Defective HLA Class I Expression and Patterns of Lymphocyte Infiltration in Chordoma Tumors.

BACKGROUND: There are no effective systemic therapies for chordoma. The recent successes of immunotherapeutic strategies in other cancers have resulted in a resurgence of interest in using immunotherapy in chordoma. These approaches rely on a functional interaction between the host's immune system and the expression of tumor peptides via the human leukocyte antigen (HLA) Class I antigen. It is not known whether chordoma cells express the HLA Class I antigen. QUESTIONS/PURPOSES: (1) Do chordoma tumors exhibit defects in HLA Class I antigen expression? (2) What is the pattern of lymphocyte infiltration in chordoma tumors? METHODS: Patients with chordoma treated at Massachusetts General Hospital between 1989 and 2009 were identified with permission from the institutional review board. Of the 75 patients who were identified, 24 human chordoma tumors were selected from 24 distinct patients based on tissue availability. Histology slides from these 24 formalin-fixed paraffin-embedded chordoma tissue samples were deparaffinized using xylene and ethanol and underwent heat-induced antigen retrieval in a citrate buffer. Samples were incubated with monoclonal antibodies directed against HLA Class I antigen processing machinery components. Antibody binding was detected via immunohistochemical staining. Staining intensity (negative, weakly positive, strongly positive) was assessed semiquantitatively and the percentage of chordoma cells stained for HLA Class I antigen subunits was assessed quantitatively. Hematoxylin and eosin-stained histology slides from the same 24 chordoma samples were assessed qualitatively for the presence of tumor-infiltrating lymphocytes and histologic location of these lymphocytes. Immunohistochemical staining with monoclonal antibodies directed against CD4 and CD8 was performed in a quantitative manner to identify the lymphocyte subtype present in chordoma tumors. All results were scored independently by two investigators and were confirmed by a senior bone and soft tissue pathologist. RESULTS: Seven of 24 chordoma samples exhibited no staining by the anti-HLA-A heavy chain monoclonal antibody HC-A2, two had weak staining intensity, and eight had a heterogeneous staining pattern, with fewer than 60% of chordoma cells exhibiting positive staining results. Four of 24 samples tested were not stained by the anti-HLA-B/C heavy chain monoclonal antibody HC-10, five had weak staining intensity, and 11 displayed a heterogeneous staining pattern. For the anti-ß-2-microglobulin monoclonal antibody NAMB-1, staining was detected in all samples, but 11 had weak staining intensity and four displayed a heterogeneous staining pattern. Twenty-one of 24 samples tested had decreased expression in at least one subunit of HLA Class I antigens. No tumors were negative for all three subunits. Lymphocytic infiltration was found in 21 of 24 samples. Lymphocytes were primarily found in the fibrous septae between chordoma lobules but also within the tumor lobules and within the fibrous septae and tumor lobules. Twenty-one of 24 tumors had CD4+ T cells and 11 had CD8+ T cells. CONCLUSION: In chordoma tissue samples, HLA Class I antigen defects commonly were present, suggesting a mechanism for escape from host immunosurveillance. Additionally, nearly half of the tested samples had cytotoxic CD8+ T cells present in chordoma tumors, suggesting that the host may be capable of mounting an immune response against chordoma tumors. The resulting selective pressure imposed on chordoma tumors may lead to the outgrowth of chordoma cell subpopulations that can evade the host's immune system. CLINICAL RELEVANCE: These findings have implications in the design of immunotherapeutic strategies for chordoma treatment. T cell recognition of tumor cells requires HLA Class I antigen expression on the targeted tumor cells. Defects in HLA Class I expression may play a role in the clinical course of chordoma and may account for the limited or lack of efficacy of T cell-based immunity triggered by vaccines and/or checkpoint inhibitors.

Factors associated with infection after reconstructive shoulder surgery for proximal humerus tumors.

BACKGROUND: The main reconstruction techniques for proximal humerus tumors include osteoarticular allografts (OAs), endoprostheses (EPs), or allograft prosthetic composites (APCs). A common complication is infection, and constructs involving the use of allografts are believed to be at a higher risk of infection. Literature comparing infection rates between different modalities of reconstruction is scarce and underpowered. The study purposes were (1) to determine and compare the prevalence of infection in patients who underwent reconstruction of the proximal humerus including OAs, EPs, and APCs; (2) to identify preoperative, perioperative, and postoperative predictors of infection that might be modifiable; and (3) to present our protocol of treatment in patients with superficial and deep infections. METHODS: We reviewed 150 patients of all ages with proximal humerus tumors treated by an OA, EP, or APC at 2 tertiary institutions. The prevalence of infection for each modality was calculated and compared between groups. We identified potential predictors of infection with stepwise backward multivariate Cox regression analysis. RESULTS: An infection developed in 19 patients (12%): 5 of 45 (11%) in the OA group, 12 of 85 (14%) in the EP group, and 2 of 20 (10%) in the APC group (P = .740). A lower preoperative hemoglobin blood level and low preoperative albumin blood level were independently associated with infection. CONCLUSIONS: We found similar infection rates compared with previously reported series. However, we did not identify a higher infection prevalence in constructs using allografts. Patients with a lower preoperative hemoglobin or albumin level are at higher risk of infection and should undergo optimization before surgery.

Is Social Support Associated With Upper Extremity Disability?

BACKGROUND: Pain intensity and disability correlate with psychosocial factors such as depression and pain interference (the degree to which pain interferes with activities of daily living) as much or more than pathophysiology in upper extremity illness. However, other factors like emotional support (perception of being cared for and valued as a person), instrumental support (perception of availability of tangible assistance when needed), positive psychosocial impact (perception and focus on the positive side of a difficult situation, sometimes characterized as posttraumatic growth, benefit-finding, or meaning making), also might be associated with disability in patients with upper extremity orthopaedic illness. This is the first published study, to our knowledge, addressing the potential association of emotional support, instrumental support, and positive psychosocial illness impact with disability in patients with upper extremity illness. QUESTIONS/PURPOSES: We asked: (1) Is there a correlation between the QuickDASH and the Patient-reported Outcomes Measurement Information System (PROMIS(®)) emotional support Computer Adaptive Testing (CAT)? (2) Is there a correlation between the QuickDASH and PROMIS(®) instrumental support CAT? (3) Is there a correlation between the QuickDASH and PROMIS(®) positive psychosocial illness impact CAT? (4) Among the PROMIS(®) measures of depression, emotional support, instrumental support, positive illness impact, and pain interference, which accounts for the most variance in QuickDASH scores? METHODS: One hundred ninety-three patients with upper extremity illness (55% women; average age, 51 ± 18 years) of 213 approached (91% recruitment rate) completed the QuickDASH, and five different PROMIS(®) CATs: pain interference (the degree to which pain interferes with accomplishing one's goals), depression, emotional support, psychosocial illness impact, and instrumental support. We recruited patients from the practice of three surgeons in hand service of the department of orthopaedic surgery at a major urban university hospital. RESULTS: Pearson Product Moment Correlations showed that emotional support (r = -0.18; p = 0.014) and instrumental support (r = -0.19; p = 0.008) were weakly and inversely associated with the QuickDASH), while positive psychosocial illness impact was moderately and inversely associated with the QuickDASH (r = -0.36; p < 0.001). In multivariable analyses, pain interference, but not the social support measures, was the only psychosocial factor associated with the QuickDASH and alone explained 66% of variance. CONCLUSIONS: Emotional support, instrumental support and positive psychosocial illness impact are all individually associated with disability to a small degree, but pain interference (the degree to which pain interferes with accomplishing one's goals) has the strongest influence on magnitude of disability. LEVEL OF EVIDENCE: Level 1, prognostic study.

Opioid Use, Satisfaction, and Pain Intensity After Orthopedic Surgery.

BACKGROUND: Patients in other countries use fewer opioids than patients in the United States with satisfactory pain relief. OBJECTIVE: This study tested the null hypothesis that opioid intake after orthopedic surgery does not influence satisfaction with pain management. METHODS: A total of 232 orthopedic surgical inpatients completed measures of pain self-efficacy and symptoms of depression at enrollment and commonly used measures of pain intensity, satisfaction with pain relief, and satisfaction with hospital staff attention to pain approximately 14 days after surgery. Inpatient opioid intake per 24-hour period was quantified. RESULTS: At a phone evaluation approximately 2 weeks after discharge from the hospital, patients who were always satisfied with their pain relief in hospital and always satisfied with staff attention to pain used significantly less opioids on day 1 compared with patients who were not always satisfied. There were no differences in satisfaction by type of surgery. The final multivariable model for not always satisfied with pain relief included greater opioid use on day 1 (odds ratio = 1.2), and preadmission diagnosis of depression (odds ratio = 2.6). Greater opioid use on day 1 was the only factor associated with less than always satisfied with the staff attention to pain relief (odds ratio = 1.3). CONCLUSIONS: Patients who take more opioids report less satisfaction with pain relief and greater pain intensity. Evidence-based interventions to increase self-efficacy merit additional study for the management of postoperative pain. LEVEL OF EVIDENCE: Prognostic, Level 1.

Does verbal and nonverbal communication of pain correlate with disability?

BACKGROUND: Illness (symptoms and disability) consistently correlates more with coping strategies and symptoms of depression than with pathophysiology or impairment. OBJECTIVE: This study tested the primary null hypothesis that there is no correlation between verbal and nonverbal communication of pain (pain behavior) and upper extremity-specific disability in patients with hand and upper extremity illness. METHODS: A total of 139 new and followed up adult patients completed the QuickDASH, an ordinal rating of pain, and 4 Patient-Reported Outcomes Measurement Information System (PROMIS) Computer Adaptive Testing instruments: (1) PROMIS pain behavior, (2) PROMIS pain interference (measuring the degree to which pain interferes with achieving ones physical goals), (3) PROMIS physical function, and (4) PROMIS depression. RESULTS: Factors associated with a higher QuickDASH score in bivariate analysis included a higher PROMIS pain behavior score, not working, being separated/divorced or widowed, having sought treatment before, having other pain conditions, a higher PROMIS pain interference score, a higher PROMIS depression score, and lower education level. The final multivariable model of factors associated with QuickDASH included PROMIS pain interference, having other pain conditions, and being separated/divorced or widowed, and it explained 64% of the variability. CONCLUSION: PROMIS pain behavior (verbal and nonverbal communication of pain) correlates with upper extremity disability, but PROMIS pain interference (the degree to which pain interferes with activity) is a more important factor. LEVEL OF EVIDENCE: Level IV, cross-sectional study.

Do corresponding authors take responsibility for their work? A covert survey.

BACKGROUND: Publication of a manuscript does not end an author's responsibilities. Reasons to contact an author after publication include clarification, access to raw data, and collaboration. However, legitimate questions have been raised regarding whether these responsibilities generally are being met by corresponding authors of biomedical publications. QUESTIONS/PURPOSES: This study aims to establish (1) what proportion of corresponding authors accept the responsibility of correspondence; (2) identify characteristics of responders; and (3) assess email address decay with time. We hypothesize that the response rate is unrelated to journal impact factor. METHODS: We contacted 450 corresponding authors throughout various fields of biomedical research regarding the availability of additional data from their study, under the pretense of needing these data for a related review article. Authors were randomly selected from 45 journals whose impact factors ranged from 52 to 0; the source articles were published between May 2003 and May 2013. The proportion of corresponding authors who replied, along with author characteristics were recorded, as was the proportion of emails that were returned for inactive addresses; 446 authors were available for final analysis. RESULTS: Fifty-three percent (190/357) of the authors with working email addresses responded to our request. Clinical researchers were more likely to reply than basic/translational scientists (51% [114/225] versus 34% [76/221]; p<0.001). Impact factor and other author characteristics did not differ. Logistic regression analysis showed that the odds of replying decreased by 15% per year (odds ratio [OR], 0.85; 95% CI, 0.79-0.91; p<0.001), and showed a positive relationship between clinical research and response (OR, 2.0; 95% CI, 1.3-2.9; p=0.001). In 2013 all email addresses (45/45) were reachable, but within 10 years, 49% (21/43) had become invalid. CONCLUSIONS: Our results suggest that contacting corresponding authors is problematic throughout the field of biomedical research. Defining the responsibilities of corresponding authors by journals more explicitly-particularly after publication of their manuscript-may increase the response rate on data requests. Possible other ways to improve communication after research publication are: (1) listing more than one email address per corresponding author, eg, an institutional and personal address; (2) specifying all authors' email addresses; (3) when an author leaves an institution, send an automated reply offering alternative ways to get in touch; and (4) linking published manuscripts to research platforms.

Incidence of surgical site infection after spine surgery: what is the impact of the definition of infection?

BACKGROUND: Orthopaedic surgical site infections (SSIs) can delay recovery, add impairments, and decrease quality of life, particularly in patients undergoing spine surgery, in whom SSIs may also be more common. Efforts to prevent and treat SSIs of the spine rely on the identification and registration of these adverse events in large databases. The effective use of these databases to answer clinical questions depends on how the conditions in question, such as infection, are defined in the databases queried, but the degree to which different definitions of infection might cause different risk factors to be identified by those databases has not been evaluated. QUESTIONS/PURPOSES: The purpose of this study was to determine whether different definitions of SSI identify different risk factors for SSI. Specifically, we compared the International Classification of Diseases, 9th Revision (ICD-9) coding, Centers for Disease Control and Prevention (CDC) criteria for deep infection, and incision and débridement for infection to determine if each is associated with distinct risk factors for SSI. METHODS: In this single-center retrospective study, a sample of 5761 adult patients who had an orthopaedic spine surgery between January 2003 and August 2013 were identified from our institutional database. The mean age of the patients was 56 years (± 16 SD), and slightly more than half were men. We applied three different definitions of infection: ICD-9 code for SSI, the CDC criteria for deep infection, and incision and débridement for infection. Three hundred sixty-one (6%) of the 5761 surgeries received an ICD-9 code for SSI within 90 days of surgery. After review of the medical records of these 361 patients, 216 (4%) met the CDC criteria for deep SSI, and 189 (3%) were taken to the operating room for irrigation and débridement within 180 days of the day of surgery. RESULTS: We found the Charlson Comorbidity Index, the duration of the operation, obesity, and posterior surgical approach were independently associated with a higher risk of infection for each of the three definitions of SSI. The influence of malnutrition, smoking, specific procedures, and specific surgeons varied by definition of infection. These elements accounted for approximately 6% of the variability in the risk of developing an infection. CONCLUSIONS: The frequency of SSI after spine surgery varied according to the definition of an infection, but the most important risk factors did not. We conclude that large database studies may be better suited for identifying risk factors than for determining absolute numbers of infections. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

The PROMIS physical function correlates with the QuickDASH in patients with upper extremity illness.

BACKGROUND: To assess disability more efficiently with less burden on the patient, the National Institutes of Health has developed the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function-an instrument based on item response theory and using computer adaptive testing (CAT). Initially, upper and lower extremity disabilities were not separated and we were curious if the PROMIS Physical Function CAT could measure upper extremity disability and the Quick Disability of Arm, Shoulder and Hand (QuickDASH). QUESTIONS/PURPOSES: We aimed to find correlation between the PROMIS Physical Function and the QuickDASH questionnaires in patients with upper extremity illness. Secondarily, we addressed whether the PROMIS Physical Function and QuickDASH correlate with the PROMIS Depression CAT and PROMIS Pain Interference CAT instruments. Finally, we assessed factors associated with QuickDASH and PROMIS Physical Function in multivariable analysis. METHODS: A cohort of 93 outpatients with upper extremity illnesses completed the QuickDASH and three PROMIS CAT questionnaires: Physical Function, Pain Interference, and Depression. Pain intensity was measured with an 11-point ordinal measure (0-10 numeric rating scale). Correlation between PROMIS Physical Function and the QuickDASH was assessed. Factors that correlated with the PROMIS Physical Function and QuickDASH were assessed in multivariable regression analysis after initial bivariate analysis. RESULTS: There was a moderate correlation between the PROMIS Physical Function and the QuickDASH questionnaire (r=-0.55, p<0.001). Greater disability as measured with the PROMIS and QuickDASH correlated most strongly with PROMIS Depression (r=-0.35, p<0.001 and r=0.34, p<0.001 respectively) and Pain Interference (r=-0.51, p<0.001 and r=0.74, p<0.001 respectively). The factors accounting for the variability in PROMIS scores are comparable to those for the QuickDASH except that the PROMIS Physical Function is influenced by other pain conditions while the QuickDASH is not. CONCLUSIONS: The PROMIS Physical Function instrument may be used as an upper extremity disability measure, as it correlates with the QuickDASH questionnaire, and both instruments are influenced most strongly by the degree to which pain interferes with achieving goals. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Instructions for Authors for a complete description of levels of evidence.

Patients with greater symptom intensity and more disability are more likely to be surprised by a hand surgeon's advice.

BACKGROUND: A clash between a patient's assumptions and a doctor's advice can feel adversarial which might influence satisfaction ratings and compliance with treatment recommendations. A better understanding of sources of patients' bewilderment might lead to improved strategies for conveying counterintuitive information that improve patient comfort and wellbeing. QUESTIONS/PURPOSES: This study addressed the following questions: (1) Are magnitude of disability, pain intensity, symptoms of depression, or health anxiety associated with a higher level of surprise when a patient is presented with diagnostic information and/or therapeutic recommendations? (2) Does the surgeon accurately perceive the patient's bewilderment? (3) Does the surgeon's perception of patient bewilderment correlate with diagnosis or a patient's magnitude of disability, pain intensity, symptoms of depression, or health anxiety? PATIENTS AND METHODS: In this prospective cohort study, we invited new patients who met prespecified criteria during a 3-month period in one hand-surgery practice to enroll; of 93 patients invited, 84 (90%) agreed to participate. Patients reported demographics and completed the short versions of the DASH questionnaire (QuickDASH), the Patient Health Questionnaire, the Pain Self-Efficacy Questionnaire, and the Short Health Anxiety Inventory; rated their pain intensity; and rated the degree to which the information given by the surgeon was unexpected or surprising on an 11-point ordinal scale. The surgeon also rated his impression of the patient's surprise on an 11-point ordinal scale. RESULTS: Only greater symptom intensity and magnitude of disability (QuickDASH) correlated with greater unexpected information when rated by the patient (ß = 0.058; p < 0.001). There was a correlation between patient surprise and the surgeon's perception of the patient's surprise (r = 0.58; p < 0.001). Greater surgeon-perceived patient surprise correlated with nonspecific illness (p = 0.007; ß = 3.0). CONCLUSIONS: Patients with greater symptom intensity and magnitude of disability, and perhaps also patients with nonspecific diagnoses, are more likely to be surprised by a hand surgeon's advice. Future research might address the ability of previsit preparation (using decision aids or other alternative means of education) to ameliorate the discordance between patient assumptions and hand surgeon advice.

The creation of an abbreviated version of the PSEQ: the PSEQ-2.

BACKGROUND: Self-efficacy is an effective coping strategy associated with less pain and disability. The Pain Self-Efficacy Questionnaire (PSEQ) is a valid and reliable tool to measure this strategy, but could be inconvenient to implement in a busy surgical practice owing to its length. OBJECTIVE: The purpose of this study was to develop a shorter version of the 10-item PSEQ. METHODS: A total of 316 patients (53% men, mean age of 46 y) with a variety of upper extremity diagnosis were enrolled in this study. In addition to demographic information, patients completed the PSEQ measure of self-efficacy, the QuickDASH measure of disability, and an ordinal measure of pain intensity. We conducted inter-item correlation analyses for the PSEQ and selected questions based on the magnitude of their correlation. RESULTS: Questions 8 and 9 were selected to form the PSEQ-2. The PSEQ-2 showed good internal consistency (α = 0.90) and had a large correlation with the original PSEQ (r = 0.76). Both the PSEQ-2 and the original PSEQ correlated significantly with QuickDASH and pain intensity. CONCLUSIONS: This study provides preliminary evidence that a shortened version of the PSEQ might be useful as a screening instrument to identify patients with hand and upper extremity conditions who have low self-efficacy and might benefit from cognitive behavioral therapy. LEVEL OF EVIDENCE: Diagnostic level III.

Outcome after reconstruction of the proximal humerus for tumor resection: a systematic review.

BACKGROUND: Tumors of the appendicular skeleton commonly affect the proximal humerus, but there is no consensus regarding the best reconstructive technique after proximal humerus resection for tumors of the shoulder. QUESTIONS/PURPOSES: We wished to perform a systematic review to determine which surgical reconstruction offers the (1) best functional outcome as measured by the Musculoskeletal Tumor Society (MSTS) score, (2) longest construct survival, and (3) lowest complication rate after proximal humerus resection for malignant or aggressive benign tumors of the shoulder. METHODS: We searched the literature up to June 1, 2013, from MEDLINE, EMBASE, and the Cochrane Library. Only studies reporting results in English, Dutch, or German and with followups of 80% or more of the patients at a minimum of 2 years were included. Twenty-nine studies with 693 patients met our criteria, seven studies (24%) were level of evidence III and the remainder were level IV. Studies reported on reconstruction with prostheses (n = 17), osteoarticular allografts (n = 10), and allograft-prosthesis composites (n = 11). Owing to substantial heterogeneity and bias, we narratively report our results. RESULTS: Functional scores in prosthesis studies ranged from 61% to 77% (10 studies, 141 patients), from 50% to 78% (eight studies, 84 patients) in osteoarticular graft studies, and from 57% to 91% (10 studies, 141 patients) in allograft-prosthesis composite studies. Implant survival ranged from 0.38 to 1.0 in the prosthesis group (341 patients), 0.33 to 1.0 in the osteoarticular allograft group (143 patients), and 0.33 to 1.0 in allograft-prosthesis group (132 patients). Overall complications per patient varied between 0.045 and 0.85 in the prosthesis group, 0 and 1.5 in the osteoarticular graft group, and 0.19 and 0.79 in the prosthesis-composite graft group. We observed a higher fracture rate for osteoarticular allografts, but other specific complication rates were similar. CONCLUSIONS: Owing to the limitations of our systematic review, we found that allograft-prosthesis composites and prostheses seem to have similar functional outcome and survival rates, and both seem to avoid fractures that are observed with osteoarticular allografts. Further collaboration in the field of surgical oncology, using randomized controlled trials, is required to establish the superiority of any particular treatment.

Measurement of upper extremity disability using the Patient-Reported Outcomes Measurement Information System.

PURPOSE: Current questionnaires used to measure upper extremity-specific disability can be time-consuming and subject to ceiling effects. The National Institutes of Health developed Patient-Reported Outcomes Measurement Information System (PROMIS) measures based on computer adaptive testing (CAT), a technique that is more efficient and less subject to floor and ceiling effects than traditional questionnaires with a fixed number of questions. This study tested the correlation of the Physical Function-Upper Extremity CAT with the Quick-Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. METHODS: Patients presenting to our orthopedic outpatient clinic were invited to participate in this observational cross-sectional study between August and October 2013. A study sample of 84 patients completed the QuickDASH and PROMIS Physical Function-Upper Extremity CAT, and 3 other PROMIS measures, as well as the 2-question Pain Self-efficacy Questionnaire and the 2-question Patient Health Questionnaire. RESULTS: A strong correlation was found between QuickDASH and PROMIS Physical Function-Upper Extremity CAT, with a significantly shorter completion time for the latter. CONCLUSIONS: We recommend the PROMIS Upper Extremity CAT because it is valid, reliable, and easy to use, and it provides easy reference to population norms (a score of 50 represents the norm in the United States population, and every 10 points represents a standard deviation from the norm). TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic I.

Chondroitin sulfate proteoglycan 4 expression in chondrosarcoma: A potential target for antibody-based immunotherapy.

Chondrosarcoma is a common primary bone malignancy whose phenotype increases with its histologic grade. They are relatively resistant to chemotherapy and radiation therapy limiting curative options for disseminated disease. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is highly expressed across various human cancers, including chondrosarcoma, and has restricted distribution in healthy tissues, making it an attractive target for the antibody-based therapy. CSPG4 specific chimeric antigen receptor (CAR) T cell therapies have been shown to be effective in treating other cancers such as melanoma and triple negative breast cancer. The goal of this study was to assess the prevalence of CSPG4 in human chondrosarcoma and to assess the efficacy of CSPG4 specific CAR T cells in lysing chondrosarcoma cells in vitro. Using immunohistochemistry (IHC), we stained a tissue microarray containing primary conventional and dedifferentiated chondrosarcoma from 76 patients with CSPG4 specific monoclonal antibodies (mAbs). In addition, we incubated 2 chondrosarcoma cell lines with CSPG4-targeting CAR T cells and subsequently evaluated cell survival. Our results showed medium to high expression of CSPG4 in 29 of 41 (71%) conventional chondrosarcoma tumors and in 3 of 20 (15%) dedifferentiated chondrosarcoma tumors. CSPG4 expression showed a positive association with time to metastasis and survival in both subtypes. CSPG4 CAR T treated cell lines showed a lysis of respectively >80% and 70% demonstrating CSPG4-targeted CAR T cells effective in killing CSPG4-positive chondrosarcoma tumors.

High TIL, HLA, and Immune Checkpoint Expression in Conventional High-Grade and Dedifferentiated Chondrosarcoma and Poor Clinical Course of the Disease.

PURPOSE: The aim of this study was to characterize chondrosarcoma tumor infiltration by immune cells and the expression of immunologically relevant molecules. This information may contribute to our understanding of the role of immunological events in the pathogenesis of chondrosarcoma and to the rational design of immunotherapeutic strategies. PATIENTS AND METHODS: A tissue microarray (TMA) containing 52 conventional and 24 dedifferentiated chondrosarcoma specimens was analyzed by immunohistochemical staining for the expression of parameters associated with tumor antigen-specific immune responses, namely, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) and the expression of HLA class I heavy chain, beta-2 microglobulin (ß2m), HLA class II and immune checkpoint molecules, B7-H3 and PD-1/PD-L1. The results were correlated with histopathological characteristics and the clinical course of the disease. RESULTS: CD8+ TILs were present in 21% of the conventional and 90% of the dedifferentiated chondrosarcoma tumors tested. B7-H3 was expressed in 69% of the conventional and 96% of the dedifferentiated chondrosarcoma tumors tested. PD-1 and PD-L1 were expressed 53% and 33% respectively of the dedifferentiated tumors tested. PD-L1 expression was associated with shorter time to metastasis. CONCLUSION: The tumor infiltration by lymphocytes suggests that chondrosarcoma is immunogenic. Defects in HLA class I antigen and expression of the checkpoint molecules B7-H3 and PD-1/PD-L1 suggest that tumor cells utilize escape mechanisms to avoid immune recognition and destruction. This data implies that chondrosarcoma will benefit from strategies that enhance the immunogenicity of tumor antigens and/or counteract the escape mechanisms.

Progression of Heterotopic Ossification around the Elbow after Trauma.

BACKGROUND: This study addresses the null hypothesis that there is no expansion of heterotopic ossification (HO) in the elbow beyond what can be seen early on. METHODS: The area of HO was measured on lateral radiographs of 38 consecutive patients that had operative treatment of HO between 2000 and 2013. Measurements from radiographs obtained between 3 to 7 weeks were compared to measurements from radiographs made 3 months or more after injury. RESULTS: There was no significant difference between the average area of HO on the first (median 2.8 square centimeters, Q1: 1.5, Q3: 5.1) and later radiographs (median of 2.8 square centimeters, Q1: 1.4, Q3: 5.0) (P = 0.99). CONCLUSION: According to our results the area of HO does not expand beyond what can be seen early in the disease process.

The Association of Complementary Health Approaches With Mood and Coping Strategies Among Orthopedic Patients.

Background: Variation in pain intensity and magnitude of disability among patients with musculoskeletal illness is largely accounted for by variations in symptoms of depression, catastrophic thinking, and heightened illness concern. It is possible that patients with greater stress, distress, and less effective coping strategies might be more likely to seek the use of Complementary Health Approaches (CHA). This study addressed the primary null hypothesis that there are no demographic, illness-related, or psychological factors associated with CHA use among patients with upper extremity illness. Methods: A cohort of 170 patients completed a web-based Complementary and Alternative Medicine (CAM) questionnaire the Patient Reported Outcomes Measurement Information System (PROMIS) Depression and Pain Interference questionnaires. We evaluated differences between patients who sought CAM treatment regarding the PROMIS Pain Interference and PROMIS Depression scores. Ninety-four patients (56%) use or plan to use CAM treatment. A CAM provider was consulted by 61 patients (37%): most commonly a massage therapist (30/61), chiropractor (26/61), or acupuncturist (14/61). Results: In bivariate analysis patients who sought CAM reported greater average PROMIS Pain Interference than those who did not. In multivariable logistic regression, CAM use was associated with a higher Pain Interference Score and the specific surgeon. Conclusion: In conclusion, CHA use is prevalent amongst orthopaedic patients and associated with less effective coping strategies. Orthopaedic surgeons might consider asking patients about CHA use and determining whether those patients are interested in cognitive behavioral therapy.

Finger Stiffness.

Background Finger stiffness varies substantially in patients with hand and upper extremity illness and can be notably more than expected for a given pathophysiology. In prior studies, pain intensity and magnitude of disability consistently correlate with coping strategies such as catastrophic thinking and kinesiophobia, which can be characterized as overprotectiveness. In this retrospective study we address the primary research question whether patients with finger stiffness are more often overprotective when the primary pathology is outside the hand (e.g. distal radius fracture) than when it is located within the hand. Methods In an orthopaedic hand surgery department 160 patients diagnosed with more finger stiffness than expected for a given pathophysiology or time point of recovery between December 2006 and September 2012 were analyzed to compare the proportion of patients characterized as overprotective for differences by site of pathology: (1) inside the hand, (2) outside the hand, and (3) psychiatric etiology (e.g. clenched fist). Results Among 160 subjects with more finger stiffness than expected, 132 (82 %) were characterized as overprotective including 88 of 108 (81 %) with pathology in the hand, 39 of 44 (89 %) with pathology outside the hand, and 5 of 8 (63 %) with psychiatric etiology. These differences were not significant. Conclusions Overprotectiveness is common in patients with more finger stiffness than expected regardless the site and type of primary pathology. It seems worthwhile to recognize and treat maladaptive coping strategies early during recovery to limit impairment, symptoms, and disability.

No Difference in Adverse Events Between Surgically Treated Reduced and Unreduced Distal Radius Fractures.

OBJECTIVES: To determine if closed reduction is worthwhile for the subset of patients who choose operative treatment before attempted reduction of their distal radius fracture. We hypothesize that there are no differences in (1) adverse events and (2) subsequent surgeries between patients treated with manipulative reduction compared with those that were splinted without reduction. DESIGN: Retrospective cohort study. SETTING: Three affiliated urban hospitals in a single city in the United States. PATIENTS/PARTICIPANTS: One thousand five hundred eleven consecutive adult patients who underwent open reduction and internal fixation of their distal radius fracture between January 1, 2007, and December 31, 2012, of whom 102 (7%) were not reduced before surgery. INTERVENTION: Manipulative reduction compared with splinting without reduction. MAIN OUTCOME MEASUREMENTS: Adverse events were defined as any infections, hematomas treated operatively, disproportionate finger stiffness, (transient) neuropathology after surgery, delayed carpal tunnel release, malunion, reoperation for loss of alignment, hardware removal, and tendon ruptures within 1 year after surgery. Outcome measures were grouped to determine the overall adverse event rate and subsequent surgery rate. RESULTS: We found no difference in specific adverse events between unreduced and reduced fractures. After adjusting for possible confounding variables by logistic regression, we found no difference in overall rates of adverse events (adjusted odds ratio unreduced fractures 1.2, 95% confidence interval 0.67-2.0) and subsequent surgeries (adjusted odds ratio unreduced fractures 0.65, 95% confidence interval 0.23-1.8). CONCLUSIONS: Leaving the fracture unreduced before surgery was not associated with increased adverse events or subsequent surgeries. For patients who make an informed decision to undergo operative treatment for their closed neurovascular intact displaced distal radius fracture, manipulative reduction may not be helpful.

Disability and depression after orthopaedic trauma.

INTRODUCTION: Musculoskeletal injury is a common cause of impairment (pathophysiology), but the correlation of impairment with pain intensity and magnitude of disability is limited. Psychosocial factors explain a large proportion of the variance in disability for various orthopaedic pathologies. The aim of this study is to prospectively assess the relationship between psychological factors and magnitude of disability in a sample of orthopaedic trauma patients in The Netherlands. MATERIAL AND METHODS: One hundred and one adult patients between 1 and 2 months after one or more fractures, tendon or ligament injuries were enrolled. Four eligible patients refused to participate. Thirty-five women and 30 men with an average age of 50 years (range, 22-92 years) completed the follow-up evaluation between 5 and 8 months after their injury and their data was analyzed. The patients completed a measure of disability (the Short Musculoskeletal Function Assessment-Netherlands, SMFA-NL), the Dutch Centre for Epidemiologic Study of Depression-scale (CES-D), the Dutch Impact of Event Scale (SVL), and the Dutch Pain Catastrophizing Scale (PCS) at the time of enrollment and again 5-8 months after injury. RESULTS: There were moderate correlations between symptoms of depression (CES-D, r=0.48, p<0.001) and symptoms of PTSD (SVL, r=0.35, p=0.004) at enrollment and magnitude of disability 5-8 months after trauma. Catastrophic thinking (PCS) at enrollment and magnitude of disability 5-8 months after trauma showed a small correlation (PCS, r=0.26, p=0.034). The Pain Catastrophizing Scale (Beta=0.29; p=0.049), surgery (Beta=0.26; p=0.034), additional surgery (Beta=0.26; p=0.019) and other pain conditions (Beta=0.31; p=0.009) were the significant predictors in the final model (adjusted R-squared=0.35; p<0.001) for greater disability 5-8 months after trauma. DISCUSSION AND CONCLUSIONS: In The Netherlands, symptoms of depression measured 1-2 months after musculoskeletal trauma correlate with disability 5-8 months after this trauma. The psychological aspects of recovery from musculoskeletal injury merit greater attention. LEVEL OF EVIDENCE: Level II, Prognostic study.

The Identification of Prognostic Factors and Survival Statistics of Conventional Central Chondrosarcoma.

Introduction. Chondrosarcomas are malignant bone tumors that are characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effect on chondrosarcoma, treatment of most patients depends on surgical resection. We conducted this study to identify independent predictive factors and survival characteristics for conventional central chondrosarcoma and dedifferentiated central chondrosarcoma. Methods. A systematic literature review was performed in September 2014 using the Pubmed, Embase, and Cochrane databases. Subsequent to a beforehand-composed selection procedure we included 13 studies, comprising a total of 1114 patients. Results. The prognosis of central chondrosarcoma is generally good for the histologically low-grade tumors. Prognosis for the high-grade chondrosarcoma and the dedifferentiated chondrosarcoma is poor with lower survival rates. Poor prognostic factors in conventional chondrosarcoma for overall survival are high-grade tumors and axial/pelvic tumor location. In dedifferentiated chondrosarcoma the percentage of dedifferentiated component has significant influence on disease-free survival. Conclusion. Despite the fact that there are multiple prognostic factors identified, as shown in this study, there is a need for prospective and comparative studies. The resulting knowledge about prognostic factors and survival can give direction in the development of better therapies. This could eventually lead to an evidence-based foundation for treating chondrosarcoma patients.