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.

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.

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.

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.

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.

Non-Private Health Insurance Predicts Advanced Stage at Presentation and Amputation in Lower Extremity High Grade Bone Sarcoma: A National Cancer Database Study : Amputation Predicts Survival: An Effect Most Pronounced in Pediatric and AYA Age Group.

INTRODUCTION: Advances in diagnostic and treatment modalities for high grade bone sarcomas (HGBS) of lower extremity (LE) have enabled limb salvage resections as a feasible first-line surgical option. However, amputations are still performed. Impact of amputation on survival and predictive factors for amputation and the stage at presentation for HGBS of LE remain unknown. METHODS: National Cancer Database was used to extract 5781 cases of high-grade bone sarcoma of the LE from 2004 to 2017. Kaplan-Meier and Cox regression were used to determine the impact of amputation on survival. Chi square test and logistic regression were used to assess the correlation of predictive factors with amputation and stage at presentation. RESULTS: Amputation [hazard ratio (HR) 1.516; 95% confidence interval (CI) 1.259-1.826; p < 0.001] and advanced stage (HR 0.248; 95% CI 0.176-0.351; p < 0.001) were independent predictors of poor overall survival. The impact of amputation on survival was most pronounced for pediatric and adolescents and young adults (AYA) age groups (18% decrease in 10-year survival). Amputation was more likely to be performed among those with nonprivate insurance (HR 1.736; 95% CI 1.191-2.531; p = 0.004), a finding that was mirrored for advanced stage at presentation (HR 0.611; 95% CI 0.414-0.902; p = 0.013). DISCUSSION: Amputation is an independent predictor of poor outcomes among patients with HGBS of LE. The impact of amputation on survival is the highest for the pediatric and AYA age group. Nonprivate insurance is associated with increased likelihood of amputation and an advanced stage at presentation among patients with high-grade bone sarcoma of the LE. This is the largest study highlighting insurance-related disparities in this cohort.

Impact of local treatment modality on overall- and disease-specific survival for nonmetastatic pelvic and sacral Ewing sarcoma.

PURPOSE: The ideal local treatment modality for pelvic and sacral Ewing sarcoma (EWS) is controversial. METHODS: We present the data from the American College of Surgeon's National Cancer Database (NCDB) and the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) database to investigate the impact of local treatment modalities on survival for nonmetastatic pelvic and sacral Ewing sarcoma. Local treatment includes "surgery," "radiation," and a combination of "surgery and radiation." RESULTS: A total of 235 cases from SEER and 285 cases from NCDB were analyzed. Patients with "localized" stage (intraosseous) in the SEER database did not show any statistically significant difference in the disease-specific survival (DSS) for any of the local treatment modalities. Similar findings were observed for overall survival among patients with American Joint Committee on Cancer (AJCC) stage II and III in the NCDB database. However, patients with nonmetastatic disease, particularly regional disease (extraosseous), showed improved DSS with surgery only, in the SEER. CONCLUSION: We found similar levels of efficacy for different treatment modalities for patients with intraosseous and AJCC II and III pelvic and sacral EWS. "Radiotherapy" is the most common local treatment modality employed in the United States. A prospective, randomized controlled trial with a direct head-to-head comparison is needed for a definitive conclusion.

Sex, racial/ethnic and socioeconomic disparities in patients with metastatic bone disease.

BACKGROUND: We have analyzed sex, race/ethnicity or socioeconomic disparities in the incidence of metastatic bone disease (MBD). METHODS: Patients with the diagnosis of MBD at presentation for five most common primary anatomical sites was extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset. Mean incidence of MBD for different sex, racial/ethnic and socioeconomic groups were compared. RESULTS: The five most common anatomical sites with MBD at presentation include "lung: (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal" (n = 7718) and "colon" (n = 3068). There was an increase in incidence of MBD among cancers originating from prostate (annual percentage change [APC] 4.94), renal (APC 2.55), and colon (APC 3.21) (p < 0.05 for all). Non-Hispanic Blacks had higher incidence of MBD for prostate and breast primary sites (p < 0.001). Non-Hispanic American Indian Alaskan Native had higher incidence of MBD for cancers originating from renal (p < 0.001) and colon (p = 0.049). A higher incidence of MBD was seen in lower socioeconomic status (SES) groups for the selected sites (p < 0.001). CONCLUSIONS: These findings suggest that there are multiple sex-related, racial/ethnic and SES disparities in the incidence of MBD from the 5 most common primary sites. Higher incidence seen among lower SES suggests delay in diagnosis and limited access to screening modalities.

Prognostic factors, disparity, and equity variables impacting prognosis in bone sarcomas of the hand: SEER database review.

BACKGROUND: Primary sarcomas originating from the bones of hand and wrist are rare but carry a significant burden of morbidity. METHODS: National Cancer Institute's Surveillance, Epidemiology and End Result database from 1975 to 2017 was queried to report incidence and survival data in 237 patients in the United States. Kaplan-Meier and Cox regression were used to determine the prognostic factors affecting survival. χ2 test was used to assess the correlation. RESULTS: Incidence of hand and wrist sarcoma was 0.017 per 100 000 persons in 2017 and has not significantly changed since 1975 (p > 0.05). Disease-specific 5-year and 10-year survival for the entire cohort was 90% and 84%, respectively. On multivariate analysis race "others," histology other than "osteosarcoma," "undifferentiated" grade, and size "≥6 cm" were predictors of worse disease-specific survival. Cross-tabulation of race with other significant prognostic factors on univariate analysis revealed a significant correlation of race with every other significant prognostic factor except for grade. CONCLUSIONS: The current study is an analysis of a population-based registry reporting incidence and survival data for patients with sarcoma of hand and wrist. Independent prognostic factors include race, histology, grade, and size. There is a lack of improvement in survival over the last four decades.

Primary mobile vertebral column sarcomas: Prognostic factors vary by histologic subtypes.

BACKGROUND: Primary sarcomas originating from the mobile spine portends a particularly sinister outcome. Rarity of the disease process has resulted in inconsistent data due to small sample size and heterogeneity in patient selection and analytics. METHODS: Surveillance, Epidemiology and End Result (SEER) database from 1975 to 2017 was queried to report incidence and survival data in 712 patients in the United States. Kaplan-Meier and Cox Regression were used to determine the prognostic factors affecting survival. RESULTS: Incidence of spinal sarcoma was 0.019 per 100,000 persons in 2017 and has not significantly changed since 2000 (p > 0.05). Disease-specific 5-year survival for the entire cohort was 57%. Osteosarcoma has the worst 5-year survival (39%) and chondrosarcoma has the best 5-year survival (69%). Independent predictors of survival for the entire cohort included age, grade, and stage. Stage was an independent predictor of survival for every histologic subtype. Additional predictors of survival for spinal osteosarcoma, Ewing sarcoma, and chondrosarcoma included age, size, and grade, respectively. CONCLUSIONS: The current study is an analysis of a population-based registry reporting incidence survival data for patients with sarcoma of mobile vertebral column. Survival and prognostic factors vary by histologic subtypes. There is lack of improvement in survival over the last three decades.

Malignant neoplasms originating from the bones of the foot: Predilection of hematological malignancies and sex-related and ethnic disparities in amputation.

PURPOSE: Neoplasms originating from the "small bones of the lower limb and the overlapping joints" are rare but portend a serious prognosis. Current study utilizes a population-based registry in the United States to characterize the malignancies of the foot. METHODS: National Cancer Institute's Surveillance, Epidemiology and End Result database from 1975 to 2017 was queried to report incidence and survival data in 514 patients in the Uited States. Kaplan-Meier and Cox Regression were used to determine the prognostic factors affecting survival. Chi square test was used to assess the correlation. RESULTS: Hematological malignancies constituted 14.8% of the entire cohort. Incidence of the foot neoplasms was 0.024 per 100 000 persons in 2017 and has not significantly changed since 1975 (p > 0.05). Disease-specific-5-year survival for the entire cohort was 73%. On multivariate analysis younger age groups, "localized" stage and extent of surgical resection were predictors of improved outcomes. A significant correlation was found between amputation with male sex and Hispanic ethnicity. CONCLUSIONS: The current study analyzes data from population-based registry reporting incidence and survival data for patients with neoplasms of the foot. Independent prognostic factors include age, stage and extent of surgical resection. Amputation was found to be associated with male sex and Hispanic ethnicity.

Surgical and oncologic outcomes following arterial resection and reconstruction for advanced solid tumors.

BACKGROUND AND OBJECTIVES: Although arterial involvement for advanced tumors is rare, vascular resection may be indicated to achieve complete tumor resection. Given the potential morbidity of this approach, we sought to evaluate perioperative outcomes, vascular graft patency, and survival among patients undergoing tumor excision with en bloc arterial resection and reconstruction. METHODS: From 2010 to 2020, we identified nine patients with tumors encasing or extensively abutting major arterial structures for whom en bloc arterial resection and reconstruction was performed. RESULTS: Mean age was 53 ± 20 years, and 89% were females. Diagnoses were primary sarcomas (5), recurrent gynecologic carcinomas (3), and benign retroperitoneal fibrosis (1). Tumors involved the infrarenal aorta (2), iliac arteries (6), and superficial femoral artery (1). Three patients (33%) had severe perioperative morbidity (Grade III + ) with no mortality. At a median follow-up of 23 months, eight patients (89%) had primary graft patency, and five patients (56%) had no evidence of disease. CONCLUSIONS: Arterial resection and reconstruction as part of the multimodality treatment of regionally advanced tumors is associated with acceptable short- and long-term outcomes, including excellent graft patency. In appropriately selected patients, involvement of major arterial structures should not be viewed as a contraindication to attempted curative surgery.

Radiotherapy is Associated With Improved Survival in Patients With Synovial Sarcoma Undergoing Surgery: A National Cancer Database Analysis.

BACKGROUND: Previous studies have demonstrated an association of perioperative radiotherapy (RT) with improved survival in patients with synovial sarcoma (SS) undergoing surgery, but the mechanism for this is unknown. In this study, we sought to further analyze this association using a hospital-based data set where data on chemotherapy administration and surgical margin status are available. METHODS: Using the National Cancer Database, we identified 1216 patients with SS (aged ≥18 y) from 2004-2012 undergoing surgery. Cox proportional hazards analysis was used to study the effect of clinicopathologic variables on overall survival (OS). RESULTS: Mean age at diagnosis was 41.5 y (range 18-90), and 71.3% of tumors were high grade; 22.9% underwent surgery alone, 59.6% received RT with surgery, 44.2% received chemotherapy with surgery, and 26.3% received trimodality therapy. Age, sex, grade, Charlson-Deyo score, and RT (hazard ratio, 0.676; 95% confidence interval, 0.519-0.880; P = 0.004) were associated with improved OS, whereas chemotherapy (hazard ratio, 1.20; 95% confidence interval, 0.899-1.60; P = 0.217) and surgical margin status were not. Trimodality therapy with surgery, RT, and chemotherapy was associated with improved OS when compared with therapy with surgery and chemotherapy alone. CONCLUSIONS: In patients with SS undergoing surgery, we observed a significant improved association of OS with the addition of RT when adjusting for comorbidity score, margin status, and receipt of chemotherapy. These data further support routine implementation of RT in the treatment of patients with SS, including those receiving aggressive multimodality and trimodality care.

Opportunistic muscle measurements on staging chest CT for extremity and truncal soft tissue sarcoma are associated with survival.

BACKGROUND AND OBJECTIVES: Computed tomography (CT) measurements of sarcopenia have been proposed as biomarkers associated with outcomes in various cancers and have typically been evaluated at the L3 vertebral level. However, staging imaging for patients with extremity and truncal soft tissue sarcoma (STS) often only includes chest CT imaging which precludes evaluation at L3. Therefore, we sought to evaluate muscle metrics at T12 on standard staging chest CT scans and evaluate for correlation with overall and event-free survival in patients with STS. METHODS: CT chest imaging for 89 patients with intermediate and high-grade STS (53 male, 36 female; 58.5 ± 19.0 years old, follow-up 37.4 ± 27.1 months) was reviewed on PACS at T12 for skeletal muscle density (SMD) and skeletal muscle index (SMI). RESULTS: Overall survival increased with increased SMD on univariate (hazard ratio [HR] = 0.61 [0.43, 0.86]) and age-adjusted analysis (HR = 0.65 [0.42, 0.89]. Event-free survival also increased with increased SMD in univariate analyses (HR = 0.68 [0.49, 0.95]) but did not maintain significance after adjusting for age (HR = 0.68 [0.43, 1.07]). SMI was not a predictor of overall or event-free survival. CONCLUSIONS: Higher SMD measured on routinely obtained staging chest CTs in STS patients is associated with improved survival.

Clinical Outcomes and Costs Following Unplanned Excisions of Soft Tissue Sarcomas in the Elderly.

BACKGROUND: Surgical guidelines for soft tissue sarcoma (STS) emphasize pretreatment evaluation and reports of the perils of unplanned excision exist. Given the paucity of population-based data on this topic, our objective was to analyze clinical outcomes and costs of planned versus unplanned STS excisions in the Medicare population. METHODS: We analyzed 3913 surgical patients with STS ≥66 y old from 1992 to 2011 using the Surveillance, Epidemiology, and End Results-Medicare datafiles. Planned excisions were classified based on preoperative MRI and/or biopsy, whereas unplanned excisions were classified by excision as the first procedure. Inverse probability of treatment weighting with propensity scores was used to adjust for clinicopathologic differences. Re-excisions, complications, and Medicare payments were compared with multivariate models. Overall survival and disease-specific survival were analyzed using Cox proportional hazards and competing risk models. RESULTS: Before the first excision, 24.3% had an MRI and biopsy, 27.3% had an MRI, 11.4% had a biopsy, and 36.9% were unplanned. Re-excision rates were highest for unplanned excisions: 46.3% compared to 18.1%, 36.4%, and 29.7% for other groups (P < 0.0001). There was no difference in disease-specific survival or overall survival between groups (P > 0.05). Planned excisions were associated with increased Medicare costs (P < 0.05), with the first resection contributing to the majority of costs. Subgroup analyses by histologic grade and tumor size revealed similar results. CONCLUSIONS: Survival was comparable with greater health care costs in elderly patients undergoing planned STS excision. Although unplanned excisions remain a quality of care issue with high re-excision rates, these data have important implications for the surgical management of STS in the elderly.

Extremity soft tissue sarcoma in the elderly: Are we overtreating or undertreating this potentially vulnerable patient population?

BACKGROUND: As the U.S. population ages, differences in oncologic outcomes among the elderly have been recognized. Our objective was to analyze the clinical, pathologic, and treatment outcomes for elderly soft tissue sarcoma (STS) patients, hypothesizing significant differences in the management and response to therapy. METHODS: Using the National Cancer Database, we identified 33 859 patients with nonmetastatic extremity STS. We defined elderly as ≥74 years in age and compared patient and treatment variables between adult and elderly patients. Cox-proportional hazards analysis was used to determine predictors of overall survival (OS). RESULTS: We identified 8504 elderly patients. Significant differences in histologic subtype, grade, and facility type between elderly and nonelderly patients (P < 0.05) exist. Elderly patients were less likely to undergo R0 resection (P = 0.001) and had a higher 90-day mortality (P = 0.001). Surgical elderly patients experienced superior OS compared with nonsurgical patients (P = 0.001). Among elderly patients, younger age, and female sex, lower Charlson-Deyo score, lower grade, smaller tumors, surgical resection, negative surgical margins, and radiation therapy were associated with better OS. CONCLUSIONS: Key differences exist in elderly extremity STS patients, including a narrower benefit/risk ratio with surgical management. These data highlight that elderly patients represent a distinct cohort for whom more careful selection appears indicated.

Using a kidney pump to perfuse a free filet flap for reconstruction after hemipelvectomy: A case report.

Long ischemia times adversely affect free flap survival, and large muscle flaps are particularly vulnerable. Hypothermic machine perfusion (HMP) is a well-established method of organ preservation, and recent literature has detailed the use of HMP to extend free flap ischemia times, predominantly in the laboratory setting. One limitation in the study and adoption of free flap HMP has been the availability of standardized perfusion machinery, as thus far institutions have built their own devices. We present a case of a 75-year-old woman with dedifferentiated chondrosarcoma of her right proximal femur. She underwent a "spare parts" surgery using a filet flap from her lower leg. Due to an obligate long ischemia time between flap harvest and revascularization, a kidney transplant perfusion pump was used to flush and cool the flap. After completion of the disarticulation, free tissue transfer proceeded successfully. The patient had an uncomplicated post-operative course until developing a local recurrence at three months post-resection. We believe that the perfusion technology already created for solid organ transplant will have expanding indications in the future of free tissue transfer and limb replantation.