Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases.

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression of genes repressed by histone methyltransferase EZH2, including members of the WNT pathway, a known target pathway of EZH2. Exogenous IL-11 increased the global levels of histone H3 lysine 27 trimethylation, evidence of EZH2 activation. Treatment with the EZH2 inhibitor GSK126 significantly reduced in vitro proliferation and increased cell-cycle arrest and apoptosis, which were partially mediated through the WNT pathway. In vivo, treatment of an orthotopic nude mouse model of OS with GSK126 inhibited lung metastatic growth and prolonged survival. In addition, significantly shorter recurrence-free survival was seen in OS patients with high levels of EZH2 in their primary tumors (P < .05). This suggests that IL-11Rα promotes OS lung metastasis via activation of EZH2. Thus, blocking EZH2 activity may be an effective strategy for inhibiting OS lung metastasis and improving prognosis.

Changes in walking function and neural control following pelvic cancer surgery with reconstruction.

Introduction: Surgical planning and custom prosthesis design for pelvic cancer patients are challenging due to the unique clinical characteristics of each patient and the significant amount of pelvic bone and hip musculature often removed. Limb-sparing internal hemipelvectomy surgery with custom prosthesis reconstruction has become a viable option for this patient population. However, little is known about how post-surgery walking function and neural control change from pre-surgery conditions. Methods: This case study combined comprehensive walking data (video motion capture, ground reaction, and electromyography) with personalized neuromusculoskeletal computer models to provide a thorough assessment of pre- to post-surgery changes in walking function (ground reactions, joint motions, and joint moments) and neural control (muscle synergies) for a single pelvic sarcoma patient who received internal hemipelvectomy surgery with custom prosthesis reconstruction. Pre- and post-surgery walking function and neural control were quantified using pre- and post-surgery neuromusculoskeletal models, respectively, whose pelvic anatomy, joint functional axes, muscle-tendon properties, and muscle synergy controls were personalized using the participant's pre-and post-surgery walking and imaging data. For the post-surgery model, virtual surgery was performed to emulate the implemented surgical decisions, including removal of hip muscles and implantation of a custom prosthesis with total hip replacement. Results: The participant's post-surgery walking function was marked by a slower self-selected walking speed coupled with several compensatory mechanisms necessitated by lost or impaired hip muscle function, while the participant's post-surgery neural control demonstrated a dramatic change in coordination strategy (as evidenced by modified time-invariant synergy vectors) with little change in recruitment timing (as evidenced by conserved time-varying synergy activations). Furthermore, the participant's post-surgery muscle activations were fitted accurately using his pre-surgery synergy activations but fitted poorly using his pre-surgery synergy vectors. Discussion: These results provide valuable information about which aspects of post-surgery walking function could potentially be improved through modifications to surgical decisions, custom prosthesis design, or rehabilitation protocol, as well as how computational simulations could be formulated to predict post-surgery walking function reliably given a patient's pre-surgery walking data and the planned surgical decisions and custom prosthesis design.

Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Percutaneous Cementation for Improvement of Pain and Function for Osteolytic Pelvic Metastasis: A Systematic Review.

INTRODUCTION: Pelvic metastasis is a common presentation among patients presenting with skeletal metastasis. Image-guided percutaneous cementation of these lesions is becoming increasingly popular for the treatment of these lesions. The objective of this study was to conduct a systematic review that investigates clinical outcomes after percutaneous cementation for pelvic metastasis. METHODS: A systematic review was registered with International Prospective Register of Systematic Reviews and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I to IV clinical studies published in the English language investigating the clinical outcomes after percutaneous cementation for pelvic metastasis were included. RESULTS: Fourteen studies with 579 patients (278 men, 301 women) and 631 metastatic pelvic lesions were included in the study. The mean follow-up range was 0.7 to 26.4 months. Percutaneous cementation alone was performed in 441 patients (76.2%). Supplemental ablative procedures were performed in 77 patients (13.3%), and supplemental internal fixation using cannulated screws was performed in 107 patients (18.5%). Twelve studies with 430 patients (74.2%) reported pain-related and/or functional outcome scores, of which all studies reported overall clinically notable improvement at short-term follow-up. All studies reported periprocedural complications. Local cement leakage was the most common complication (162/631 lesions, 25.7%) followed by transient local pain (25/579 patients, 4.3%). There were no reported cases of major complications. Seven patients (1.2%) underwent re-intervention for persistent symptoms. CONCLUSIONS: Percutaneous cementation may be an effective method for treating pain and function related to pelvic metastasis. The most common complication was cement leakage surrounding the lesion. The rates of major complications were low, and most complications appeared minor and transient. Additional prospective studies are needed to further assess the efficacy of this procedure. LEVEL OF EVIDENCE: IV, systematic review of level I to IV therapeutic studies.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

The risk of neurological deterioration while using neoadjuvant denosumab on patients with giant cell tumor of the spine presenting with epidural disease: a meta-analysis of the literature.

BACKGROUND CONTEXT: Giant cell tumor (GCT) of bone is most commonly a benign but locally aggressive primary bone tumor. Spinal GCTs account for 2.7% to 6.5% of all GCTs in bone. En bloc resection, which is the preferred treatment for GCT of the spine, may not always be feasible due to the location, extent of the tumor, and/or the patient's comorbidities. Neoadjuvant denosumab has recently been shown to be effective in downstaging GCT, decreasing the size and extent of GCTs. However, the risk of neurologic deterioration is of major concern for patients with epidural spinal cord compression due to spinal GCT. We experienced this concern when a patient presented to our institution with a midthoracic spinal GCT with progressive epidural disease. The patient was not a good surgical candidate due to severe cardiac disease and uncontrolled diabetes. In considering nonoperative management for this patient, we asked ourselves the following question: What is the risk that this patient will develop neurologic deterioration if we do not urgently operate and opt to treat him with denosumab instead? PURPOSE: The purpose of this study was to assess the literature to (1) determine the risk of neurological deterioration in patients receiving neoadjuvant denosumab for the treatment of spinal GCT and (2) to evaluate the secondary outcomes including radiographic features, surgical/technical complexity, and histological features after treatment. STUDY DESIGN/SETTING: Meta-analysis of the literature. PATIENT SAMPLE: Surgical cases of spinal GCT that (1) presented with type III Campanacci lesions, (2) had epidural disease classified as Bilsky type 1B or above and (3) received neoadjuvant denosumab therapy. OUTCOME MEASURES: The primary outcome measure of interest was neurologic status during denosumab treatment. Secondary outcome measures of interest included radiographic features, surgical/technical complexity, histological features, tumor recurrence, and metastasis. METHODS: Using predetermined inclusion and exclusion criteria, PubMed and Embase electronic databases were searched in August 2022 for articles reporting spinal GCTs treated with neoadjuvant denosumab and surgery. Keywords used were "Spine" AND "Giant Cell Tumor" AND "Denosumab." RESULTS: A total of 428 articles were identified and screened. A total of 22 patients from 12 studies were included for review. 17 patients were female (17/22, 77%), mean age was 32 years (18-62 years) and average follow-up was 21 months. Most GCTs occurred in the thoracic and thoracolumbar spine (11 patients, 50%), followed by 36% in the lumbar spine and 14% in the cervical spine. Almost half of the patients had neurological deficits at presentation (10/22 patients, 45%), and more than 60% had Bilsky 2 or 3 epidural spinal cord compression. None of the patients deteriorated neurologically, irrespective of their neurological status at presentation (p-value=.02, CI -2.58 to -0.18). There were no local recurrences reported. One patient was found to have lung nodules postoperatively. More than 90% of cases had decreased overall tumor size and increased bone formation. Surgical dissection was facilitated in more than 85% of those who had documented surgical procedures. Four patients (18%) underwent initial spinal stabilization followed by neoadjuvant denosumab and then surgical excision of the GCT. Regarding the histologic analyses, denosumab eradicated the giant cells in 95% of cases. However, residual Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL)-positive stromal cells were noted, in 27% (6 cases). CONCLUSIONS: Neoadjuvant denosumab was a safe and effective means of treating spinal GCTs prior to surgery. Neurologic status remained stable or improved in all cases included in our review, irrespective of the presenting neurologic status. The most appropriate dosage and duration of denosumab therapy is yet to be determined. We recommend future well-designed studies to further evaluate the use of neoadjuvant denosumab for patients with spinal GCT.

Comparing Fibula Flap Insetting Techniques for Pediatric Oncologic Extremity Reconstruction.

BACKGROUND: Extremity reconstruction in skeletally immature patients presents unique challenges in terms of operative technique, bone healing, and limb function. A variety of insetting techniques have been described, with no clearly superior option. The authors hypothesized that vascularized fibula flaps placed in the intramedullary space are associated with shorter union times and better functionality compared with onlay flaps. METHODS: In a cohort study, the authors retrospectively reviewed the medical records of all pediatric patients who underwent fibula flap extremity reconstruction at a single center from 2001 through 2018. Comorbidities, complications, and outcomes were analyzed. Complete fibula union was based on radiographic evidence of significant cortical bridging. RESULTS: Thirty-three patients (mean age, 13.6 years; range, 2 to 18 years) underwent pedicled ( n = 7) or free ( n = 26) fibula flap reconstructions in 12 upper extremities and 21 lower extremities. Median follow-up was 69.5 months (interquartile range, 16.3 to 114.6 months). Onlay and intramedullary fibula position compared with intercalary placement (median, 13.5 and 14.6 months versus 3.4 months; P = 0.002) were associated with longer time to complete bone union. Complications including allograft fracture ( P = 0.02) and hardware removal ( P = 0.018) were also associated with longer time to complete union and eventual conversion to megaprosthesis ( P = 0.02, P = 0.038). Thirty-two patients (97%) achieved full union and a functional reconstruction. CONCLUSIONS: Fibula flap reconstruction is safe and effective for pediatric long-bone reconstruction. Longer fibula union times were associated with onlay and intramedullary fibula placement, allograft fracture, and hardware removal. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Reconstruction of Bony Defects With Motorized Intramedullary Nails After Tumor Resection.

Motorized intramedullary lengthening nails allow for transport of a bone segment for limb lengthening, deformity correction, healing of nonunion, and intercalary distraction osteogenesis. Resection of tumors involving the bone can result in substantial defects that require reconstruction. Use of these nails allows for a biologic reconstruction with the incorporation of allograft or by distraction osteogenesis. Limb lengthening after an internal hemipelvectomy where the hip joint is resected can be performed to improve gait, decrease pain, and prevent the need for a custom shoe or shoe lift. Using these nails in compression aids the incorporation of intercalary allografts and prevents stress shielding and stress risers within the graft when compared with plating. It also allows for a subsequent lengthening of the limb using the same implant. Plate-assisted bone segment transport or the use of a bone transport nail allows for a true biologic reconstruction of an intercalary defect using distraction osteogenesis. These implants provide the orthopaedic oncologist with more options for reconstruction and the potential to improve the function and outcomes of their patients.

The Use of Photodynamic Bone Stabilization to Tamponade Bleeding in a Pathologic Humeral Shaft Fracture: A Case Report.

Introduction: Hypervascular tumors such as renal and thyroid carcinoma have a significant risk of intraoperative bleeding. To help mitigate bleeding, interventional preoperative embolization is traditionally used; however, it is success is highly variable. This is the first case report to discuss using expandable balloon implants with a minimally invasive approach to achieve fracture fixation and tamponade acute intraoperative bleeding. Case Report: A 48-year-old male with clear-cell renal cell carcinoma presented with a left humeral shaft pathologic fracture. The patient was scheduled to undergo open biopsy, curettage of tumor, and fracture fixation with an intramedullary device. Intraoperatively, during open biopsy and curettage, brisk bleeding was encountered, which ceased after inserting an intramedullary photodynamic bone stabilization implant (IlluminOss). The implant's balloon expanded to the diameter of the humerus allowing for tamponade, fracture stability, and a minimally invasive approach. Conclusion: We present a possible intraoperative option for achieving control of bleeding in pathologic long bone fractures by deploying a photodynamic stabilization device. The method described can have applications in specific patients and obviate the need for pre-operative embolization for highly vascular tumors due to the implant's ability to create tamponade within the bone.

Clinico-Genomic Profiling of Conventional and Dedifferentiated Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse Outcomes.

PURPOSE: Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes. EXPERIMENTAL DESIGN: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas. RESULTS: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1-3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease. CONCLUSIONS: IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes.

Outcomes of Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces for Chronic Pain Control in the Oncologic Amputee Population.

BACKGROUND: Outcomes of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) in the oncologic population are limited. We sought to examine the safety and effectiveness of TMR and RPNI in controlling postamputation pain in the oncologic population. STUDY DESIGN: A retrospective cohort study of consecutive patients who underwent oncologic amputation followed by immediate TMR or RPNI was conducted from November 2018 to May 2022. The primary study outcome was postamputation pain, assessed using the Numeric Pain Scale and Patient-Reported Outcomes Measurement Information System (PROMIS) for residual limb pain (RLP) and phantom limb pain (PLP). Secondary outcomes included postoperative complications, tumor recurrence, and opioid use. RESULTS: Sixty-three patients were evaluated for a mean follow-up period of 11.3 months. The majority of patients (65.1%) had a history of previous limb salvage. At final follow-up, patients had an average Numeric Pain Scale score for RLP of 1.3 ± 2.2 and for PLP, 1.9 ± 2.6. The final average raw PROMIS measures were pain intensity 6.2 ± 2.9 (T-score 43.5), pain interference 14.6 ± 8.3 (T-score 55.0), and pain behavior 39.0 ± 22.1 (T-score 53.4). Patient opioid use decreased from 85.7% preoperatively to 37.7% postoperatively and morphine milligram equivalents decreased from a mean of 52.4 ± 53.0 preoperatively to 20.2 ± 38.4 postoperatively. CONCLUSIONS: In the oncologic population TMR and RPNI are safe surgical techniques associated with significant reductions in RLP, PLP, and improvements in patient-reported outcomes. This study provides evidence for the routine incorporation of TMR and RPNI in the multidisciplinary care of oncologic amputees.

What Is the Prosthetic Survival After Resection and Intercalary Endoprosthetic Reconstruction for Diaphyseal Bone Metastases of the Humerus and Femur?

BACKGROUND: Large metastatic lesions of the diaphysis can cause considerable pain and result in difficult surgical challenges. Resection and cemented intercalary endoprosthetic reconstruction offer one solution to the problem, but it is an extensive operation that might not be tolerated well by a debilitated patient. The risk of aseptic loosening and revision after intercalary endoprosthetic replacement has varied in previous reports, which have not examined the risk of revision in the context of patient survival. QUESTIONS/PURPOSES: (1) In a small case series from one institution, what is the survivorship of patients after cemented intercalary endoprosthetic replacement for diaphyseal metastasis, and what is the cumulative incidence of revision for any reason? (2) What are the complications associated with cemented intercalary reconstruction? (3) What is the functional outcome after the procedure as assessed by the MSTS93 score? METHODS: We retrospectively studied 19 patients with diaphyseal long bone metastases who were treated with resection and cemented intercalary endoprosthetic reconstruction by five participating surgeons at one referral center from 2006 to 2017. There were 11 men and eight women with a median age of 59 years (range 46 to 80 years). The minimum follow-up required for this series was 12 months; however, patients who reached an endpoint (death, radiographic loosening, or implant revision) before that time were included. One of these 19 patients was lost to follow-up but was not known to have died. The median follow-up was 24 months (range 0 to 116 months). Eight of the 19 patients presented with pathologic fractures. Ten of 19 lesions involved the femur, and nine of 19 were in the humerus. The most common pathologic finding was renal cell carcinoma (in 10 of 19). Survival estimates of the patients were calculated using the Kaplan-Meier method. A competing risks estimator was used to evaluate implant survival, using death of the patient as the competing risk. We also estimated the cumulative incidence of aseptic loosening in a competing risk analysis. Radiographs were analyzed for radiolucency at the bone-cement-implant interfaces, fracture, integrity of the cement mantle, and component position stability. Complications were assessed using record review that was performed by an individual who was not involved in the initial care of the patients. Functional outcomes were assessed using the MSTS93 scoring system. RESULTS: Patient survivorship was 68% (95% CI 50% to 93%) at 1 year, 53% (95% CI 34% to 81%) at 2 years, and 14% (95% CI 4% to 49%) at 5 years; the median patient survival time after reconstruction was 25 months (range 0 to 116 months). In the competing risk analysis, using death as the competing risk, the cumulative incidence of implant revision was 11% (95% CI 2% to 29%) at 1 year and 16% (95% CI 4% to 36%) at 5 years after surgery; however, the cumulative incidence of aseptic loosening (with death as a competing risk) was 22% (95% CI 6% to 43%) at 1 year and 33% (95% CI 13% to 55%) at 5 years after surgery. Other complications included one patient who died postoperatively of cardiac arrest, one patient with delayed wound healing, two patients with bone recurrence, and one patient who experienced local soft tissue recurrence that was excised without implant revision. Total MSTS93 scores improved from a mean of 12.6 ± 8.1 (42% ± 27%) preoperatively to 21.5 ± 5.0 (72% ± 17%) at 3 months postoperatively (p < 0.001) and 21.6 ± 8.5 (72% ± 28%) at 2 years postoperatively (p = 0.98; 3 months versus 2 years). CONCLUSION: Resection of diaphyseal metastases with intercalary reconstruction can provide stability and short-term improvement in function for patients with advanced metastatic disease and extensive cortical destruction. Aseptic loosening is a concern, particularly in the humerus; however, the competing risk analysis suggests the procedure is adequate for most patients, because many in this series died of disease without undergoing revision. LEVEL OF EVIDENCE: Level IV, therapeutic study .

Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101).

PURPOSE: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma. EXPERIMENTAL DESIGN: In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021. RESULTS: Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P < 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P < 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P < 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P < 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis. CONCLUSIONS: Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.

Changes in psoas muscle size and ambulatory function after internal hemipelvectomy without reconstruction.

Internal hemipelvectomy without reconstruction of the pelvis is a viable treatment for pelvic sarcoma; however, the time it takes to return to excellent function is quite variable. Some patients require greater time and rehabilitation than others. To determine if psoas muscle recovery is associated with changes in ambulatory function, we retrospectively evaluated psoas muscle size and limb-length discrepancy (LLD) before and after treatment and their correlation with objective functional outcomes. T1-weighted MR images were evaluated at three intervals for 12 pelvic sarcoma patients following interval hemipelvectomy without reconstruction. Correlations between the measured changes and improvements in Timed Up and Go test (TUG) and gait speed outcomes were assessed both independently and using a stepwise multivariate regression model. Increased ipsilesional psoas muscle size from three months postoperatively to latest follow-up was positively correlated with gait speed improvement (r = 0.66). LLD at three months postoperatively was negatively correlated with both TUG (r = -0.71) and gait speed (r = -0.61). This study suggests that psoas muscle strengthening and minimizing initial LLD will achieve the greatest improvements in ambulatory function. LLD and change in hip musculature remain substantial prognostic factors for achieving the best clinical outcomes after internal hemipelvectomy. Changes in psoas size were correlated with the amount of functional improvement. Several patients in this study did not return to their preoperative ipsilateral psoas size, indicating that monitoring changes in psoas size could be a beneficial rehabilitation strategy.

Free Fibula Flap for Extremity Oncologic Defects: Factors Influencing Union and Functional Outcomes.

BACKGROUND: The goal of this study was to evaluate outcomes after vascularized bone flap (VBF) reconstruction of oncologic bony extremity defects. A secondary goal was to compare union rates based on various insetting methods, including onlay, intermedullary, and intercalary. METHODS: The authors conducted a retrospective review of consecutive patients who received an extremity reconstruction with a fibula flap after oncologic resection between 2001 and 2019. RESULTS: The authors identified a total of 60 fibular VBFs in 55 patients (67% lower extremity, 33% upper extremity). The overall union rate was 91.7% (55 of 60). For lower extremity reconstructions, the mean time to full weightbearing was 16 months (range, 4 to 44 months). Fibula VBFs were onlay in 65% of cases, intercalary in 23%, and intramedullary in 12%. Forty-three percent of patients required a reoperation as a result of a surgical complication. Immediate femur reconstruction subgroup analysis demonstrated that onlay fibula flap orientation was associated with a significantly increased risk for any complication (odds ratio, 6.3; 95% CI, 1.4 to 28.7; P = 0.03) as well as an increased risk for requiring conversion to endoprostheses because of nonunion (OR, 12.1; 90% CI, 1.03 to 143.5; P = 0.03) compared with intramedullary placement. CONCLUSIONS: The free vascularized fibula flap is a reliable option for functional reconstruction of any long bone extremity defect, but complications in these complex procedures are not uncommon. In patients with immediate femur reconstructions, intramedullary fibula placement was associated with significantly lower complication and lower metallic implant conversion rates and a trend toward a more rapid early union compared with onlay VBF. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.