Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.

PURPOSE OF REVIEW: The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS: Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Loss of Stag2 cooperates with EWS-FLI1 to transform murine Mesenchymal stem cells.

BACKGROUND: Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin. It is probable that genetic perturbations other than EWS-FLI1 cooperate with it to produce the tumor. Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans. In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs). METHODS: Mice bearing an inducible EWS-FLI1 transgene were crossed to p53-/- mice in pure C57/Bl6 background. MSCs were derived from the bone marrow of the mice. EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively. The cells were then treated with ionizing radiation to 10 Gy. Anchorage independent growth in vitro was assessed by soft agar assays. Cellular migration and invasion were evaluated by transwell assays. Cells were injected with Matrigel intramuscularly into C57/Bl6 mice to test for tumor formation. RESULTS: Primary murine MSCs with the genotype EWS-FLI1 p53-/- were resistant to transformation and did not form tumors in syngeneic mice without irradiation. Stag2 inhibition increased the efficiency and speed of sarcoma formation significantly in irradiated EWS-FLI1 p53-/- MSCs. The efficiency of tumor formation was 91% for cells in mice injected with Stag2-repressed cells and 22% for mice receiving cells without Stag2 inhibition (p < .001). Stag2 knockdown reduced survival of mice in Kaplan-Meier analysis (p < .001). It also increased MSC migration and invasion in vitro but did not affect proliferation rate or aneuploidy. CONCLUSION: Loss of Stag2 has a synergistic effect with EWS-FLI1 in the production of sarcomas from murine MSCs, but the mechanism may not relate to increased proliferation or chromosomal instability. Primary murine MSCs are resistant to transformation, and the combination of p53 null mutation, EWS-FLI1, and Stag2 inhibition does not confer immediate conversion of MSCs to sarcomas. Irradiation is necessary in this model, suggesting that perturbations of other genes beside Stag2 and p53 are likely to be essential in the development of EWS-FLI1-driven sarcomas from MSCs.

Synovial Sarcoma: A Complex Disease with Multifaceted Signaling and Epigenetic Landscapes.

PURPOSE OF REVIEW: Aside from a characteristic SS18-SSX translocation identified in almost all cases, no genetic anomalies have been reliably isolated yet to drive the pathogenesis of synovial sarcoma. In the following review, we explore the structural units of wild-type SS18 and SSX, particularly as they relate to the transcriptional alterations and cellular pathway changes imposed by SS18-SSX. RECENT FINDINGS: Native SS18 and SSX contribute recognizable domains to the SS18-SSX chimeric proteins, which inflict transcriptional and epigenetic changes through selective protein interactions involving the SWI/SNF and Polycomb chromatin remodeling complexes. Multiple oncogenic and developmental pathways become altered, collectively reprogramming the cellular origin of synovial sarcoma and promoting its malignant transformation. Synovial sarcoma is characterized by complex epigenetic and signaling landscapes. Identifying the operational pathways and concomitant genetic changes induced by SS18-SSX fusions could help develop tailored therapeutic strategies to ultimately improve disease control and patient survivorship.

Cortical suture button fixation vs. bicortical screw fixation in the Latarjet procedure: a biomechanical comparison.

BACKGROUND: The Latarjet procedure traditionally has been performed with 2 screws in an open manner. Recently, cortical suture button fixation for coracoid transfer has been used in hopes of mitigating complications seen with screw placement. The aim of this study was to evaluate a cortical suture button and technique currently available in the United States compared with screw fixation in the Latarjet procedure in a cadaveric model. METHODS: We randomly assigned 9 matched pairs of fresh-frozen cadaveric shoulders (N = 18) to undergo the Latarjet procedure with either screw fixation or cortical suture button fixation. After fixation, all shoulders underwent biomechanical testing with direct loading on the graft vas a material testing system. Cyclic testing was performed for 100 cycles to determine axial displacement with time; each graft was then monotonically loaded to failure. RESULTS: The maximum cycle displacement was significantly less for screw fixation vs. cortical suture button fixation (3.1 ± 1.3 mm vs. 8.9 ± 2.1 mm, P < .0001). The total load at failure was 481.1 ± 88.8 N for screws and 175.5 ± 95.8 N for cortical suture buttons (P < .0001). Bony damage to the surrounding anatomy was more extensive at failure in the screw-fixation group. CONCLUSION: At time zero, the cortical button fixation and technique did not resist direct loads to the graft as much as traditional screw fixation, although bony damage to the surrounding anatomy was more extensive in screw fixation than button fixation. In the event of unanticipated loading, this could place a patient at higher risk of graft migration, which could lead to unintended early outcomes. These results support the need for implants and techniques specifically tailored to the Latarjet procedure and should bring into question the adoption of a cortical button and technique not specific to the procedure.

Do Early Results of Proximal Humeral Allograft-Prosthetic Composite Reconstructions Persist at 5-year Followup?

BACKGROUND: Insufficiency of the rotator cuff is a major problem after resections of proximal humeral tumors and can limit shoulder motion despite preservation of the deltoid muscle and axillary nerve. Allograft-prosthetic composite reconstruction offers one method to reattach the rotator cuff tendons and has been successful in small studies with short followup. However, data are lacking with regard to implant durability, changes in Musculoskeletal Tumor Society (MSTS) scores over time, and delayed complications with extended followup. QUESTIONS/PURPOSES: (1) What is the cumulative incidence of allograft-prosthetic composite revision surgery 5 years after the procedure? (2) What are the early- and intermediate-term MSTS scores of allograft-prosthetic composite reconstruction of the shoulder? (3) What are the complications of allograft-prosthetic composite reconstruction? METHODS: Twenty-one patients underwent allograft-prosthetic composite reconstruction after tumor resection of the proximal humerus between 2000 and 2015. Six patients who were lost to followup were not included. All patients had malignant or aggressive benign tumors that could be treated with a wide intraarticular approach preserving the deltoid muscle, axillary nerve, and glenoid. Cumulative incidence of implant revision was calculated with death of the patient as a competing risk. Minimum followup was 24 months (with the exception of one patient who died at 22 months), and median followup was 97 months (range, 20-198 months). The upper extremity MSTS score was used to assess function. Various complications were identified from radiographs and charts. RESULTS: The cumulative risk of implant revision was 10.1% at 5 years (95% confidence interval [CI], 1.6%-28.0%). Mean MSTS scores were 86% (± SD 9%) at 1 year and 78% (± SD 13%) at 5 years (mean difference ± SD 9% ± 14%, p = 0.015). Mean active forward elevation was 101° (± SD 33°) at 1 year and 92° (± SD 34°) at 5 years (mean difference ± SD 8° ± 36°, p = 0.41). Notable adverse events included progressive radiographic superior subluxation > 1 cm after 12 months followup (12 of 21 patients), delayed union > 12 months (10 of 21 patients), resorption of the greater tuberosity (nine of 21 patients), and aseptic loosening (three of 21 patients). CONCLUSIONS: At intermediate 5-year followup, allograft-prosthetic composite reconstruction of the proximal humerus has an acceptable overall MSTS score and a low incidence of implant revision, but loss of patients to followup and exclusion from the study likely make the results seem better than they actually are. The MSTS score deteriorates between 1 and 5 years. Decreased active forward elevation is not likely to be the sole reason for worsening MSTS scores. A variety of delayed complications including delayed union, resorption of the greater tuberosity, and superior subluxation occurs frequently and may contribute to overall scores. Future studies that compare allograft-prosthetic composites against other forms of reconstruction should attempt to control for possible selection bias and have sufficiently long followup to detect the deterioration of MSTS scores that occur with time. LEVEL OF EVIDENCE: Level IV, therapeutic study.

AZGP1 inhibits soft tissue sarcoma cells invasion and migration.

BACKGROUND: One of the major challenges in soft tissue sarcomas is to identify factors that predict metastasis. AZGP1 is a potential biomarker of cancer progression, but its value in soft tissue sarcomas remains unknown. The aim of this study is to determine the expression level of AZGP1 in soft tissue sarcomas, and to analyze its influence on tumor progression. METHODS: AZGP1 immunohistochemistry (IHC) and RT-PCR were performed in 86 patients with soft tissue sarcomas. The relationships between AZGP1 levels and clinicopathologic features were analyzed. In vitro experiments were performed using fibrosarcoma (HT1080), rhabdomyosarcoma (RD) and synovial sarcoma (SW982) cell lines to corroborate our findings. We used lentiviral over-expression and knockdown assays to examine how changes of AZGP1 expressions might affect cellular migration and invasion. RESULTS: The quantitative RT-PCR results showed that AZGP1 expression was negatively correlated with metastasis and overall survival in soft tissue sarcomas (p < 0.05). Immunohistochemical staining showed lower expression of AZGP1 in patients with metastasis than in those without. Kaplan-Meier survival analysis showed that patients with low expression of AZGP1 had shorter overall (p = 0.056) and metastasis-free survivals (p = 0.038). These findings were corroborated by our in vitro experiments. Over-expression of AZGP1 significantly decreased RD cellular migration and invasion by 64% and 78%, respectively. HT1080 cells migration was inhibited by 2-fold, whereas their invasion was repressed by 7-fold after AZGP1 knockdown. CONCLUSIONS: Our study reveals that reduced AZGP1 expression correlates with in vitro cellular migration and invasion. In vivo, it is associated with higher metastatic risk and shorter survival in patients with soft tissue sarcomas.

Mesenchymal Chondrosarcoma: a Review with Emphasis on its Fusion-Driven Biology.

Mesenchymal chondrosarcoma is a rare but deadly form of chondrosarcoma that typically affects adolescents and young adults. While curative intent is possible for patients with localized disease, few options exist for patients in the unresectable/metastatic setting. Thus, it is imperative to understand the fusion-driven biology of this rare malignant neoplasm so as to lead to the future development of better therapeutics for this disease. This manuscript will briefly review the clinical and pathologic features of mesenchymal chondrosarcoma followed by an appraisal of existing data linked to the fusions, HEY1-NCOA2 and IRF2BP2-CDX1, and the associated downstream pathways.

Synovial Sarcoma: Advances in Diagnosis and Treatment Identification of New Biologic Targets to Improve Multimodal Therapy.

Synovial sarcoma is a translocation-associated soft-tissue malignancy that frequently affects adolescents and young adults. It is driven by one of the fusion oncoproteins SS18-SSX1, SS18-SSX2, or rarely, SS18-SSX4. Prognosis of patients with recurrent or metastatic disease is generally poor, and newer therapeutic strategies are needed. In this review, we present recent discoveries in the pathogenesis, diagnosis, and treatment of synovial sarcoma. We discuss potential therapeutic strategies to improve clinical outcomes in this disease.

Prognosis of T1 synovial sarcoma depends upon surgery by oncologic surgeons.

BACKGROUND: The prognosis of early stage synovial sarcomas is not well-defined since long-term follow-up is lacking in most studies. The optimal use of surgery, radiation, and chemotherapy needs to be clarified for this group. METHODS: From 1994 to 2012, 63 patients were treated for localized synovial sarcoma with T1 (<5 cm) tumors. There were 27 males and 36 females. Mean follow-up was 85 months (range 13-210). RESULTS: At 10 years, local recurrence-free survival was 82% (95% confidence interval [CI] 67-97%), and distant recurrence-free survival was 95% (95%CI 89-100%). Two patients developed metastases after 10 years. Local recurrence was associated with lack of re-excision and treatment by non-oncologic surgeons. Microscopic residual tumor was found in 43% of re-excised specimens. Metastasis was associated with local recurrence, tumor size ≥3 cm, and treatment by non-oncologic surgeons. Radiation and chemotherapy treatment did not have a significant effect in this patient cohort. CONCLUSIONS: Early stage synovial sarcomas with T1 tumors have a relatively favorable prognosis but the potential for late relapse, and long-term follow-up beyond 10 years is recommended. Re-excision of the tumor bed and definitive treatment by trained oncologic surgeons may decrease the risk of local recurrence and metastasis. J. Surg. Oncol. 2016;114:490-494. © 2016 Wiley Periodicals, Inc.

Osteofibrous dysplasia and adamantinoma: A summary of diagnostic challenges and surgical techniques.

Osteofibrous dysplasia is an indolent benign fibro-osseous tumor, while adamantinoma is a locally aggressive biphasic malignancy with epithelial and fibro-osseous components. Predominantly arising in the tibial diaphysis of children and young adults, both tumors are resistant to chemotherapy and radiation. Wide surgical resection is regarded as the mainstay of therapy for adamantinoma, and limb-salvage reconstructive procedures can achieve good functional outcomes, albeit with non-negligible rates of complications. This review discusses emerging advances in the pathogenesis, histogenesis, and diagnosis of these entities and presents advantages and limitations of the most common surgical techniques used for their management.

Surgical drainage after limb salvage surgery and endoprosthetic reconstruction: is 30 mL/day critical?

BACKGROUND: Periprosthetic infection is a major cause of failure after segmental endoprosthetic reconstruction. The purpose of this study is to determine whether certain aspects of drain output affect infection risk, particularly the 30 mL/day criterion for removal. METHODS: Two hundred and ninety-five patients underwent segmental bone resection and lower limb endoprosthetic reconstruction at one institution. Data on surgical drain management and occurrence of infection were obtained from a retrospective review of patients' charts and radiographs. Univariate and multivariate Cox regression analyses were performed to identify factors associated with infection. RESULTS: Thirty-one of 295 patients (10.5%) developed infection at a median time of 13 months (range 1-108 months). Staphylococcus aureus was the most common organism and was responsible for the majority of cases developing within 1 year of surgery. Mean output at the time of drain removal was 72 mL/day. Ten of 88 patients (11.3%) with ≤ 30 mL/day drainage and 21 of 207 patients (10.1%) with > 30 mL/day drainage developed infection (p = 0.84). In multivariate analysis, independent predictive factors for infection included sarcoma diagnosis (HR 4.13, 95% CI 1.4-12.2, p = 0.01) and preoperative chemotherapy (HR 3.29, 95% CI 1.1-9.6, p = 0.03). CONCLUSION: Waiting until drain output is < 30 mL/day before drain removal is not associated with decreased risk of infection for segmental endoprostheses of the lower limb after tumor resection. Sarcoma diagnosis and preoperative chemotherapy were independent predictors of infection.

Complete Decompression of a Forearm Neonatal Compartment Syndrome Using a Volar Approach: A Surgical Technique.

Fasciotomy of the forearm is a well-described technique for the treatment of compartment syndrome in adults; however, it has not been discussed with sufficient details in the setting of neonatal compartment syndrome. When performing a fasciotomy, it is imperative to decompress all compartments within the forearm to limit the ischemic damage and prevent the progression of the disease. Although it is common to utilize both volar and dorsal incisions to release these compartments, we describe a method that potentially allows for total decompression through a single volar incision with minimal to no morbidity. This novel technique provides sufficient soft-tissue exposure while improving upon the cosmesis that results from a traditional approach.

Diagnostic Value of TLE1 in Synovial Sarcoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Synovial sarcoma can present morphologically in multiple forms, including biphasic and monophasic subtypes. As a result, the histological diagnosis can sometimes be challenging. Transducin-Like Enhancer 1 (TLE1) is a transcriptional corepressor that normally is involved in embryogenesis and hematopoiesis but is also expressed in certain tumors. This systematic review examines the potential role of TLE1 as a diagnostic biomarker for the synovial sarcoma. Materials and Methods. A literature review and meta-analysis were conducted using the electronic databases Pubmed, the Cochrane Library, and Google Scholar. Thirteen studies met our eligibility criteria and were selected for in-depth analysis. RESULTS: The mean sensitivity and specificity of TLE1 in detecting synovial sarcoma were 94% (95% CI 91%-97%) and 81% (95% CI 72%-91%), respectively, when all studies were aggregated together. The mean positive predictive value (PPV) of TLE1 was 75% (95% CI 62%-87%), whereas the negative predictive value (NPV) was 96% (95% CI 93%-98%). CONCLUSION: TLE1 is a sensitive and specific marker for synovial sarcoma that can aid in its diagnosis. Due to its involvement in several relevant signaling pathways, TLE1 might have direct relevance to the pathophysiology of the disease.

Modular endoprosthetic implant for maximizing residual limb length: A case report.

BACKGROUND:: For transfemoral amputations, the residual femoral length is critically important to prosthetic function. The aim of this report is to describe a novel method of extending femoral length and to assess its stability over time. CASE DESCRIPTION AND METHODS:: A 57-year-old woman with recurrent parosteal osteosarcoma was treated with above-knee amputation. A portion of the distal femoral endoprosthesis, which included uncemented fixation with a Compress® stem, was retained in an effort to extend the short femoral remnant and maximize stump length. FINDINGS:: At 3 years follow-up, the Compress stem remained well-fixed, and there was no soft tissue breakdown over the implant. The patient ambulated with a prosthetic limb and no external support. OUTCOMES AND CONCLUSION:: To the best of our knowledge, this is the first report of using the Compress device as a means to maintain stable fixation and extend residual femoral length following above-knee amputation. CLINICAL RELEVANCE: Extension of residual bone length in amputated limbs can help improve prosthetic fitting and function. The Compress device may be useful in this application as a means of secure fixation for a modular metallic prosthesis.

Scientific publication misrepresentation among orthopaedic residency applicants.

BACKGROUND: The predictors of erroneous publication reporting among orthopaedic surgery residency applicants have not been established. METHODS: A retrospective analysis of the reported scholarly activity of candidates who applied to our orthopaedic surgery department for a first-year residency position in 2017 was conducted to determine the incidence of scientific publication misrepresentation and analyze its association with pre-residency criteria. RESULTS: Out of 510 candidates, 264 (51.8%) applicants included accepted, in-press, or published scholarly activity on their resumes. The incidence of misrepresentation was 20.5%, and did not differ statistically based on the candidates' academic performance (United States Medical Licensing Examination - USMLE - steps 1 and 2 scores), Alpha Omega Alpha (AOA) membership, immigration status, or or additional academic degrees (p > 0.05). CONCLUSIONS: Misrepresentation is a persistent problem among residency training program applicants, and did not correlate with an applicant's academic performance, AOA membership, immigration status, or additional advanced academic degrees.

Impact of orthopaedic candidate interview timing on successful matching.

INTRODUCTION: The impact of the interview date on matching in orthopaedic surgery residency is unknown. MATERIALS AND METHODS: A retrospective review of interviewed applicants for a first-year orthopaedic surgery residency was conducted to determine the likelihood of matching based on being interviewed early versus late at our program. The United States Medical Licensing Examination (USMLE) scores were compared between early and late interviewees. RESULTS: Between 2012 and 2016, 316 candidates interviewed for residency positions. Twenty matched at our program and 230 at other institutions. No difference existed in USMLE scores. Late interviewees had significantly higher chances of matching at our center, but not nationwide in orthopaedic surgery (p = 0.025 and p = 0.58, respectively). CONCLUSION: Later applicant interview was associated with greater chance of matching at our institution, but did not impact the candidate's ability to match in orthopaedic surgery at other programs.

Biomechanical Evaluation of Dual Plate Configurations for Femoral Shaft Fracture Fixation.

AIM: This study aimed at comparing the mechanical properties of conventional and locking dual plates in adjacent and orthogonal orientations for the surgical fixation of transverse femoral shaft fractures. It also assessed the failure mechanics after dual adjacent and orthogonal locking plate removal. METHODS: Thirty-two composite femurs were transversally osteotomized and randomly assigned for fixation with either dual locking or compression plates in an adjacent or orthogonal configuration. Sixteen specimens were preloaded axially to 20 N and single-leg stance loads were simulated. The remaining sixteen constructs were subjected to torsional loads of 10 Nm at a rate of 10 Nm/s in external and internal rotation of the femoral head in relation to the knee. Overall combined rotational stiffness was calculated. Eight different specimens with no osteotomy underwent the same experiments after dual locked plate removal and were tested to failure in combined eccentric axial and torsional modes. Data were statistically processed using a two-tailed t-test and one-way analysis of variance for the comparison of means between two or more groups, respectively. RESULTS: Orthogonal constructs were statistically stiffer in axial loading compared to their adjacent counterparts in both conventional and locking configurations (p<0.001). Dual locking plates provided higher torsional stiffness than conventional ones within each plate orientation (p<0.01). Neither axial/torsional strength nor failure loads differed between constructs that had adjacent or orthogonal dual locking plates instrumented and then removed (p>0.05). CONCLUSIONS: In both orthogonal and adjacent orientations, double locking plates provide higher stability than their dual conventional counterparts. Orthogonal dual plate configuration is more stable and biomechanically superior to dual adjacent plating for constructs fixed with either standard compression or locking plates.

Sulodexide Monotherapy in Chronic Idiopathic Subjective Tinnitus: A Randomized Controlled Trial.

Objective To report the therapeutic value of sulodexide monotherapy in the management of patients with chronic subjective idiopathic tinnitus. Study Design Randomized double-blinded controlled trial. Setting Single tertiary care institution. Subjects and Methods Observations from 124 patients who received either sulodexide or placebo were collected from the patients' medical records. Computer-generated tables were used to allocate treatments. Patients took 1 tablet of the drug or placebo each morning and evening for 40 consecutive days. The response was assessed by the Tinnitus Handicap Inventory and the Mini-Tinnitus Questionnaire. Results Between 2014 and 2017, 124 patients were divided into 2 treatment arms. The sulodexide group encompassed 63 patients, whereas the placebo arm contained 61 patients. Tinnitus Handicap Inventory and Mini-Tinnitus Questionnaire scores were more decreased in the sulodexide arm compared to the placebo group ( P = .03 and P < .01, respectively). Conclusions Sulodexide monotherapy decreases chronic subjective idiopathic tinnitus.

Sphingomonas paucimobilis-related bone and soft-tissue infections: A systematic review.

BACKGROUND: Sphingomonas paucimobilis is an emerging opportunistic bacterium with a particular tropism toward bones and soft tissues. It is a gram-negative rod that can infect immunosuppressed or immunocompetent individuals in the community or hospital settings. Prognosis of infected patients is generally good, but morbidity and mortality cases have both been documented. OBJECTIVES: To present and discuss all reported Sphingomonas paucimobilis-mediated bone and soft-tissue infections, and shed light upon the relevance of this organism in orthopaedic surgery. DATA SOURCES: Pubmed and Cochrane Library. STUDY ELIGIBILITY CRITERIA: Studies reporting at least one human bone or soft-tissue infection due to Sphingomonas paucimobilis. RESULTS: Ten articles describing 19 patients met the inclusion criteria. Common infections included osteomyelitis, cellulitis, and septic arthritis. Fifteen patients (78.9%) had community-acquired diseases. All patients were successfully treated with antibiotic therapy and only one (5.3%) had a residual complication. LIMITATIONS: The study included a small sample size presenting with bone or soft-tissue infections. Some cases had lacking data. CONCLUSION: Despite being associated with a good prognosis in most cases, Sphingomonas paucimobilis-related orthopaedic infections may exhibit some complications.