Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone.

BACKGROUND: Giant cell lesions are locally aggressive intraosseous neoplasms with capacity to metastasize. The role of immune surveillance in the pathophysiology of giant cell lesions is poorly understood, and understanding what role the immune system plays in giant cell lesions may lead to the development of more effective treatment. The aim of this study was to explore the role of immune surveillance in giant cell lesions by examining the expression of the HLA class I and class II antigens and tumor infiltrating lymphocytes. In addition, we examined the role of the immune modulating surface antigen B7-H3, which belongs to the B7 superfamily, a group of molecules that modulates T-cell responses. QUESTIONS/PURPOSES: (1) Is an immune response elicited by giant cell lesions? (2) Do clinically relevant human leukocyte antigen (HLA) defects exist in giant cell lesions? (3) Is B7-H3 a clinically relevant immune modulator? METHODS: The study sample was derived from the population of patients presenting to the Massachusetts General Hospital for evaluation and management of giant cell lesions from 1993 to 2008. We included patients with histologically confirmed giant cell lesions with a minimum followup of 6 months. Patients with systemic diseases (n = 4 [3%]), syndromes associated with giant cell lesions (n = 4 [3%]), and those without sufficient followup (n = 26 [19%]), inadequate records (n = 7 [5%]), or inadequate tissue available (n = 2 [1%]) were excluded. Tissue microarray, containing 288 tissue cores for 93 patients, was carefully constructed. This contained tissue from 45 patients with maxillofacial lesions, 38 with aggressive and seven with nonaggressive lesions, and 48 patients with axial and appendicular lesions, 30 with aggressive lesions and 18 with nonaggressive lesions. The population mean age was 28 ± 12 years and the duration of followup was 4 ± 3 years. The tissue microarray was immunohistochemically stained with monoclonal antibodies specific for HLA classes I and II and B7-H3 antigens and analyzed for tumor infiltrating lymphocytes. Antigen expression was examined in multinucleated giant cells and mononuclear stromal cells. The results were correlated with local invasion and tumor aggressiveness, which is based on accepted staging criteria. RESULTS: Tumor infiltrating lymphocytes were detected in all the tumors. The mean number of CD8+ T cell infiltration was lower in aggressive tumors (median, 4.8; interquartile range [IQR], 0.4-13.4), when compared with nonaggressive tumors (median, 15.8; IQR, 4.3-46.3; p = 0.007). HLA class I antigens were highly expressed by multinucleated giant cells in all tumors, but were lightly expressed on mononuclear stromal cells in 53% (45 of 84) to 73% (56 of 77) of tumors. HLA class I antigen low expression in mononuclear stromal cells was associated with tumor aggressiveness (odds ratio [OR], 4.3; p = 0.005). Low HLA class I expression combined with low CD8+ T cell infiltration was most highly associated with tumor aggressiveness (OR, 7.81; p = 0.011). B7-H3 antigen was expressed in 36.9% mononuclear stroma cells and also was associated with local tumor invasion (OR, 1.36; p < 0.001). Similarly, giant cell lesions with high B7-H3 expression and low CD8+ tumor infiltrating lymphocytes were associated with increased tumor aggressiveness (OR, 8.89; p = 0.0491). CONCLUSIONS: Locally aggressive giant cell lesions are associated with low HLA class 1 antigen expression, low CD8+T cell infiltration, and high expression of the immune modulator B7-H3. CLINICAL RELEVANCE: Failure of immune surveillance implies that there may be an opportunity to target aspects of the immune surveillance machinery to treat giant cell lesions.

Evaluation of first ray instability using the double dorsiflexion test: A prospective observational case-controlled study.

BACKGROUND: First-Ray (FR) stability allows for foot propulsion in-stance, taking 60% weight. First-ray instability (FRI) is associated with middle column overload, synovitis, deformity and osteoarthritis. Clinical detection can still be challenging. We propose to develop a clinical test that helps identify FRI using two simple manual manoeuvres. METHODS: 10 patients with unilateral FRI were recruited. Unaffected contralateral feet were used as controls. Stringent exclusion criteria were applied including hallux MTP pain, laxity, inflammatory arthropathy and collagen disorders. A Klauemeter directly measured the sagittal plane dorsal first metatarsal head translation of affected vs unaffected feet. Maximum passive proximal phalanx 1st MTP joint dorsiflexion was measured using a video capture and Tracker motion software analysis with and without applying a dorsal force at the 1st metatarsal head using a Newton meter. Proximal phalanx motion was compared in affected vs unaffected feet with and without dorsal metatarsal head force application and compared to direct measurements using the Klaumeter. P value of < 0.05 was considered significant. RESULTS: FRI feet had dorsal translation greater than 8 mm (median, 11.94; interquartile range [IQR], 10.23-13.81) vs 1.77 for unaffected control feet was (median, 1.77; interquartile range [IQR], 1.23-2.96) using the Klauemeter. The percentage reduction in 1st MTP joint dorsiflexion ROM when applying the double dorsiflexion test FRI (mean reduction of 67.98%) when compared to control feet (mean reduction of 28.44%)(P < 0.01). Receiver operating characteristic (ROC) analysis showed that a 50% reduction in dorsiflexion ROM of 1st MTPJ when performing the double dorsiflexion test achieved a specificity of 100% and sensitivity of 90% (AUC =0.990, 95%CI [0.958-1.000], P > 0.0001). CONCLUSION: The double dorsiflexion (DDF) is easy to perform with two relatively simple manual manoeuvres that avoids the need for complex instrumented and radiation-based assessment. Greater than 50% decrease in proximal phalanx motion has an over 90% sensitivity in identifying feet with FRI. LEVEL OF EVIDENCE: This was a prospective case-controlled study of consecutive cases of a level II evidence.

Quantifying increased lateral column instability in Adult Acquired Flatfoot Deformity (AAFD).

AAFD comprises ligamentous failure and tendon overload, mainly focused on the symptomatic posterior tibial tendon and the spring ligament. Increased lateral column (LC) instability arising in AAFD is not defined or quantified. This study aims to quantify the increased LC motion in unilateral symptomatic planus feet, using the contralateral unaffected asymptomatic foot as an internal control. In this case matched analysis, 15 patients with unilateral stage 2 AAFD foot and an unaffected contralateral foot were included. Lateral foot translation was measured as a guide to spring ligament competency. Medial and LC dorsal sagittal instability were assessed by direct measurement of dorsal 1st and 4th/5th metatarsal head motion and further video analysis. The mean increase in dorsal LC sagittal motion (between affected vs unaffected foot) was 5.6 mm (95% CI [4.63-6.55], p < 0.001). The mean increase in the lateral translation score was 42.8 mm (95% CI [37.48-48.03], p < 0.001). The mean increase in medial column dorsal sagittal motion was 6.8 mm (95% CI [5.7-7.8], p < 0.001). Video analysis also showed a statistically significant increase in LC dorsal sagittal motion between affected and unaffected sides (p < 0.001). This is the first study that quantifies a statistically significant increased LC dorsal motion in feet with AAFD. Understanding its pathogenesis and its link to talonavicular/spring ligament laxity improves foot assessment and may allow the development of future preventative treatment strategies.

Spring ligament insufficiency and hallux valgus as an independent risk factors for first ray instability.

INTRODUCTION: First ray instability (FRI) arising from failed plantar/interosseous ligaments is strongly associated with planovalgus, leading to synovitis and deformity. Our hypothesis is that proximal spring ligament insufficiency (SLI) drives secondary FRI in the absence of hallux valgus (HV) and may be an independent risk factor. METHODS: Patients with FRI, screened by Klaue's test, were recruited. Patients' normal contralateral feet with previous radiographs were included as controls. First ray dorsal translation was measured with a digital Klauemeter. Spring ligament integrity was assessed using lateral translation distance as an indirect measure of spring ligament strain. Intermetatarsal angle and hallux valgus angle were recorded to classify the severity of HV. RESULTS: Seventy feet included, 54 had symptomatic FRI and 16 were asymptomatic contralateral feet included as control. Twenty-three feet had moderate/severe HV and 47 had mild/normal HV. Moderate/severe HV was associated with FRI (OR, 10.31; p = 0.029). Forty-five feet with SLI had a strong association with FRI (OR, 100.7; p < 0.0001). SLI without moderate/severe HV was the most prevalent group (31/54), followed by SLI with moderate/severe HV, 29.63% (16/54). Moderate/severe HV without SLI was prevalent in 11.1% (6/54) and 1.85% (1/54) had no SLI or moderate/severe HV. In a multivariate logistic regression analysis model, both SLI and severe/moderate HV were independent predictors of FRI. CONCLUSION: This is the first study that links SLI and HV as independent risk factors to FRI. 98.15% of FRI can be attributed to SLI, HV or both. First ray instability may allude to the strong presence of spring ligament insufficiency in the absence of hallux valgus. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

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.

Idiopathic tumoral calcinosis-like lesion in the lower cervical spine causing acute central cord syndrome: case report.

A 57-year-old male presented with recurrent falls, bilateral lower-limb paresthesia, and severe neck pain. Imaging revealed a mass compressing his spinal cord. He was admitted for further workup for spinal cord compression. Within 24 hours of admission, he developed upper-extremity weakness while maintaining lower-extremity function. He underwent urgent decompression of his spinal cord. During exposure, a white, creamy odorless substance was noted. This same substance was found under pressure within the spinal canal. The mass was grossly removed, and the patient's weakness improved postoperatively. Based on the clinical picture, intraoperative presentation, and final histological examination, idiopathic tumoral calcinosis-like lesion was considered as the most appropriate diagnosis.

PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma.

PURPOSE: More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells. EXPERIMENTAL DESIGN: Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated. RESULTS: Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8(+) T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. CONCLUSIONS: ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression.