Search

Background: Ultraporous β-tricalcium phosphate (TCP) synthetic graft material (Vitoss; Orthovita) persists for a year or longer in some cases. In this study, we prospectively examined healing of cavitary defects filled with TCP versus TCP and bone marrow aspirate (TCP/BM) with the hypothesis that bone-marrow aspirate speeds incorporation of bone graft substitute.Methods: Fifty-five patients with a benign bone lesion undergoing surgical curettage were randomized to receive TCP (N = 26; mean duration of follow-up [and standard deviation], 20.2 ± 7.2 months) or TCP/BM (N = 29; mean duration of follow-up, 18.0 ± 7.7 months). There were no significant differences between the groups with regard to demographic or defect parameters. Clinical and radiographic evaluations were done at 1.5, three, six, twelve, eighteen, and twenty-four months, and computed tomography [CT] scans were performed at twelve months. An independent radiographic review was done to evaluate six parameters.Results: There was a significant (p < 0.001) increase in trabeculation through the defect and graft resorption with decreases in the persistence of the graft in both soft tissue and the defect as well as a decreased radiolucent rim around the graft over time. No significant differences were observed between the TCP and TCP/BM groups in terms of any radiographic parameter. No complications related to the graft material or BM were identified.Conclusions: While significant improvements in radiographic parameters were observed in both TCP groups over two years of follow-up, the addition of BM was not found to provide any significant benefit. Results should not be extrapolated to other bone graft substitutes used for this purpose. [ABSTRACT FROM AUTHOR]

Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFbeta, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFbeta and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFbeta1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas. [ABSTRACT FROM AUTHOR]

An understanding of differential gene expression in highly metastatic osteosarcoma could provide gene targets for treatment of metastases. We compared gene expression profiles of high- (LM7) and low- (LM2) metastatic SaOS2-derived cell lines in an in vitro tissue culture model and examined several differentially regulated genes in vivo in a murine orthotopic xenograft model. We hypothesized an orthotopic inoculation of LM2 and LM7 cells would establish a primary lesion and the gene expression profile of cells grafted in this fashion would resemble the gene expression profile observed in an in vitro model. Thirty-five days after inoculation, animals were euthanized and both tibiae were harvested and rapidly frozen in liquid nitrogen. Human-specific GAPDH mRNA was present in two of four tibias inoculated with LM2 cells and three of four tibias inoculated with LM7 cells. Tibiae displaying the presence of human cells were assayed by semiquantitative reverse transcriptase polymerase chain reaction. We observed poor correspondence of in vitro to in vivo gene expression for either cell line. Accordingly, in vitro osteosarcoma gene expression data must be interpreted with caution until confirmed in vivo. Our orthotopic injection model allowed in vivo study of differential gene expression between these two cell lines but did not show radiographic evidence of an established primary lesion. [ABSTRACT FROM AUTHOR]

Unlabelled: Since publication of the results of a first-generation intercalary humeral spacer, a newer design has been available that addressed the weaknesses of the first. This study evaluated the hypothesis that the second-generation lap joint junction intercalary humeral spacer reduced complications compared with the original male-female taper design. We retrospectively reviewed the charts of 32 consecutive patients who had undergone placement of an intercalary humeral spacer. Twenty-one with the male-female taper (minimum followup 0 months, mean 19.2 months) were compared with 11 with the lap joint configuration (minimum followup 0 months, mean 20.3 months). Demographic, tumor, treatment, and radiographic variables were similar between groups. We observed a lower complication rate in the lap joint group (three of 11 versus 11 of 21). The most common complications in the male-female group, neuropraxia, periprosthetic fracture, and disengagement, were not seen in the lap joint group. Aseptic loosening was more frequent in the lap joint group. There were no differences in blood loss, operative time, or Musculoskeletal Tumor Society scores between groups. We noted improvement in Musculoskeletal Tumor Society scores from preoperatively to postoperatively in both groups. Use of these implants should be reserved for patients with limited life expectancy.Level Of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Unlabelled: Mirels' rating system is commonly used to predict risk of fracture in patients with metastatic bone lesions to long bones, but it has not been independently validated for use in humeral bone lesions. We asked whether this system was a valid and reproducible instrument for predicting impending pathologic fractures in the humerus. We presented 17 case histories and plain radiographs of 16 patients with humeral metastases through a web-based survey to 39 physicians with varying training and experience. Participants scored each case using Mirels' criteria and provided a fracture prediction, which was compared with actual outcome in the subset of 12 patients with three fractures not treated prophylactically. Using Mirels' definition of impending pathologic fracture (nine points or greater), the sensitivity and specificity for determining the likelihood of pathologic humeral fracture were 14.5% and 82.9%, respectively. When we used seven or more points as the definition of impending pathologic humeral fracture, sensitivity improved to 81% but specificity was reduced to 32%. Kappa analysis suggested moderate reproducibility across groups for prediction of pathologic fracture. The Mirels rating system for humeral lesions is reproducible and valid, but low specificity at acceptable sensitivity levels as reported remains a problem as for femoral lesions.Level Of Evidence: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Predicting pathologic fractures of long bones caused by metastatic disease continues to be a challenging clinical problem. We assessed the ability of noninvasive imaging and computational techniques to predict the strength of bones with osteolytic lesions. A murine model of induced tumor osteolysis to the distal femur was used as a model system resulting in a wide range of lesion sizes. Microcomputed tomography scans were obtained and specimen-specific, voxel-based, finite element analyses were performed and results were compared with direct measurement of biomechanical strength via axial compressive loading of the distal femur. Additional indirect surrogates of bone strength included dual-energy xray absorptiometry to determine bone mineral density, radiographic scoring, and computed tomography volume/mineral estimates. Predicted bone strength was weakest (r(2) = 0.55) for the dual-energy xray absorptiometry measure and strongest (r(2) = 0.91) for the direct computed tomography voxel-based, finite element analysis. The relative success of the voxel-based, finite element modeling approach to estimate bone strength in a murine osteolytic tumor model indicates this approach, with further development and validation, could serve as a way to nondestructively estimate bone strength in a clinical setting. [ABSTRACT FROM AUTHOR]

Parachordoma, or myoepithelioma, is a very rare tumor histologically resembling chordoma but occurring in the nonaxial soft tissues. It typically has an indolent nature, with occasional late recurrence and even rare metastases. Review of existing literature reveals a male predilection, with the tumor typically occurring in the fourth decade of life in the lower extremity. It typically is managed with wide resection. We report the case of a 60-year-old woman with a right distal upper arm parachordoma treated with wide resection of the tumor. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) is a potent mitogenic factor for cells of mesodermal and ectodermal origin, and its over-expression is associated with a variety of cancers. We asked whether oncogene coexpression occurs in mesenchymal neoplasms, if coexpression correlates with EGF transcription, and whether coexpression can be attributed to the EGF-induced overexpression of oncogenes. We quantified the mRNA concentrations of EGF and 14 oncogenes in 42 primary sarcomas, 31 benign tumors, and 10 skeletal muscle controls, and compared mRNA concentrations and gene pair correlations in EGF positive (EGF+) tumors to transcript concentrations and correlations in EGF negative (EGF-) tumors. Transcripts were detected by real time reverse transcription-polymerase chain reaction. Pearson's correlation coefficients identified gene associations, and gene synchrony associated with EGF expression was evaluated using chi square. Transcript concentrations in tumors were compared graphically and with t tests. Gene correlations predominated in EGF+ benign tumors and in EGF- primary sarcomas. The dichotomy in oncogene coexpression evident in benign and malignant tumors could not be attributed to statistical differences in mRNA content between EGF+ and EGF- tumors. EGF may enhance, or may indicate the presence of, oncogene coexpression in benign mesenchymal lesions, but counters gene synchronization in sarcomas. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma metastases to bone are classically considered radioresistant. We reviewed 28 patients who underwent irradiation for metastatic renal cell carcinomas to bone to test the hypothesis that irradiation of renal metastases to bone provides adequate palliation in carefully selected patients. Metastases were multifocal in all patients. All patients were followed until death. Overall, 36 index radiotherapy treatments were given as palliative initial treatment for 36 osseous metastatic sites. Twenty-five of 36 sites (69.5%) had no subsequent radiotherapy. Eight sites (22.2%) underwent repeat radiotherapy at a mean 28.9 weeks after treatment. Two (5.6%) additional sites underwent surgery at the site at an average 74 weeks later, and a pathologic fracture occurred at one (2.8%) site 3 weeks after irradiation. Overall, 33 of 36 (91.7%) sites had only radiotherapy as their source of palliation. Median times to return to pretreatment pain and functional levels, however, were 2 months and 1 month, respectively. Radiotherapy to osseous sites appears to control pain for the short term and generally prevents fractures and avoids the need for surgery in renal cell carcinoma patients with multiple bone metastases. [ABSTRACT FROM AUTHOR]

Context. - Needle core biopsy has been reported to be the choice of biopsy for musculoskeletal tumors. Fine-needle aspiration, on the other hand, has been widely accepted for nonmusculoskeletal tumors, but is only used in selected medical centers for musculoskeletal tumors. While fine-needle aspiration appears to have advantages to needle core biopsy in the aspects of simplicity and cost, the diagnostic accuracy should be the most critical parameter in determining the choice of biopsy. However, few studies comparing the diagnostic accuracy of these 2 biopsy methods have been performed. Objective. - This study was designed to compare the diagnostic accuracy of fine-needle aspiration and needle core biopsy in musculoskeletal tumors. Design. - Prospective study was performed in patients aged 10 years or older. Diagnostic accuracy was compared in 50 consecutive concurrent needle core biopsies and fine-needle aspirations of musculoskeletal lesions. Results. - For primary musculoskeletal lesions, fine-needle aspiration achieved a diagnostic accuracy rate of 88% for nature of lesion, 64% for specific diagnosis, 78% for histologic grading, and 74% for histologic typing. Needle core biopsy achieved an accuracy rate of 93 % for nature of lesions, 83 % for specific diagnosis, 83 % for histologic grading, and 90% for histologic typing. Both biopsy methods have a higher diagnostic accuracy rate for high-grade tumors than for low-grade or benign lesions in determining the nature, specific diagnosis, and histologic grading. Conclusions. - The needle core biopsy has a higher diagnostic accuracy than fine-needle aspiration in all aspects, including determining the nature of the tumor, establishing the histologic type and grade, and achieving a specific diagnosis. [ABSTRACT FROM AUTHOR]

Amyloidoma (localized tumorlike amyloidosis) in the soft tissues is rare. We present an instructive case of recurrent amyloidoma in the soft tissue of the ankle in a 45-year-old man with multiple surgical procedures and chronic osteomyelitis of the underlying bones. The lesion evaded diagnosis because of a florid giant cell reaction that led to various misdiagnoses, including giant cell tumor of tendon sheath, foreign body reaction secondary to surgery, and pseudogout. This case demonstrates the importance of considering the possibility of amyloidoma when a giant cell--rich lesion is encountered in the soft tissues. [ABSTRACT FROM AUTHOR]

Background: The proximal femur is a common site of bone metastasis. The Mirels' score is a frequently utilized system to identify patients at risk for pathologic fracture and while it has consistently demonstrated strong sensitivity, specificity has been relatively poor. Our group previously developed a Modified Mirels' scoring system which demonstrated improved ability to predict cases at risk of fracture in this patient population through modification of the Mirels' location score. The purpose of the present study is to internally validate this newly developed scoring system on an independent patient series., Methods: Retrospective review was performed to identify patients who were evaluated for proximal femoral bone lesions. Patients were stratified into one of two groups: 1) those who went on to fracture within 4 months after initial evaluation (Fracture Group) and 2) those who did not fracture within 4 months of initial evaluation (No Fracture Group). Retrospective chart review was performed to assign an Original Mirels' (OM) Score and Modified Mirels' (MM) score to each patient at the time of initial evaluation. Descriptive statistics, logistic regression, receiver operating curve, and net benefit analyses were performed to determine the predictability of fractures when utilizing both scoring systems., Results: The use of the MM scoring improved fracture prediction over OM scoring for patients observed over a 4 month follow up based on logistic regression. Decision curve analysis showed that there was a net benefit using the MM score over the OM scoring for a full range of fracture threshold probabilities. Fracture prevalence was similar for current internal validation dataset when compared to the dataset of our index study with a comparable reduction in misclassification of fracture prediction when utilizing the modified scoring system versus the original., Conclusions: Use of MM scoring was found to improve fracture prediction over OM scoring when tested on an internal validation set of patients with disseminated metastatic lesions to the proximal femur. The improvement in fracture prediction demonstrated in the present study mirrored the results of our index study during which the MM system was developed., (© 2024. The Author(s).)

Introduction: Metallosis from total hip arthroplasty is usually due to trunnionosis and is associated with elevated serum cobalt and chromium levels. Titanium levels usually remain normal., Methods: Here, we report two rare cases of elevated titanium levels, both with the same mechanism, which is a previously unreported cause of titanium metallosis., Results: In these cases, contact between cables and the titanium stem were the source., Discussion: Reports of isolated high titanium levels associated with total hip arthroplasty are rare. These cases illustrate a new mechanism from which this situation may arise., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: Nonossifying fibroma (NOF) and fibrous cortical defect (FCDs), the most common benign pediatric bone lesions, are usually incidental x-ray findings. Surveillance of characteristic lesions has been recommended to monitor for enlargement and assess fracture risk. However, no accepted fracture risk prediction guidelines exist, so indications for prophylactic surgery are unclear. The study's purposes were to (1) characterize the timing of NOF/FCD-associated fractures, (2) quantify the resources devoted to surveillance, and (3) evaluate the potential for surveillance to prevent pathologic fracture., Methods: A single institution retrospective review was conducted to identify pediatric patients (below 18 y old) with clinical-radiographic documentation of an NOF or FCD diagnosis from 2012 to 2020. Patients who presented with fracture were tallied but excluded from the surveillance analysis. Patients without at least one follow-up visit were also excluded. Lesional radiographic features were characterized on initial imaging. The number of visits and imaging studies devoted to surveillance were tabulated. The number of fractures and prophylactic surgeries were recorded to quantify the potential of surveillance to prevent pathologic fractures., Results: The study population presenting without fracture consisted of 301 patients with 364 lesions with a mean follow-up of 20 months. By contrast, over the same period, 38 patients presented with NOF/FCD associated pathologic fractures. Surveillance included 1037 additional imaging tests over 1311 follow-up visits, or on average, 3.4 imaging studies and 4.4 visits per patient. During surveillance, only 2 (0.55%) lesions fractured. Another 10/364 (2.8%) patients underwent curettage and grafting, suggesting that-at best-the potential for preventing pathologic fracture by surveillance, assuming all 10 patients who underwent surgery would have subsequently fractured along with the 2 documented fractures, is 3.3% of lesions (12/364)., Conclusions: The small number of fractures and surgeries during the follow-up period probably does not justify additional resources for surveillance beyond the initial visit, except in symptomatic patients with large lesions. However, subsequent visits may play a role in educating patients and their families regarding the natural history of these lesions., Level of Evidence: Prognostic Level II-retrospective study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Competing Interests: The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Nonossifying fibroma (NOF) is a common benign bone neoplasm and is usually observed in the first 2 decades of life. Most NOFs occur in the metaphysis of long bones of the lower extremities and migrate toward the diaphysis during skeletal maturation. Epiphyseal involvement by NOF has been rarely reported, with only one case found in the English literature. The authors report the second case of NOF involving the epiphysis of a long bone, the proximal tibia of a 21-year-old woman. Clinicians and pathologists should be aware of the rare possibility of epiphyseal involvement of long bones by this condition. Pathologists should select appropriate immunohistochemistry markers to rule out alternative diagnoses., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Paget osteosarcoma is a rare but serious complication of Paget disease requiring immediate management before further malignant transformation. This case report examines the progression of a previously reported case of Paget disease with atypical pseudotumor manifestation, mimicking osteosarcoma over a 21-year time lapse. After presenting with substantial pain and elevated alkaline phosphatase levels, imaging proved extensive bony expansion of the lesion with high-grade trabecular and cortical thickening and extraosseous soft-tissue extension, prompting the need for biopsy to rule out Paget sarcoma. The atypical features of the pseudotumor's development helps distinguish key radiographic and clinical criteria for malignant development., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C155)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Case: A 68-year-old woman presented with a paraspinal mass of indeterminate imaging characteristics. Workup and computed tomography-guided Fine Needle Aspiration (FNA) aspiration revealed extramedullary hematopoiesis (EMH) adjacent to a prior compression fracture in the setting of pernicious anemia., Conclusion: The combination of findings suggests a possible relationship of the compression fracture and the EMH because of traumatic extravasation of marrow contents, with the patient's underlying anemia possibly providing an underlying predisposition to EMH., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C90)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Correctly identifying patients at risk of femoral fracture due to metastatic bone disease remains a clinical challenge. Mirels criteria remains the most widely referenced method with the advantage of being easily calculated but it suffers from poor specificity. The purpose of this study was to develop and evaluate a modified Mirels scoring system through scoring modification of the original Mirels location component within the proximal femur., Methods: Computational (finite element) experiments were performed to quantify strength reduction in the proximal femur caused by simulated lytic lesions at defined locations. Virtual spherical defects representing lytic lesions were placed at 32 defined locations based on axial (4 axial positions: neck, intertrochanteric, subtrochanteric or diaphyseal) and circumferential (8 circumferential: 45-degree intervals) positions. Finite element meshes were created, material property assignment was based on CT mineral density, and femoral head/greater trochanter loading consistent with stair ascent was applied. The strength of each femur with a simulated lesion divided by the strength of the intact femur was used to calculate the Location-Based Strength Fraction (LBSF). A modified Mirels location score was next defined for each of the 32 lesion locations with an assignment of 1 (LBSF > 75%), 2 (LBSF: 51-75%), and 3 (LBSF: 0-50%). To test the new scoring system, data from 48 patients with metastatic disease to the femur, previously enrolled in a Musculoskeletal Tumor Society (MSTS) cross-sectional study was used. The lesion location was identified for each case based on axial and circumferential location from the CT images and assigned an original (2 or 3) and modified (1,2, or 3) Mirels location score. The total score for each was then calculated. Eight patients had a fracture of the femur and 40 did not over a 4-month follow-up period. Logistic regression and decision curve analysis were used to explore relationships between clinical outcome (Fracture/No Fracture) and the two Mirels scoring methods., Results: The location-based strength fraction (LBSF) was lowest for lesions in the subtrochanteric and diaphyseal regions on the lateral side of the femur; lesions in these regions would be at greatest risk of fracture. Neck lesions located at the anterior and antero-medial positions were at the lowest risk of fracture. When grouped, neck lesions had the highest LBSF (83%), followed by intertrochanteric (72%), with subtrochanteric (50%) and diaphyseal lesions (49%) having the lowest LBSF. There was a significant difference (p < 0.0001) in LBSF between each axial location, except subtrochanteric and diaphyseal which were not different from each other (p = 0.96). The area under the receiver operator characteristic (ROC) curve using logistic regression was greatest for modified Mirels Score using site specific location of the lesion (Modified Mirels-ss, AUC = 0.950), followed by a modified Mirels Score using axial location of lesion (Modified Mirels-ax, AUC = 0.941). Both were an improvement over the original Mirels score (AUC = 0.853). Decision curve analysis was used to quantify the relative risks of identifying patients that would fracture (TP, true positives) and those erroneously predicted to fracture (FP, false positives) for the original and modified Mirels scoring systems. The net benefit of the scoring system weighed the benefits (TP) and harms (FP) on the same scale. At a threshold probability of fracture of 10%, use of the modified Mirels scoring reduced the number of false positives by 17-20% compared to Mirels scoring., Conclusions: A modified Mirels scoring system, informed by detailed analysis of the influence of lesion location, improved the ability to predict impending pathological fractures of the proximal femur for patients with metastatic bone disease. Decision curve analysis is a useful tool to weigh costs and benefits concerning fracture risk and could be combined with other patient/clinical factors that contribute to clinical decision making., (© 2023. The Author(s).)

Competing Interests: The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Purpose: The oncogenic fusion protein EWS::FLI1 is an attractive therapeutic target in Ewing sarcoma (ES). Mithramycin A (MithA) is a potent and specific inhibitor of EWS::FLI1 that can selectively radiosensitize ES cells through transcriptional inhibition of DNA double-strand break (DSB) repair. Here, we evaluate temporal changes in cell cycle progression and apoptosis in ES cells treated with MithA and/or ionizing radiation (RTx), testing the hypothesis that combining MithA with ionizing radiation would synergistically impair cell cycle progression and enhance apoptotic elimination to a greater extent than either agent alone., Materials and Methods: Four EWS::FLI1 + ES cell lines TC-71, RD-ES, SK-ES-1, and A673, and one EWS::ERG cell line (CHLA-25) were exposed to 10nM MithA or vehicle and followed 24 h later by exposure to 2 Gy x-radiation or sham irradiation. Reactive oxygen species (ROS) activity was evaluated by cytometric assay, and assay of antioxidant gene expression by RT-qPCR. Cell cycle changes were evaluated by flow cytometry of nuclei stained with propidium iodide. Apoptosis was assessed by cytometric assessment of Caspase-3/7 activity and by immunoblotting of PARP-1 cleavage. Radiosensitization was evaluated by clonogenic survival assay. Proliferation (EdU) and apoptosis (TUNEL) were evaluated in SK-ES-1 xenograft tumors following pretreatment with 1 mg/kg MithA, followed 24 h later by a single 4 Gy fraction of x-radiation., Results: MithA-treated cells showed reduced levels of ROS, and were associated with increased expression of antioxidant genes SOD1 , SOD2, and CAT . It nonetheless induced persistent G 0 /G 1 arrest and a progressive increase of the sub-G 1 fraction, suggesting apoptotic degeneration. In vitro assays of Caspase-3/7 activity and immunoblotting of Caspase-3/7 dependent cleavage of PARP-1 indicated that apoptosis began as early as 24 h after MithA exposure, reducing clonogenic survival. Tumors from xenograft mice treated with either radiation alone, or in combination with MithA showed a significant reduction of tumor cell proliferation, while apoptosis was significantly increased in the group receiving the combination of MithA and RTx., Conclusions: Taken together, our data show that the anti-proliferative and cytotoxic effects of MithA are the prominent components of radiosensitization of EWS::FLI1 + ES, rather than the result of acutely enhanced ROS levels.

Postradiotherapy bone fragility fractures are a frequent late-onset complication in cancer survivors. There is a critical need to develop preventative interventions, and the use of Food and Drug Administration-approved drugs remains an attractive option. Prior data from our lab and others have shown that parathyroid hormone [1-34] mitigates radiotherapy-induced bone loss, but only for the duration of drug delivery. Utilizing a murine hindlimb radiotherapy model, we investigated whether orchestrated delivery of single-dose zoledronic acid could extend these anabolic benefits after cessation of parathyroid hormone delivery. We then explored the potential use of parathyroid hormone as a bone marrow radioprotectant. While the addition of zoledronic acid to parathyroid hormone increased irradiated bone mass, there was no increase in femur bending strength. In this model, the parathyroid hormone was not effective as a marrow radioprotectant, although this could be due to the short course of parathyroid hormone treatment. Marrow repopulation kinetics differed from those in total body irradiation, with hematopoietic stem cell repopulation occurring relatively early at four weeks postirradiation. Furthermore, we found radiation induced a loss of marrow stromal cells and an increase in inflammatory monocytes. Statement of Clinical Significance: Staged delivery of parathyroid hormone and zoledronic acid shows promise as an off-the-shelf intervention to mitigate post-radiotherapy bone damage in cancer patients, but parathyroid hormone is unlikely to function as a broad-spectrum marrow radioprotectant., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Accurate comparison of prophylactic surgical treatment (PST) to after fracture treatment (AF) of patients with femoral metastatic disease requires more accurately identifying patients for impending fracture, such as with CT-based structural rigidity analysis (CTRA). This study compares a more accurately defined PST group (of impending fractures defined by CTRA) to AF for metastatic femoral disease., Methods: PST patients were enrolled and treated by the PI in a longitudinal multicenter study of impending pathologic fractures evaluated for accuracy by CTRA. The AF patients were also treated by the senior author and were identified by retrospective chart review. Fifty-five patients were treated surgically for metastatic femoral lesions and were divided into three groups for the purpose of this study: Group I (AF), Group II (PST-high), and Group III (PST-low). Demographic information, comorbidities, and clinical variables of interest were collected by retrospective chart review; cost data was collected by collaboration with our hospital financial personnel (office of the Chief Financial Officer)., Results: Survival showed statistically significant differences favoring Group II. Transfusions in Group I were nearly twice those of Groups II and III, but there was no statistically significant (NS) difference between groups. Estimated blood loss (EBL) was generally with NS difference. Similarly, there were NS differences in LOS between groups. Discharge disposition showed statistically significant differences between groups (P=0.012, global). Discharge to home was highest in Group II (76%) and lowest in Group I (27%). Discharge to rehab was lowest in Group II (24%) and highest in Group I (47%). There were no discharges to hospice or morgue in Group II, while both occurred in Group I. Mean direct and total costs were highest in Group I ($18,837 and $31,997, respectively) and lowest in Group II ($16,094 and $27,357) but the differences were NS., Conclusions: This study shows benefits of PST over AF in a group of PST patients more accurately defined to have impending pathologic fractures by CTRA definition., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoj.amegroups.com/article/view/10.21037/aoj-20-92/coif). The series “Bone Metastasis” was commissioned by the editorial office without any funding or sponsorship. TAD declares that other than the musculoskeletal tumor society funding, which has long since been completed, and ongoing related work examining other aspects of fracture risk prediction, none of the sources of funding represent related sources or conflicts. The authors have no other conflicts of interest to declare., (2022 Annals of Joint. All rights reserved.)

Background and Objectives: The "four-quadrant approach" (FQA) for triage of benign enchondromas (E) and low-grade malignant chondrosarcomas (LGC) divides patients into treatment categories based on the presence or absence of pain and observation of aggressive or benign radiographic features. This article evaluates the usefulness of the FQA in predicting E versus LGC and operative versus nonoperative outcome., Methods: Patients had working diagnosis of E or LGC, 1-year minimum follow-up, imaging, clinical data, outcomes, and no radiographic evidence of high-grade chondrosarcoma. Statistical analysis determined whether quadrant distribution correlated to E versus LGC and operative versus nonoperative intervention., Results: Of 56 lesions (49 patients), 9 were LGC and 47 E. Twenty-five lesions (all 9 LGC, 16 E) were treated operatively and 31 (all E) nonoperatively. There were statistically significant correlations between quadrant distribution and both tumor type (p = 1.9 × 10 -6 ) and operative intervention (p = 6.28 × 10 -6 )., Conclusions: The FQA is a promising diagnostic tool to distinguish between E and LGC hyaline cartilage tumors, along with determining operative versus nonoperative intervention. Prospective evaluation is warranted., (© 2021 Wiley Periodicals LLC.)

Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Case: Osseous hydatidosis caused by Echinococcus is rare, especially in long bones. To the best of our knowledge, this is the third femoral hydatidosis case with successful osseous eradication through total femoral resection and total femoral megaprosthesis. Unlike the previous 2 cases, we uniquely illustrate recurrent soft-tissue hydatidosis episodes requiring additional hydatid resections for local control with no evidence of disease at final 16-year follow-up, the longest follow-up period of the 3 reported cases., Conclusion: Despite radical bone resection for osseous hydatidosis eradication, additional complex surgical interventions may be needed to locally control soft-tissue disease., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B697)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Aseptic loosening of total knee arthroplasty continues to be a challenging clinical problem. The progression of the loosening process, from the initial well-fixed component, is not fully understood. In this study, loss of fixation of cemented hemiarthroplasty was explored using 9-month-old Sprague-Dawley rats with 0, 2, 6, 12, 26 week end points. Morphological and cellular changes of cement-bone fixation were determined for regions directly below the tibial tray (epiphysis) and distal to the tray (metaphysis). Loss of fixation, with a progressive increase in cement-bone gap volume was found in the epiphysis (0.162  mm 3 /week), but did not progress appreciably in the metaphysis (0.007 mm 3 /week). In the epiphysis, there was an early and sustained elevation of osteoclasts adjacent to the cement border and development of a fibrous tissue layer between the cement and bone. There was early formation of bone around the cement in the metaphysis, resulting in a condensed bone layer without osteoclastic bone resorption or development of a fibrous tissue layer. Implant positioning was also an important factor in the cement-bone gap formation, with greater gap formation for implants that were placed medially on the tibial articular surface. Loss of fixation in the rat model mimicked patterns found in human arthroplasty where cement-bone gaps initiate under the tibial tray, at the periphery of the implant. This preclinical model could be used to study early biological response to cemented fixation and associated contributions of mechanical instability, component alignment, and periprosthetic inflammation., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

One of the key roles of an orthopedic surgeon treating metastatic bone disease (MBD) is fracture risk prediction. Current widely used impending fracture risk tools such as Mirels scoring lack specificity. Two newer methods of fracture risk prediction, CT-based structural rigidity analysis (CTRA) and finite element analysis (FEA), have each been shown to be more accurate than Mirels. This case series illustrates comparative Mirels, CTRA, and FEA for 8 femurs in 7 subjects. These cases were selected from a much larger data set to portray examples of true positives, true negatives, false positives, and false negatives as defined by CTRA relative to the fracture outcome. Case illustrations demonstrate comparative Mirels and FEA. This series illustrates the use, efficacy, and limitations of these tools. As all current tools have limitations, further work is needed in refining and developing fracture risk prediction., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Shannon M. Kaupp et al.)

Post-radiotherapy (RTx) bone fragility fractures are a late-onset complication occurring in bone within or underlying the radiation field. These fractures are difficult to predict, as patients do not present with local osteopenia. Using a murine hindlimb RTx model, we previously documented decreased mineralized bone strength and fracture toughness, but alterations in material properties of the organic bone matrix are largely unknown. In this study, 4 days of fractionated hindlimb irradiation (4 × 5 Gy) or Sham irradiation was administered in a mouse model (BALB/cJ, end points: 0, 4, 8, and 12 weeks, n = 15/group/end point). Following demineralization, the viscoelastic stress relaxation, and monotonic tensile mechanical properties of tibiae were determined. Irradiated tibiae demonstrated an immediate (day after last radiation fraction) and sustained (4, 8, 12 weeks) increase in stress relaxation compared to the Sham group, with a 4.4% decrease in equilibrium stress (p < .017). While tensile strength was not different between groups, irradiated tibiae had a lower elastic modulus (-5%, p = .027) and energy to failure (-12.2%, p = .012) with monotonic loading. Gel electrophoresis showed that therapeutic irradiation (4 × 5 Gy) does not result in collagen fragmentation, while irradiation at a common sterilization dose (25 kGy) extensively fragmented collagen. These results suggest that altered collagen mechanical behavior has a role in postirradiation bone fragility, but this can occur without detectable collagen fragmentation. Statement of Clinical Significance: Therapeutic irradiation alters bone organic matrix mechanics and which contribute to diminished fatigue strength, but this does not occur via collagen fragmentation., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Purpose: The oncogenic EWS:Fli1 fusion protein is a key transcriptional mediator of Ewing sarcoma initiation, progression, and therapeutic resistance. Mithramycin A (MithA) is a potent and specific inhibitor of transcription mediated by the EWS:Fli1. We tested the hypothesis that pretreatment with MithA could selectively radiosensitize EWS:Fli1 + tumor cells by altering the transcriptional response to radiation injury., Methods and Materials: A panel of 4 EWS:Fli1 + and 3 EWS:Fli1 - Ewing sarcoma cell lines and 1 nontumor cell line were subjected to MithA dose-response viability assays to determine the relative potency of MithA in cells possessing or lacking the EWS:Fli1 fusion. Radiosensitization by MithA was evaluated by clonogenic survival assays in vitro and in a murine xenograft model. DNA damage was evaluated by comet assay and γ-H2Ax flow cytometry. Immunoblotting, flow cytometry, and reverse-transcription, polymerase chain reaction were used to evaluate DNA damage-induced signaling and repair processes and apoptosis., Results: We found that MithA alone could potently and selectively inhibit the growth of EWS:Fli1 + tumor cells, but not cells lacking this fusion. Pretreatment with MithA for 24 hours before irradiation significantly reduced clonogenic survival in vitro and delayed tumor regrowth in vivo, prolonging survival of EWS:Fli1 + tumor-bearing mice. Although MithA did not increase the level of DNA double-strand breaks, mechanistic studies revealed that MithA pretreatment selectively inhibited DNA double-strand break repair through downregulation of EWS:Fli1-mediated transcription, leading to tumor cell death by apoptosis., Conclusions: Our data indicate that MithA is an effective radiosensitizer of EWS:Fli1 + tumors and may achieve better local control at lower doses of radiation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: The author certifies that neither he, nor any members of his immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Proximal humeral reconstructive options following radical resection of proximal humeral primary and metastatic bone malignancies have evolved over time. With the relatively recent advent of the reverse total shoulder (RTSA), this technique has been increasingly employed in this setting over hemiarthroplasty techniques. An array of options, including proximal humeral allograft-prosthetic composites (including both RTSA and hemiarthroplasty), megaprostheses, and osteoarticular allografts, is reviewed from the perspective of their indications, techniques, complications, and published results. An extensive case-based pictorial presentation illustrates these options., Competing Interests: Conflicts of interest Not applicable.

Metastatic breast, prostate, lung, and other cancers often affect bone, causing pain, increasing fracture risk, and decreasing function. Management of metastatic bone disease (MBD) is clinically challenging when there is potential but uncertain risk of pathological fracture. Management of MBD has become a major focus within orthopedic oncology with respect to fracture and impending fracture care. If impending skeletal-related events (SREs), particularly pathologic fracture, could be predicted, increasing evidence suggests that prophylactic surgical treatment improves patient outcomes. However, current fracture risk assessment and radiographic metrics do not have high accuracy and have not been combined with relevant patient survival tools. This review first explores the prevalence, incidence, and morbidity of MBD and associated SREs for different cancer types. Strengths and limitations of current fracture risk scoring systems for spinal stability and long bone fracture are highlighted. More recent computed tomography (CT)-based structural rigidity analysis (CTRA) and finite element (FE) analysis methods offer advantages of increased specificity (true negative rate), but are limited in availability. Other fracture prediction approaches including parametric response mapping and positron emission tomography/computed tomography measures show early promise. Substantial new information to inform clinical decision-making includes measures of survival, clinical benefits, and economic analysis of prophylactic treatment compared to after-fracture stabilization. Areas of future research include use of big data and machine learning to predict SREs, greater access and refinement of CTRA/FE approaches, combination of clinical survival prediction tools with radiographically based fracture risk assessment, and net benefit analysis for fracture risk assessment and prophylactic treatment., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Case: Extraskeletal myxoid chondrosarcomas (EMCs) are rare soft-tissue malignancies. Intra-articular occurrence is even more rare. To our knowledge, this case is one of only 2 reported intra-articular EMC cases of the knee free of local recurrence and/or amputation at follow-up. This case is also distinctive for being fluorescence in-situ hybridization-negative for the typical EMC-balanced translocation t(9;22) which fuses EWSR1 with NR4A3, harboring instead a variant translocation resulting in fusion of NR4A3 with a less common gene fusion partner., Conclusion: This is a unique case of intra-articular EMC of the knee with a rare molecular fingerprint and an unusually positive outcome.

Background: Cancer patients receiving radiotherapy for soft tissue sarcomas are often at risk of post-irradiation (post-RTx) bone fragility fractures, but our understanding of factors controlling radiation-induced bone injury is limited. Previous studies have evaluated post-RTx changes to cortical bone composition in the periosteum of irradiated tibiae, but have not evaluated effects of irradiation in deeper tissues, such as endosteal or mid-cortical bone, and whether there are differential spatial effects of irradiation. In this study, we hypothesize that post-RTx changes to cortical bone composition are greater in endosteal compared to mid-cortical or periosteal bone., Methods: A pre-clinical mouse model of limited field hindlimb irradiation was used to evaluate spatial and temporal post-RTx changes to the metaphyseal cortex of irradiated tibiae. Irradiation was delivered unilaterally to the hindlimbs of 12-wk old female BALB/cJ mice as 4 consecutive daily doses of 5 Gy each. RTx and non-RTx tibiae were obtained at 0, 2, 4, 8, and 12 wks post-RTx ( n  = 9 mice/group/time). Raman spectroscopy was used to evaluate spatial and temporal post-RTx changes to cortical bone composition in age-matched RTx and non-RTx groups., Results: Significant early spatial differences in mineral/matrix and collagen crosslink ratios were found between endosteal and periosteal or mid-cortical bone at 2-wks post-RTx. Although spatial differences were transient, mineral/matrix ratios significantly decreased and collagen crosslink ratios significantly increased with post-RTx time throughout the entire tibial metaphyseal cortex., Conclusions: Irradiation negatively impacts the composition of cortical bone in a spatially-dependent manner starting as early as 2-wks post-RTx. Long-term progressive post-RTx changes across all cortical bone sites may eventually contribute to the increased risk of post-RTx bone fragility fractures., Competing Interests: All authors state they have no conflicts of interest., (© 2020 The Author(s).)

Trabecular resorption from interdigitated regions between cement and bone has been found in postmortem-retrieved knee replacements, but the viability of interdigitated bone, and the mechanism responsible for this bone loss is not known. In this work, a Sprague-Dawley (age 12 weeks) rat knee replacement model with an interdigitated cement-bone interface was developed. Morphological and cellular changes in the interdigitated region of the knee replacement over time (0, 2, 6, or 12 weeks) were determined for ovariectomy (OVX) and Sham OVX treatment groups. Interdigitated bone volume fraction (BV/TV) increased with time for Sham OVX (0.022 BV/TV/wk) and OVX (0.015 BV/TV/wk) group, but the rate of increase was greater for the Sham OVX group (p = 0.0064). Tissue mineral density followed a similar increase with time in the interdigitated regions. Trabecular resorption, when it did occur, started at the cement border with medullary-adjacent bone in the presence of osteoclasts. There was substantial loss of viable bone (~80% empty osteocyte lacunae) in the interdigitated regions. Pre-surgical fluorochrome labels remained in the interdigitated regions, and did not diminish with time, indicating that the bone was not remodeling. There was also some evidence of continued surface mineralization in the interdigitated region after cementing of the knee, but this diminished over time. Statement of clinical significance: Interdigitated bone with cement provides mechanical stability for success of knee replacements. Improved understanding of the fate of the interdigitated bone over time could lead to a better understanding of the loosening process and interventions to prevent loss of fixation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2163-2171, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)