Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing.

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

Effects of Radiotherapy Upon Bone Structure-Strength Relationships Vary With Sex and Fractionation of Dosing.

Background: Radiotherapy for tumor treatment in or near bones often causes osteopenia and/or osteoporosis, and the resulting increased bone fragility can lead to pathologic fractures. Bone mineral density (BMD) is often used to screen for fracture risk, but no conclusive relationship has been established between BMD and the microstructural/ biomechanical changes in irradiated bone. Understanding the effects of radiation dosing regimen on the bone structure-strength relationship would improve the ability to reduce fracture-related complications resulting from cancer treatment. Methods: Thirty-two C57B6J mice aged 10 - 12 weeks old were randomized to single dose (1 x 25 Gy) and fractionated dose (5 x 5 Gy) irradiation groups. Right hindlimbs were irradiated while the contralateral hindlimbs served as the non-irradiated control. Twelve weeks after irradiation, BMD and bone microstructure were assessed with micro-computed tomography, and mechanical strength/stiffness was assessed with a torsion test. The effects of radiation dosing regimen on bone microstructure and strength were assessed using ANOVA, and bone strength-structure relationships were investigated through correlation analysis of microstructural and mechanical parameters. Results: Fractionated irradiation induced significantly greater losses in BMD in the femur (23% - male mice, p=0.016; 19% - female mice) and the tibia (18% - male mice; 6% - female mice) than the single-dose radiation. The associated reductions in trabecular bone volume (-38%) and trabecular number (-34% to -42%), and the increase in trabecular separation (23% to 29%) were only significant in the male mice with fractionated dosing. There was a significant reduction in fracture torque in the femurs of male (p=0.021) and female (p=0.0017) mice within the fractionated radiation group, but not in the single dose radiation groups. There was moderate correlation between bone microstructure and mechanical strength in the single-dose radiation group (r = 0.54 to 0.73), but no correlation in the fractionated dosing group (r=0.02 to 0.03). Conclusion: Our data indicate more detrimental changes in bone microstructure and mechanical parameters in the fractionated irradiation group compared to the single dose group. This may suggest the potential for protecting bone if a needed therapeutic radiation dose can be delivered in a single session rather than administered in fractions.

Characteristics and Long-Term Outcome of Surgically Managed High-Grade Extremity Chondrosarcoma.

Background: Dedifferentiated chondrosarcoma (DCS) is a highly malignant variant that portends a poor prognosis. Although factors such as clinico-pathological characteristics, surgical margin, and adjuvant modalities likely play a role in overall survival, debate continues with varying results on the importance of these indicators. The purpose of this study is (1) To delineate the characteristics, local recurrence (LR), and survival of patients with intermediate (IGCS), high (HGCS) and dedifferentiated (DCS) chondrosarcoma of the extremity by utilizing detailed cases at one tertiary institution. (2) To assess survival between high grade chondrosarcoma and DCS utilizing a less detailed but large cohort from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Twenty-six cases of high-grade (conventional FNCLCC grades 2 and 3, dedifferentiated) chondrosarcoma were identified from an ongoing prospective cohort of 630 sarcoma patients managed surgically at a tertiary referral university hospital between 9/1/2010-12/30/2019. A retrospective review of demographics, tumor characteristics, surgical procedure, treatment course, and survival data was performed to determine prognostic factors for survival. An additional 516 cases of chondrosarcoma were identified from the SEER database. Using the Kaplan-Meier method, both the large database and case series were evaluated, and estimated cause-specific survival was calculated at 1, 2, and 5 years. Results: There were 12 IGCS, 5 HGCS, and 9 DCS patients in the single institution cohort. DCS had a higher stage at diagnosis (p=0.04). Limb salvage was the most common procedure performed in every group (11/12 IGCS, 5/5 HGCS, and 7/9 DCS; p=0.56). Margins included 8/12 wide and 3/12 intralesional for IGCS. For HGCS, there were 3/5 wide, 1/5 marginal, and 1/5 intralesional. A majority of DCS margins were wide (8/9) with only 1 marginal. There was no difference of associated margins between the groups (p=0.85), however there was a difference when margins were classified based on numerical measurement (IGCS: 0.125cm (0.1-0.35); HGCS: 0cm (0-0.1); DCS: 0.2cm (0.1-0.5); p=0.03). The overall median follow-up was 26 months (IQR:16.1-70.8). The time interval from resection to death was lower in DCS (11.5 months (10.7-12.2)), followed by IGCS (30.3 months (16.2-78.2)), and HGCS (55.1 months (32.0-78.2; p=0.047). LR occurred in 5/9 DCS, 1/5 HGCS, and 1/14 IGCS patients. Of the DCS patients only 2/6 who received systemic therapy had LR, while all 3/3 who did not receive systemic therapy had LR. Overall systemic therapy and radiation did not impact incidence of LR (p=0.67; p=0.34). However, patients who had LR were 17.5 times more likely to die within one year (HR=17.5, 95%CI (1.01-303.7), p=0.049), after adjusting for the age at the surgery. There was no correlation with the utilization of systemic therapy, radiation therapy, or margin and overall survival (p=0.63, p=0.52, p=0.74). In the SEER patient cohort, 149 cases (28.9%) were DCS and 367 (71.1%) were HGCS. At final follow-up, 49.6% (n=256) of the cohort had a cause of death due to chondrosarcoma. HGCS was associated with higher chance of 1-year survial (p<0.001), 2-year survival (p<0.001), 5-year survival (p<0.001), and overall survival (p<0.001). Additionally, decreased survival was associated with metastatic disease at presentation (p=0.01). Overall limb salvage was most utilized for both HGCS (76.5%) and DCS (74.3%). In regard to limb salvage vs. amputation, there was no difference in survival at 1 year (p=0.10) or 2 year (p=0.13) between the groups, however those who underwent limb salvage procedure had a significantly better chance of survival at 5 years when compared to amputation (HR=1.49 (1.11-1.99); p=0.002). Conclusion: High-grade chondrosarcoma remains a fatal disease in many patients, particularly if associated with dedifferentiated subtype. Interestingly, all (100%) DCS patients who did not receive systemic therapy had LR. However, chemotherapy and radiation did not significantly increase survival. In this case series and large database study, HGCS had the smallest surgical margin, but with the longest time interval for both LR and death. Additionally, using the SEER database, DCS and amputation had worse prognosis at the 5-year survival time. Further studies on valuable prognostic influences as well as earlier identification of this rare disease may help in developing better management options. Level of Evidence: III.

Finite Element Model-Computed Mechanical Behavior of Femurs with Metastatic Disease Varies Between Physiologic and Idealized Loading Simulations.

Background and objectives: Femurs affected by metastatic bone disease (MBD) frequently undergo surgery to prevent impending pathologic fractures due to clinician-perceived increases in fracture risk. Finite element (FE) models can provide more objective assessments of fracture risk. However, FE models of femurs with MBD have implemented strain- and strength-based estimates of fracture risk under a wide variety of loading configurations, and "physiologic" loading models typically simulate a single abductor force. Due to these variations, it is currently difficult to interpret mechanical fracture risk results across studies of femoral MBD. Our aims were to evaluate (1) differences in mechanical behavior between idealized loading configurations and those incorporating physiologic muscle forces, and (2) differences in the rankings of mechanical behavior between different loading configurations, in FE simulations to predict fracture risk in femurs with MBD. Methods: We evaluated 9 different patient-specific FE loading simulations for a cohort of 54 MBD femurs: strain outcome simulations-physiologic (normal walking [NW], stair ascent [SA], stumbling), and joint contact only (NW contact force, excluding muscle forces); strength outcome simulations-physiologic (NW, SA), joint contact only, offset torsion, and sideways fall. Tensile principal strain and femur strength were compared between simulations using statistical analyses. Results: Tensile principal strain was 26% higher (R 2 = 0.719, P < .001) and femur strength was 4% lower (R 2 = 0.984, P < .001) in simulations excluding physiologic muscle forces. Rankings of the mechanical predictions were correlated between the strain outcome simulations (ρ = 0.723 to 0.990, P < .001), and between strength outcome simulations (ρ = 0.524 to 0.984, P < .001). Conclusions: Overall, simulations incorporating physiologic muscle forces affected local strain outcomes more than global strength outcomes. Absolute values of strain and strength computed using idealized (no muscle forces) and physiologic loading configurations should be used within the appropriate context when interpreting fracture risk in femurs with MBD.

Adjuvant treatment of surgically treated bone metastasis patients: association with hospital characteristics and trends over time.

Patients with metastatic disease of the bone (MDB) often require surgical stabilization; however, there is not widespread consensus on subsequent adjuvant management. This study aimed to characterize utilization of perioperative adjuvant treatment among MDB patients. We identified 9413 surgically treated MDB patients with primary (breast, kidney, lung, prostate, or multiple myeloma) cancer from Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for receipt of chemotherapy, radiation, and bisphosphonates, respectively, in the adjuvant setting (90 days before or after surgery) by hospital characteristics-medical school affiliation, surgery volume, and Commission on Cancer (CoC) accreditation. Trends in treatment utilization by year of surgery were assessed via bar charts and Chi-square tests for trend. Patients surgically treated at major medical schools or high-volume facilities (compared to no medical school affiliation and low volume) had significantly higher odds of receiving radiation and chemotherapy, independent of patient and tumor characteristics (OR (95% CI); medical school: radiation 1.33 (1.19-1.49), chemotherapy 1.15 (1.02-1.30); and high volume: radiation 1.22 (1.11-1.34), chemotherapy 1.11 (1.02-1.22)). Patients surgically treated at CoC-accredited institutions, compared to non-accredited, had significantly higher odds of receiving radiation and bisphosphonates [radiation 1.24 (1.13-1.36); bisphosphonates 1.15 (1.04-1.28)]. Use of chemotherapy and bisphosphonates increased while radiation use declined over the study period from 1991 to 2014. Medical school affiliation, hospital volume, and CoC accreditation are associated with receipt of adjuvant treatment to prevent or manage pathologic fractures in MDB patients. Further investigation is needed to determine whether these associations reflect delivery of optimal care.

Transcutaneous Oximetry Does Not Reliably Predict Wound-healing Complications in Preoperatively Radiated Soft Tissue Sarcoma.

BACKGROUND: Surgical wound-healing complications after tumor resections in tissue that has been preoperatively radiated are a major clinical problem. Most studies have reported that complications occur in more than 30% of patients undergoing such resections in the lower extremity. There is currently no available method to predict which patients are likely to have a complication. Transcutaneous oximetry has been identified in preliminary studies as potentially useful, but the available evidence on its efficacy for this application thus far is inconclusive. QUESTIONS/PURPOSES: (1) Does transcutaneous oximetry measurement below 25 mmHg at any location in the surgical wound bed predict a wound-healing complication? (2) Does recovery (increase) in transcutaneous oxygen measurement during the rest period between the end of radiation and the time of surgery protect against wound-healing complications? METHODS: A prospective, multi-institution study was coordinated to measure skin oxygenation at three timepoints in patients undergoing surgery for a lower extremity soft tissue sarcoma after preoperative radiation. Between 2016 and 2020, the five participating centers treated 476 patients for lower extremity soft tissue sarcoma. Of those, we considered those with a first-time sarcoma treated with radiation before limb salvage surgery as potentially eligible. Based on that, 21% (98 of 476) were eligible; a further 12% (56 of 476) were excluded because they refused to participate or ultimately, they were treated with a flap, amputation, or skin graft. Another 1% (3 of 476) of patients were lost because of incomplete datasets or follow-up less than 6 months, leaving 8% (39 of 476) for analysis here. The mean patient age was 62 ± 14 years, 62% (24 of 39) of the group were men, and 18% (7 of 39) of patients smoked cigarettes; 87% (34 of 39) of tumors were intermediate/high grade, and the most common histologic subtype was undifferentiated pleomorphic sarcoma. In investigating complications, a cutoff of 25 mmHg was chosen based on a pilot investigation that identified this value. All patients were assessed for surgical wound-healing complications, which were defined as: those resulting in a return to the operating room, initiation of oral or IV antibiotics, intervention for seroma, or prolonged wound packing or dressing changes. To answer the first research question, we compared the proportion of patients who developed a wound-healing complication between those patients who had any reading below 25 mmHg (7 of 39) and those who did not (32 of 39). To answer the second question, we compared the group with stable or decreased skin oxygenation (22 of 37 patient measurements [two patients missed the immediate postoperative measurement]) to the group that had increased skin oxygen measurement (15 of 37 measurements) during the period between the end of radiation and the surgical procedure; again, the endpoint was the development of a wound-healing complication. This study was powered a priori to detect an unadjusted odds ratio for wound-healing complications as small as 0.71 for a five-unit (5 mmHg) increase in TcO 2 between the groups, with α set to 0.05, ß set to 0.2, and a sample size of 40 patients. RESULTS: We found no difference in the odds of a wound-healing complication between patients whose transcutaneous oxygen measurements were greater than or equal to 25 mmHg at all timepoints compared with those who had one or more readings below that threshold (odds ratio 0.27 [95% confidence interval (CI) 0.05 to 1.63]; p = 0.15). There was no difference in the odds of a wound-healing complication between patients who had recovery of skin oxygenation between radiation and surgery and those who did not (OR 0.63 [95% CI 0.37 to 5.12]; p = 0.64). CONCLUSION: Transcutaneous oximetry cannot be considered a reliable test in isolation to predict wound-healing complications. This may be a function of the fact that transcutaneous oximetry samples a relatively small portion of the landscape in which a wound-healing complication could potentially arise. In the absence of a reliable diagnostic test, clinicians must still use their best judgment regarding surgical timing and work to address modifiable risk factors to avoid complications. The unanswered question that remains is whether there is a skin perfusion or oxygenation issue at the root of these complications, which seems likely. Alternative approaches that can assess the wound more broadly and in real time, such as fluorescent probes, may be deserving of further investigation. LEVEL OF EVIDENCE: Level II, diagnostic study.

T2* Imaging Assessment of Neoadjuvant Radiation Therapy Combined With Pharmacological Ascorbate in Extremity Soft-Tissue Sarcomas: A Pilot Study.

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T2*, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T2* maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T2* values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6. Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T2* measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68). Conclusion: T2* measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T2* mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV.

Mechanical Gains Associated With Virtual Prophylactic Intramedullary Nail Fixation in Femurs With Metastatic Disease.

Background: Many patients with metastatic bone disease (MBD) of the femur undergo prophylactic surgical fixation for impending pathologic fractures; intramedullary nailing (IMN) being the most common fixation type. However, surgeons often question if IMN fixation provides sufficient improvements in mechanical strength for particular metastatic lesions. Our goal was to use patient-specific finite element (FE) modeling to computationally evaluate the effects of simulated IMN fixation on the mechanics of femurs affected with MBD. Methods: Computed tomography (CT) scans were available retrospectively from 48 patients (54 femurs) with proximal femoral metastases. The CT scans were used to create patient-specific, non-linear, voxel-based FE models of the femur, simulating the instant of peak hip joint contact force during normal walking. FE analyses were repeated after incorporating virtual IMN fixation (Smith and Nephew, TRIGEN INTERTAN) into the same femurs. Femur strength and load-to-strength ratio (LSR; lower LSR indicates lower fracture risk) were compared between untreated and IMN conditions using statistical analyses. Results: IMN fixation resulted in a very modest average 10% increase in mechanical strength (p<0.001), which was associated with a slight 7% reduction in fracture risk (p<0.001). However, there was considerable variation in fracture risk reduction between individual femurs (0.13-50%). In femurs with the largest reduction in fracture risk (>10%), IMN hardware directly passed through a considerable section of that femur's metastatic lesion. Femurs with lytic (10%) and diffuse (9%) metastases tended to have greater reductions in fracture risk compared to femurs with blastic (5%) and mixed (4%) metastases (p=0.073). Conclusion: Given the mechanically strong baseline condition of most femurs in this cohort, evident by the low fracture risk at the time of CT scanning, the relative increase in stiffness with the addition of the IMN hardware may not make a substantial contribution to overall mechanical strength. The mechanical gains of IMN fixation in femurs with MBD appear most beneficial when the hardware traverses an adequate section of the lesion. Level of Evidence: III.

A Pilot Study of Nutritional Supplementation in Soft Tissue Sarcoma Patients.

Background: Wound healing is particularly important for sarcoma patients who undergo neoadjuvant radiation therapy. Previous studies have demonstrated wound complications in this population approaching 35%. With this high rate of wound healing issues, identifying treatment modalities to minimize these complications is of paramount importance. Methods: All patients with high grade bone and soft tissue sarcoma received 15 days of twice daily amino acid supplementation starting in the immediate post-operative period. We documented the healing status of the surgical wound, the primary outcome, at all follow up appointments until six months after surgery. Non-healing wounds were defined as any wound requiring 1) a return visit to the OR for debridement, 2) IV antibiotics (ABX), and 3) unhealed wounds at 6 months post-operatively.1 For each patient, we collected biometrics with lean body mass analysis at preoperative appointment, and two and six weeks postoperatively. The proportion with non-healing wounds was compared with a historical patient cohort using the chi-square test. In a subgroup of participants with body composition measurements, we also compared changes in mean fat mass, lean mass, and psoas index from pre-operative baseline to 6 months post-operative using generalized linear models. Results: A total of 33 consecutive patients were supplemented with a branched chain amino acid (BCAA) formulation. The historical cohort included 146 participants from the previous 7 years (2010-2017). 26% of patients in the historical cohort experienced wound complications compared to 30% in the supplemented group. (p=0.72) When focusing specifically on lower extremity sarcomas treated with neoadjuvant radiation therapy, 46% of patients in the supplemented group experienced wound healing complications compared to 39% in the non-supplemented group (p=0.68). BCAA supplementation was found to be protective with regards to decreasing muscle wasting with no difference in psoas index measurements throughout the study period compared to a 20% muscle loss in the historical cohort (p=0.02). Conclusion: In our limited sample size, there was no difference in wound healing complications between sarcoma patients who received postoperative BCAA supplementation compared to a historical cohort who were not supplemented. Patients who did not receive supplementation had a significant decline in post-operative psoas index following operative sarcoma removal. Level of Evidence: III.

The Influence of Hospital Characteristics on Patient Survival in Surgically Managed Metastatic Disease of Bone: An Analysis of the SEER-Medicare Linked Database.

OBJECTIVES: We investigated whether patients receiving surgical treatment for metastatic disease of bone (MDB) at hospitals with higher volume, medical school affiliation, or Commission on Cancer accreditation have superior outcomes. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 9413 patients surgically treated for extremity MDB between 1992 and 2014 at the age of 66 years or older. Cox proportional hazards models were used to calculate the hazards ratios (HR) for 90-day and 1-year mortality and 30-day readmission according to the characteristics of the hospital where bone surgery was performed. RESULTS: We observed no notable differences in 90-day mortality, 1-year mortality, or 30-day readmission associated with hospital volume. Major medical school affiliation was associated with lower 90-day (HR: 0.88, 95% confidence interval [CI]: 0.80-0.96) and 1-year (HR: 0.92, 95% CI: 0.87-0.99) mortality after adjustments for demographic and tumor characteristics. Surgical treatment at Commission on Cancer accredited hospitals was associated with significantly higher risk of death at 90 days and 1 year after the surgery. This effect appeared to be driven by lung cancer patients (1-year HR: 1.17, 95% CI: 1.07-1.27). CONCLUSIONS: Our findings suggest surgical management of MDB at lower-volume hospitals does not compromise survival or readmissions. There may be benefit to referral or consultation with an academic medical center in some tumor types or clinical scenarios.

The Relationship Between Lesion Size and Load to Failure After Stabilization of Simulated Metastatic Lesions of the Proximal Femur.

Background: As overall cancer survival continues to improve, the incidence of metastatic lesions to the bone continues to increase. The subsequent skeletal related events that can occur with osseous metastasis can be debilitating. Complete and impending pathologic femur fractures are common with patients often requiring operative fixation. However, the efficacy of an intramedullary nail construct, on providing stability, continue to be debated. Therefore, the purpose of this study was to utilize a synthetic femur model to determine 1) how proximal femur defect size and cortical breach impact femur load to failure (strength) and stiffness, and 2) and how the utilization of an IMN, in a prophylactic fashion, subsequently alters the overall strength and stiffness of the proximal femur. Methods: A total of 21 synthetic femur models were divided into four groups: 1) intact (no defect), 2) 2 cm defect, 3) 2.5 cm defect, and 4) 4 cm defect. An IMN was inserted in half of the femur specimens that had a defect present. This procedure was performed using standard antegrade technique. Specimens were mechanically tested in offset torsion. Force-displacement curves were utilized to determine each constructs load to failure and overall torsional stiffness. The ultimate load to failure and construct stiffness of the synthetic femurs with defects were compared to the intact synthetic femur, while the femurs with the placement of the IMN were directly compared to the synthetic femurs with matching defect size. Results: The size of the defect invertedly correlated with the load the failure and overall stiffness. There was no difference in load to failure or overall stiffness when comparing intact models with no defect and the 2 cm defect group (p=0.98, p=0.43). The 2.5 cm, and 4.5 cm defect groups demonstrated significant difference in both load to failure and overall stiffness when compared to intact models with results demonstrating 1313 N (95% CI: 874-1752 N; p<0.001) and 104 N/mm (95% CI: 98-110 N/mm; p=0.03) in the 2.5 cm defect models, and 512 N (95% CI: 390-634 N, p<0.001) and 21 N/mm (95% CI: 9-33 N/mm, p<0.001) in the models with a 4 cm defect. Compared to the groups with defects, the placement an IMN increased overall stiffness in the 2.5 cm defect group (125 N/mm; 95% CI:114-136 N/mm; p=0.003), but not load to failure (p=0.91). In the 4 cm defect group, there was a significant increase in load to failure (1067 N; 95% CI: 835-1300 N; p=0.002) and overall stiffness (57 N/mm; 95% CI:46-69 N/mm; p=0.001). Conclusion: Prophylactic IMN fixation significantly improved failure load and overall stiffness in the group with the largest cortical defects, but still demonstrated a failure loads less than 50% of the intact model. This investigation suggests that a cortical breach causes a loss of strength that is not completely restored by intramedullary fixation. Level of Evidence: II.

Detection of Ferritin Expression in Soft Tissue Sarcomas With MRI: Potential Implications for Iron Metabolic Therapy.

Background: Cancer cells often have altered iron metabolism relative to non-malignant cells with increased transferrin receptor and ferritin expression. Targeting iron regulatory proteins as part of a cancer therapy regimen is currently being investigated in various malignancies. Anti-cancer therapies that exploit the differences in iron metabolism between malignant and non-malignant cells (e.g. pharmacological ascorbate and iron chelation therapy) have shown promise in various cancers, including glioblastoma, lung, and pancreas cancers. Non-invasive techniques that probe tissue iron metabolism may provide valuable information for the personalization of iron-based cancer therapies. T2* mapping is a clinically available MRI technique that assesses tissue iron content in the heart and liver. We aimed to investigate the capacity of T2* mapping to detect iron stores in soft tissue sarcomas (STS). Methods: In this study, we evaluated T2* relaxation times ex vivo in five STS samples from subjects enrolled on a phase Ib/IIa clinical trial combining pharmacological ascorbate with neoadjuvant radiation therapy. Iron protein expression levels (ferritin, transferrin receptor, iron response protein 2) were evaluated by Western blot analysis. Bioinformatic data relating clinical outcomes in STS patients and iron protein expression levels were evaluated using the KMplotter database. Results: There was a high level of inter-subject variability in the expression of iron protein and T2* relaxation times. We identified that T2* relaxation time is capable of accurately detecting ferritin-heavy chain expression (r = -0.96) in these samples. Bioinformatic data acquired from the KMplot database revealed that transferrin receptor and iron-responsive protein 2 may be negative prognostic markers while ferritin expression may be a positive prognostic marker in the management of STS. Conclusion: These data suggest that targeting iron regulatory proteins may provide a therapeutic approach to enhance STS management. Additionally, T2* mapping has the potential to be used a clinically accessible, non-invasive marker of STS iron regulatory protein expression and influence cancer therapy decisions that warrants further investigation. Level of Evidence: IV.

Local Recurrence of Soft Tissue Sarcoma Revisited: Is there a Role for "Selective" Radiation?

Background: Radiation therapy (RT) is often utilized in cases of high-grade soft tissue sarcoma (STS), but there remain situations where treatment is with surgical excision alone. Our goals were to determine (1) the local recurrence (LR) rate with and without perioperative RT and (2) associations between local recurrence, patient, tumor, and treatment variables. Methods: We performed a retrospective review of 165 consecutive STS patients. A Cox proportional hazards model was used to investigate variables associated with local recurrence. Results: LR occurred in 15/78 (19%) without RT, 4/29 (14%) with postoperative RT, and 0/58 with preoperative RT (p=0.002). We found increased rates of local recurrence at 24 months for myxofibrosarcoma (p=0.001) and no-RT (p=0.003). Myxofibrosarcoma accounted for 33 (20%) of the study patients and 12 (63%) of the local recurrences. Conclusion: The LR rate in patients treated with surgery alone was disproportionately attributable to myxofibrosarcoma (11/23 cases, 48%). Other subtypes demonstrated a lower rate of LR in the absence of RT (4/55 cases, 7%), and no LR occurred when final margins were >2 mm. In certain circumstances treatment with a negative margin surgical resection followed by close observation is justifiable. RT is effective and should continue to be considered routinely in myxofibrosarcoma or when surgical margins are inadequate. Level of Evidence: III.

Finite element analysis potentially identifies nonessential prophylactic stabilization in femurs with metastatic disease.

Metastatic bone disease (MBD) is often managed by non-specialized orthopedic surgeons who rely on Mirels' criteria to predict pathologic fracture risk. However, low specificity of Mirels' criteria implies many lesions are scored at high fracture risk when the actual mechanical fracture risk is minimal. Our goal was to retrospectively compare mechanical fracture risk in MBD patients to Mirels' score and clinical treatment received. Using a CT-based finite element (FE) model of the proximal femur affected by MBD, femur strength and load-to-strength ratio (LSR) were determined for 52 femurs from 48 patients. Associations of femur strength with pain and Mirels' scores (Pearson r/Spearman ρ correlations), and the decision to operate (percentile analysis), and associations of LSR with pain and Mirels' scores (Spearman correlations) were determined. Nineteen of 52 femurs (37%) had a very low computed mechanical fracture risk (LSR < 0.4); 5 of those 19 underwent prophylactic stabilization, suggesting that clinical decision-making in MBD is substantially influenced by non-mechanical factors that likely overestimate pathologic fracture risk. Of the 30 femurs managed non-operatively, 24 had a low computed mechanical fracture risk (LSR ≤ 0.5), none of which (0%) experienced a fracture within 9 months. Patient-reported pain did not correlate with femur strength (r = -0.05, p = 0.748) nor with LSR (ρ = 0.07, p = 0.632). Mirels' score correlated weakly with femur strength (ρ = -0.32, p = 0.019) and with LSR (ρ = 0.29, p = 0.034). Computational mechanical tools like this FE model could be used as a clinical decision aid when considering non-surgical management in appropriate patients, potentially alleviating nonessential surgical treatment in some patients with femur MBD.

The preoperative machine learning algorithm for extremity metastatic disease can predict 90-day and 1-year survival: An external validation study.

BACKGROUND: The prediction of survival is valuable to optimize treatment of metastatic long-bone disease. The Skeletal Oncology Research Group (SORG) machine-learning (ML) algorithm has been previously developed and internally validated. The purpose of this study was to determine if the SORG ML algorithm accurately predicts 90-day and 1-year survival in an external metastatic long-bone disease patient cohort. METHODS: A retrospective review of 264 patients who underwent surgery for long-bone metastases between 2003 and 2019 was performed. Variables used in the stochastic gradient boosting SORG algorithm were age, sex, primary tumor type, visceral/brain metastases, systemic therapy, and 10 preoperative laboratory values. Model performance was calculated by discrimination, calibration, and overall performance. RESULTS: The SORG ML algorithms retained good discriminative ability (area under the cure [AUC]: 0.83; 95% confidence interval [CI]: 0.76-0.88 for 90-day mortality and AUC: 0.84; 95% CI: 0.79-0.88 for 1-year mortality), calibration, overall performance, and decision curve analysis. CONCLUSION: The previously developed ML algorithms demonstrated good performance in the current study, thereby providing external validation. The models were incorporated into an accessible application (https://sorg-apps.shinyapps.io/extremitymetssurvival/) that may be freely utilized by clinicians in helping predict survival for individual patients and assist in informative decision-making discussion before operative management of long bone metastatic lesions.

Novel Scoring Criteria for Preoperative Prediction of Neoadjuvant Chemotherapy Response in Osteosarcoma.

Background: The extent of tumor necrosis after neoadjuvant chemotherapy is an important predictive factor of survival in osteosarcoma. However, the response to chemotherapy is not known until after the definitive resection and limits the utility of this information for operative planning. Our study questions include: 1) Are there clinical and radiographic factors following neoadjuvant chemotherapy, but prior to the tumor resection, that may aid in predicting response to treatment? 2) Can we combine these criteria into a predictive composite score that can identify good and poor responders to chemotherapy? Methods: We identified consecutive patients diagnosed with osteosarcoma and managed with neoadjuvant chemotherapy prior to surgical resection. We assessed post-chemotherapy tumor ossification, tumor size and growth, and the presence of pain to devise a scoring criteria to predict the percent necrosis on the final histologic specimen. Bivariate analyses were done, and a receiver operating characteristic curve was constructed to determine predictive capacity. Results: Out of the 40 patients included in this study, 15 (38%) had a good response (≥ 90% necrosis) to treatment and ten patients (25%) had a poor response with ≤ 50% necrosis. Tumor size, growth and increase in ossification were significantly associated with a good response to treatment. For good responders, a composite score of 6 was seen to attain the highest sensitivity and specificity, 100% and 84%, respectively. Tumor size, no change in ossification, and post-chemotherapy pain were significantly associated with a poor response to treatment. For poor responders, a composite score of 7 was seen to have the highest sensitivity and specificity, 100% and 63%, respectively. Conclusion: Compared to the use of one single factor, our combined scoring criteria demonstrated a far improved accuracy in identifying good responders to neoadjuvant chemotherapy, where a score of 6 or less is predictive of a good response. However, the specificity of this scoring criteria to predict poor responders was low, indicating that this criterion may not be the most accurate method to identify poor responders. The utility of this score has implications regarding pre-operative counseling of the patient and operative planning.Level of Evidence: III.

Accuracy of X-Ray and Magnetic Resonance Imaging in Defining the Tumor Margin in Primary Bone Sarcoma.

Background: Limb-salvage surgery for primary bone sarcomas are preceded by X-ray and MRI for surgical planning. However, the accuracy of X-ray and MRI predicted margins are not well described. Our study examined these questions: (1) How accurately do X-ray and MRI margin measurements reflect the true margin on pathology reports? (2) Do X-ray or MRI margin measurements have smaller differences compared to pathology reports? (3) How many X-ray or MRI margin measurement differences were greater than 1 cm, 2 cm, and 3 cm from pathology reports? (4) Is there an X-ray or MRI view that consistently results in a smaller difference from pathology reports? Methods: This retrospective chart review examined patients with primary bone sarcoma treated with limb-salvage surgery. Reviewers used electronic measurement tools to determine margins from X-ray or MRI based on the resection length of the pathologic specimen. Mean differences of margin measurements to pathology reports were calculated. We determined outliers of imaging margin measurements at 1 cm, 2 cm, and 3 cm differences to pathology reports. Results: In the total cohort of 39 patients, the mean difference of X-ray and MRI margins compared to pathology reports were 1.09 cm (st dev 0.79 cm) and 0.71 cm (st dev 0.70 cm), respectively. MRI margin measurements had smaller differences compared to pathology reports than X-ray in 32 of 38 cases (84%) with complete imaging. X-ray outliers at 1 cm, 2 cm, and 3 cm differences were 36, 14 and 2 respectively for 70 margin measurements and MRI outliers at 1 cm, 2 cm, and 3 cm differences were 17, 6, and 0 respectively for 66 margin measurements. The views with the smallest difference were anterior-posterior X-rays and MRI views with the closest predicted margin. Conclusion: Electronic MRI margin measurements with the closest predicted margin provided the smallest differences with pathology reports and are therefore the most accurate for preoperative planning. When there is adequate residual diaphysis for reconstructive fixation, surgeons should plan for a 3 cm bone margin using MRI measurements to ensure complete removal of the intramedullary extent of sarcoma.Level of Evidence: IV.

Skeletal Related Events are Rare After Radiation Treatment for Metastatic Disease of the Femur.

BACKGROUND: Pain is a common presenting symptom in patients with metastatic disease to the femur (MDF), and it is often difficult to differentiate pain from the tumor itself versus pain from an impending pathologic fracture. Radiation therapy (RT) is commonly used in the management of pain secondary to MDF but is not adequate in isolation when the underlying bone is structurally compromised. QUESTIONS/ PURPOSES: The purposes of this study were to determine 1) the incidence of skeletal related events (SREs) following RT to the femur, 2) the frequency and implications of orthopedic evaluation prior to RT, and 3) the frequency of patients presenting with a pathologic fracture. METHODS: A retrospective, single-institution review of 86 patients with MDF treated with RT from 2005 to 2018 was performed. Patient demographics, primary cancer type, pathologic fracture, orthopedic interventions, and RT details were assessed. Patients were followed to evaluate the occurrence of skeletal related events of the femur until death or time of last recorded clinical follow-up. RESULTS: In our cohort of 86 patients, the mean RT dose was 22.3 Gy (8-55.8 Gy) delivered over 6.5 fractions (1-31 fractions). Fifteen patients (17%) received RT less than one month, 30 (35%) less than three months, and 49 (57%) less than six months prior to death. Prior to RT, 42 patients (48.9%) had an orthopedic evaluation, 16 of which (38.1% of those evaluated) received prophylactic stabilization with an intramedullary nail (IMN). Ten patients (11.6%) presented with a pathologic fracture. Following RT, five patients (5.8%) had at least one SRE. Three patients sustained a pathologic fracture, three required repeat RT, and three required further surgical intervention. CONCLUSION: Metastatic disease of bone is a common condition that affects many cancer patients. In our institution's series of MDF treated with RT, we only found one patient who sustained a pathologic fracture after RT treatment with an unrecognized impending fracture. As only half of the patients were referred for an orthopedic evaluation prior to RT, continued education of medical and radiation oncologists regarding the signs and symptoms of impending pathologic fracture is warranted.Level of Evidence: IV.