma", "adult", "seizure control", "treatment", "surgical intervention", and "observation", alone and in combination was performed. The inclusion criteria for articles were that: (i) clinical outcomes were reported specifically for gangliogliomas; (ii) data were reported for adult patients older than the age of 18 years; (iii) treatment data were included for the treatment of gangliogliomas; and (iv) ganglioglioma was the only pathological diagnosis for the evaluation of the tumor. Data were analyzed as a whole then stratified into two groups: early and late treatment intervention. The query identified a total of 99 articles including 1,089 cases of ganglioglioma meeting our inclusion and exclusion criteria. There was a 55% prevalence of males, representing a statistically significant predilection (51-59%, 95% confidence interval). Seizure control was significantly improved when surgical intervention occurred less than 3 years after symptom onset (78% versus 48%; p = 0.0001). Ganglioglioma in adults represents a rare group of tumors, and our systematic analysis suggests a higher prevalence in males. Our findings also support that an early surgical intervention is significantly associated with improved clinical seizure control.

A prospective study of hearing preservation in untreated vestibular schwannomas.

OBJECT: The authors previously published a systematic review of the English language literature regarding the natural history of untreated vestibular schwannomas (VSs). This analysis found that the best predictor of future hearing loss was tumor growth > 2.5 mm/year on serial imaging, a factor that doubled the rate of hearing loss. In this paper the authors present an analysis of prospectively collected outcomes in patients with untreated VS from their institution that confirms their previous findings. METHODS: Clinical, radiographic, and audiometric data for all patients evaluated for VS at the authors' institution over a 22-year period were prospectively collected in a database. All patients in this database who had serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery Grade A or B) on initial presentation were selected, and underwent serial observation. Magnetic resonance imaging and audiometric data were analyzed, and the time from presentation until hearing loss was analyzed using Kaplan-Meier analysis. RESULTS: Fifty-nine patients with VS who initially presented with serviceable hearing were treated conservatively over this period. Consistent with the authors' previous findings, patients with a tumor growth rate > 2.5 mm/year at any point during follow-up lost their hearing at a much faster rate than those who had slower growing tumors. The median time to hearing loss was 7.0 years in those patients with tumor growth rate > 2.5 mm/year compared to 14.8 years in the other patients (p < 0.0001). The estimated median time to hearing loss in the 3 initial tumor size groups was 11.6 years in the intracanalicular group, 10.3 years in the group with 0.1-1 cm extension into the CPA cistern, and 9.3 years in the group with > 1 cm extension into the CPA cistern (p value nonsignificant). Initial tumor size, age at diagnosis, and neurofibromatosis Type 2 status did not affect the time to loss of serviceable hearing. Interestingly, many patients who were followed up for more than a decade eventually lost their hearing, regardless of whether the tumor displayed any documented interval growth. CONCLUSION: The authors confirmed the findings of their systematic review of the literature using a prospectively followed group of patients with untreated VS. Collectively, these data suggest that the expectation for more rapid hearing loss should be communicated to patients, and the decision for surgical or other intervention should be made in the context of the known risk of continued observation of fast growing tumors.

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.