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Purpose: Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes., Methods: AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m 2 /cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m 2 /day over 20 h (2 days) and 17.5 mg/m 2 /day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics., Results: Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules., Conclusions: The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SGD has received consulting fees from Amgen, Bayer, and Jazz as well as travel expenses from Loxo, Roche, and Salarius. MDK has received consulting fees from Merck, Sharpe and Dhome. KAJ has received consulting fees from Bayer and Ipsen and honoraria from Takeda and Foundation Medicine. The remaining authors have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression., Significance: NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interactions in sarcomagenesis and disease progression., (©2022 American Association for Cancer Research.)

Inflammation associated with increased risk of comorbidities persists in people living with HIV (PWH) on combination antiretroviral therapy (ART). A recent placebo-controlled trial of low-dose methotrexate (MTX) in PWH found that numbers of total CD4 and CD8 T cells decreased in the low-dose MTX arm. In this report we analyzed T cell phenotypes and additional plasma inflammatory indices in samples from the trial. We found that cycling (Ki67+) T cells lacking Bcl-2 were reduced by MTX but plasma inflammatory cytokines were largely unaffected. In a series of in vitro experiments to further investigate the mechanisms of MTX activity, we found that MTX did not inhibit effector cytokine production but inhibited T cell proliferation downstream of mTOR activation, mitochondrial function, and cell cycle entry. This inhibitory effect was reversible with folinic acid, suggesting low-dose MTX exerts anti-inflammatory effects in vivo in PWH largely by blocking T cell proliferation via dihydrofolate reductase inhibition, yet daily administration of folic acid did not rescue this effect in trial participants. Our findings identify the main mechanism of action of this widely used anti-inflammatory medicine in PWH and may provide insight into how MTX works in the setting of other inflammatory conditions., Competing Interests: JS has received personal fees from Lilly for being on a data and safety monitoring board and a core laboratory grant from Novartis. JC has received grants from Theratechnologies. PH has received honoraria from Gilead and Merck. LC has consulted for Genentech-Roche. ML has received competitive funding from Gilead Sciences and consulted for Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Freeman, Clagett, Moisi, Yeh, Morris, Ryu, Rodriguez, Stein, Deeks, Currier, Hsue, Anthony, Calabrese, Ribaudo and Lederman.)

Background: Patients with substance use disorders are seven times more likely hospitalized than the general population. However, causes of death for recently hospitalized patients with Opioid Use Disorder (OUD) are not well described. This study describes causes of death in the year post-discharge among hospitalized patients with OUD., Methods: We analyzed data from participants who were at least 18 years old, with Medicaid insurance, and had a diagnosis of OUD during a general hospital admission in Oregon between April 2015 and December 2017., Results: During the study window, 6,654 Oregon Medicaid patients with an OUD diagnosis were hospitalized. Patients were predominately female (56.7%) and White (72.2%), an average age of 44.2 years (SD = 15.4 years) and average hospital length of stay of 6.5 days (SD = 10.9 days). In the 12 months post-discharge, 522 patients died (7.8%); 301 patients from a drug or substance related cause (4.5%), including 71 from drug overdose (1.1%). Stated another way, of those who died within 12 months, 58% of deaths were attributed to drug-related causes, including 13.6% of deaths attributed to overdose; 42% died of non-drug related causes. Drug-related death was the most frequent cause of mortality., Conclusions: Hospitalized patients with OUD are at high risk of death, from drug and non-drug related causes, in the year after discharge. Future research should consider not only overdose, but a more comprehensive definition of drug-related death in understanding post-discharge mortality among hospitalized patients with OUD, and care systems should work to mitigate the risk of death in this population., Competing Interests: The authors do not have financial conflicts of interest. Dr. Korthuis serves as principal investigator for NIH-funded trials that accept donated study medications from Alkermes (extended-release naltrexone) and Indivior (buprenorphine-naloxone)., (Copyright © 2021 American Society of Addiction Medicine.)

Background: Clear cell sarcoma of soft tissue (CCS), epithelioid sarcoma, and synovial sarcoma are rare tumors historically identified as high risk for lymph node metastasis. This study investigates incident nodal metastasis and associated survival in children and young adults with these subtypes., Procedure: Using the National Cancer Database (2004-2015), we created a retrospective cohort of 1303 patients (aged ≤25 years) who underwent local control therapy for CCS, epithelioid sarcoma, and synovial sarcoma. Kaplan-Meier curves estimated overall survival (OS) by subtype. Stratifying on subtype, Cox regressions assessed OS by lymph node sampling status and nodal metastasis., Results: There were 103 (7.9%) patients with CCS, 221 (17.0%) with epithelioid sarcoma, and 979 (75.1%) with synovial sarcoma. Lymph node sampling was more frequent in patients with CCS (56.3%) and epithelioid sarcoma (52.5%) versus synovial sarcoma (20.5%, p < .001). Synovial sarcoma metastasized to lymph nodes less frequently than CCS or epithelioid sarcoma (2.1% vs. 14.6% and 14.9%, p < .001). Across all subtypes, lymph node metastasis was associated with inferior OS (HR 2.02, CI 1.38-2.95, p < .001). Lymph node sampling was associated with improved OS in CCS (HR 0.35, CI: 0.15-0.78, p = .010), inferior OS in synovial sarcoma (HR 1.60, CI: 1.13-2.25, p = .007), and no statistical association with OS in epithelioid sarcoma., Conclusions: Lymph node metastasis is rare in children and young adults with synovial sarcoma. Lymph node sampling procedures were not consistently performed for patients with CCS or epithelioid sarcoma, but improved OS supports routine lymph node sampling in children and young adults with CCS., (© 2021 Wiley Periodicals LLC.)

Background: Surgical principles and techniques used during primary sarcoma excision focus on acquiring negative margins, reducing the risk of local recurrence, and minimizing contamination. These principles and techniques within orthopaedic oncology are not well documented in the literature. No standardized surgical hand-off or approach to education across disciplines on orthopaedic oncology principles and techniques has been published. Currently, education on intraoperative approaches is passed down by oral tradition., Objectives: Our objective was to survey members of the Musculoskeletal Tumor Society (MSTS) to identify their core principles and practices in orthopaedic oncology. We aimed to 1) provide descriptive analyses of surgeon technique patterns; 2) determine correlations between individual practice patterns; and 3) identify distinct clusters of surgeons on the basis of common practice tendencies., Methods: A web-based, 16-question survey regarding orthopaedic oncology intraoperative principles and techniques was distributed online to all 349 members of the MSTS in 2021. There were 137 (39%) unique respondents, all of whom completed the entire survey. The 16 survey questions were grouped into 4 key aspects of sarcoma excision: pre-incision, exposure of the mass, delivery of the mass, and closure. The questions inquired about respondent preference on draping, back table setup, instrument use, and intraoperative decision making. These questions were selected on the basis of existing reports, as well as the senior author's experience. We analyzed the responses using 3 methods: 1) descriptive statistics, 2) correlations between question responses, and 3) clustering analysis. We used an artificial intelligence-based clustering algorithm to cluster respondents according to their practice patterns. The results of our correlation analyses are reported as Spearman's rho (ρ) correlation coefficients., Results: Most respondents (mean, 71%; standard deviation, 22%) reported using the described surgical techniques "most of the time" or "in all cases." A strong positive correlation was found between respondents who answered "yes" to both of the following questions: "Do you change your surgical gloves after passing off the tumor specimen?" and "Does your entire surgical team change their gloves after passing off the tumor specimen?" (ρ = 0.88). A moderate positive correlation was found between those who answered "yes" to both of the following questions: "Do you change your surgical gloves after passing off the tumor specimen (i.e., prior to closure)?" and "Do you use new and/or unused surgical instruments for the final closure?" (ρ = 0.60). The cluster analysis identified 3 distinct clusters of respondents. The conservative technique cluster (N = 42) was more likely to answer "yes" to 9 of the 10 questions regarding incision management, consultant team communication, gloving, and instrument use, whereas the permissive technique cluster (N = 41) was more likely to answer "no" to questions regarding gloving, draping, and instrument use., Conclusions: Our findings indicate that most respondents perform the surveyed techniques, and there is homogeneity in the practice patterns of members of the MSTS; however, we identified distinct clusters of respondents who were significantly more likely to perform certain techniques. These results support establishing a standardized set of intraoperative techniques and formal surgical education regarding intraoperative principles and techniques in orthopaedic oncology., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Leiomyosarcomas (LMS) are malignancies with smooth muscle differentiation. Metastasis to the bone is not uncommon. The literature on the clinical course and management of such metastases is limited. Our study describes the clinical course of LMS to the bone, including survival rates, prognostic factors, and surgical management., Methods: We retrospectively reviewed 396 LMS patients presenting at an academic center between 1995 and 2020. We included LMS patients diagnosed with bone metastases and excluded patients with primary LMS of bone. We evaluated survival time with the Kaplan-Meier survival method and used Cox's proportional hazards regression analysis to determine factors associated with survival., Results: Forty-five patients with LMS (11%) had bone metastases. The most common LMS subtypes with bone metastases were uterine ( N  = 18, 40%) and retroperitoneal ( N  = 15, 33%). Bone metastasis was not an independent predictor of mortality by Cox regression analysis (HR 1.0, 95% CI: 0.67-1.5). Patients more frequently metastasized to the axial ( N  = 29, 64%) than to the appendicular ( N  = 5, 11%) skeleton. Bone was the first site of metastasis in 13 patients (29%). Patients presented with bone metastases at a median of 32.7 months (IQR: 5.2, 62.6) after initial LMS diagnosis. Twelve patients (27%) sustained a pathologic fracture. Twenty (44%) required surgical management, with 30 surgeries total. Three (15%) had a failure of reconstructive constructs. The median overall survival time was 69.7 months (IQR: 43.2, 124.5). There were no associations between the LMS subtype and survival. Pathologic fracture was an independent predictor of mortality by Cox regression analysis (HR 5.4, 95% CI: 1.8-16)., Conclusion: The majority of patients with metastatic LMS to bone survive greater than 5 years and frequently require surgical intervention. Extended survival in this patient population should inform fixation and implant choice. No anatomic subtype was associated with risk for bone metastases. Pathologic fracture was associated with worse survival., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Christa L. LiBrizzi et al.)

Background: Pathologic fracture of the long bones is a common complication of bone metastases. Intramedullary nail stabilization can be used prophylactically (for impending fractures) or therapeutically (for completed fractures) to preserve mobility and quality of life. However, local disease progression may occur after such treatment, and there is concern that surgical instrumentation and the intramedullary nail itself may seed tumor cells along the intramedullary tract, ultimately leading to loss of structural integrity of the construct. Identifying factors associated with local disease progression after intramedullary nail stabilization would help surgeons predict which patients may benefit from alternative surgical strategies., Questions/purposes: (1) Among patients who underwent intramedullary nail stabilization for impending or completed pathologic fractures of the long bones, what is the risk of local progression, including progression of the existing lesion and development of a new lesion around the nail? (2) Among patients who experience local progression, what proportion undergo reoperation? (3) What patient characteristics and treatment factors are associated with postoperative local progression? (4) What is the difference in survival rates between patients who experienced local progression and those with stable local disease?, Methods: Between January 2013 and December 2019, 177 patients at our institution were treated with an intramedullary nail for an impending or completed pathologic fracture. We excluded patients who did not have a pathologic diagnosis of metastasis before fixation, who were younger than 18 years of age, who presented with a primary soft tissue mass that eroded into bone, and who experienced nonunion from radiation osteitis or an avulsion fracture rather than from metastasis. Overall, 122 patients met the criteria for our study. Three fellowship-trained orthopaedic oncology surgeons involved in the care of these patients treated an impending or pathologic fracture with an intramedullary nail when a long bone lesion either fractured or was deemed to be of at least 35% risk of fracture within 3 months, and in patients with an anticipated duration of overall survival of at least 6 weeks (fractured) or 3 months (impending) to yield palliative benefit during their lifetime. The most common primary malignancy was multiple myeloma (25% [31 of 122]), followed by lung carcinoma (16% [20 of 122]), breast carcinoma (15% [18 of 122]), and renal cell carcinoma (12% [15 of 122]). The most commonly involved bone was the femur (68% [83 of 122]), followed by the humerus (27% [33 of 122]) and the tibia (5% [6 of 122]). A competing risk analysis was used to determine the risk of progression in our patients at 1 month, 3 months, 6 months, and 12 months after surgery. A proportion of patients who ultimately underwent reoperation due to progression was calculated. A univariate analysis was performed to determine whether lesion progression was associated with various factors, including the age and sex of the patient, use of adjuvant therapies (radiation therapy at the site of the lesion, systemic therapy, and antiresorptive therapy), histologic tumor type, location of the lesion, and fracture type (impending or complete). Patient survival was assessed with a Kaplan-Meier curve. A p value < 0.05 was considered significant., Results: The cumulative incidence of local tumor progression (with death as a competing risk) at 1 month, 3 months, 6 months, and 12 months after surgery was 1.9% (95% confidence interval 0.3% to 6.1%), 2.9% (95% CI 0.8% to 7.5%), 3.9% (95% CI 1.3% to 8.9%), and 4.9% (95% CI 1.8% to 10.3%), respectively. Of 122 patients, 6% (7) had disease progression around the intramedullary nail and 0.8% (1) had new lesions at the end of the intramedullary nail. Two percent (3 of 122) of patients ultimately underwent reoperation because of local progression. The only factors associated with progression were a primary tumor of renal cell carcinoma (odds ratio 5.1 [95% CI 0.69 to 29]; p = 0.03) and patient age (difference in mean age 7.7 years [95% CI 1.2 to 14]; p = 0.02). We found no associations between local disease progression and the presence of visceral metastases, other skeletal metastases, radiation therapy, systemic therapy, use of bisphosphonate or receptor activator of nuclear factor kappa-B ligand inhibitor, type of fracture, or the direction of nail insertion. There was no difference in survivorship curves between those with disease progression and those with stable local disease (= 0.36; p = 0.54)., Conclusion: Our analysis suggests that for this population of patients with metastatic bone disease who have a fracture or impeding fracture and an anticipated survival of at least 6 weeks (completed fracture) or 3 months (impending fracture), the risk of experiencing local progression of tumor growth and reoperations after intramedullary nail stabilization seems to be low. Lesion progression was not associated with the duration of survival, although this conclusion is limited by the small number of patients in the current study and the competing risks of survival and local progression. Based on our data, patients who present with renal cell carcinoma should be cautioned against undergoing intramedullary nailing because of the risk of postoperative lesion progression., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

Rationale: Soft tissue masses are common within the general population with a minority diagnosed as soft tissue neoplasms. Differing between benign and malignant soft tissue processes can be a challenge given the overlapping clinical and imaging characteristics. We present the case of a 69-year-old female referred to the Orthopaedic Oncology Service for evaluation of a suspected soft tissue sarcoma in the upper arm., Patient Concerns: She reported a mass localized over the deltoid with associated tenderness 1 month after influenza vaccination., Diagnosis: After thorough consideration of the patient's clinical course, history, advanced imaging, and physical examination, the diagnosis of injection granuloma associated with recent influenza vaccination was considered., Interventions: Biopsy was deferred and close interval follow-up with clinical and imaging evaluation revealed a resolving process., Outcomes: The patient was followed until complete resolution of all symptoms, which occurred 5 months after initial presentation., Lessons: It was hypothesized that due the patient's body habitus, the injection contents intended for intramuscular administration remained in the subcutaneous tissues and elicited a granulomatous reaction. This case highlights several important factors for physicians to consider in the work up of suspicious masses for which injection granuloma is on the differential diagnosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with stage IV cancer often experience diminished quality of life and pain. Although palliative amputation (PA) can reduce pain, it is infrequently performed because of the morbidity associated with amputation and the limited life expectancy in this population. Here, we describe the indications for PA in patients with stage IV carcinoma or sarcoma and discuss their clinical courses and outcomes. We hypothesized that PA would be associated with reduced pain and improved quality of life in these patients., Methods: We retrospectively reviewed medical records of all patients who underwent major amputation (proximal to the ankle or wrist) for metastatic sarcoma or carcinoma from January 1995 to April 2021. We excluded patients who underwent amputation for indications other than palliation. Cox proportional hazards regression analysis was used to determine factors associated with survival after PA., Results: Twenty-six patients underwent PA (11 for carcinoma, 15 for sarcoma). The most common indications for PA were pain (all patients) and fungating tumor (16 patients). PA was the initial surgery in 7 patients. Forequarter amputations were the most common procedure (6 patients). All patients reported reduced pain after PA, with the mean (±standard deviation) visual analog pain score (on a 10-point scale) decreasing from 5.7 ± 2.9 preoperatively to 0.43 ± 1.3 postoperatively (p < 0.001). The mean preoperative ECOG score was 1.9 ± 0.2 compared with 1.3 ± 0.1 postoperatively (p < 0.001). Fourteen patients were fitted for prostheses (6 upper extremity, 8 lower extremity). Two patients had local recurrence, both within 6 months after PA. The mean survival time after PA was 13 ± 12 months, and mean follow-up was 28 ± 29 months. Mean survival time after PA was not significantly different between patients with sarcoma (11 ± 11 months) versus carcinoma (15 ± 14 months) (p = 0.51). Adjuvant chemotherapy was positively associated with survival; no other factors were associated with survival., Conclusions: PA was associated with significantly reduced pain in all patients with stage IV cancer. PA should be considered for those with intractable pain, fungating tumors, or symptoms that diminish quality of life., Level of Evidence: Level III., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Illicitly manufactured fentanyl (IMF) is increasing in international drug supply chains, and IMF-related opioid overdose deaths are rising in North America. Hospitalizations among patients with opioid use disorder (OUD) are also rising; and, hospitalized patients are at increased risk of overdose and death following hospital discharge. Hospitalization is a key opportunity to engage patients with OUD. Addiction consult services (ACS) can provide effective treatment for patients hospitalized with OUD. This study aims to estimate the effect of increasing IMF contamination on drug-related death among patients hospitalized with OUD, and simulate the role of ACS expansion to mitigate these effects., Methods: We used a Markov model to mirror care systems for adult patients hospitalized with OUD in Oregon, from the time of hospital admission through 12-months post-discharge, and simulated patients through modeled care systems to evaluate the expansion of Addiction Consult Services in the context of increasing IMF in the drug supply., Results: In a simulated cohort of 10,000 patients, we estimate that 537 patients would die from drug-related causes within 12-months of hospital discharge. In the context of increased IMF in the drug supply, this estimate increased to 913. ACS referral at baseline was 4%; increasing ACS referral to accommodate 10%, 50%, or 100% of hospitalized OUD patients in the state reduces drug-related deaths to 904, 849, and 780, respectively. The number needed to treat for ACS to avoid one drug-related death in the context of increased IMF was 73., Conclusions: Hospitals should expand interventions to help reduce IMF-related opioid overdoses, including through implementation of ACS. In the context of rising IMF-related deaths, ACS expansion could help connect patients to treatment, offer harm reduction interventions, or both, which can help reduce the risk of opioid-related death., Competing Interests: Declarations of Interest Dr. Korthuis serves as principal investigator for NIH-funded studies that accept donated study medication from Alkermes (extended-release naltrexone) and Indivior (buprenorphine). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Bone cement implantation syndrome (BCIS) occurs during and after cementation of implants and is associated with hypotension, hypoxia, and cardiovascular collapse. In this study, we aimed to identify risk factors and potential mitigating factors of BCIS in the oncologic adult cohort undergoing cemented arthroplasty., Methods: We retrospectively reviewed oncologic patients aged 18 years or older who underwent cemented arthroplasty of either the hip or knee from 2015 to 2020. All implants were stemmed. We classified BCIS into three separate categories: (1) grade 1: intraoperative moderate hypoxia (<94%) or drop in systolic blood pressure >20%; (2) grade 2: intraoperative severe hypoxia or drop in systolic blood pressure >40%; and (3) grade 3: cardiovascular collapse requiring cardiopulmonary resuscitation. Demographics, primary malignancy diagnosis, intraoperative factors including cement timing, development of BCIS, 30-day postoperative outcomes, and mortality up to 2 years postoperatively were evaluated. Bivariate analyses and multivariate logistic regression were performed., Results: Sixty-seven patients met inclusion criteria. Of these, 31 patients (46%) developed BCIS. No difference was found in age (65.5 versus 60.9 years; P = 0.15) or body mass index (28.8 kg/m2 versus 29.3 kg/m2; P = 0.76), comorbidities, intraoperative factors, or postoperative surgical outcomes between those who developed BCIS and those who did not (all; P > 0.05). An association with the type of anesthesia administered and development of BCIS in patients receiving general anesthesia alone (17/24 patients, 71%), neuraxial and general (4/15 patients, 27%), and regional and general anesthesia (10/28 patients 36%, P = 0.01) was found. Compared With neuraxial and regional anesthesia, general anesthesia alone had 5.8 (P = 0.007) and 4.5 times (P = 0.006) greater odds of developing BCIS, respectively. No differences were noted in rates of BCIS between regional and neuraxial anesthesia (P = 0.81)., Discussion: Addition of regional or neuraxial anesthesia may be protective in reducing development of BCIS in the orthopaedic oncologic cohort undergoing hip and knee arthroplasty., Level of Evidence: III., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Purpose: Benign, intermediate-grade and malignant tumors sometimes have overlapping imaging and clinical characteristics. The purpose of this study was to evaluate the added value of contrast-enhanced sequences (dynamic contrast enhancement (DCE)), diffusion-weighted imaging (DWI), and chemical shift imaging (CSI) to noncontrast MRI sequences for the characterization of indeterminate lipomatous tumors., Materials and Methods: Thirty-two consecutive patients with histologically proven peripheral lipomatous tumors were retrospectively evaluated. Two musculoskeletal radiologists recorded the MRI features in three sessions: (1) with noncontrast T1-weighted and fluid-sensitive sequences; (2) with addition of static pre- and post-contrast 3D volumetric T1-weighted sequences; and (3) with addition of DCE, DWI, and CSI. After each session, readers recorded a diagnosis (benign, intermediate/atypical lipomatous tumor (ALT), or malignant/dedifferentiated liposarcoma (DDL)). Categorical imaging features (presence of septations, nodules, contrast enhancement) and quantitative metrics (apparent diffusion coefficient values, CSI signal loss) were recorded., Results: For 32 tumors, the diagnostic accuracy of both readers did not improve with the addition of contrast-enhanced sequences, DWI, or CSI (53% (17/32) session 1; 50% (16/30) session 2; 53% (17/32) session 3). Noncontrast features, including thick septations (p = 0.025) and nodules ≥ 1 cm (p < 0.001), were useful for differentiating benign tumors from ALTs and DDLs, as were DWI (p = 0.01) and CSI (p = 0.009) metrics., Conclusion: The addition of contrast-enhanced sequences (static, DCE), DWI, and CSI to a conventional, noncontrast MRI protocol did not improve diagnostic accuracy for differentiating benign, intermediate-grade, and malignant lipomatous tumors. However, we identified potentially useful imaging features by DCE, DWI, and CSI that may help distinguish these entities., (© 2021. Italian Society of Medical Radiology.)

Background: Racial disparities in outcomes after orthopaedic surgery have been well-documented in the fields of arthroplasty, trauma, and spine surgery; however, little research has assessed differences in outcomes after surgery for oncologic musculoskeletal disease. If racial disparities exist in the treatment of patients with pathologic long bone fractures, then they should be identified and addressed to promote equity in patient care., Questions/purposes: (1) How do wait times between hospital admission and operative fixation for pathologic fractures of long bones differ between Black and non-Hispanic white patients, after controlling for confounding variables using propensity score matching? (2) How does the proportion of patients with 30-day postoperative complication differ between these groups after controlling for confounding variables using propensity score matching?, Methods: Using the National Surgical Quality Improvement Program database, we analyzed 828 patients who underwent fixation for pathologic fractures from 2012 to 2018. This database not only provides a large enough sample of pathologic long bone fracture patients to conduct the present study, but also it contains variables such as time from hospitalization to surgery that other national databases do not. After excluding patients with incomplete data (4% of the initial cohort), 775 patients were grouped by self-reported race as Black (12% [94]) or white (88% [681]). Propensity score matching using a 1:1 nearest-neighbor match was then used to match 94 Black patients with 94 white patients according to age, gender, BMI, American Society of Anesthesiologists physical status classification, anemia, endstage renal disease, independence in performing activities of daily living, congestive heart failure, and pulmonary disease. The primary outcome of interest was the number of days between hospital admission and operative fixation, which we assessed using a Poisson regression and report as an incidence risk ratio. The secondary outcomes were the occurrences of major 30-day postoperative adverse events (failure to wean off mechanical ventilation, cerebrovascular events, renal failure, cardiovascular events, reoperation, death), minor 30-day adverse events (reintubation, wound complications, pneumonia, and thromboembolic events), and any 30-day adverse events (defined as the pooling of all adverse events, including readmissions). These outcomes were analyzed using a bivariate analysis and logistic regression with robust estimates of variance and are reported as odds ratios. Because any results on disparities rely on rigorous control of other baseline demographics, we performed this multivariable approach to ensure we were controlling for confounding variables as much as possible., Results: After controlling for potentially confounding variables such as age and gender, we found that Black patients had a longer mean wait time (incidence risk ratio 1.5 [95% CI 1.1 to 2.1]; p = 0.01) than white patients. After controlling for confounding variables, Black patients also had greater odds of having any postoperative adverse event (OR 2.1 [95% CI 1.1 to 3.8]; p = 0.02), including readmission (OR 3.3 [95% CI 1.5 to 7.6]; p = 0.004)., Conclusion: The racial disparities in pathologic long bone fracture care found in our study may be attributed to fundamental racial biases, as well as systemic socioeconomic disparities in the US healthcare system. Identifying and eliminating the racial, socioeconomic, and sociocultural biases that drive these disparities would improve care for patients with orthopaedic oncologic conditions. One possible way to reduce these disparities would be to implement standardized surgical care pathways for pathological long bone fractures across different institutions to minimize variation in important aspects of care, such as time to surgical fixation. Further insight is needed on the types of standardized care pathways and the implementation mechanisms that are most effective., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors., Competing Interests: Declaration of interests J.C.M.W. and N.R. are inventors/contributors on patents covering methods for ctDNA detection (including WO/2020/104670). P.R. reports institutional research funding from Novartis, Grail/Illumina, ArcherDx/Invitae, Inivata, Epic Sciences, and Tempus; advisory board/honoraria from Novartis, AstraZeneca, Foundation Medicine, Pfizer, Epic Sciences, Inivata, and Natera; and consulting for Tempus. Y.-S.Y. reports honoraria/consultancy from Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, and Specialised Therapeutics and travel support from Pfizer, Eisai, and Roche. S.-J.D. has received research funding from Roche Genentech and Cancer Therapeutics (CTx) CRC and has been an advisory board member for AstraZeneca and Inivata. S.K. serves on the advisory board and is a consultant for Inivata and Natera. N.R. and C.D.M. are officers of Inivata. T.I.M., P.R., E.L.M., R.G., I.T., Y.-S.Y., W.A.R., B.B., A.B., and J.T. served on the advisory board and consulted for Inivata., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An 81-year-old woman with multiply recurrent undifferentiated pleomorphic sarcoma of the foot underwent wide excision and reconstruction with an anterolateral thigh free flap. Six years postoperatively, she developed biopsy-proven recurrence within the harvest site. No other sites of disease were detected on staging workup. The flap site recurrence was attributed to iatrogenic implantation at the time of harvesting. Iatrogenic metastases are thought to be caused by tumor implantation, which may be attributable to cross-contamination from instrumentation and surgical techniques. In the present article, we highlight preventive techniques and oncologic surgical principles intended to reduce the likelihood of iatrogenic metastasis. Increased awareness by all members of the surgical team may prevent this unfortunate complication., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission., (Published by Elsevier Inc.)

Background: Total en bloc sacrectomy provides the best long-term local control for large primary bony sacral tumors, but often requires lumbosacral nerve root sacrifice leading to loss of ambulation and/or bowel, bladder, and/or sexual dysfunction. Nerve-sparing techniques may be an option for some patients that avoid these outcomes and accordingly improve postoperative quality of life., Objective: To describe the technique for a posterior-only en bloc hemisacrectomy with maximal nerve root preservation and to summarize the available literature., Methods: A 38-yr-old woman with a 7.7 × 5.4 × 4.5 cm biopsy-proven grade 2 chondrosarcoma involving the left L5-S2 posterior elements underwent a posterior-only left hemisacrectomy tri-rod L3-pelvis fusion. A systematic review of the English literature was also conducted to identify other descriptions of high sacrectomy with distal sacral nerve root preservation., Results: Computer-aided navigation facilitated an extracapsular resection that allowed preservation of the left-sided L5 and S3-Co roots. Negative margins were achieved and postoperatively the patient retained ambulation and good bowel/bladder function. Imaging at 9-mo follow-up showed no evidence of recurrence. The systematic review identified 4 prior publications describing 6 total patients who underwent nerve-sparing sacral resection. Enneking-appropriate resection was only obtained in 1 case though., Conclusion: Here we describe a technique for distal sacral nerve root preservation during en bloc hemisacrectomy for a primary sacral tumor. Few prior descriptions exist, and the present technique may help to reduce the neurological morbidity of sacral tumor surgery., (© Congress of Neurological Surgeons 2021.)

Background: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes., Results: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers., Conclusions: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 ., (© 2021. The Author(s).)

Introduction: Addiction consult services (ACS) engage hospitalized patients with opioid use disorder (OUD) in care and help meet their goals for substance use treatment. Little is known about how ACS affect mortality for patients with OUD. The objective of this study was to design and validate a model that estimates the impact of ACS care on 12-month mortality among hospitalized patients with OUD., Methods: We developed a Markov model of referral to an ACS, post-discharge engagement in SUD care, and 12-month drug-related and non-drug related mortality among hospitalized patients with OUD. We populated our model using Oregon Medicaid data and validated it using international modeling standards., Results: There were 6,654 patients with OUD hospitalized from April 2015 through December 2017. There were 114 (1.7%) drug-related deaths and 408 (6.1%) non-drug related deaths at 12 months. Bayesian logistic regression models estimated four percent (4%, 95% CI = 2%, 6%) of patients were referred to an ACS. Of those, 47% (95% CI = 37%, 57%) engaged in post-discharge OUD care, versus 20% not referred to an ACS (95% CI = 16%, 24%). The risk of drug-related death at 12 months among patients in post-discharge OUD care was 3% (95% CI = 0%, 7%) versus 6% not in care (95% CI = 2%, 10%). The risk of non-drug related death was 7% (95% CI = 1%, 13%) among patients in post-discharge OUD treatment, versus 9% not in care (95% CI = 5%, 13%). We validated our model by evaluating its predictive, external, internal, face and cross validity., Discussion: Our novel Markov model reflects trajectories of care and survival for patients hospitalized with OUD. This model can be used to evaluate the impact of other clinical and policy changes to improve patient survival., Competing Interests: Dr. Korthuis serves as principal investigator for NIH-funded studies that accept donated study medication from Alkermes (extended-release naltrexone) and Indivior (buprenorphine). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Sciatic notch tumors are rare and have numerous etiologies. Tumor presentation varies widely and no uniform recommendations exist for approaching resection. Most studies on the topic have been small case series, with the approach dictated by surgeon experience and comfort. We provide an overview of surgical approaches for resecting sciatic notch tumors reported in the literature, as well as a conceptual framework for application of these approaches based on standard oncologic principles. The advantages and disadvantages of each approach are described on the basis of anatomic location of the tumor. For tumors that span the notch with intra- and extra-pelvic extension, notchplasty is a novel technique that provides superior visualization and access for en-bloc excision., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

»: Fractures that result from radiation-induced bone damage are a recognized adverse effect of radiation therapy (RT)., »: The mechanisms of damage from RT are thought to be related to impaired vascularity, aberrations in osteoclast and osteoblast-mediated bone turnover, and compromise of cortical and trabecular microarchitecture., »: Treatment of radiation-associated fractures is challenging, with rates of delayed union and nonunion of >50%., »: Fracture management strategies, each with its own profile of risks and benefits, include prophylactic intramedullary nailing of long bones, open reduction and internal fixation with adjunctive iliac crest or vascularized fibular grafting, and endoprosthetic reconstruction., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A737)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Patients with fungating extremity soft-tissue sarcoma (STS) can develop lymphadenopathy, which can represent nodal metastasis or benign reactive adenopathy., Methods: In 1787 patients with STS, 67 (3.7%) had fungating extremity STS. In the 62 patients who met our inclusion criteria, we evaluated prevalence and histopathology of lymphadenopathy, factors associated with lymphadenopathy and nodal metastasis, and prevalence of and factors associated with lung metastasis and survival time from fungation. Logistic regression and Cox proportional-hazards models were used to analyze node pathology, lung metastasis, and survival duration with α = 0.05., Results: Lymphadenopathy occurred in 11 of 62 patients (18%), 6 with nodal metastasis and 5 with reactive adenopathy. The only factor associated with lymphadenopathy was location of primary tumor in the upper extremity (p = 0.02). No tumor characteristics were associated with nodal metastasis. In all five patients with reactive adenopathy, the condition was recognized within 3 days after tumor fungation. Lymphadenopathy recognized more than 3 days after tumor fungation was likely to be nodal metastasis. Forty-one percent of patients developed lung metastasis, which was not associated with presence of lymphadenopathy or any patient or tumor characteristic. Age, tumor size, and Black and Asian race were independently associated with greater risk of death., Conclusions: Eighteen percent of patients with fungating extremity STS developed lymphadenopathy. Approximately half of cases represented nodal metastasis, and half represented reactive adenopathy. Lymphadenopathy that develops within 3 days after tumor fungation should increase suspicion for reactive adenopathy versus nodal metastasis.

Aims: Rotating-hinge knee prostheses are commonly used to reconstruct the distal femur after resection of a tumour, despite the projected long-term burden of reoperation due to complications. Few studies have examined the factors that influence their failure and none, to our knowledge, have used competing risk models to do so. The purpose of this study was to determine the risk factors for failure of a rotating-hinge knee distal femoral arthroplasty using the Fine-Gray competing risk model., Methods: We retrospectively reviewed 209 consecutive patients who, between 1991 and 2016, had undergone resection of the distal femur for tumour and reconstruction using a rotating-hinge knee prosthesis. The study endpoint was failure of the prosthesis, defined as removal of the femoral component, the tibial component, or the bone-implant fixation; major revision (exchange of the femoral component, tibial component, or the bone-implant fixation); or amputation., Results: Multivariate Fine-Gray regression analyses revealed different hazards for each Henderson failure mode: percentage of femoral resection (p = 0.001) and extent of quadriceps muscle resection (p = 0.005) for overall prosthetic failure; extent of quadriceps muscle resection (p = 0.002) and fixation of femoral component (p = 0.011) for type 2 failure (aseptic loosening); age (p = 0.009) and percentage of femoral resection (p = 0.019) for type 3 failure (mechanical failure); and type of joint resection (p = 0.037) for type 4 (infection) were independent predictors. A bone stem ratio of > 2.5 reliably predicted aseptic loosening., Conclusion: We identified independent risk factors for overall and cause-specific prosthetic failure after rotating-hinge knee distal femoral arthroplasty using a competing risk Fine-Gray model. A bone stem ratio > 2.5 reliably predicts aseptic loosening. An accurate knowledge of the risks of distal femoral arthroplasty after resection for tumour assists surgical planning and managing patient expectations. Cite this article: Bone Joint J  2021;103-B(8):1405-1413.

Case: A 30-year-old man presented with progressive lower right extremity pain and swelling, initially diagnosed as a deep venous thrombosis. He returned 18 months later after 2 episodes of gross hemoptysis, with chest computed tomography angiography findings concerning for tumor thrombus in the left pulmonary artery. Subsequent advanced imaging showed a lesion arising from his right femoral vein, which open biopsy revealed to be a primary intravascular mesenchymal chondrosarcoma. He underwent medical therapy, with improvement of pain and swelling and successful return to work., Conclusion: Mesenchymal chondrosarcoma is a rare pathology, and its intravascular origin makes this case extraordinarily uncommon., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B585)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

The anatomic extent of a pelvic bone tumor and the need for reconstruction dictate the type of pelvic resection (limb salvage pelvic resection or amputation). If a pelvic bone tumor resection involves two or more critical anatomic structures (the sciatic nerve, femoral neurovascular bundle or the hip joint), then reasonable functional recovery after limb salvage is less likely and amputation should be considered. Both limb salvage and amputation approaches to the pelvis are technically arduous surgeries with significant associated morbidity and complications. As such, imaging plays an important role in the post-operative management of patients who have undergone pelvic bone tumor resection. In this article, we will review optimal imaging techniques as well as the expected post-operative appearance after pelvic bone tumor resection and important complications including infection, tumor recurrence, and complications related to complex soft tissue and osseous reconstruction.

Background: Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy., Methods: 66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung 'PM interface' and 'PM interior' regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection., Results: IHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS., Conclusions: Osteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy., Competing Interests: Competing interests: GC is an employee/paid consultant for Compugen LTD. DMC reports grant support from AstraZeneca and Rainier Pharmaceuticals. DMP reports grant support from Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma., Methods: The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence., Results: In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p  = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p  = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%., Conclusions: Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Gregory C. Stachelek et al.)

Chondroblastoma is a rare benign tumor of immature cartilage cells that generally occurs in an epiphyseal location of skeletally immature individuals. However, a few studies have reported cases in older patients. The purpose of this study was to evaluate the clinical, radiographic, and pathologic features of chondroblastoma in an adult population. The pathology archives of our institution were searched for cases of chondroblastoma diagnosed in patients ≥25 years of age. Of 14 patients identified, 8 were male and 6 were female with a median age of 34 years (range = 29-54 years). Most lesions occurred in short bones of hands and feet (N = 7, 50%), followed by the long tubular bones (N = 4, 28%). All demonstrated typical histologic features of chondroblastoma, but more extensive calcification, necrosis, and degenerative changes were also seen. At follow-up (median = 73.5 months), 2 patients (17%) had local recurrence. None had metastasis. In summary, chondroblastoma in adults tends to involve the short bones of the hands and feet and demonstrate histologic changes associated with long-standing growth of a benign tumor.

Background: Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors., Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria., Results: Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies., Conclusions: Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The general efficacy of quitlines has been widely demonstrated, but uncertainty exists regarding how quitlines might best intervene for persons with mental health conditions. A total of 1 in 5 people in the U.S. has a diagnosable psychiatric disorder. These individuals smoke at 2‒4 times the rate of smoking among those without a mental health condition and face high rates of related death and disability. About half of quitline callers self-report a mental health condition, but until recently, quitline protocols tailored to these smokers did not exist., Methods: This paper provides initial results for tailored mental health programs from the largest quitline providers in the U.S., Optum and National Jewish Health. From 2017 to 2018, cohorts of callers with a mental health condition who enrolled in tailored programs were compared with cohorts with a mental health condition who received standard care. Both mental health programs offered participants additional calls, longer duration of combination nicotine-replacement therapy, and attention to mental health issues. Analyses were conducted in 2018-2019., Results: Findings suggest that callers with a mental health condition benefit from both standard care and tailored mental health services. Tailored programming did well in engaging people with mental health conditions. At the same time, there were no significant differences in abstinence rates when comparing mental health programs with standard care. Mental health cohorts did receive significantly greater service durations, more counseling calls, and longer nicotine-replacement therapy duration., Conclusions: Tailored mental health quitline programs present a promising framework for testing the services that address psychiatric symptoms as well as other frequent population characteristics such as chronic illness. Implications for increasing reach to the often underserved population with a mental health condition are discussed., (Copyright © 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Stratification of the fracture risk is an important treatment component for patients with multiple myeloma, which is associated with up to an 80% risk of pathologic fracture. The Mirels score, which is commonly used to estimate the fracture risk for patients with osseous lesions, was evaluated in a cohort in which fewer than 15% of lesions were caused by multiple myeloma. The behavior of multiple myeloma lesions often differs from that of lesions caused by metastatic disease, and accurate risk stratification is critical for effective care. To our knowledge, the Mirels score has not been validated specifically for multiple myeloma., Questions/purposes: Our purpose was: (1) To develop a novel scoring system for the prediction of pathologic fracture in patients with long-bone lesions from multiple myeloma; and (2) to compare the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) area under curve (AUC) between the novel scoring system and the Mirels system., Methods: Between 2003 and 2017, 763 patients at one center with the diagnosis of multiple myeloma were reviewed, of whom 174 presented with long-bone disease involvement. Of those, 5% (nine of 174) were missing data or radiographs at a minimum of 1 year and had not reached an endpoint (fracture or surgery) before that time and were therefore excluded. Many patients have more than one lesion; consequently, we used the largest lesion in each patient, resulting in 163 lesions in as many patients. Ten percent (16 of 163) of these patients eventually developed a fracture and 4% (six of 163) underwent prophylactic stabilization (excluded from analysis because of outcome uncertainty). During the study period, prophylactic stabilization was performed at the discretion of the orthopaedic oncologist. Fifty-one percent (83 of 163) of patients were female, and the mean (± SD) age was 60 ± 10 years at radiographic lesion identification. All lesions were characterized before determining whether the patient underwent pathologic fracture. We identified variables associated with pathologic fracture on univariate analysis. Variables independently significant on logistic regression analysis were used to generate scoring algorithms at varying weights and scoring cutoffs for comparison via ROC curves. We then selected a novel score based on ROC performance, and compared the sensitivity, specificity, PPV, and NPV of that scoring system to that of Mirels score. ROC AUCs were compared after bootstrapping 100,000 iterations. Alpha was set at 0.05., Results: After controlling for potential confounders, such as age, sex, and duration of myeloma diagnosis, we found the following factors were independently associated with the occurrence of pathologic fracture: larger lesion size (area, cm2) (log odds 0.17; p = 0.03), longer lesion latency (years from diagnosis to lesion identification) (log odds 0.25; p = 0.03), presence of pain (relative risk [RR] 2.9; p = 0.04), and metaphyseal location (RR 3.2, compared with epiphyseal or diaphyseal; p = 0.003). These variables were used to formulate a novel scoring system. Compared with the Mirels system, the novel system was more sensitive (69% [95% CI 61 to 76] versus 38% [95% CI 30 to 46]; p < 0.05) but not different in terms of specificity (87% [95% CI 80 to 91] versus 87% [95% CI 81 to 92]; p > 0.05), PPV (37% [95% CI 29 to 45] versus 25% [95% CI 19 to 33]; p > 0.05), NPV (96% [95% CI 91 to 99] versus 92% [95% CI 87 to 96]; p > 0.05), or AUC (0.85 [95% CI 0.74 to 0.92] versus 0.67 [95% CI 0.51 to 0.81]; p > 0.05)., Conclusion: The novel scoring system was found to be more sensitive than the Mirels system for predicting pathologic fracture in our retrospective cohort of patients with multiple myeloma-related bone disease. Specificity, PPV, NPV, and ROC AUC were not different with the numbers available. Thus, the novel scoring system may serve as a more effective screening tool to determine which patients with multiple myeloma would benefit from further radiologic or orthopaedic evaluation based on a skeletal survey., Level of Evidence: Level III, diagnostic study., Competing Interests: Each author certifies that neither he nor she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Background: Radiation-induced fibrosis is a long-term adverse effect of external beam radiation therapy for cancer treatment that can cause pain, loss of function, and decreased quality of life. Transforming growth factor beta (TGF-β) is believed to be critical to the development of radiation-induced fibrosis, and TGF-β inhibition decreases the development of fibrosis. However, no treatment exists to prevent radiation-induced fibrosis. Therefore, we aimed to mitigate the development of radiation-induced fibrosis in a mouse model by inhibiting TGF-β., Question/purposes: Does TGF-β inhibition decrease the development of muscle fibrosis induced by external beam radiation in a mouse model?, Methods: Twenty-eight 12-week-old male C57BL/6 mice were assigned randomly to three groups: irradiated mice treated with TGF-βi, irradiated mice treated with placebo, and control mice that received neither irradiation nor treatment. The irradiated mice received one 50-Gy fraction of radiation to the right hindlimb before treatment initiation. Mice treated with TGF-c (n = 10) received daily intraperitoneal injections of a small-molecule inhibitor of TGF-β (1 mg/kg) in a dimethyl sulfoxide vehicle for 8 weeks (seven survived to histologic analysis). Mice treated with placebo (n = 10) received daily intraperitoneal injections of only a dimethyl sulfoxide vehicle for 8 weeks (10 survived to histologic analysis). Control mice (n = 8) received neither radiation nor TGF-β treatment. Control mice were euthanized at 3 months because they were not expected to exhibit any changes related to treatment. Mice in the two treatment groups were euthanized 9 months after radiation, and the quadriceps of each thigh was sampled. Masson's trichome stain was used to assess muscle fibrosis. Slides were viewed at 10 × magnification using bright-field microscopy, and in a blinded fashion, five representative images per mouse were used to quantify fibrosis. The mean ± SD fibrosis pixel densities in the TGF-βi and radiation-only groups were compared using Mann-Whitney U tests. The ratio of fibrosis to muscle was calculated using the mean fibrosis per slide in the TGF-βi group to standardize measurements. Alpha was set at 0.05., Results: The mean (± SD) percentage of fibrosis per slide was greater in the radiation-only group (1.2% ± 0.42%) than in the TGF-βi group (0.14% ± 0.09%) (odds ratio 0.12 [95% CI 0.07 to 0.20]; p < 0.001). Among control mice, mean fibrosis was 0.05% ± 0.02% per slide. Mice in the radiation-only group had 9.1 times the density of fibrosis as did mice in the TGF-βi group., Conclusion: Our study provides preliminary evidence that the fibrosis associated with radiation therapy to a quadriceps muscle can be reduced by treatment with a TGF-β inhibitor in a mouse model., Clinical Relevance: If these observations are substantiated by further investigation into the role of TGF-β inhibition on the development of radiation-induced fibrosis in larger animal models and humans, our results may aid in the development of novel therapies to mitigate this complication of radiation treatment., Competing Interests: Each author certifies that neither he or she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy., Competing Interests: Competing interests: BG is a consultant for Quest Imaging and a speaker for Castle Biosciences. PKA has partner salary from Pfizer. GB has sponsored research agreements with Takeda Oncology, Olink Proteomics, and Palleon, honorarium from Novartis, and consulting for NW Biotherapeutics. SB is a consultant for BMS. LHB is a consultant for StemImmune/Calidi, NextCure, Replimmune, Western Oncolytics, Torque Therapeutics, Khloris, Pyxis, Cytomix, and Roche-Genentech. PEF is a consultant for Monteris Medical. RLF is a consultant for Aduro Biotech, Amgen, Astra-Zeneca/Medimmune, Bain Capital Life Sciences, BMS, EMD Serono, GSK, Iovance, Lilly, MacroGenics, Merck, Nanobiotx, Numab Therapeutics, Oncorus, Ono Pharmaceutcal Co., Pfizer, PPD, Regeneron, Tesaro, Torque Therapeutics, TTMS, and VentiRx Pharmaceuticals; has contracted research agreements with Astra-Zeneca/Medimmune, BMS, Merck, Tesaro, and TTMS, has partner consulting for Janssen, Lilly, Scibase, DermTech, BMS, and Pfizer, and has partner contracted research agreements with Regeneron, Janssen, BMS, Abbvie, BI, Castle Biosciences and Lilly.YF has relationships with Imagene, Merck, Eureka and Surgamo, and partner interest in Pfizer. MLim is a consultant for Tocagen, VBI and Strykes, and receives research funding from Arbor, BMS and Biohaven. MLotze receives salary from Nurix, Inc., royalty from Cellatrope, has IP rights in Intrexon, consults for Myst, Instill, Checkmate, Carisma and Surface Oncology, and has ownership interest in iRepertoire. HM has contracted research with Puma Biotechnology. RIN is a consultant for Novartis, Castle Biosciences, and Sanofi-Granzyme and has contracted research with Regeneron and Castle Biosciences. AO is a cofounder of Tactiva Therapeutics, Inc., and receives research support from AstraZeneca and Tesaro. SP is a consultant for Abbvie, Astra-Zeneca, Cue Biopharma, Fusion Biopharma, Merck, Newlink Genetics, Oncolys Biopharma, Oncosec, Replimmune and Sensei Bio, contracted research with Abbvie, Astra-Zeneca, Cue Biopharma, Sensei Bio and Tesaro, and investigator-initiated trials with ASTX Pharmaceuticals, Astra-Zeneca, Cue Biopharma, ImmuneDesign and Merck. SAR has patents held by the NCI and cooperative research agreements with Kite, Iovance and Ziopharm. CLS is a consultant for Celldex, CureVac and Castle Biosciences, and has institutional support from Celldex, Polynoma, GSK, Merck, 3M, Theraclion and Immatics. VKS is a consultant for Array, BMS, Merck, Novartis, Pfizer, Polynoma, Regeneron and Replimmune. JBS is on the advisory board of ABL Bio and is the scientific founder of Indapta Therapeutics. ST is a consultant for TVM Life Science, received honoraria from Astra-Zeneca, Celgene and Exactis Innovation, and has research grants from BMS and Iovance. CY is a consultant for Loxo, Merck and Adaptive Biotechnologies, has contracted research with Obi and Pfizer, and has ownership interest in Molpath Dx, LLC. HLK is an employee of Immuneering Coporation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The U.S. is in the midst of an opioid epidemic. At the same time, tobacco use remains the leading cause of preventable death and disability. While the shared biological underpinnings of nicotine and opioid addiction are well established, clinical implications for co-treatment of these two substance use disorders has not been emphasized in the literature, nor have researchers, clinicians, and policy makers adequately outlined pathways for incorporating co-treatment into existing clinical workflows. The current brief review characterizes the metabolic and neural mechanisms which mediate co-use of nicotine and opioids, and then outlines clinical and policy implications for concurrently addressing these two deadly epidemics. Screening, assessment, medication-assisted treatment (MAT), and tobacco-free policy are discussed. The evidence suggests that clinical care and policies that facilitate co-treatment are an expedient means of delivering healthcare to individuals that result in better health for the population while also meeting patients' substance abuse disorder recovery goals.

Improvements in cancer treatment have led to prolonged survival and increased rates of cure. An estimated 14 million cancer survivors live in the United States. The cornerstones of cancer treatment, including radiation, chemotherapy, and surgery, give rise to a host of chronic health conditions, some of which affect the musculoskeletal system. As survivorship continues to improve, orthopaedic surgeons across all subspecialties will be tasked with managing these complications of treatment. This article reviews orthopaedic health concerns secondary to cancer treatment that are likely to present to orthopaedic surgeons for evaluation, such as osteoporosis, osteonecrosis, secondary malignancies, radiation-associated fractures, exercise tolerance, and perioperative evaluation.

Background: Vitamin C (500 mg·day -1 ) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported., Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age., Methods: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day -1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance., Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec -1 for FEF 75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec -1 for FEF 50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec -1 for FEF 25-75 (95% CI, 9.7 to 100.5; p=0.013)., Conclusions: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway., (Copyright ©ERS 2020.)

Case: A 78-year-old man was followed for an incidentally found, asymptomatic lesion in his right proximal femur that was unchanged radiographically for 11 years. He developed pain and was believed to have experienced a stress fracture through the lesion. The lesion was biopsied, showing a high-grade pleomorphic sarcoma with an underlying senescent intraosseous lipoma. He was ultimately treated with wide excision and reconstruction of the proximal femur., Conclusion: This case highlights the importance of obtaining a tissue diagnosis for lesions that become symptomatic.

Clinical and Translational Science Award (CTSA) TL1 trainees and KL2 scholars were surveyed to determine the immediate impact of the COVID-19 pandemic on training and career development. The most negative impact was lack of access to research facilities, clinics, and human subjects, plus for KL2 scholars lack of access to team members and need for homeschooling. TL1 trainees reported having more time to think and write. Common strategies to maintain research productivity involved time management, virtual connections with colleagues, and shifting to research activities not requiring laboratory/clinic settings. Strategies for mitigating the impact of the COVID-19 pandemic on training and career development are described., Competing Interests: The authors have no conflicts of interest to disclose., (© The Association for Clinical and Translational Science 2020.)

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.

We compared short-term outcomes after operative versus nonoperative treatment of pathologic humeral fractures. We hypothesized that patients who underwent operative fixation would heal faster and have better pain control. A retrospective review was conducted of 25 patients who underwent operative fixation and 6 who received nonoperative treatment from 2005-2017. Operative patients healed significantly earlier than nonoperative patients (p = 0.02). At 16-week follow-up, radiographs showed evidence of healing in 24 of 25 operatively treated patients and 2 of 6 nonoperatively treated patients (p < 0.01). Pain improved during the inpatient stay in 24 of 25 operatively treated patients and none of the nonoperatively treated patients (p < 0.01). All operatively treated patients returned to self-reported baseline motor function by final follow-up, whereas none of the nonoperatively treated patients returned to baseline (p = 0.01). Operative treatment was associated with earlier healing, pain control and return to function compared with nonoperative treatment of pathologic humeral fractures. Level of Evidence: 3. (Journal of Surgical Orthopaedic Advances 29(3):177-181, 2020).

Despite the use of digital technology in healthcare, telemedicine has not been readily adopted. During the COVID-19 pandemic, healthcare systems have begun crisis management planning. To appropriately allocate resources and prevent virus exposure while maintaining effective patient care, our orthopaedic surgery department rapidly introduced a robust telemedicine program during a 5-day period. Implementation requires attention to patient triage, technological resources, credentialing, education of providers and patients, scheduling, and regulatory considerations. This article provides practical instruction based on our experience for physicians who wish to implement telemedicine during the COVID-19 pandemic. Between telemedicine encounters and necessary in-person visits, providers may be able to achieve 50% of their typical clinic volume within 2 weeks. When handling the massive disruption to the routine patient care workflow, it is critical to understand the key factors associated with an accelerated introduction of telemedicine for the safe and effective continuation of orthopaedic care during this pandemic. LEVEL OF EVIDENCE:: V.

Background and Objectives: The development of desmoid fibromatosis after tumor resection may mimic local recurrence. To our knowledge, this phenomenon has not been reported after extremity sarcoma resection. We report four cases of desmoid-type fibromatosis ("desmoid tumors") mimicking local recurrence after extremity sarcoma resection., Methods: We retrospectively reviewed the records of patients treated for extremity sarcoma by our orthopedic oncology service from 2014 to 2019 and identified four patients with biopsy-proven desmoid tumors. We extracted clinical, pathologic, radiographic, and operative data for the primary neoplasms and desmoid tumors., Results: Four patients with postresection surveillance magnetic resonance imaging suspicious for local recurrence underwent further analysis showing desmoid tumors. Patients underwent image-guided needle biopsy, with specimens demonstrating fibromatosis-type histologic characteristics. Two cases were β-catenin positive. Desmoid tumors were managed with observation. No patient had experienced local or distant recurrence of the primary tumor at a mean follow-up of 30 months after resection (range, 23-34 months); none underwent surgery for symptoms of desmoid tumors., Conclusions: Desmoid tumors should be considered part of the differential diagnosis when assessing patients with radiographic concern for postresection local recurrence of extremity bone and soft-tissue sarcoma. An image-guided needle biopsy can inform diagnosis and management., (© 2020 Wiley Periodicals, Inc.)

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS., (© 2020 Wiley Periodicals, Inc.)

Background: Atopic dermatitis (AD) is a common, chronic skin disorder often beginning in infancy. Skin barrier dysfunction early in life serves as a central event in the pathogenesis of AD. In infants at high risk of developing AD, preventative application of lipid-rich emollients may reduce the risk of developing AD. This study aims to measure the effectiveness of this intervention in a population not selected for risk via a pragmatic, randomized, physician-blinded trial in the primary care setting., Methods: Infant-parent dyads are recruited from a primary care practice participating through one of four practice-based research networks in Oregon, Colorado, Wisconsin, and North Carolina. Eligible dyads are randomized to the intervention (daily use of lipid-rich emollient) or the control (no emollient) group (n = 625 infants in each) and are followed for 24 months. The primary outcome is the cumulative incidence of physician-diagnosed AD and secondary outcomes include caregiver-reported measures of AD and development of other atopic diseases. Data collection occurs via chart review and surveys, with no study visits required. Data will be analyzed utilizing intention-to-treat principles., Discussion: AD is a common skin condition in infants that affects quality of life and is associated with the development of other atopic diseases. If a safe intervention, such as application of lipid-rich emollients, in the general population effectively decreases AD prevalence, this could alter the guidance given by providers regarding routine skin care of infants. Because of the pragmatic design, we anticipate that this trial will yield generalizable results., Trial Registration: ClinicalTrials.gov: NCT03409367. Registered on 11 February 2018.

Purpose: Patients with large, high-grade soft tissue sarcomas are commonly treated with aggressive limb preservation regimens. This study aimed to assess cancer control outcomes of patients treated with neoadjuvant chemoradiation (CRT) compared with radiation therapy (RT) alone., Methods: We reviewed records of patients with high-grade extremity or trunk soft tissue sarcomas ≥5 cm who were treated with neoadjuvant radiation with or without chemotherapy. Patient and disease characteristics were compared using t test and χ 2 tests. Standardized mortality ratio weighted method was used to compare overall survival (OS), local control, and disease-free (DFS) survival. Acute radiation and surgical toxicity were reported., Results: In the study, 64 patients (34 CRT and 30 RT) treated between 1997 and 2015 were analyzed. In the RT group compared with the CRT group, the patient population was older, with a median age of 65 versus 50 years ( P < .001), and more likely to have cardiovascular disease (CVD; 30% vs 0%, P < .001). At a median follow-up of 41 months, after adjusting for propensity score of receiving RT, the 3-year LC was 87.3% versus 86.1%, DFS was 58.5% versus 56.6%, and OS was 75.6% versus 69.0% for the CRT and RT groups, respectively ( P > .05). Acute dermatitis occurred in 18% versus 3% and surgical complications occurred in 32% versus 17% of CRT and RT patients, respectively., Conclusions: In this study, patients receiving RT alone were more likely to be older and have comorbid cardiovascular disease. When controlling for baseline differences, neoadjuvant CRT and RT provided similar rates of LC, DFS, and OS., (© 2019 The Authors.)

Background: Metastatic carcinoma to skeletal muscle and/or subcutaneous fat is a rare event. Only 27 cases of esophageal cancer to soft tissue have been described in the English-language literature., Purpose: Our goal was to describe the prevalence and clinical characteristics of soft-tissue metastasis among patients with primary esophageal cancer at a single institution., Methods: We performed a retrospective review of all patients with primary esophageal cancer. Data points analyzed included histologic subtype, anatomic location, metastasis pattern, treatment, and survival. Kaplan-Meier curves were used to estimate survival time, and log-rank tests were used for comparisons. For all analyses, P < 0.05 was considered significant., Results: Of 1341 patients with primary esophageal cancer, 25 (1.9%) had metastases to soft tissue. Soft-tissue metastases were diagnosed at a median age of 64 years, a median 9.6 months after esophageal cancer diagnosis. Adenocarcinoma was the predominant histopathological type, and soft-tissue metastasis was most common in the lower extremity. Local intervention was used for 10 symptomatic patients with favorable prognoses. Chemotherapy was the only treatment modality in 18 patients. Median survival time after diagnosis of soft-tissue metastasis was 8.9 months and was longer in patients with metastasis in soft tissue only (24.6 months, P = 0.007) and in those who received local intervention (11.1 months vs those who did not, P = 0.020)., Conclusion: We estimate the prevalence of soft-tissue metastasis to be 1.9% among patients with esophageal cancer. Local intervention may be beneficial for patients in otherwise good health with symptomatic soft-tissue lesions.