Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy.

Characterization of the diverse malignant and stromal cell states that make up soft tissue sarcomas and their correlation with patient outcomes has proven difficult using fixed clinical specimens. Here, we employed EcoTyper, a machine-learning framework, to identify the fundamental cell states and cellular ecosystems that make up sarcomas on a large scale using bulk transcriptomes with clinical annotations. We identified and validated 23 sarcoma-specific, transcriptionally defined cell states, many of which were highly prognostic of patient outcomes across independent datasets. We discovered three conserved cellular communities or ecotypes associated with underlying genomic alterations and distinct clinical outcomes. We show that one ecotype defined by tumor-associated macrophages and epithelial-like malignant cells predicts response to immune-checkpoint inhibition but not chemotherapy and validate our findings in an independent cohort. Our results may enable identification of patients with soft tissue sarcomas who could benefit from immunotherapy and help develop new therapeutic strategies.

Patterns of Local Recurrence and Risk of Skin Recurrence in Soft Tissue Sarcomas After Surgical Resection.

PURPOSE: Although there is a theoretical risk of skin seeding during surgical resection of soft tissue sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during radiation therapy (RT). However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT. METHODS AND MATERIALS: We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007 and 2021. For patients who developed LR, the depth was evaluated. Progression-free survival and overall survival were analyzed from time of first LR using the Kaplan-Meier method. Cumulative incidence of distant metastasis was calculated with competing risk analysis from date of LR. RESULTS: Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, 5 patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had preoperative RT, 53.3% had postoperative RT, and bolus was used in 46.7%. Surgical margins were close (<1 mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone, and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within the RT field in 13 patients (86.7%). At 1 year after LR, progression-free survival was 70.3%, overall survival was 81.7%, and cumulative incidence of distant metastasis was 5.9%. CONCLUSIONS: Skin recurrences were rare after surgical resection of STSs and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.

Local Control Outcomes Using Stereotactic Body Radiation Therapy or Surgical Resection for Metastatic Sarcoma.

PURPOSE: Traditional management of metastatic sarcoma primarily relies on systemic therapy, with surgery often used for tumor control. We analyzed the rates of recurrence, overall survival, and treatment complications in patients undergoing either surgical resection or stereotactic body radiation therapy (SBRT) for metastatic sarcoma of the bone and/or soft tissue. METHODS AND MATERIALS: The records of patients with metastatic sarcoma between 2009 and 2020 were reviewed. Local recurrence (LR) was defined as tumor growth or recurrence at the tumor site. Cumulative LR incidence was analyzed accounting for the competing risk of death, and groups were compared using the Gray test. Overall survival (OS) was assessed using the Kaplan-Meier method and log-rank test. Hazard ratios were determined using the Cox proportional hazards model. RESULTS: A total of 525 metastatic lesions in 217 patients were analyzed. The mean age of patients was 57 years (range, 4-88 years). The lung was the predominant site treated (50%), followed by intra-abdominal (13%) and soft tissue (11%). Two-year cumulative incidences of LR for surgery and SBRT were 14.8% (95% confidence interval [CI], 11.6%-18.5%) and 1.7% (95% CI, 0.1%-8.2%), respectively (P = .003). Local recurrence occurred in 72 (16.5%) of 437 tumors treated with surgery and 2 (2.3%) of 88 tumors treated with SBRT. The adjusted hazard ratio for LR of lesions treated surgically was 11.5 (P = .026) when controlling for tumor size and tumor site. Median OS was 29.8 months (95% CI, 25.6-40.9 months). There were 47 surgical complications among a total of 275 procedures (18%). Of 58 radiation treatment courses, radiation-related toxic effects were reported during the treatment of 7 lesions (12%), and none were higher than grade 2. CONCLUSIONS: We observed excellent local control among patients selected for treatment with SBRT for metastatic sarcoma, with no evidence of an increase in LR after SBRT compared with surgical management. Further investigation is necessary to better define the most appropriate local control strategies for metastatic sarcoma.

Metastatic Pattern of Truncal and Extremity Leiomyosarcoma: Retrospective Analysis of Predictors, Outcomes, and Detection.

Leiomyosarcomas (LMS) are a heterogenous group of malignant mesenchymal neoplasms with smooth muscle origin and are classified as either non-uterine (NULMS) or uterine (ULMS). Metastatic pattern, prognostic factors, and ideal staging/surveillance studies for truncal and extremity LMS have not been defined. A retrospective analysis of patients diagnosed with histopathology-confirmed truncal or extremity LMS between 2009 and 2019 was conducted. Data collected included demographics, tumor characteristics, staging, surveillance, and survival endpoints. The primary site was defined as: (1) extremity, (2) flank/Pelvis, or (3) chest wall/Spine. We identified 73 patients, 23.3% of which had metastatic LMS at primary diagnosis, while 68.5% developed metastatic disease at any point. The mean metastatic-free survival from primary diagnosis of localized LMS was 3.0 ± 2.8 years. Analysis of prognostic factors revealed that greater age (≥50 years) at initial diagnosis (OR = 3.74, p = 0.0003), higher tumor differentiation scores (OR = 12.09, p = 0.002), and higher tumor necrosis scores (OR = 3.65, p = 0.026) were significantly associated with metastases. Older patients (≥50 years, OR = 4.76, p = 0.017), patients with larger tumors (≥5 cm or ≥10 cm, OR = 2.12, p = 0.02, OR = 1.92, p = 0.029, respectively), higher differentiation scores (OR = 15.92, p = 0.013), and higher necrosis scores (OR = 4.68, p = 0.044) show worse survival outcomes. Analysis of imaging modality during initial staging and during surveillance showed greater tumor detection frequency when PET imaging was employed, compared to CT imaging (p < 0.0001). In conclusion, truncal and peripheral extremity LMS is an aggressive tumor with high metastatic potential and mortality. While there is a significant risk of metastases to lungs, extra-pulmonary tumors are relatively frequent, and broad surveillance may be warranted.

Ferumoxytol magnetic resonance imaging detects joint and pleural infiltration of bone sarcomas in pediatric and young adult patients.

BACKGROUND: The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others. OBJECTIVE: To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration. MATERIALS AND METHODS: We retrospectively identified 15 pediatric and young adult patients (mean age: 16±4 years) with bone sarcomas who underwent 18 MRI scans at 1 h (n=7) or 24 h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test. RESULTS: MRI scans 24 h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration. CONCLUSION: This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration.

National Metrics Improved Timeliness of Antibiotic Administration for Open Extremity Fractures.

INTRODUCTION: Antibiotics have been shown to be an essential component in the treatment of open extremity fractures. The American College of Surgeons' Trauma Quality Improvement Program, based on a committee of physician leaders including orthopaedic trauma surgeons, publishes best-practice guidelines for the management of open fractures. Accordingly, it established the tracking of antibiotic timing as a metric with a plan to use that metric before trauma center site reviews. Our hypothesis was that this physician-led effort at the national level would provide the necessary incentive to effect change within our institution. METHODS: A retrospective review of all patients treated at our institution for open extremity fractures was performed over 3 periods separated by 2 quality initiatives. The first initiative was an institution-driven effort to increase awareness and educate specific departments about the importance of prompt antibiotic administration. The second initiative was the tracking of antibiotic order and administration times with quarterly audits following newly published guidelines. RESULTS: Neither antibiotic order placement within 1 hour nor administration within 1 hour improved after our first institution-specific initiative. Both outcome measures significantly improved after the second quality initiative, as did median times from arrival to antibiotic order and administration. CONCLUSIONS: Metrics developed and measured by a physician-led national organization led to practice changes at our hospital. Tracking of antibiotic timing for open fracture treatment was more effective than institutional education of healthcare providers alone. This study suggests that nationally published guidelines, developed and measured by physician leaders, will be found to be relevant by other physicians and can be a powerful tool to drive change.

Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy.

BACKGROUND: Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS. PROCEDURE: Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity. RESULTS: Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2 Gy fractions (EQD2) was 40.0 Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5 days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140 days (range, 1-882). Higher EQD2 correlated with longer duration of response (r = 0.39, P = 0.0003). Imaging revealed local failure in 3 of 14 courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%). CONCLUSIONS: RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

Staging of Bone and Soft-tissue Sarcomas.

The purpose of staging in orthopaedic oncology is to provide a framework for classifying tumors based on their risk of local recurrence and distant metastasis to guide treatment decisions. Two separate systems are commonly used to categorize bone and soft-tissue sarcomas. The Musculoskeletal Tumor Society system for bone sarcomas and the Enneking system for soft-tissue sarcomas are the original staging systems developed by orthopaedic surgeons. The American Joint Committee on Cancer staging systems for bone and soft-tissue sarcomas are periodically updated based on new data, and they are currently on their eighth edition.

Conservative management of desmoid tumors is safe and effective.

BACKGROUND: Surgical resection of desmoid tumors has traditionally been the mainstay of therapy, but this is a potentially morbid approach with high rates of recurrence. Given increasing reports of active surveillance in this disease, we sought to evaluate our experience with conservative management hypothesizing this would be an effective strategy. MATERIALS AND METHODS: Using a prospectively maintained database of sarcoma patients from 2008 to 2015, we identified 47 patients with a diagnosis of desmoid tumor from all anatomic sites. Data points were abstracted on clinical and pathologic factors, disease stability or progression, and follow-up time. Main outcome measurements were tumor recurrence after surgical resection versus tumor progression with conservative management. RESULTS: In our cohort, 20 patients were managed with surveillance, 24 patients with surgery, and three patients with other approaches. Clinical and tumor characteristics between treatment groups were not significantly different. With a median follow-up of 35.7 mo, there was one complete regression, five partial regressions, and 13 stable diseases among the surveillance group. Only one patient under observation progressed, crossing over to surgical resection. Among 24 patients managed with surgery, 13 patients developed local recurrence. Kaplan-Meier analysis revealed a statistically superior progression-free survival in the surveillance group (P = 0.001). CONCLUSIONS: This retrospective analysis adds to the growing body of evidence that observation of desmoid tumors is safe and effective with high rates of stable disease. These data further support an initial conservative approach to desmoid tumors that may spare patients the morbidity and risk of recurrence that accompanies potentially extensive operations.

Emerging concepts in upper extremity trauma: humeral shaft fractures.

Fractures of the humeral shaft are common in low-energy and high-energy trauma, and optimal clinical management remains controversial. Nonsurgical management has been supported as the preferred treatment based on high union rates and minimal functional deficit due to a rich vascular supply from overlying muscle and the wide motion available at the glenohumeral joint. Recent studies of nonoperative management have challenged surgeons' understanding of these fractures and the perception of favorable outcomes. Current considerations support expanded operative indications with traditional open-plate fixation and with the use of minimally invasive techniques, implants, and a reconsideration of intramedullary nailing.

Humeral shaft fractures.

Management of humeral shaft fractures has historically been largely conservative. A significant body of literature, dating back to the 1970s, has shown that functional bracing may achieve greater than 90 % union rates and acceptable functional outcomes. More recently, however, with the advent of new surgical techniques and implant options, less tolerance for acceptable deformity and functional deficits, and less patience with conservative management, many treating orthopaedic surgeons are increasingly likely to consider surgical intervention. This article reviews the current recommendations for treatment of humeral shaft fractures, including both nonoperative and operative intervention. It also discusses the current thinking and operative trends in humeral shaft fracture fixation.

Factors associated with recurrence of primary aneurysmal bone cysts: is argon beam coagulation an effective adjuvant treatment?

BACKGROUND: Our goal was to assess the effectiveness and safety of argon beam coagulation as an adjuvant treatment for primary aneurysmal bone cysts, to reevaluate the adjuvant effectiveness of the use of a high-speed burr alone, and, secondarily, to identify predictors of aneurysmal bone cyst recurrence. METHODS: We retrospectively reviewed the records of ninety-six patients with primary aneurysmal bone cysts who were managed at our institution from January 1, 1983, to December 31, 2008. Forty patients were managed with curettage, a high-speed burr, and argon beam coagulation; thirty-four were managed with curettage and a high-speed burr without argon beam coagulation; and the remaining twenty-two were managed with curettage with argon beam coagulation alone, curettage with no adjuvant treatment, or resection of the entire lesion. Demographic, clinical, and radiographic data were viewed comparatively for possible predictors of recurrence. Kaplan-Meier survival analysis with a log-rank test was performed to measure association and effectiveness. RESULTS: The median age at the time of diagnosis was fifteen years (range, one to sixty-two years). The median duration of follow-up was 29.5 months (range, zero to 300 months). The overall rate of recurrence of aneurysmal bone cyst after surgical treatment was 11.5%. The rate of recurrence was 20.6% after curettage and high-speed-burr treatment alone and 7.5% after curettage and high-speed-burr treatment plus argon beam coagulation. The five-year Kaplan-Meier survival estimate was 92% for patients managed with curettage and adjuvant treatment with a high-speed burr and argon beam coagulation, compared with 73% for patients managed with curettage and a high-speed burr only (p = 0.060). CONCLUSIONS: Surgical treatment of aneurysmal bone cyst with curettage and adjuvant argon beam coagulation is effective. Postoperative fracture appears to be a common complication of this treatment and needs to be studied further. Treatment with curettage and high-speed burr alone may not reduce recurrence.

Ascorbic acid recycling by cultured beta cells: effects of increased glucose metabolism.

Ascorbic acid is necessary for optimal insulin secretion from pancreatic islets. We evaluated ascorbate recycling and whether it is impaired by increased glucose metabolism in the rat beta-cell line INS-1. INS-1 cells, engineered with the potential for overexpression of glucokinase under the control of a tetracycline-inducible gene expression system, took up and reduced dehydroascorbic acid to ascorbate in a concentration-dependent manner that was optimal in the presence of physiologic D-glucose concentrations. Ascorbate uptake did not affect intracellular GSH concentrations. Whereas depletion of GSH in culture to levels about 25% of normal also did not affect the ability of the cells to reduce dehydroascorbic acid, more severe acute GSH depletion to less than 10% of normal levels did impair dehydroascorbic acid reduction. Culture of inducible cells in 11.8 mM D-glucose and doxycycline for 48 h enhanced glucokinase activity, increased glucose utilization, abolished D-glucose-dependent insulin secretion, and increased generation of reactive oxygen species. The latter may have contributed to subsequent decreases in the ability of the cells both to maintain intracellular ascorbate and to recycle it from dehydroascorbic acid. Cultured beta cells have a high capacity to recycle ascorbate, but this is sensitive to oxidant stress generated by increased glucose metabolism due to culture in high glucose concentrations and increased glucokinase expression. Impaired ascorbate recycling as a result of increased glucose metabolism may have implications for the role of ascorbate in insulin secretion in diabetes mellitus and may partially explain glucose toxicity in beta cells.

Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines.

Pancreatic beta cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on beta cells and results in beta cell dysfunction and ultimately beta cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to beta cells, we used two model systems where glucose metabolism was increased in beta cell lines by enhancing glucokinase (GK) activity and exposing cells to physiologically relevant increases in extracellular glucose (3.3-20 mm). Exposure of cells with enhanced GK activity to 20 mm glucose accelerated glycolysis, but reduced cellular NAD(P)H and ATP, caused accumulation of intracellular reactive oxygen species (ROS) and oxidative damage to mitochondria and DNA, and promoted apoptotic cell death. These changes required both enhanced GK activity and exposure to elevated extracellular glucose. A ROS scavenger partially prevented the toxic effects of increased glucose metabolism. These results indicate that increased glucose metabolism in beta cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in beta cells. The level of beta cell GK may also be critical in this process.