Rose, Peter S.

ABSTRACT Background and Objectives Non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS) account for less than 4% of pediatric cancers. Treatment and outcomes have been described in adults, but pediatric data are lacking. The purpose of this study is to review our institution's outcomes of extremity NRSTS in pediatric patients. Methods Ninety‐eight (56 male: 42 female) pediatric patients with NRSTS of the extremity at our institution were reviewed. Mean age at diagnosis was 11 ± 5 years, and mean follow‐up was 12 ± 10 years. The most common diagnosis was synovial sarcoma (27%), and 60% were high‐grade. Results Treatment included surgical resection in all patients, with 33% receiving radiation and 37% receiving systemic therapy. 20‐year local recurrence‐ (LRFS) and metastatic disease‐free survival (MDFS) were 91% and 91%, respectively, with 92% disease specific survival (DSS). High grade tumors were associated with lower LRFS ( p = 0.02) and DSS ( p = 0.03). Tumor size < 5 cm demonstrated improved MDFS ( p = 0.03), and stage 3 tumors showed worse MDFS ( p < 0.01). Conclusions Treatment of pediatric NRSTS was variable, with large, deep, high‐grade tumors more likely to receive neoadjuvant and adjuvant treatments. Multidisciplinary treatment was associated with high rates of local control and durable survival. This study provides an extended follow‐up of pediatric patients to identify late complications.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Objective: This single institutional analysis explored outcomes and factors associated with local control and survival in pediatric patients with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Methods: Patients 18 years of age or younger diagnosed between October 1990 and November 2021 who received external beam radiotherapy (EBRT) were retrospectively identified. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and univariate Cox models. Results: Among 51 included patients, there were 33 extremity tumors (65%), with 80% T1/T2 and 90% M0. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received EBRT, with brachytherapy or intraoperative radiotherapy boosts in 21/51 (41%). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow-up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS. Two-year local failure incidence was 18.1% for EBRT versus 5.3% for EBRT+boost (HR 3.67, P =0.24). Among 6 local failures, 5 received EBRT alone, including 3 with positive margins. Two treated with EBRT+boost had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. Although complete resection remains essential, and the modern incidence of R1 resection has declined, IORT/brachytherapy boost may continue to have a role in selected patients with a high local recurrence risk.

Abstract Background: Pediatric and AYA sarcomas are rare, biologically heterogeneous tumors with limited noninvasive biomarkers to guide diagnosis, personalized treatment, and disease monitoring. Standard-of-care evaluation relies on invasive biopsies that carry procedural risks and imaging modalities with limited sensitivity for detecting minimal residual disease and distinguishing tumor types. Cell-free DNA (cfDNA) methylation profiling offers a minimally invasive alternative capable of capturing tumor-derived epigenomic alterations and has consistently shown strong clinical utility in adult malignancies. However, genome-wide cfDNA methylation patterns across diverse pediatric and AYA sarcoma subtypes remain poorly defined. Methods: Plasma was collected from 93 pediatric and AYA patients (pediatric &lt;18 years; AYA 15-39 years) representing 27 Ewing sarcoma, 17 rhabdomyosarcoma, 11 liposarcoma, 10 chordoma, 8 synovial sarcoma, 7 chondrosarcoma, 6 osteosarcoma, and 6 fibrosarcoma cases, plus 19 matched healthy donors. cfDNA was isolated from 1 mL plasma, quantified by Qubit, and assessed by Bioanalyzer. Libraries were prepared using the NEBNext EM-seq v2 workflow with PCR cycles scaled to cfDNA input amount. Genome-wide sequencing (15× target depth) was followed by alignment, deduplication, and methylation calling. MultiQC was used to assess depth, duplication rate, conversion efficiency, and CpG coverage. Global methylation summaries were computed, and methylKit was used to generate per-CpG and 1-kb tiling matrices and initiate differential methylation analyses. Results: Ewing sarcoma patients had significantly higher plasma cfDNA concentrations than age- and sex-matched healthy donors (24.4 vs 4.6 ng/mL, p &lt; 0.0001), whereas cfDNA levels for other sarcoma subtypes overlapped with the healthy cohort. Low or undetectable cfDNA concentrations by Qubit were far more common among non-Ewing sarcoma samples (23 of 66) than Ewing sarcoma (1 of 27). All samples achieved sufficient CpG coverage for genome-wide methylation modeling. Global methylation summaries revealed no significant differences in mean β-values across sarcoma subtypes or versus healthy donors. An independent analysis of the Ewing subset identified 299 significant differentially methylated regions (DMRs), supporting the detectability of disease-specific methylation changes. Conclusions: These results demonstrate the feasibility of high-quality cfDNA methylome profiling across a large and diverse pediatric and AYA sarcoma cohort, including in plasma samples with cfDNA concentrations below the limit of detection. While global methylation levels appear broadly similar across subtypes, proof-of-concept DMR analysis in Ewing sarcoma suggests that subtype-specific epigenomic signatures could enable future noninvasive diagnostic tools for pediatric and AYA sarcomas. Citation Format: Lilli J. Greiner, Roman O. Kowalchuk, Jeff Szymanski, Pradeep S. Chauhan, Adam Amundson, Peter J. Schoettler, Wendy Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly Bailey, Linda McAllister-Lucas, Anita Mahajan, Nadia Laack, Aadel Chaudhuri. Defining genome-wide cfDNA methylation landscapes in pediatric and adolescent and young adult (AYA) bone and soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7885.

Abstract Introduction: Detectable circulating tumor DNA (ctDNA) is associated with inferior outcomes in Ewing sarcoma (ES); however, ctDNA clears in nearly all patients within 2 of the 6 chemotherapy cycles before radiotherapy (RT) or surgery. Given a 3-year EFS of 37% on AEWS 1221 (metastatic) and 5-year EFS of 78% on AEWS 1031 (localized), current ctDNA testing fails to predict most relapses. Extracellular vesicles (EVs) are microscopic particles studied as a biomarker in multiple cancer types. We hope to improve the sensitivity of ctDNA in ES and provide the first application of EVs in ES. Methods: cfDNA was isolated from 1mL plasma, quantified by Qubit, and sequenced as NEBNext Enzymatic Methyl-seq v2 libraries. We performed a systematic unsupervised clustering analysis of 27 ES plasma cfDNA profiles using 4 differentially methylated regions (DMR) subsets (63 strong DMRs, top 30, top 15, and 10 promoter-proximal loci), 3 clustering algorithms (k-means, Ward hierarchical, PAM), and k=2-5 clusters, testing associations with tumor burden and progression. EV analysis involved antibody detection against ES surface markers, including LINGO1, ENPP1, CDH11, and CD99. Concentrations of EVs were determined by standardized and calibrated high-resolution flow cytometry then analyzed with custom-built software to automatically determine and apply gates. Samples were de-identified, randomly coded, and run in triplicates. The senior research technologist responsible for EV analysis was blinded to patient information and clinical data. Results: EV analysis included 36 pre-RT samples from 16 metastatic and 20 localized ES patients from a prospectively maintained biobank, with 27 pre-RT samples in the cfDNA analysis and 19 healthy donor (HD) samples. 35 of 36 patients had chemotherapy before sample collection. cfDNA concentrations were markedly elevated in ES patients compared with HD (24.4 vs 4.6 ng/mL, p&lt;0.0001), and 74% of ES samples exceeded the HD 95th-percentile detectability threshold (7.0 ng/mL). Across clustering configurations, ES cfDNA profiles consistently exhibited reproducible methylation substructure. One configuration (PAM clustering, k = 5, 63 strong DMRs) showed a modest but permutation-supported association with primary tumor size (nominal p ≈ 0.04; empirical p ≈ 0.03-0.04). ES samples had increased EV concentration compared to HD (p&lt;0.001), with AUC 0.988 for distinguishing between ES and HD ENPP1 (p&lt;0.0001). The highest ENPP1 EV values were in patients with large primary tumors (&gt;8 cm vs. ≤ 8cm) and metastatic disease (p=0.066). Conclusions: cfDNA- and EV-based liquid biopsy provide encouraging signals for high ES detectability pre-RT. We also show the first study of EVs as a novel biomarker in ES, which may provide complementary information to ctDNA. Multimodal liquid biopsy in ES may identify candidate patients for systemic or local therapy escalation and facilitate personalized care. Citation Format: Roman O. Kowalchuk, Lilli J. Greiner, Yohan Kim, Rubia Noori, Jeffrey Szymanski, William S. Harmsen, Pradeep S. Chauhan, Adam C. Amundson, Andrea M. McMahon, Peter J. Schoettler, Wendy A. Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly M. Bailey, Linda M. McAllister-Lucas, Anita Mahajan, Fabrice Lucien-Matteoni, Nadia N. Laack, Aadel A. Chaudhuri. Multimodal liquid biopsy of Ewing sarcoma reveals high sensitivity prior to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1149.

Aims A type III internal hemipelvectomy includes resection of the pubic rami. Although bony reconstruction is not necessary, the integrity of the abdominal wall is deficient following resection. The aim of this study was to report the outcome of soft-tissue reconstruction following these resections. Methods We retrospectively reviewed all isolated type III internal hemipelvectomies which were undertaken at the Mayo Clinic (Rochester, USA) between January 2002 and December 2022. The group included 25 patients, of whom 14 (56%) were male. Their median age was 45 years (IQR 61 to 31) at the time of surgery. Most patients (n = 18; 72%) underwent resection for a sarcoma. Soft-tissue flaps were used in 21 patients (84%) and nine also had a mesh reconstruction. Results The five-year disease-specific survival was 65% following surgery, with significantly worse survival in patients with locally advanced tumour (35% (95% CI 12 to 100) vs 76% (95% CI 59 to 99); p = 0.036). Complications were common, with 21 patients (84%) having at least one complication, and 12 (48%) having several complications. Most commonly, this included seroma or haematoma (44%), wound dehiscence (40%), and infection (40%). The use of a soft-tissue flap did not significantly reduce the risk of infection (hazard ratio (HR) 0.68 (95% CI 0.14 to 3.28); p = 0.638) or seroma or haematoma (HR 0.31 (95% CI 0.30 to 4.14); p = 0.088), but patients who did not have a soft-tissue flap were significantly more likely to develop a hernia (odds ratio 9.0 (95% CI 1.14 to 71.03); p = 0.027). A total of three of 21 patients (14%) whose reconstruction involved a flap had donor site complications. Conclusion Soft-tissue reconstruction following a type III internal hemipelvectomy reduces the risk of postoperative hernia formation, with a low rate of donor site complications. This additional procedure should be considered for all patients undergoing this type of resection. Cite this article: Bone Joint J 2026;108-B(4):561–566.

Background: Myxofibrosarcomas are notoriously highly infiltrative soft-tissue sarcomas, making negative surgical margins difficult to obtain. Recently, vacuum-assisted closure (VAC) is used to delay wound closure until a negative margin has been achieved; however, this can delay care and increase costs. Our institution has historically performed single-stage resections with intraoperative frozen margin analysis and reconstruction in these patients. The purpose of this study is to report the outcomes of this technique. Methods: We reviewed 112 patients (62 males, mean age 70 ± 14 years) with superficial myxofibrosarcoma. Eighty-eight patients received preoperative radiation. All patients underwent surgical resection with intraoperative frozen margin analysis, and the planned reconstruction was performed in a single anesthetic. Results: The 10-year local recurrence-free survival was 90%; positive intraoperative frozen section (HR 7.44, p = 0.004) and final permanent margins (HR 8.53, p = 0.007) were associated with local recurrence. Intraoperative margins were negative in 103 (92%) of patients, 1 of which was positive on final permanent section. There were nine cases of microscopically positive margins, of which seven underwent immediate re-excision to a negative margin. The accuracy of frozen margin assessment for myxofibrosarcoma was between 92.92 and 98.23%. All patients underwent reconstruction at the time of resection, with 19% needing an additional procedure, most commonly due to a wound complication (12%). Conclusions: Multidisciplinary single-stage excision with intraoperative frozen margin assessment and soft-tissue reconstruction yields low rates of local recurrence in patients with superficial myxofibrosarcoma.

OBJECTIVE Spinal stereotactic radiosurgery (SSRS) is an established treatment modality for spinal metastatic disease. A common complication of SSRS is postradiation pathologic fracture. The authors evaluated the risk of pathologic fracture in sacral SSRS. METHODS All patients receiving SSRS in 1 to 5 fractions to 1 or more sacral levels between 2011 and 2020 at participating institutions were included. Demographic, histological, anatomical, and outcome data were obtained from electronic medical records. Data were analyzed using SPSS version 28. RESULTS Of 67 total patients, 50 (74.6%) were men and 17 (25.4%) were women. The most common tumor histologies were prostate adenocarcinoma (n = 16 [23.9%]) and renal cell carcinoma (n = 12 [17.9%]). Median (range) age at treatment was 63 (8–87) years. The mean ± SD (range) number of levels treated was 1.5 ± 0.7 (1–4) levels. Mean ± SD (range) bone density at S1 was 208.0 ± 74.4 (−3.0 to 443.3) Hounsfield units (HUs). Median (range) follow-up was 16.6 (1.5–132) months, median ± SD (range) overall survival was 24 ± 21.0 (1.7–83.3) months, and the 1-year local control rate was 83.6%. Fourteen patients (20.9%) experienced fracture within the radiation field. There was no association between fracture and patient sex (p = 0.32), age (p = 0.40), S1 HU (p = 0.28), tumor location according to Denis classification (p = 0.87), presence of pain (p = 0.66), single versus multifraction radiation (p = 0.44), or number of levels treated (p = 0.52). Patients experiencing in-field progression were more likely to experience fracture (61.5% vs 10.2%, p < 0.001), and patients experiencing fracture had a higher average Spine Instability Neoplastic Score than patients without fracture (5.7 vs 4.3, p = 0.049). Only local control remained as a factor associated with sacral fracture in the multivariate analysis. Of the patients experiencing fracture, 10 (71.4%) were symptomatic and 3 of those (30.0%) underwent post-SSRS surgical intervention. CONCLUSIONS Pathologic fracture may occur after sacral SSRS in a significant number of patients and is significantly associated with failure of local control.

OBJECTIVE The purpose of this study was to identify risk factors for mechanical complications following complex spinal reconstruction for spondylectomy of primary spinal column tumors. METHODS A retrospective chart review identified patients treated with spondylectomy for primary spinal column tumors in the thoracic or lumbar spine followed by posterior instrumentation and anterior column reconstruction. Variables collected included basic demographics, smoking status, chronic steroid use, frailty (Charlson Comorbidity Index), extent of resection, Weinstein-Boriani-Biagini classification, tumor volume, Spine Instability Neoplastic Score, anterior column reconstruction and fixation techniques, rod characteristics, Hounsfield units (HUs), and neoadjuvant/adjuvant chemoradiation. RESULTS Twenty-five patients were included (14 men, 11 women) with an average (± SD) age of 45 ± 18 years, BMI of 28 ± 5.7, and follow-up of 6.0 ± 6.2 years. Primary spinal column tumor pathology included chordoma (40%), chondrosarcoma (16%), giant cell tumor (16%), osteosarcoma (16%), osteoblastoma (8%), and aneurysmal bone cyst (4%). Six patients (24%) experienced mechanical complications, including rod fractures (n = 5) and distal junctional failure (n = 1). Of the 6 patients with mechanical complications, 4 (67%) underwent reoperation. The length of follow-up was the only statistically significant risk factor for patients with mechanical complications (average 11 years) compared to those without complications (average 4.4 years, p = 0.047). Average HUs were 144 for mechanical complication patients versus 180 for those without (p = 0.08). Anterior column reconstruction materials included a titanium cage (13 patients, 3 failures), structural allograft (6 patients, 2 failures), vascularized fibular strut autograft (6 patients, no failures), nonvascularized structural autograft (5 patients, 1 failure), vascularized rib autograft (5 patients, 2 failures), and a polyetheretherketone cage (2 patients, no failures). The vascularized fibular strut autograft had a 0% mechanical failure rate, but this did not reach statistical significance (p = 0.28). Twelve patients (48%) had anterior fixation placed, with a 17% rate of mechanical complications (p = 0.65). Five patients (20%) had > 2-rod constructs, with a 20% mechanical complication rate (p = 0.99). CONCLUSIONS Reconstruction following primary spinal column tumor resection is a significant challenge, as evident by a high rate of mechanical complications and instrumentation failure. Future studies are needed with larger sample sizes to identify techniques that may mitigate the risk of failure.

ABSTRACTBackgroundSkip lesions in bone sarcoma are a poorly described entity. Reports on skip lesions in osteosarcoma and Ewing sarcoma suggest that whole bone MRI should be obtained to evaluate for additional tumor foci given the association with worse outcomes. However, there is limited evidence to support whole bone imaging in chondrosarcoma.MethodsBetween 1995 and 2022, 129 patients with long bone chondrosarcoma were evaluated at our institution. Lesions were located most commonly in the femur in 64 patients and the humerus in 54 patients. All imaging studies and pathology reports were reviewed to determine the presence of skip lesions, defined as an area of histology‐confirmed chondrosarcoma that was separated from the primary lesion by normal bone on pathology.ResultsWhole bone imaging was obtained during initial staging in 107 patients with two‐thirds of patients receiving MRI, CT, or bone scan. Five patients (3.9%) were found to have skip lesions in the same bone as the primary tumor. There were no transarticular skip lesions. Skip lesions were detected in three patients with low grade chondrosarcoma (4.6%) and two patients with high grade chondrosarcoma (3.2%). All lesions were within 2 cm of the primary tumor. All were visible on MRI and CT of the primary site and one was visible on plain radiographs. The presence of skip lesions did not alter the type of surgical treatment in any patients.ConclusionSkip lesions in long bone chondrosarcoma are rare. All skip lesions in this study were in close proximity to the primary tumor and the same grade as the main lesion. Our results suggest that advanced imaging of the whole bone may be of low utility for evaluating the presence of skip lesions. The clinical significance of skip lesions in chondrosarcoma remains unclear, however, their presence did not impact the treatment plan in this series.