Mapping the Course of Recovery Following Limb-Salvage Surgery for Soft-Tissue Sarcoma of the Extremities.

BACKGROUND: Despite the goal of an acceptable functional result, the surgical treatment of soft-tissue sarcoma can portend a prolonged course of recovery. More comprehensive data on the expected course of recovery following extremity sarcoma surgery are needed to help to inform physicians and patients. The purpose of the present study was to describe the typical course of functional recovery following limb-salvage resection of a soft-tissue sarcoma and to identify factors associated with a delayed postoperative course of recovery. METHODS: A retrospective review of a prospectively maintained institutional database was performed for all patients undergoing surgical treatment with limb salvage of a soft-tissue sarcoma of the extremities or pelvis with at least 1 year of follow-up after the definitive surgical procedure. All patients were required to have preoperative functional outcomes recorded for either the Toronto Extremity Salvage Score (TESS) or the Musculoskeletal Tumor Society (MSTS) score and functional outcome measures at 1 year postoperatively. The primary outcome measures were time to recovery and maximal functional improvement. RESULTS: In this study, 916 patients met inclusion criteria following surgical resection of a soft-tissue sarcoma of the extremities. The median follow-up was 74 months. Patients typically achieved a return to their baseline preoperative level of function for all functional outcome measures by 1 to 2 years and achieved maximal functional recovery by 2 years postoperatively. Older age, female sex, deep tumor location, larger tumor size, pelvic location, osseous resection, motor nerve resection, free and/or rotational soft-tissue coverage, and postoperative complications were independently associated with worse TESS and/or MSTS scores (p ≤ 0.05). Tumor recurrence was associated with worse functional outcomes scores. An analysis was performed to determine which patients had a prolonged course of recovery (i.e., were considered to still be recovering). Older age, female sex, larger tumor size, osseous resection, and motor nerve resection were associated with a delayed course of recovery (p ≤ 0.04). Complications and tumor recurrence were associated with delayed functional recovery across all domains. CONCLUSIONS: Most patients will achieve maximal recovery by 2 to 3 years following surgical resection for soft-tissue sarcoma of the extremities. Older age, female sex, larger tumor size, osseous resection, motor nerve resection, postoperative complications, and tumor recurrence portend poorer functional outcomes and a delayed course of recovery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Management of bone disease with concurrent chimeric antigen receptor T-cell therapy for multiple myeloma.

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.

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.

Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, we performed bulk RNA-Seq, single-cell RNA-Seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and IFN-γ. CpG+RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG+RT, TCR clonality analysis suggests an increase in clonal T cell dominance. Collectively, these findings demonstrate that CpG+RT significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft-tissue sarcoma.

Reconstructive Allograft Preparation for Long Bone Intercalary Segments After Tumor Resections: Toronto Sarcoma Protocol.

Background: The Reconstructive Allograft Preparation by Toronto Sarcoma (RAPTORS) protocol is reliable and reproducible without substantially adding to the surgical reconstruction time or cost. Our technique includes clearance of debris, lavage of the medullary canal, pressurized filling of the medullary canal with antibiotic-laden cement for its mechanical and antimicrobial properties, and insertion of cancellous autograft at the allograft-host junctional ends prior to dual-plate compression to fix the allograft into the defect1-3. Our experience with large intercalary allograft reconstruction has demonstrated high rates of long-term success and addresses the most common causes of large allograft failure (infection, fracture, and nonunion)4, as shown in our long-term outcome study1. Description: Once the tumor is resected, it is used as a template for cutting and shaping the allograft to fit the bone defect and to restore length and anatomy. The frozen allograft is thawed in a container with povidone iodine and bacitracin saline solution until it reaches room temperature. The allograft is size-matched, and clearance of its intramedullary marrow contents is performed with use of curets and intramedullary reamers7. If 1 end of the allograft includes the metaphysis and is covered by dense cancellous bone, we try not to ream through this end because maintaining this metaphyseal cancellous surface will expedite bone healing. The segment is then thoroughly lavaged with "triple wash" solutions to clear out any remaining marrow contents and to ensure sterilization of the allograft. This serial-wash technique involves the use of 3 discrete antiseptic modalities and has been utilized at our institution with low rates of allograft infection. These antiseptic modalities include 10% weight-per-volume povidone iodine diluted 1:1 with normal saline solution, 3% weight-per-volume hydrogen peroxide diluted 1:1 with normal saline solution, and 50,000 units of sterile bacitracin lyophilized powder dissolved in 500 mL of normal saline solution. Following the triple wash, the medullary canal is filled with antibiotic-laden methylmethacrylate bone cement. If both ends are open, the far end of the segment is first plugged with the surgeon's finger or with gauze, or if 1 end is covered with cancellous bone, then retrograde filling of the canal with cement is performed from the open end. The cement is then pressurized to ensure complete filling of the intramedullary space. Before it sets, 1 cm of cement is removed from each open end of the allograft to allow for packing of autograft bone cancellous chips and to ensure that cement does not impede anatomic reduction of the allograft-host bone junction. For this step, cancellous autograft from the iliac crest is harvested with use of a separate sterile surgical setup in order to prevent contamination of the autograft site by instruments used for tumor resection. The cancellous autograft is packed into the space created after recessing the cement at the end(s) of the allograft and, using a bone tamp, the autograft is compressed into this cavity and into the corresponding end of the host long bone in order to improve the healing potential at the allograft-host bone junction(s)8. Finally, a dual compression plate construct is utilized for upper as well as lower-extremity reconstructions in most cases. The cement in the allograft must be completely hardened before drilling into it. The allograft-host bone junctions are sequentially compressed at both the proximal and distal ends to allow for maximal apposition of the osseous surfaces. Only 1 or 2 unicortical screws are placed into the allograft to hold it in place and to facilitate maximal compression at both bone junctions. Patient compliance during postoperative rehabilitation is essential to optimize healing and provide reliable and durable outcomes. Postoperative care following the RAPTORS technique includes limited early rehabilitation and long periods of non-weight-bearing until radiographic union is noted across both bone junctions, followed by gradual resumption of weight-bearing and more aggressive physiotherapy. See the Appendix for further details regarding each step of the procedure. Alternatives: Intercalary reconstruction alternatives include various biological or endoprosthetic constructs. The other biological reconstruction options include the use of a free vascularized bone graft, distraction osteogenesis, combined vascularized fibula and allograft (i.e., the Capanna technique), or recycled tumor bones. Intercalary prostheses offer another reconstruction option for diaphyseal defects, but their feasibility is more limited in cases of periarticular segments with very short residual medullary canals. In such cases, there may be inadequate stem length for fixation, or the segment may require a custom implant that takes time to design and manufacture, which can be associated with high costs5. Rationale: Major factors limiting the widespread use of allografts include infection, graft fracture, graft nonunion, and, in some locations, availability4,6. Our technique of allograft preparation with dual compression plating and triple-washing to provide mechanical and antimicrobial protection as well as augmented healing has shown reproducible results with low complication rates compared with the literature. Expected Outcomes: There have been high rates of long-term allograft survival (84.4%) following intercalary long-bone reconstruction at our institution, with lower complication rates than those presented in the literature. Important Tips: Transverse osteotomies of the allograft, made perpendicular to the long axis of the diaphysis/anatomical axis, are important to replicate the resected host bone. Transverse osteotomies, while inherently less stable than step-cut ones, allow for adjusting the rotation of the allograft segment as needed for maximal contact and compression, as well as restoration of anatomical limb rotation.It is important to perform meticulous clearance of the intramedullary contents while preserving the endosteal bone and allograft integrity. We would utilize hand-reaming rather than a power drill device, in order to prevent overreaming or breaking through the allograft bone.Place as few unicortical screws as possible into the allograft-cement construct in order to maintain its structural strength and minimize potential sites for vascular ingrowth and bone resorption. Acronyms & Abbreviations: K-wires = Kirschner wiresW/V = weight per volume.