The Benefit of an Umbrella Protocol: Reducing Challenges in Orthopedic Oncology Research.

Background: Orthopedic oncology research is hindered by the scarcity of musculoskeletal tumors and research administrative inefficiencies. This paper introduces observational research through an innovative institution-specific methodology-termed an umbrella protocol. This protocol outlines a comprehensive standard procedure to expedite ethical approval for future aligned studies, reducing administrative barriers to research. Methods: We developed an umbrella protocol at an academic center, involving meticulous methodological identification and coordination with the institutional review board (IRB) to adhere to local guidelines. The protocol encompasses identifying investigators, research objectives, study goals, and data and safety monitoring frameworks necessary for typical standards. Results: Implementation of the umbrella protocol took 110 days to achieve exemption status, following multiple discussions with the IRB and extensive revisions. At the authors institution, this protocol significantly reduces protocol review times from an average of six-to-eight weeks to nearly instantaneous, facilitating a streamlined research process. Additionally, we established a dedicated orthopedic oncology patient registry to enhance future research endeavors. Conclusions: The adoption of umbrella protocols represents a pioneering strategy in orthopedic oncology. This approach mitigates research administrative burdens and broadens research scope in the field. It underscores the necessity of IRB collaboration, methodological precision, and stringent data management. The article also reflects on the ethical implications and potential biases introduced by emerging technologies like artificial intelligence, advocating for diligent ethical oversight. The establishment of an umbrella protocol marks a significant step towards more efficient research methodologies, ultimately aiming to improve patient care and outcomes for individuals with rare musculoskeletal conditions.

Receipt of Guideline-Concordant Care Is Associated With Improved Survival in Patients With Osteosarcoma in California: A Population-Based Analysis.

PURPOSE: To examine the relationship between guideline-concordant care (GCC) on the basis of national clinical practice guidelines and survival in children (0-14 years), adolescents and young adults (AYAs, 15-39 years), and adults (40 years and older) with osteosarcoma, and to identify sociodemographic and clinical factors associated with receipt of GCC and survival. METHODS: We used data from the California Cancer Registry (CCR) on patients diagnosed with osteosarcoma during 2004-2019, with detailed treatment information extracted from the CCR text fields, including chemotherapy regimens. Multivariable logistic and Cox proportional hazard regression were used for statistical analyses. RESULTS: Of 1,716 patients, only 47% received GCC, with variation by age at diagnosis: 67% of children, 43% of AYAs, and 30% of adults. In multivariable models, patients who received part or all care (v none) at specialized cancer centers were more likely to receive GCC. AYAs and adults were less likely to receive GCC than children (odds ratio [OR], 0.38 [95% CI, 0.30 to 0.50] and OR, 0.40 [95% CI, 0.28 to 0.56], respectively). In a model excluding adults, patients treated by pediatric (v medical) oncologists were more likely to receive GCC (OR, 3.44 [95% CI, 2.40 to 4.94]). Patients with metastatic osteosarcoma at diagnosis who did not receive GCC had a greater hazard of death (hazard ratio [HR], 2.02 [95% CI, 1.55 to 2.63]) but no statistical differences were found in those diagnosed at earlier stages (HR, 1.15 [95% CI, 0.92 to 1.43]). CONCLUSION: GCC was associated with improved survival in patients with metastatic osteosarcoma in California. However, we found disparities in the delivery of GCC, highlighting the need for target interventions to improve delivery of GCC in this patient population.

Effect of ALDH1A1 and CD44 on Survival and Disease Recurrence in Patients With Osteosarcoma.

PURPOSE: Emerging evidence suggests that osteosarcoma stem cells (OSCs) may be responsible for tumor initiation propagation, recurrence, and resistance to therapy. We set out to evaluate the relationship between the abundance of ALDH1A1 and CD44-positive cells in biopsy and resection samples on disease recurrence and overall survival. METHODS: A retrospective review of 20 patients, including biopsy and resection samples, was performed at a comprehensive cancer center. Additionally, we queried the publicly available TARGET dataset of osteosarcoma patients. RESULTS: Neither the percentages of ALDH1A1-positive cells nor CD44-positive cells were significantly associated with overall mortality or disease recurrence in either biopsy or resection samples. Unlike our institutional data, overall survival was significantly correlated to higher ALDH1A1 expression in the TARGET dataset both in univariate and age-adjusted analyses. CONCLUSIONS: ADLH1 and CD44, potential markers of OSCs, were not found to be reliable clinical immunohistochemical prognostic markers for osteosarcoma patient survival, specifically disease-free survival. Osteosarcoma patients with high ALDH1A1 RNA expression showed improved overall survival in examining a national genomic database of osteosarcoma patients but again no association with disease-free survival. The potential of CD44 and ALDH1A1 as cellular-specific prognostic markers of survival, and as possible molecular targets, may be limited in osteosarcoma.

Active surveillance of diffuse-type tenosynovial giant cell tumors: A retrospective, multicenter cohort study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumor (D-TGCT) is a mono-articular, soft-tissue tumor. Although it can behave locally aggressively, D-TGCT is a non-malignant disease. This is the first study describing the natural course of D-TGCT and evaluating active surveillance as possible treatment strategy. METHODS: This retrospective, multicenter study included therapy naïve patients with D-TGCT from eight sarcoma centers worldwide between 2000 and 2019. Patients initially managed by active surveillance following their first consultation were eligible. Data regarding the radiological and clinical course and subsequent treatments were collected. RESULTS: Sixty-one patients with primary D-TGCT were initially managed by active surveillance. Fifty-nine patients had an MRI performed around first consultation: D-TGCT was located intra-articular in most patients (n = 56; 95 %) and extra-articular in 14 cases (24 %). At baseline, osteoarthritis was observed in 13 patients (22 %) on MRI. Most of the patients' reported symptoms: pain (n = 43; 70 %), swelling (n = 33; 54 %). Eight patients (13 %) were asymptomatic. Follow-up data were available for 58 patients; the median follow-up was 28 months. Twenty-one patients (36 %) had radiological progression after 21 months (median). Eight of 45 patients (18 %) without osteoarthritis at baseline developed osteoarthritis during follow-up. Thirty-seven patients (64 %) did not clinically deteriorate during follow-up. Finally, eighteen patients (31 %) required a subsequent treatment. CONCLUSION: Active surveillance can be considered adequate for selected therapy naïve D-TGCT patients. Although follow-up data was limited, almost two-thirds of the patients remained progression-free, and 69 % did not need treatment during the follow-up period. However, one-fifth of patients developed secondary osteoarthritis. Prospective studies on active surveillance are warranted.

Minimizing the Environmental Impacts of Plastic Pollution through Ecodesign of Products with Low Environmental Persistence.

While plastic pollution threatens ecosystems and human health, the use of plastic products continues to increase. Limiting its harm requires design strategies for plastic products informed by the threats that plastics pose to the environment. Thus, we developed a sustainability metric for the ecodesign of plastic products with low environmental persistence and uncompromised performance. To do this, we integrated the environmental degradation rate of plastic into established material selection strategies, deriving material indices for environmental persistence. By comparing indices for the environmental impact of on-the-market plastics and proposed alternatives, we show that accounting for the environmental persistence of plastics in design could translate to societal benefits of hundreds of millions of dollars for a single consumer product. Our analysis identifies the materials and their properties that deserve development, adoption, and investment to create functional and less environmentally impactful plastic products.

Emerging innovations and advancements in the treatment of extremity and truncal soft tissue sarcomas.

In this special edition update on soft tissue sarcomas (STS), we cover classifications, emerging technologies, prognostic tools, radiation schemas, and treatment disparities in extremity and truncal STS. We discuss the importance of enhancing local control and reducing complications, including the role of innovative imaging, surgical guidance, and hypofractionated radiation. We review advancements in systemic and immunotherapeutic treatments and introduce disparities seen in this vulnerable population that must be considered to improve overall patient care.

Scrutinizing the use of contrasted chest CTs in extremity sarcoma staging and surveillance.

BACKGROUND: Since 2015, the American College of Radiology (ACR) has recommended staging for lung metastasis via chest computed tomography (CT) without contrast for extremity sarcoma staging and surveillance. The purpose of this study was to determine our institutional compliance with this recommendation. METHODS: This was a retrospective chart review of patients diagnosed with sarcoma in the extremities who received CT imaging of the chest for pulmonary staging and surveillance at our institution from 2005 to 2023. A total of 1916 CT studies were included for analysis. We scrutinized ordering patterns before and after 2015 based on the ACR-published metastasis staging and screening guidelines. An institutional and patient cost analysis was performed between CT modalities. RESULTS: The prevalence of CT scans ordered and performed with contrast was greater than those without contrast both prior and post-ACR 2015 guidelines. Furthermore, 79.2% of patient's final surveillance CTs after 2015 were performed with contrast. A cost analysis was performed and demonstrated an additional $297 704 in patient and institutional costs. CONCLUSIONS: At our institution, upon review of CT chest imaging for pulmonary staging and surveillance in patients with extremity sarcoma the use of contrast has been routinely utilized despite a lack of evidence for its necessity and contrary to ACR guidelines.

Engineered bone marrow as a clinically relevant ex vivo model for primary bone cancer research and drug screening.

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O2) and standard (21% O2) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, this work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening.

Late lower extremity free flap vascular compromise and salvage in a Pediatric patient diagnosed with monophasic synovial sarcoma.

Free tissue flap transfer can be utilized for reconstruction following tumor resection. While flap failure occurs primarily within 72 h post-operation, late failure after day 7 is rare. We present the case of a 14-year-old with a late lower extremity free flap vascular compromise, along with the successful flap salvage.

Socioeconomic disparities in musculoskeletal oncology.

Musculoskeletal oncology is a clinical specialty dealing with a diverse population of patients with metastatic bone disease, hematological malignancies with musculoskeletal manifestations, primary bone malignancies and soft tissue sarcomas. There are wide-spread disparities including socioeconomic (SES) and insurance-related disparities reported in the literature. In this review, we'll summarize the disparities surrounding the musculoskeletal oncology.

Intratumoral NKp46+ natural killer cells are spatially distanced from T and MHC-I+ cells with prognostic implications in soft tissue sarcoma.

Introduction: Soft tissue sarcomas (STS) are rare, heterogenous malignancies with an unmet need for novel immunotherapies. Tumor infiltrating lymphocytes (TILs) have been linked with favorable outcomes in STS patients, though the contribution of natural killer (NK) cells and spatial relationships of TILs with MHC-I expressing cells lacks detailed characterization. Experimental design: Using archived and prospectively collected specimens, we evaluated intratumoral NK cells by immunohistochemistry (IHC), flow cytometry, and immunofluorescence (IF). We assessed spatial localization of NK and T cells by multiplex IF, analyzing the effects of MHC-I expression status on NK and T cell clustering. Results: Both intratumoral NKp46 and CD56dim expression were associated with significantly improved overall survival (P=0.05), while higher infiltrates of CD56bright NK cells predicted a worse prognosis (P=0.05). The presence of intratumoral NK cells was inversely proportional to CD3+ T cells. Spatial analyses showed NK cells preferentially clustering close to other NK cells with sparse CD3+ T and CD8+ T cells in range (P<0.0001). Additionally, CD3+ T and CD8+ T cells showed significantly greater co-localization with MHC-I+ cells, compared to NK cells (P<0.0001). After neoadjuvant radiotherapy, there was greater CD8 clustering, while after neoadjuvant chemotherapy, there was overall lower TIL clustering. Conclusion: Intratumoral NK cells are prognostic in STS and localize closer to MHC-I- cells than T cells. Although both NK and T cells are associated with improved survival in STS, their differential distribution in the TME based on MHC-I expression status may serve as a biomarker for improved immunotherapy treatment selection.

Surgical Duration Is Independently Associated with an Increased Risk of Surgical Site Infection and May Not Be Mitigated by Prolonged Antibiotics: A Secondary Analysis of the PARITY Trial of Infection After Lower-Extremity Endoprosthetic Reconstruction for Bone Tumors.

BACKGROUND: Infection after tumor resection and endoprosthetic reconstruction is a potentially limb-threatening complication. The duration of surgery has been shown to be a risk factor for infection, but the ability of an extended duration of postoperative prophylactic antibiotics to potentially minimize that risk has not been specifically studied. The objective of this study was to determine whether extended postoperative antibiotic therapy protects against surgical site infection (SSI) in the setting of prolonged surgical duration in patients undergoing endoprosthetic reconstruction after tumor resection. METHODS: This study was a planned secondary analysis of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial data set. Patients in the PARITY trial were randomized to receive 24 hours or 5 days of postoperative prophylactic antibiotics. The current study assessed the risk of SSI in those cohorts on the basis of surgical duration. A multivariable regression model was used to examine the adjusted effects of the duration of surgery on SSI, after controlling for other significant risk factors and potential confounders. RESULTS: All 604 patients who had been included in the final data analysis in the PARITY trial were also included in this secondary analysis. Those who sustained an SSI had a greater mean duration of surgery (6.2 hours) compared with those who did not sustain an SSI (4.9 hours, p < 0.0001). There was no specific time point at which the risk of infection significantly increased. Extended postoperative prophylactic antibiotic therapy did not appear to mitigate the risk of SSI even in patients with prolonged surgical duration. CONCLUSIONS: Increased surgical duration was an independent risk factor for SSI in orthopaedic patients undergoing endoprosthetic reconstruction after tumor resection. However, surgical duration is multifactorial and is influenced by several variables. For example, there may be protective features of flap coverage that increase surgical duration while paradoxically decreasing the risk of SSI. Extended postoperative antibiotic therapy did not mitigate the risk of infection in this cohort, and other risk mitigation strategies will need to be considered in future studies. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A rare case of chondroblastoma involving the distal phalanx of the ring finger.

Chondroblastoma, a rare benign bone tumor, is typically found in the epiphysis of long bones, with hand involvement being particularly uncommon. We present a case of an 11-year-old female with chondroblastoma involving the fourth distal phalanx of the hand. Imaging revealed a lytic, expansile lesion with sclerotic margins and no soft tissue component. A preoperative differential diagnosis included intraosseous glomus tumor, epidermal inclusion cyst, enchondroma, and chronic infection. The patient underwent open surgical biopsy and curettage for both diagnostic and treatment purpose. The final histopathologic diagnosis was chondroblastoma.

The dynamic microenvironment associated with metastatic bone disease: Current concepts.

Patients with bone metastases may experience debilitating pain, neurological conditions, increased risk of pathological fractures, and death. A deeper understanding of the bone microenvironment, the molecular biology of cancer types prone to metastasis, and how bone physiology promotes cancer growth, may help to uncover targeted treatment options. The purpose of this paper is to outline the current concepts relevant to topics including bone remodeling, angiogenesis, and immunomodulation as it relates to metastatic bone disease.

Coccidioidomycosis in Joint Replacement: A Review of the Literature With Case Presentations.

Coccidioidomycosis is a fungal infection endemic to certain regions of the Americas. In some cases, the organism may infect the musculoskeletal system, resulting in a prosthetic joint infection (PJI). Due to its difficulty in diagnosis, treatment of coccidioidomycosis in PJI is often delayed. Furthermore, with limited number of case reports, a standard of care in treatment has yet to be established. We present 2 cases of coccidioidomycosis PJI, the extensive evaluation that led to the diagnosis, and the treatment provided. This report highlights the natural progression of coccidioidomycosis in a prosthetic joint, the diagnostic features including histology, advanced imaging, and final treatment administered.

Localized Synovial Sarcoma: A Population-Based Analysis of Treatment Patterns and Survival.

Purpose: Synovial sarcoma (SS) is a rare, high-grade soft tissue tumor that requires multidisciplinary and multimodal care with surgery, radiotherapy, and chemotherapy. We examined the impact of sociodemographic and clinical factors on treatment patterns and survival in localized SS patients. Methods: Adolescents and young adults (AYAs, 15-39 years) and older adults ("adults," ≥40 years) diagnosed with localized SS from 2000 to 2018 were identified in the California Cancer Registry. Multivariable logistic regression identified clinical and sociodemographic factors associated with receipt of chemotherapy and/or radiotherapy. Cox proportional hazards regression identified factors associated with overall survival (OS). Results are reported as odds ratios (ORs) and hazard ratios (HRs), respectively, with 95% confidence intervals (CIs). Results: More AYAs (n = 346) than adults (n = 272) received chemotherapy (47.7% vs. 36.4%) and radiotherapy (62.1% vs. 58.1%). Age at diagnosis, tumor size, treatment at National Cancer Institute-Children's Oncology Group (NCI-COG)-designated facilities, insurance status, and neighborhood socioeconomic status (SES) influenced treatment patterns. Among AYAs, treatment at NCI-COG-designated facilities was associated with receiving chemotherapy (OR 2.74, CI 1.48-5.07) and low SES was associated with worse OS (HR 2.28, 1.09-4.77). In adults, high SES was associated with receiving chemoradiotherapy (OR 3.20, CI 1.40-7.31), whereas public insurance was associated with decreased odds of chemoradiotherapy (OR 0.44, CI 0.20-0.95). With regard to treatment, absence of radiotherapy (HR 1.94, CI 1.18-3.20) was associated with worse OS in adults. Conclusion: In localized SS, both clinical and sociodemographic factors influenced treatment patterns. Further research should investigate how SES-related factors produce treatment disparities and identify interventions to improve treatment equity and outcomes.

One-Stage Synovectomies Result in Improved Short-Term Outcomes Compared to Two-Stage Synovectomies of Diffuse-Type Tenosynovial Giant Cell Tumor (D-TGCT) of the Knee: A Multicenter, Retrospective, Cohort Study.

Diffuse-type tenosynovial giant cell tumors' (D-TGCTs) intra- and extra-articular expansion about the knee often necessitates an anterior and posterior surgical approach to facilitate an extensive synovectomy. There is no consensus on whether two-sided synovectomies should be performed in one or two stages. This retrospective study included 191 D-TGCT patients from nine sarcoma centers worldwide to compare the postoperative short-term outcomes between both treatments. Secondary outcomes were rates of radiological progression and subsequent treatments. Between 2000 and 2020, 117 patients underwent one-stage and 74 patients underwent two-stage synovectomies. The maximum range of motion achieved within one year postoperatively was similar (flexion 123-120°, p = 0.109; extension 0°, p = 0.093). Patients undergoing two-stage synovectomies stayed longer in the hospital (6 vs. 4 days, p < 0.0001). Complications occurred more often after two-stage synovectomies, although this was not statistically different (36% vs. 24%, p = 0.095). Patients treated with two-stage synovectomies exhibited more radiological progression and required subsequent treatments more often than patients treated with one-stage synovectomies (52% vs. 37%, p = 0.036) (54% vs. 34%, p = 0.007). In conclusion, D-TGCT of the knee requiring two-side synovectomies should be treated by one-stage synovectomies if feasible, since patients achieve a similar range of motion, do not have more complications, but stay for a shorter time in the hospital.

Survival and failure modes of the Compress® spindle and expandable distal femur endoprosthesis among pediatric patients: A multi-institutional study.

BACKGROUND: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported. METHODS: We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis. RESULTS: Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years. CONCLUSIONS: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Socioeconomic and insurance-related disparities in disease-specific survival among patients with metastatic bone disease.

BACKGROUND: Approximately 5% of cancer patients in the United States presented with metastatic bone disease (MBD) at diagnosis. Current study explores the disparities in survival for patients with MBD. METHODS: Patients with the diagnosis of MBD at presentation for the five most common primary anatomical sites were extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset (2010-2016). Kaplan-Meier and Cox Proportional Hazard models were used to evaluate survival, and prognostic factors for each cohort. Prognostic significance of socioeconomic status (SES) and insurance status were ascertained. RESULTS: The five most common anatomical-sites with MBD at presentation included "lung" (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal and urothelium" (n = 7718) and "colon" (n= 3068). Lower SES was an independent risk factor for worse disease-specific survival (DSS) for patients with MBD originating from lung, prostate, breast and colon. Lack of insurance was an independent risk factor for worse DSS for MBD patients with primary tumors in lung and breast. CONCLUSIONS: MBD patients from the five most common primary sites demonstrated SES and insurance-related disparities in disease-specific survival. This is the first and largest study to explore SES and insurance-related disparities among patients specifically afflicted with MBD. Our findings highlight vulnerability of patients with MBD across multiple primary sites to financial toxicity.