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INTRODUCTION: The expansion of tumor-infiltrating lymphocytes (TIL) for adoptive cellular therapy is under investigation in many solid tumors of adulthood. Marrow-infiltrating lymphocytes (MIL) have demonstrated antitumor reactivity preclinically. Successful expansion of TIL/MIL has not been reported across pediatric solid tumor histologies. The objective of this study was to demonstrate successful expansion of TIL from pediatric solid tumors for translation in an adoptive cell therapy (ACT) treatment strategy. METHODS: A prospective study of TIL/MIL expansion was performed on solid tumors of pediatric patients undergoing standard-of-care procedures. TIL/MIL expansions were performed in the presence of high-dose interleukin 2. To demonstrate a full-scale expansion to clinically-relevant cell doses for TIL therapy, initial TIL culture was followed by a rapid expansion protocol for select patients. Expanded specimens were analyzed for phenotype by flow cytometry and for anti-tumor reactivity by the interferon-gamma release assay. RESULTS: Eighteen tumor samples were obtained. Initial TIL cultures were successfully generated from 14/18 samples (77.7%). A median of 5.52 × 107 (range: 2.5 × 106-3.23 × 108) cells were produced from initial cultures, with 46.9% expressing a CD3 phenotype (46.9%). Eight samples underwent rapid expansion, demonstrating a median 458-fold expansion and a CD3 phenotype of 98%. Initial MIL cultures were successfully generated from five samples, with a predominantly CD3 phenotype (45.2%). Sufficient tumor tissue was only available for seven TIL samples to be tested for reactivity; none demonstrated responsiveness to autologous tumor. CONCLUSIONS: TIL and MIL expansion from pediatric solid tumors was successful, including the full-scale expansion process. This data supports translation to an ACT-TIL treatment strategy in the pediatric population and thus a Phase I trial of ACT-TIL in pediatric high-risk solid tumors is planned.

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Non-rhabdomyosarcoma soft tissue sarcoma (STS) comprises most STS in pediatric patients. It is a diverse set of over 30 histologic subtypes. Treatment is based on risk group determined by tumor size, grade, and the presence of metastases. Surgical resection is a cornerstone of therapy, as tumors are often resistant to chemotherapy or radiation. While patients with isolated tumors less than 5 cm may undergo upfront resection, strong consideration should be given to neoadjuvant chemoradiotherapy to ensure negative margins at surgical resection and optimal outcomes. Sentinel lymph node biopsy is strongly recommended for clear cell and epithelioid sarcomas. The most common metastatic site is the lung, and metastases should be resected at the end of therapy, when feasible. Unfortunately, many high-risk patients progress on therapy, and alternative strategies including earlier metastatic control require investigation.

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Primary bone malignancies, including osteosarcoma (OS), are rare but aggressive. Current OS treatment, involving surgical resection and chemotherapy, has improved survival for non-metastatic cases but remains ineffective for recurrent or metastatic OS. Oncolytic viral therapy (OVT) is a promising alternative, using naturally occurring or genetically modified viruses to selectively target and lyse cancer cells and induce a robust immune response against remaining OS cells. Various oncolytic viruses (OVs), such as adenovirus, herpes simplex virus, and measles virus, have demonstrated efficacy in preclinical OS models. Combining OVT with other therapeutics, such as chemotherapy or immunotherapy, may further improve outcomes. Despite these advances, challenges in reliability of preclinical models, safety, delivery, and immune response must be addressed to optimize OVT for clinical use. Future research should focus on refining delivery methods, exploring combination treatments, and clinical trials to ensure OVT's efficacy and safety for OS. Overall, OVT represents a novel approach with the potential to drastically improve survival outcomes for patients with OS.

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In the intricate landscape of multiple myeloma, a hematologic malignancy of plasma cells, bone disease presents a pivotal and often debilitating complication. The emergence of Chimeric Antigen Receptor T-cell (CAR-T) therapy has marked a pivotal shift in the therapeutic landscape, offering novel avenues for the management of MM, particularly for those with relapsed or refractory disease. This innovative treatment modality not only targets malignant cells with precision but also influences the bone microenvironment, presenting both challenges and opportunities in patient care. In this comprehensive review, we aim to examine the multifaceted aspects of bone disease in patients with multiple myeloma and concurrent CAR-T therapy, highlighting its clinical ramifications and the latest advancements in diagnostic modalities and therapeutic interventions. The article aims to synthesize current understanding of the interplay between myeloma cells, CAR-T cells, and the bone microenvironment in the context of current treatment strategies in this challenging and unique patient population.

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BACKGROUND: Children living in poverty and those of marginalized race or ethnicity experience inferior disease outcomes across many cancers. Whether survival disparities exist in osteosarcoma is poorly defined. We investigated the association between race, ethnicity, and proxied poverty exposures and event-free and overall survival for children with nonmetastatic osteosarcoma receiving care on a cooperative group trial. METHODS: We conducted a retrospective cohort study of US patients with nonmetastatic, osteosarcoma aged 5-21 years enrolled on the Children's Oncology Group trial AOST0331. Race and ethnicity were categorized to reflect historically marginalized populations, as Hispanic, non-Hispanic Black, non-Hispanic Other, and non-Hispanic White. Poverty was proxied at the household and neighborhood levels. Overall survival and event-free survival functions of time from trial enrollment were estimated using the Kaplan-Meier method. Hypotheses of associations between risks for event-free survival, death, and postrelapse death with race and ethnicity were assessed using log-rank tests. RESULTS: Among 758 patients, 25.6% were household-poverty and 28.5% neighborhood-poverty exposed. Of the patients, 21% of children identified as Hispanic, 15.4% non-Hispanic Black, 5.3% non-Hispanic Other, and 54.0% non-Hispanic White. Neither household or neighborhood poverty nor race and ethnicity were statistically significantly associated with risks for event-free survival or death. Postrelapse risk for death differed statistically significantly across race and ethnicity with non-Hispanic Black patients at greatest risk (4-year postrelapse survival 35.7% Hispanic vs 13.0% non-Hispanic Black vs 43.8% non-Hispanic Other vs 38.9% non-Hispanic White; P = .0046). CONCLUSIONS: Neither proxied poverty exposures or race and ethnicity were associated with event-free survival or overall survival, suggesting equitable outcomes following frontline osteosarcoma trial-delivered therapy. Non-Hispanic Black children experienced statistically significant inferior postrelapse survival. Investigation of mechanisms underlying postrelapse disparities are paramount.

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Chondrosarcoma is the second most common surgically treated primary bone sarcoma. Despite a large number of scientific papers in the literature, there is still significant controversy about diagnostics, treatment of the primary tumour, subtypes, and complications. Therefore, consensus on its day-to-day treatment decisions is needed. In January 2024, the Birmingham Orthopaedic Oncology Meeting (BOOM) attempted to gain global consensus from 300 delegates from over 50 countries. The meeting focused on these critical areas and aimed to generate consensus statements based on evidence amalgamation and expert opinion from diverse geographical regions. In parallel, periprosthetic joint infection (PJI) in oncological reconstructions poses unique challenges due to factors such as adjuvant treatments, large exposures, and the complexity of surgery. The meeting debated two-stage revisions, antibiotic prophylaxis, managing acute PJI in patients undergoing chemotherapy, and defining the best strategies for wound management and allograft reconstruction. The objectives of the meeting extended beyond resolving immediate controversies. It sought to foster global collaboration among specialists attending the meeting, and to encourage future research projects to address unsolved dilemmas. By highlighting areas of disagreement and promoting collaborative research endeavours, this initiative aims to enhance treatment standards and potentially improve outcomes for patients globally. This paper sets out some of the controversies and questions that were debated in the meeting.

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Background: Impending and complete pathologic fractures of the distal humerus are rare complications of metastatic cancer. Surgical treatment aims to quickly restore function and minimize pain. Plate and screw fixation (PSF) is a common method for addressing these lesions, but unlike in orthopaedic trauma, there are no clear guidelines for best management. While dual PSF theoretically provides better support and reduces the chance of reoperation due to tumor progression, single PSF is currently the more common choice. Materials and methods: Between March 2008 and September 2021, 35 consecutive patients who underwent PSF for distal humerus metastasis or multiple myeloma were retrospectively reviewed. The proportion of patients who developed various postoperative complications, including infection, nonunion, deep vein thrombosis, tumor progression, and radial nerve palsy, as well as those requiring reoperation, was calculated. Mann-Whitney U test, Pearson's chi-squared, and Fisher's exact test were used to investigate differences between the single and dual PSF groups with statistical significance defined as p ≤ 0.05. Results: There was no significant difference (p = 0.259) in revision rate, although 3 of 21 (14.3 %) single PSF patients required reoperation compared to 0 of 14 (0.0 %) dual PSF patients. The revisions were performed in one patient due to refracture and in two patients due to tumor progression. Although not statistically significant, a larger percentage of single PSF patients developed a postoperative complication compared to dual PSF patients [odds ratio 0.42 (95 % confidence interval 0.071 to 2.5); p = 0.431]. Single PSF did lead to shorter operative time compared to dual PSF [p < 0.001]. Conclusion: Dual PSF is non-inferior to single PSF and potentially results in fewer reoperations and postoperative complications in distal humerus pathologic lesions, although it leads to longer operative time. The current study is limited by small sample size due to the rarity of distal humerus metastatic lesions.

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BACKGROUND: Soft-tissue sarcomas present as a mass with nonspecific symptoms, and unplanned excisions commonly occur. The purpose of this study was to analyze the incidence of unplanned excisions performed by orthopaedic surgeons and to conduct a root cause analysis (RCA) of the steps that led to unplanned excisions in all the cases. METHODS: A retrospective case-control study was conducted. Two cohorts were identified, one including patients who underwent an unplanned excision of a soft-tissue sarcoma (n = 107) and a second cohort with patients whose entire care was performed at our sarcoma center (n = 102). A RCA was conducted with the whole sample to identify the preventable causes that led to sarcoma unplanned excisions. RESULTS: Orthopedic surgeons were the second group of physicians to perform the most unplanned excisions, only behind general surgeons. Inadequate imaging was encountered in 76.6% of the patients (n = 82, 95% confidence interval, 67.8 to 83.6). Forty-five patients (42.1%) had no imaging studies before the unplanned procedure. In the RCA, the most notable obstacles found were (1) incorrect assumption of a benign diagnosis, (2) failure to obtain the appropriate imaging study, (3) incorrectly reported imaging studies, (4) failure to order a biopsy, and (5) incorrect reporting of the biopsy. CONCLUSIONS: Despite educational efforts, unplanned excisions and the devastating consequences that sometimes follow continue to occur. Orthopaedic surgeons persist in playing a role in the unplanned procedure burden.

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PURPOSE OF REVIEW: This review summarizes current findings regarding limb amputation within the context of cancer, especially in osteosarcomas and other bony malignancies. We seek to answer the question of how amputation is utilized in the contemporary management of cancer as well as explore current advances in limb-sparing techniques. RECENT FINDINGS: The latest research on amputation has been sparse given its extensive history and application. However, new research has shown that rotationplasty, osseointegration, targeted muscle reinnervation (TMR), and regenerative peripheral nerve interfaces (RPNI) can provide patients with better functional outcomes than traditional amputation. While limb-sparing surgeries are the mainstay for managing musculoskeletal malignancies, limb amputation is useful as a palliative technique or as a primary treatment modality for more complex cancers. Currently, rotationplasty and osseointegration have been valuable limb-sparing techniques with osseointegration continuing to develop in recent years. TMR and RPNI have also been of interest in the modern management of patients requiring full or partial amputations, allowing for better control over myoelectric prostheses.

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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma among children and adolescents. The management of RMS involves risk stratification of the patients based on various clinicopathological characteristics. The multimodality treatment approach requires chemotherapy, surgery, and/or radiation. The treatment of RMS necessitates the involvement of multiple disciplines, such as pathology, pediatric oncology, surgery, and radiation oncology. The disease heterogeneity, molecular testing, evolving treatment regimens, and limited resources are some of the challenges faced by clinicians while treating a patient with RMS in low- and middle-income countries (LMICs). In this review, we endeavor to bring experts from varying fields to address clinicians' common questions while managing a child or adolescent with RMS in LMICs. This review is most applicable to level 2 centers in LMICs as per the levels of services described by the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology.

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The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard-of-care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biological features associated with poor outcomes including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations-MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are under way. Clinical trials evaluating the addition of multitargeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are under way in osteosarcoma and planned in EWS. In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

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BACKGROUND AND OBJECTIVES: The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. METHODS: Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. RESULTS: Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. CONCLUSION: The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

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BACKGROUND: Venous thromboembolism (VTE) is a frequent occurrence during treatment for adults with sarcoma. The incidence and underlying risk factors of postsurgical VTE in children and adolescents undergoing resection of sarcoma are unknown. METHODS: Using International Classification of Disease revision-9 diagnostic and procedure codes, the Pediatric Health Information System database was queried for patients aged 18 years and younger, discharged from 2004 to 2015 with a diagnosis of lower extremity malignant neoplasm who had a tumor resection or amputation performed during the encounter. Malignant neoplasms of the pelvic bones and soft tissues were categorized as "pelvis tumors", whereas malignant neoplasms of bone and soft tissues of the lower limbs were categorized as "lower limb tumors". Hospitalizations were evaluated for the occurrence of VTE. Demographic characteristics (age at admission, sex, race, and race/ethnicity) and incidence of VTE were reported. RESULTS: There were 2400 patients identified. Of these, 19 experienced VTE (0.79%) during their surgical hospitalization encounter. By anatomic group, the rate of VTE was 1.4% (CI: 0.5%-3.2%) for tumors in the pelvis and 0.6% (CI: 0.3%-1.0%) in lower limb tumors. Categorizing by age, the incidence of VTE was 1.2% in patients aged zero to 5, 0.3% in patients 6 to 13, and 1.2% in patients 14 to 18 years old. (Table 1). The extremely low rate of VTE occurrence precluded further analysis of risk factors. CONCLUSIONS: In this analysis, postsurgical VTE during hospitalization after pelvic and lower extremity sarcoma resection was an uncommon event in children and adolescents. There seemed to be an increased incidence of postsurgical VTE in pelvic tumors when compared with lower limb tumors, however, the rarity of all events precluded formal statistical analysis. A more robust data set would be required to determine if there are subsets of children and adolescents with sarcoma at higher risk of VTE that could benefit from thromboprophylaxis in the postoperative setting. LEVEL OF EVIDENCE: Level II.

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INTRODUCTION: The purpose of this historical review is to highlight the progression and development of prosthetic reconstruction with a focus on the modular distal femur with hinged total knee arthroplasty. METHOD: Scientific literature was searched for descriptions of endoprosthetic reconstruction of the extremities to provide a thorough overview of the subject, focusing the research on the evolution of limb salvage of the distal femur. RESULTS: After the first works of Gluck and Giordano, with ivory and metal and the pioneer shoulder prosthesis by Pean in the late 1890s, a great advancement was brought by reconstructions performed for injured soldiers of the Great War. By the 1940s, replacement of all the main joints had been attempted, and documented. DISCUSSION: Walldius in the 1950s developed a fully constrained hinge knee, offering for the first time a consistent and replicable method of substituting the joint. In 1953, Shiers' prosthesis allowed for good flexion and extension. Stanmore and GUEPAR group prosthesis in the 1960s were the first to have a different right and left side model. The rotating hinge was developed in 1978 by Walker, with the innovative concept of six degrees of freedom. Between 1979 and 1982, Kotz developed the modular segmental replacement that, added to a fixed hinge knee, permitted the revolutionary creation of the modern distal femur replacement. CONCLUSION: The study of the materials and mechanical solutions that was brought to the modern distal femur resection prosthesis is a good example of a virtuous multidisciplinary teamwork between orthopaedic surgeons, anatomists, and biomechanical engineers.

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The treatment of extremity rhabdomyosarcoma remains a challenge due to several adverse prognostic factors frequently associated with this tumor site. The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group Soft-Tissue Sarcoma Committee, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. The INSTRuCT surgical committee developed an internationally applicable consensus opinion document for the surgical treatment of extremity rhabdomyosarcoma. This document addresses surgical management, including biopsy, nodal staging, timing of therapy, resection and reexcision, reconstruction, and surgical approach at relapse.

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Purpose: Whether the therapeutic response of soft-tissue sarcoma to neoadjuvant treatment is predictive for clinical outcomes is unclear. Given the rarity of this disease and the confounding effects of chemotherapy, this study analyzes whether a favorable pathologic response (fPR) after neoadjuvant radiation therapy (RT) alone is associated with clinical benefits. Methods and Materials: An institutional review board-approved retrospective review was conducted on a database of patients with primary soft-tissue sarcoma treated at our institution between 1987 and 2015 with neoadjuvant RT alone followed by surgical resection. Time-to-event outcomes estimated with a Kaplan-Meier analysis included overall survival, progression-free survival (PFS), locoregional control, and distant control (DC). Cox regression analyses were performed to determine prognostic variables associated with clinical outcomes. Results: Of the overall cohort of 315 patients, 181 patients (57%) were included in the primary analysis with documented pathologic necrosis (PN) rates (mean: 59%) and a median follow up from diagnosis of 48 months (range, 4-170 months). The median neoadjuvant RT dose was 50 Gy (range, 40-60 Gy), and the majority of patients had negative surgical margins (79%). Only 35 patients (19%) achieved a fPR (PN ≥95%), which was associated with a higher R0 resection rate (94% vs. 75%; P = .013), a significant 5-year PFS benefit (74% vs. 43%; P = .014), and a nonsignificant 5-year DC benefit (76% vs. 62%; P = .12) compared with PN <95%. On multivariable analysis, fPR was an independent predictor for PFS (hazard ratio: 0.47; 95% confidence interval, 0.25-0.90; P = .022). Conclusions: Achieving fPR with neoadjuvant RT alone is associated with a higher R0 resection rate and possible DC benefit, translating into a significant improvement in PFS. Further studies to improve pathologic response rates and prospectively validate this endpoint are warranted.

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(1) Background: Pelvic Chondrosarcomas (CS) have a poor prognosis. The grade is the most important survival predictor; other factors are periacetabular location and Dedifferentiated CS subtype. The aim of the study is to investigate a series of CS of the pelvis, to analyze the prognostic factors that affect outcomes and to demonstrate how the use of intraoperative navigation can reduce the complications without worse outcomes. (2) Methods: Retrospective study on 35 patients (21 M, 14 F), median age at surgery 54 years (IQR 41−65), with pelvic CS, treated with hemipelvectomy under navigation guidance. (3) Results: 30 high-grade CS and 5 low-grade CS; mean follow-up 51.4 months. There was a positive linear correlation between the tumor volume and the presence of local recurrence at follow-up. The mean survival time of patients with larger chondrosarcoma volume was lower, but not significantly so. Lower MSTS score was associated with significantly lower survival time (p < 0.001). (4) Conclusion: in this series overall survival, LR and distant metastasis were comparable with recent literature, while complication rate was lower compared to similar series without the use of navigation. There was a correlation between tumor volume and local recurrence rate but not with the presence of metastasis at follow up.

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Neurofibromatosis type 1 (NF1) is a congenital disease which is caused by mutations in the NF1 gene on chromosome 17, resulting in an altered function of the neurofibromin protein. Owing to the ubiquitous expression of this protein, this syndrome is associated with pathology in many organ systems of the body, especially the central and peripheral nervous, musculoskeletal, and integumentary systems. This review outlines the common sequelae related to a diagnosis of NF1 and the common treatment approach to each.

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Osteosarcoma is the most common primary bone sarcoma and affects both children and adults. The cornerstone of treatment for patients with localized and oligometastatic disease remains neoadjuvant chemotherapy, surgical resection of all sites of disease, followed by adjuvant chemotherapy. This approach is associated with up to an 80% 5-year survival. However, survival of patients with metastatic disease remains poor, and overall, osteosarcoma remains a challenging disease to treat. Advances in the understanding of molecular drivers of the disease, identification of poor prognostic factors, development of risk-stratified treatment protocols, successful completion of large collaborative trials, and surgical advances have laid the ground work for progress. Advances in computer navigation, implant design, and surgical techniques have allowed surgeons to improve patients' physical functional without sacrificing oncologic outcomes. Future goals include identifying effective risk stratification algorithms which minimize patient toxicity while maximizing oncologic outcomes and continuing to improve the durability, function, and patient acceptance of oncologic reconstructions.

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