What Is the Prevalence of Clinically Important Findings Among Incidentally Found Osseous Lesions?

BACKGROUND: Patients with incidentally found musculoskeletal lesions are regularly referred to orthopaedic oncology. Most orthopaedic oncologists understand that many incidental findings are nonaggressive and can be managed nonoperatively. However, the prevalence of clinically important lesions (defined as those indicated for biopsy or treatment, and those found to be malignant) remains unknown. Missing clinically important lesions can result in harm to patients, but needless surveillance may exacerbate patient anxiety about their diagnosis and accrue low-value costs to the payor. QUESTIONS/PURPOSES: (1) What percentage of patients with incidentally discovered osseous lesions referred to orthopaedic oncology had lesions that were clinically important, defined as those receiving biopsy or treatment or those found to be malignant? (2) Using standardized Medicare reimbursements as a surrogate for payor expense, what is the value of reimbursements accruing to the hospital system for the imaging of incidentally found osseous lesions performed during the initial workup period and during the surveillance period, if indicated? METHODS: This was a retrospective study of patients referred to orthopaedic oncology for incidentally found osseous lesions at two large academic hospital systems. Medical records were queried for the word "incidental," and matches were confirmed by manual review. Patients evaluated at Indiana University Health between January 1, 2014, and December 31, 2020, and those evaluated at University Hospitals between January 1, 2017, and December 31, 2020, were included. All patients were evaluated and treated by the two senior authors of this study and no others were included. Our search identified 625 patients. Sixteen percent (97 of 625) of patients were excluded because their lesions were not incidentally found, and 12% (78 of 625) were excluded because the incidental findings were not bone lesions. Another 4% (24 of 625) were excluded because they had received workup or treatment by an outside orthopaedic oncologist, and 2% (10 of 625) were excluded for missing information. A total of 416 patients were available for preliminary analysis. Among these patients, 33% (136 of 416) were indicated for surveillance. The primary indication for surveillance included lesions with a benign appearance on imaging and low clinical suspicion of malignancy or fracture. A total of 33% (45 of 136) of these patients had less than 12 months of follow-up and were excluded from further analysis. No minimum follow-up criteria were applied to patients not indicated for surveillance because this would artificially inflate our estimated rate of clinically important findings. A total of 371 patients were included in the final study group. Notes from all clinical encounters with orthopaedic and nonorthopaedic providers were screened for our endpoints (biopsy, treatment, or malignancy). Indications for biopsy included lesions with aggressive features, lesions with nonspecific imaging characteristics and a clinical picture concerning for malignancy, and lesion changes seen on imaging during the surveillance period. Indications for treatment included lesions with increased risk of fracture or deformity, certain malignancies, and pathologic fracture. Diagnoses were determined using biopsy results if available or the documented opinion of the consulting orthopaedic oncologist. Imaging reimbursements were obtained from the Medicare Physician Fee Schedule for 2022. Because imaging charges vary across institutions and reimbursements vary across payors, this method was chosen to enhance the comparability of our findings across multiple health systems and studies. RESULTS: Seven percent (26 of 371) of incidental findings were determined to be clinically important, as previously defined. Five percent (20 of 371) of lesions underwent tissue biopsy, and 2% (eight of 371) received surgical intervention. Fewer than 2% (six of 371) of lesions were malignant. Serial imaging changed the treatment of 1% (two of 136) of the patients, corresponding to a rate of one in 47 person-years. Median reimbursements to work up the incidental findings analyzed was USD 219 (interquartile range USD 0 to 404), with a range of USD 0 to 890. Among patients indicated for surveillance, the median annual reimbursement was USD 78 (IQR USD 0 to 389), with a range of USD 0 to 2706. CONCLUSION: The prevalence of clinically important findings among patients referred to orthopaedic oncology for incidentally found osseous lesions is modest. The likelihood of surveillance resulting in a change of management was low, but the median reimbursements associated with following these lesions was also low. We conclude that after appropriate risk stratification by orthopaedic oncology, incidental lesions are rarely clinically important, and judicious follow-up with serial imaging can be performed without incurring high costs. LEVEL OF EVIDENCE: Level III, therapeutic study.

Ninety Percent or Greater Tumor Necrosis Is Associated With Survival and Social Determinants of Health in Patients With Osteosarcoma in the National Cancer Database.

BACKGROUND: The histologic response of osteosarcoma to chemotherapy is commonly cited as a prognostic factor and typically graded as the percent necrosis of the tumor at the time of surgical resection. Few studies, to our knowledge, have examined the relationship of tumor necrosis relative to other factors. Existing studies are limited by prolonged enrollment periods or analysis of patient subsets without the strongest predictor of mortality: metastasis at diagnosis. Additionally, the definitive threshold value for a good histologic response is commonly set at more than 90% tumor necrosis with little evidence; some authors advocate other values. QUESTION/PURPOSES: (1) Are there alternative cutoff values for a good response to chemotherapy in a large, national cohort of contemporarily treated patients with osteosarcoma? (2) How does the association of histologic response to survival in osteosarcoma compare with other clinicopathologic factors? (3) What patient and clinical factors are associated with the histologic response? METHODS: We identified 2006 patients with osteosarcoma diagnosed between 2010 and 2015 in the National Cancer Database (NCDB), a registry that includes 70% of all new cancers diagnosed in the United States with 90% follow-up. Patients were excluded for missing documentation of percent tumor necrosis (21% [425 of 2006]) or if definitive resection was not performed (< 1% [1 of 2006]). A total of 1580 patients were included in the analysis, with a mean follow-up duration of 37 ± 22 months. A Kaplan-Meier survival analysis, stratified by the percent tumor necrosis after chemotherapy, was performed for the 5-year period. Other covariates examined were sex, race, socioeconomic score composite, insurance type, Charlson/Deyo score, distance from the hospital, and location (metropolitan, urban, or rural). Clinical and sociodemographic data including patient-identified race from the patient's medical record is input into the NCDB by certified registrars. The NCDB only allows coding of one primary race for each patient; thus, most of our patients were grouped as White or Black race and the remaining were grouped as Other for our analysis. A multiple Cox regression analysis was performed to evaluate the effect of percent necrosis compared with other demographic, clinicopathologic, and treatment effects on survival. Finally, a multiple logistic regression analysis was performed to assess demographic and clinicopathologic characteristics associated with percent necrosis. RESULTS: Five-year overall survival for patients with histologic gradings of 90% to 94% necrosis (70% [95% confidence interval (CI) 60.6% to 79.7%) and 95% to 100% necrosis (74% [95% CI 68% to 80.3%) was not different between groups (p = 0.47). A comparison of histologic responses below 90% necrosis found no difference in survival between patients with decreasing histologic response (p > 0.05). Necrosis of less than 90% was associated with worse survival (HR 2.00 [95% CI 1.58 to 2.52]; p < 0.001 compared with more than 90% necrosis), and factors most associated with poor survival were metastasis (HR 2.85 [95% CI 2.27 to 3.59]; p < 0.001) and skip metastasis at the time of diagnosis (HR 2.52 [95% CI 1.64 to 3.88]; p < 0.001). On multivariate analysis, adjusting for demographic, clinicopathologic, and treatment factors, social determinants of health were negatively associated with percent necrosis of 90% or more, including uninsured status (OR 0.46 [95% CI 0.23 to 0.92]; p = 0.02 compared with private insurance) and lower socioeconomic status composite (OR for the lowest first and second quartiles were 0.63 [95% CI 0.44 to 0.90]; p = 0.01 and 0.70 [95% CI 0.50 to 0.96]; p = 0.03, respectively). Race other than White or Black (OR 0.61 [95% CI 0.40 to 0.94]; p = 0.02 compared with White race) was also negatively associated with percent necrosis of more than 90% after controlling for available covariates. CONCLUSION: This study suggests that a cutoff of 90% necrosis provides the best prognostic value for patients with osteosarcoma undergoing chemotherapy. Other threshold values did not show different survival benefits. Sociodemographic factors were associated with histologic response less than 90%. These associations must be carefully understood not as cause and effect but likely demonstrating the effects of health disparities and access to care. Although we controlled for multiple variables in our analysis, broad variables such as race may have been associated with histologic response due to unaccounted confounders. Medical providers should be aware of these associations to ensure equitable access and delivery of care because access to care may be responsible for these associations. Future studies should examine potential drivers of this observation, such as a delay in presentation or deviation from standard of care practices. LEVEL OF EVIDENCE: Level III, therapeutic study.

Flexible intramedullary nailing of femoral shaft fractures: closed versus open reduction.

Children's femoral shaft fractures are commonly treated with flexible intramedullary nailing after closed or open reduction, but there is little information concerning indications for open reduction. The purpose of this study was to determine radiographic and clinical features likely to lead to open reduction before flexible intramedullary nailing. Record review identified 158 femoral shaft fractures treated with flexible intramedullary nailing. In addition to patient demographics and mechanism of injury, data obtained included surgeon name, estimated blood loss, type of reduction, type and diameter of nail, type of operating table, the use of percutaneous reduction techniques or supplemental casting, time to and duration of surgery, total time in operating room, and time to union. Fracture ratios were calculated based on established radiographic protocol. Of 158 fractures, 141 were treated with closed reduction and 17 with open reduction. The anteroposterior fracture index (1.3 ± 0.4, P = 0.0007), surgeon (P = 0.002), and flattop operating table (0.05) were associated with open reduction. Smaller lateral diameter of bone at the fracture site, transverse fracture, and surgeon were all found to be independent risk factors for open reduction; patient characteristics, including age, sex, and BMI, did not seem to influence the choice of open reduction. Fractures with a lower fracture index or pattern resembling a transverse fracture rather than oblique or spiral had an increased risk of converting to an open reduction. Surgeon preference and use of flattop tables also had a significant influence on how the fracture was treated.

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.