Sarcoma in patients with Lynch syndrome and response to immunotherapy.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant genetic predisposition to multiple malignancies and is characterized by deficient DNA mismatch repair. Increased incidence of sarcomas is not formally ascribed to LS; however, increasing evidence suggests a preponderance of these malignancies in affected families. Sarcomas typically possess a low tumor mutational burden and incite a poor immune infiltrate, thereby rendering them poorly responsive to immunotherapy. METHODS: We searched the University of California, Los Angeles (UCLA) sarcoma program database for patients with a diagnosis of sarcoma and LS from 2016 to 2023. Three such patients were identified and all three were treated with PD1 blockade. RESULTS: We present three cases of LS-associated sarcomas (two soft tissue sarcoma and one osteosarcoma) with increased tumor mutational burdens. These patients were each treated with an anti-PD1 antibody and experienced a response far superior to that reported for non-LS-associated sarcomas. CONCLUSIONS: Increased mutational burden and immune infiltrate are observed for sarcomas associated with LS. Although unselected patients with sarcoma have demonstrated poor response rates to immunotherapy, our findings suggest that patients with Lynch-associated sarcomas are more likely to respond to treatment with anti-PD1. These patients should be given consideration for immunotherapy.

Fibroblast Activation Protein Expression in Sarcomas.

Objectives: Fibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas. Methods: Available tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, <25%, 25-75%; >75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168). Results: The majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression. Conclusion: The majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.

REsCue trial: Randomized controlled clinical trial with extended-release calcifediol in symptomatic COVID-19 outpatients.

OBJECTIVES: This double-blind randomized controlled trial investigated raising serum 25-hydroxyvitamin D (25D) with extended-release calcifediol (ERC) on time to symptom resolution in patients with mild to moderate COVID-19. METHODS: COVID-19 outpatients received oral ERC (300 mcg on days 1-3 and 60 mcg on days 4-27) or placebo (NCT04551911). Symptoms were self-reported daily. Primary end points were raising 25D to ≥50 ng/mL and decreasing resolution time for five aggregated symptoms (three respiratory). RESULTS: In all, 171 patients were randomized, 160 treated and 134 (65 ERC, 69 placebo) retained. The average age was 43 y (range 18-71), 59% were women. The mean baseline 25D was 37 ± 1 (SE) ng/mL. In the full analysis set (FAS), 81% of patients in the ERC group achieved 25D levels of ≥50 ng/mL versus 15% in the placebo group (P < 0.0001). In the per-protocol (PP) population, mean 25D increased with ERC to 82 ± 4 (SE) ng/mL (P < 0.0001) by day 7; the placebo group trended lower. Symptom resolution time was unchanged in the FAS by ERC (hazard ratio [HR], 0.983; 95% confidence interval [CI], 0.695-1.390; P = 0.922). In the PP population, respiratory symptoms resolved 4 d faster when 25D was elevated above baseline level at both days 7 and 14 (median 6.5 versus 10.5 d; HR, 1.372; 95% CI, 0.945-1.991; P = 0.0962; Wilcoxon P = 0.0386). Symptoms resolved in both treatment groups to a similar extent by study end. Safety concerns including hypercalcemia were absent with ERC treatment. CONCLUSION: ERC safely raised serum 25D to ≥50 ng/mL in outpatients with COVID-19, possibly accelerating resolution of respiratory symptoms and mitigating the risk for pneumonia. These findings warrant further study.

The Role of Social Media in Providing Support from Friends for Adolescent and Young Adult (AYA) Patients and Survivors of Sarcoma: Perspectives of AYA, Parents, and Providers.

Purpose: The aims of the current study were to better understand, from the perspective of adolescents and young adults (AYAs) with sarcoma, parents, and providers, the friendship support needs of AYAs with bone and soft tissue sarcoma and the role of social media in facilitating social support for AYAs with sarcoma. Methods: Semistructured interviews were conducted with 21 participants. AYA (n = 10) ranged in age from 14 to 23 years (mean 19.3, standard deviation 3.4 years; 50% female). All AYAs reported a current or past diagnosis of sarcoma, except for one patient who had another cancer diagnosis but was receiving treatment through the sarcoma clinic. Five parents of the adolescent participants were interviewed, as well as six health care providers. Data analysis was conducted using theory-driven immersion/crystallization, incorporating the Resilience in Illness Model as a framework to guide interpretation of the data. Results: Four main themes associated with social support from friends and social media were identified: (1) Social media provides a way to feel normal and connected to friends; (2) Social media accentuates the frustration of being left behind; (3) Social media facilitates the need to be understood by peers who have experienced sarcoma, and (4) Social media can lead to despair, and also provide hope for the future. Conclusions: Connecting with peers through social media can play an important role in providing support for AYAs with sarcoma, but it may also amplify feelings of frustration and anxiety. Future work is needed to determine intervention components that can maximize the benefits of social media for social support of AYAs with sarcoma. Clinical Trial Registration number: NCT03130751.

What's New in Pediatric Orthopaedic Tumor Surgery.

BACKGROUND: Pediatric Orthopaedic Oncology is a developing subspecialty within the field of Pediatric Orthopaedics. Traditionally, the field of Orthopaedic Oncology has been focused on the skeletally mature individual, and the research tends to be all encompassing rather than truly evaluating isolated populations. The purpose of this review is to summarize the most clinically relevant literature in the field of Pediatric Orthopaedic Oncology over the last 6 years. METHODS: We evaluated the PubMed database utilizing keywords for pediatric orthopaedic oncology: sarcoma, osteosarcoma, Ewing sarcoma, bone cyst. In additionally, we further broadened our search by searching for relevant articles in the contents sections of major orthopaedic surgery journals that routinely publish both pediatric and orthopaedic oncology literature. In keeping with "What's New," we selected the most clinically relevant articles published in the last 6 years from January 1, 2014 through February 2020. Basic science and systemic therapies literature was widely reviewed and the research and clinical trials most relevant to pediatric sarcoma and neoplastic processes found in the pediatric population were included. RESULTS: Our search yielded 60 articles that met general criteria, from which 14 were determined to be most relevant to the goals of this paper. Of the papers presented in this review, there were papers related to management of benign tumors/tumor-like conditions, bone cysts, limb salvage procedures, and amputation procedures. Ultimately included in the review were 5 studies related to limb salvage, 4 related to bone cysts, 1 related to multiple hereditary exostoses, 2 related to osteofibrous dysplasia, 1 related to chondroblastoma, and 1 discussing cementation in skeletally immature patients. They were level III, IV, and V studies. Basic science and systemic therapies literature was widely reviewed and the research and clinical trials most relevant to pediatric sarcoma and neoplastic processes found in the pediatric population were included. Our search of the basic science and systemic therapies literature yielded 19 sources were found to be pertinent to our aims and 18 of those sources were published between 2015 and 2020. CONCLUSIONS: There are many, varied, and creative procedures in the realm of limb salvage, though there remains a lack of high-level evidence to support some of the more novel procedures. In regards to benign bone tumors, despite a more solid base of literature, there still does not seem to be consensus as to the best treatment. In particular, there continue to be many schools of thought on the treatment of benign bone cysts. Research in the basic science arena and systemic therapies are advancing in exciting ways in regards to pediatric sarcoma. Orthopaedic oncologic research specific to the pediatric population overall continues to be impeded by low sample sizes and inadequate levels of evidence, which limits the ability of surgeons to draw definitive conclusions from the literature.

A Case of a 15-Month-Old With Periorbital Edema and Severe Anemia.

This is the case of a previously healthy 15-month-old girl who initially presented to her primary pediatrician with a 2-week history of intermittent periorbital edema. The edema had improved by the time of the visit, and a urine specimen was unable to be obtained in the clinic. A routine fingerstick demonstrated anemia to 8.8 mg/dL, so the patient was started on ferrous sulfate. She then returned to the emergency department 1 month later with severe periorbital edema and pallor but no other significant symptoms. On physical examination, she was tachycardic with striking periorbital edema and an otherwise normal physical examination. She was noted to have a severe microcytic anemia (hemoglobin of 3.9 mg/dL and mean corpuscular volume of 53.1 fL) and hypoalbuminemia (albumin of 1.9 g/dL and total protein of 3.3 g/dL). The remainder of her electrolytes and liver function test results were within normal limits. A urinalysis was sent, which was negative for protein. Our panel of experts reviews her case to determine a unifying diagnosis for both her severe anemia and her hypoalbuminemia.

Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases.

Denosumab has been used successfully to treat disease-associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3-year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12-year-old with recurrent ABC of the pelvis, a 14-year-old with CGCG of the mandible, and a 12-year-old with cherubism. All were started on a 1-year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1-month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

A Mobile-Based Mindfulness and Social Support Program for Adolescents and Young Adults With Sarcoma: Development and Pilot Testing.

BACKGROUND: Approximately 70,000 adolescents and young adults (AYA) are diagnosed with cancer each year in the United States. Sarcomas carry a particularly high symptom burden and are some of the most common cancers among AYA. Recent work has documented significant levels of unmet needs among AYA with cancer, particularly the need for psychosocial support. Mobile technology may be a cost-effective and efficient way to deliver a psychosocial intervention to AYA with cancer and cancer survivors. OBJECTIVE: The two aims of this study were to (1) develop a pilot version of a mobile-based mindfulness and social support program and (2) evaluate program usage and acceptability. An exploratory aim was to examine change in psychosocial outcomes. METHODS: Thirty-seven AYA with sarcoma or sarcoma survivors, parents, and health care providers participated in the study. Semistructured interviews were conducted with 10 AYA, parents of five of the adolescents, and six health care providers. Themes from the interviews helped to inform the development of a mobile-based mindfulness pilot program and a companion Facebook-based social support group. Twenty AYA consented to participate in a single-arm pre-post evaluation of the program; 17 downloaded the app and joined the Facebook group. Seven of these participants had participated in the semistructured interviews. Six additional health care providers consented to participate in the evaluation stage. RESULTS: On average, participants completed 16.9 of the 28 unique sessions and used the mindfulness app for a mean 10.2 (SD 8.2) days during the 28-day evaluation period. The majority of participants (16/17) engaged in the social group and posted at least one reply to the moderator's prompts. The mean number of responses per person to the moderator of the social group was 15.2 of 31 (49%, range 0%-97%). Both AYA and health care providers responded positively to the Mindfulness for Resilience in Illness program and offered useful recommendations for improvements. Exploratory psychosocial analyses indicated there were no significant differences from pretest to posttest on measures of perceived social support, mindfulness, body image, or psychological functioning. CONCLUSIONS: This study offers preliminary support for the feasibility and acceptability of a mobile-based mindfulness and Facebook-based social support program for AYA with sarcoma. The feedback from AYA and health care providers will assist in creating a fully developed intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03130751; https://clinicaltrials.gov/ct2/show/NCT03130751.

Is Core Needle Biopsy Reliable in Differentiating Between Aggressive Benign and Malignant Radiolucent Bone Tumors?

BACKGROUND: Although there is widespread acceptance of core needle biopsy (CNB) for diagnosing solid tumors, there is reluctance by some clinicians to use CNB for aneurysmal bone cysts (ABCs) as a result of concerns of safety (bleeding, nerve injury, fracture, readmission, or infection) and reliability, particularly to rule out malignant diagnoses like telangiectatic osteosarcoma. This is especially true when CNB tissue is sent from an outside hospital, where the technique used to obtain the tissue may be spurious. QUESTIONS/PURPOSES: (1) Is CNB effective (provided adequate information to indicate appropriate surgical treatment without further open biopsy) as an initial diagnostic test for ABC? (2) Is CNB accurate (pathology consistent with the subsequent definitive surgical pathologic diagnosis) in differentiating between benign lesions such as primary or secondary ABCs and malignant radiolucent lesions such as telangiectatic osteosarcoma? (3) What are the complications of CNB? (4) Is there any difference in the effectiveness or accuracy of CNB performed at outside institutions when compared with a referral center? METHODS: A retrospective study of our musculoskeletal tumor board pathology database (1990-2016) was performed using search criteria "aneurysmal bone cyst" or "telangiectatic osteosarcoma." Only patients undergoing a CNB who proceeded to definitive surgical resection with final pathology were included. Excluding outside CNBs, CNB was performed after presentation at a musculoskeletal tumor board as a result of atypical features on imaging or history concerning for malignancy. Outside CNB tissue was reviewed by our pathologists. If there was sufficient tissue for diagnosis, the patient proceeded to definitive surgery. If not, the patient underwent open biopsy. CNB diagnosis, open biopsy results, and open surgical resection pathology were reviewed. Complications, including bleeding, infection, nerve injury, readmission, or fracture, between the CNB and definitive open surgical procedure (mean 1.6 months) were documented. CNBs were considered "effective" if they yielded pathology considered sufficient to proceed with appropriate definitive surgery without additional open biopsy. CNBs were considered "accurate" if they were effective and yielded a pathologic diagnosis that matched the subsequent definitive surgical pathology. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of obtaining a malignant diagnosis using CNB were also calculated. RESULTS: A total of 81% (59 of 73) of CNBs were effective. Ninety-three percent (55 of 59) of CNBs were classified as accurate. Diagnostic CNBs had a sensitivity and specificity of 89% (eight of nine) and 100% (51 of 51), respectively. The PPV was 1.00 and the NPV was 0.82. There were no complications. With the numbers available, there was no difference in efficacy (90% [37 of 41 versus 14 of 15]; odds ratio, 0.97 [95% confidence interval {CI}, 0.41-2.27], p = 0.94) or accuracy (92% [34 of 37 versus 13 of 14]; odds ratio, 0.87 [95% CI, 0.08-9.16], p = 0.91) between CNBs performed in house and those referred from outside. CONCLUSIONS: These data suggest that CNBs are useful as an initial diagnostic test for ABC and telangiectatic osteosarcoma. Tissue from outside CNBs can be read reliably without repeat biopsy. If confirmed by other institutions, CNB may be considered a reasonable approach to the diagnosis of aggressive, radiolucent lesions of bone. LEVEL OF EVIDENCE: Level III, diagnostic study.

Alveolar soft part sarcoma in children and young adults: A report of 69 cases.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by ASPL-TFE3 translocation. Apart from complete surgical resection, there is no standard management strategy. PROCEDURE: The clinical data of 69 children and young adults less than 30 years old with ASPS diagnosed from 1980-2014 were retrospectively collected from four major institutions. RESULTS: Median age at diagnosis was 17 years (range: 1.5-30). Forty-four (64%) were female. Median follow-up was 46 months (range: 1-409). Most common primary sites were limbs (58%) and trunk (24%). ASPL-TFE3 translocation was present in all 26 patients tested. IRS postsurgical staging was I in 19 (28%), II in 7 (10%), III in 5 (7%), and IV in 38 (55%) patients. The 5-year event-free survival (EFS) and overall survival (OS) were 38% and 72%, respectively. The 5-year EFS and OS were 80% and 87%, respectively, for the 31 patients with localized tumors (IRS-I-II-III), and 7% and 61%, respectively, for the 38 patients with metastatic tumors (IRS-IV). Of 11 IRS-IV patients who received targeted therapy upfront, two had partial response, six had stable disease, and three had progressive disease. Median time to progression for IRS-IV patients was 12 months for those treated with targeted therapy, 7 months for cytotoxic chemotherapy (N = 15), and 4 months for observation only (N = 6). CONCLUSION: Localized ASPS has a good prognosis after gross total resection. ASPS is resistant to cytotoxic chemotherapy. Although there are no curative therapies for patients with metastatic disease, prolonged disease stabilization may be achieved with targeted therapies.

A single-institution retrospective cases series of childhood undifferentiated embryonal liver sarcoma (UELS): success of combined therapy and the use of orthotopic liver transplant.

BACKGROUND/INTRODUCTION: Undifferentiated embryonal liver sarcoma (UELS) makes up 9% to 15% of all malignant liver tumors in children. UELS is characteristically diagnosed between the ages of 6 and 10 years and presents with abdominal pain, vomiting, and an abdominal mass. There is currently no standardized treatment for UELS except attempt at complete surgical resection. There have been only about 150 cases of UELS reported in the literature all with historically poor overall survival of <37.5% at 5 years. This report is one of the largest single-institution reports of UELS consisting of 5 patients over 2 decades. The purpose of this study is to characterize presentation and to report treatment success in UELS in children, adolescents, and young adults and the use of liver transplantation and, lastly, to suggest a use of positron emission tomography/computed tomography (PET/CT) in monitoring of this disease process. METHODS: We conducted an Institutional Review Board-approved retrospective chart review. Data were collected from UELS patients younger than 21 years seen at the University of California Los Angeles over the past 20 years (January 2001 to September 2011). Descriptive analysis was conducted including multiple parameters of patient demographics, tumor characteristics, treatment modalities, and morbidity and mortality. RESULTS: Five patients with UELS were identified. Patients initially presented with fever, abdominal pain, or nausea. Ages ranged from 10 to 19 years old (median age 13 y old), and there was a 4:1 male-to-female predominance. Tumor size ranged from 6 to 22 cm in largest diameter. One patient presented with metastatic disease to the lungs and heart and 1 patient recurred 2 years from diagnosis with bilateral paraspinal masses. Treatment included local control surgery with neoadjuvant and adjuvant chemotherapy with an anthracycline/alkylating agent combination. One patient with recurrent and refractory disease achieved local control with an orthotopic liver transplantation (OLT). Metastatic disease was controlled with surgery and radiation therapy. 18-Fluorodeoxyglucose PET/CT was a useful imaging tool for judging response to therapy with complete loss of metabolic activity in tumor after neoadjuvant chemotherapy in 2 representative cases. Although follow-up is short for some patients, overall survival in these 5 patients was 100% with follow-up ranging from 21 to 68 months. Disease-free survival ranged from 8 to 46 months with no patients with residual disease. CONCLUSIONS: UELS is an aggressive high-grade primary liver sarcoma with high metastatic potential. This report represents one of the largest single-institution studies of UELS. Using multimodality therapy, patients have achieved 100% overall survival even in the setting of extensive disease, metastases, and recurrence. In cases of unresectable primary tumor or recurrent and refractory disease isolated to the liver, OLT is a potential therapeutic option. We report success with adjuvant chemotherapy and complete surgical resection with OLT as an alternative in unresectable or refractory cases. We also suggest a possible utility of PET/CT in monitoring treatment response in this disease.