Effect of Chemotherapy and Surgery Timing on Mortality in Upper and Lower Extremity Osteosarcoma.

BACKGROUND: Surgery with both neoadjuvant and adjuvant chemotherapy represents the standard of care for extremity osteosarcoma despite a lack of high-quality evidence for its use, and trial evidence that suggests that up-front surgery may result in better outcomes. This study estimated the difference in overall survival for the standard of care ("Neoadjuvant First") vs upfront surgery first followed by adjuvant chemotherapy ("Surgery First"). PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results data, we identified patients age 5-29, diagnosed with a primary cancer of upper or lower extremity osteosarcoma between 2007 and 2019 who received surgery and chemotherapy. Our primary endpoint was the 5-year survival difference between the Surgery First and Neoadjuvant First groups. RESULTS: Adjusted 5-year survival was 74% for Surgery First patients and 67% for Neoadjuvant First patients, with a survival difference of 6.9% (95% CI -4.2% - 16.1%). In sensitivity analyses of 5-year survival, the results were consistent, showing a 6.8% to 13.7% higher 5-year survival in Surgery First patients. Significant mortality risk factors included older age, larger tumor size, the type of resection (salvage vs amputation), and stage 3-4 disease (vs stage 1-2 disease). CONCLUSION: The evidence supporting neoadjuvant therapy in osteosarcoma care is weak. However, there is evidence that pausing chemotherapy in the peri-surgical period might affect outcomes. Consequently, this study, and its consistency with the results from the only randomized trial, suggests that there is reason to revisit a prospective, randomized trial of osteosarcoma treatment regarding the timing of surgery and chemotherapy.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Thermal necrosis in orthopedic bone tumors: experimental research.

Introduction: The extent of surgical resection in orthopedic oncology differs according to tumor biology. While malignant bone tumors are operatively managed with wide resection, benign bone tumors and metastatic carcinomas are often treated through intralesional excision and adjuvant modalities, including the elimination of residual neoplastic cells through thermal necrosis. This study investigates in vitro temperature thresholds for thermal necrosis in common orthopedic bone tumors. Methodology: Eleven cell lines, including metastatic carcinomas to bone (A549, A498, FU-UR-1, PC3, MDA-MB-231, TT, MCF7, and K1), giant cell tumor of bone, osteosarcoma (HG-63), and control non-neoplastic cells (HEK293) were cultured. Cells were exposed to thermal stress at varying times and temperatures and evaluated for survival and viability with crystal violet and MTT assays. Results: Both the MTT and crystal violet assay demonstrated statistically superior rates of viability and survival for A549 (lung carcinoma), FU-UR-1 (renal carcinoma), K1 (thyroid carcinoma), and MG-63 (osteosarcoma) cell lines compared to control (HEK293 cells) at 60°C. Additionally, the MTT assay demonstrated superior viability for PC3 (prostate carcinoma), MCF7 (breast carcinoma), and A498 (renal carcinoma) compared to control. All cell lines demonstrated significantly decreased survival and viability in temperatures more than 90°C. Conclusion: This study demonstrated in vitro thresholds for thermal necrosis for cell lines of common orthopedic tumors of bone. The A549 (lung carcinoma), K1 (thyroid carcinoma), and FU-UR-1 (renal carcinoma) cell lines demonstrated greater resistance to heat stress compared to non-neoplastic control cells. Temperatures in excess of 90°C are necessary to reliably reduce cell survival and viability to less than 10%.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Presenting features and overall survival of chondrosarcoma of the pelvis.

INTRODUCTION: Chondrosarcoma is the second most common sarcoma of bone. This sarcoma is generally unresponsive to chemotherapy and radiation and is primarily managed through surgical excision. Pelvic chondrosarcoma presents a distinct therapeutic challenge due the complexity of resection, frequent recurrence and metastasis, and high post-operative morbidity. METHODS: The SEER database was queried for pelvic chondrosarcoma diagnosed between 2004 and 2015. Cases were described by age, sex, tumor size, extension, grade, metastasis, and therapeutic intervention. These same variables were assessed for the upper extremities, lower extremities, skull and facial bones, thoracic bones, and vertebral column. RESULTS: In total, 472 cases of pelvic chondrosarcoma were identified, representing 18.4% out of 2571 cases of chondrosarcoma distributed throughout the skeletal system. Among pelvic cases, 288 were male and 184 were female, with a median age of diagnosis of 54. Median tumor size was 96 mm, 64.9% of tumors were considered extracompartmental, and 11.3% of tumors were metastatic at time of diagnosis. The 2, 5, and 10-year survival rates for all cases of primary chondrosarcoma of the pelvis are 76.7%, 61.8%, and 52.2%, respectively. Survival was worse for patients with metastasis, male sex, age >60, tumor size >8 cm, dedifferentiated histology, and no surgical resection. On multivariate assessment high grade and metastasis most significantly predicted worse overall survival. CONCLUSION: Pelvic chondrosarcoma commonly presents with high-risk features including larger tumor size, extracompartmental extension, and metastatic disease at diagnosis, predicting worse overall survival compared to non-pelvic tumors, and were the least amenable to surgical resection.

Ewing sarcoma of the pelvis: Clinical features and overall survival.

INTRODUCTION: Primary Ewing Sarcoma of Bone is a malignancy whose treatment requires both systemic chemotherapy and local control through surgical resection and/or radiation. Ewing Sarcoma of the pelvis has been noted to confer a worse prognosis relative to other anatomic sites of Ewing Sarcoma. This study explores the presenting features, treatment modalities for local control, and overall survival of primary Ewing sarcoma of the pelvis in comparison to other commonly affected anatomic sites. METHODS: The National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER) database was used to identify cases of pelvic Ewing sarcoma diagnosed between years 2004 and 2015. Demographic variables including sex, race, and age at diagnosis were described for each case, as well as therapeutic modalities including surgery and radiation. Bone-specific Collaborative Staging variables, including tumor size, tumor extension, and metastasis at diagnosis, were described for the same cohort. Univariate and multivariate assessments were performed for statistical comparison between presenting factors, treatment modalities, and between anatomic locations of presentation. RESULTS: Within the database, 296 patients with Ewing sarcoma of the pelvic bones were available for review, which represented 25.7% of the 1152 cases surveyed across all anatomic sites. In the subset of patients with Ewing Sarcoma of the pelvis, 63.5% were male; the median age of diagnosis was 17 years; extra-compartmental tumor extension was noted in 82.1%; average tumor size was 9.7 cm; and metastasis at diagnosis was noted in 46.1% of the cohort. Only 28.6% of the pelvis sarcoma patients received surgical resection as part or all of their local control treatment, while 67.6% received some form of radiation therapy. When compared to the presenting features of Ewing Sarcoma from other anatomic sites, patients with pelvic tumors had larger tumors at time of diagnosis, higher rates of metastatic disease, and were less likely to undergo surgical intervention. The 2-, 5-, and 10-year overall survival rates for the patients presenting with Ewing Sarcoma of the pelvis was 70.3%, 49.7%, and 41.9%, respectively, which were significantly lower across all time-points than any other anatomic site. DISCUSSION AND CONCLUSION: Ewing Sarcoma of the pelvis is an aggressive malignancy that presents with relatively large tumors and a high rate of metastatic dissemination. Surgical intervention is less frequent when Ewing Sarcoma presents in the pelvis than when it presents in other anatomic locations. These factors may contribute to the worse overall survival of Ewing Sarcoma when compared to the same diagnosis originating in other anatomic sites. Prospective, randomized study is required to determine the true causal effects of these factors on survival.

Radiation Therapy in Conjunction With Surgical Stabilization of Impending or Pathologic Fractures Secondary to Metastasis: Is There a Difference Between Single and Multifraction Regimens?

PURPOSE: Patients who undergo surgical stabilization for impending or pathologic fractures secondary to metastasis are often treated with radiation therapy to the involved site. We sought to retrospectively analyze outcomes from single versus multifraction regimens of radiation therapy in this setting. METHODS AND MATERIALS: From our institutional radiation database, we identified 87 patients between 2004 and 2016 who had an impending or pathologic fracture from metastatic disease and who underwent surgical fixation in conjunction with either neoadjuvant (within 5 weeks before surgery) or adjuvant (within 10 weeks after surgery) radiation therapy, representing 99 total treatment sites. Patients were included on the basis of intention to treat with bimodality therapy. Baseline patient characteristics were compared using 2-sided t tests and Fisher's exact tests. Cumulative incidence of local failure, reirradiation, and reoperation were calculated using the Fine-Gray method for competing risks. Freedom from complication was calculated using the Kaplan-Meier method. RESULTS: Baseline characteristics between the single (n = 52) and multifraction (n = 47) cohorts were similar with the exception of higher rates of synchronous bony metastasis (83% vs 60%, P = .01) and female patients (71% vs 43%, P = .004) in the single fraction cohort. There was no significant difference in overall survival between treatment groups. After a median follow-up of 13 months, there was no significant difference in the single and multifraction cohorts, respectively, in the 1-year cumulative incidence rates of local failure (4% vs 7%, P = .58), reirradiation (5% vs 4%, P = .95), reoperation (4% vs 0%, P = .30), or 1-year freedom from complication (90% vs 95%, P = .40). CONCLUSIONS: This is the first study comparing outcomes between single and multifraction radiation therapy in conjunction with surgical stabilization of an impending or pathologic fracture. We found no difference in outcomes between single and multifraction regimens in this setting. Given these findings, single fraction perioperative radiation therapy may be a viable treatment option in appropriately selected patients pending prospective validation of these findings.

Advances in segmental endoprosthetic reconstruction for extremity tumors: a review of contemporary designs and techniques.

BACKGROUND: Improved understanding and advances in treatment regimens have led to increased longevity among patients diagnosed with extremity soft tissue sarcomas. Limb salvage techniques and implants have improved and continue to evolve to accommodate the increasing demands and survival of these patients. METHODS: The current report is a review of the literature for recent advancements in techniques, implant design, and outcomes in the field of limb salvage therapy using segmental megaprostheses for the treatment of extremity sarcomas. We report on our experience in this field utilizing a classification system of failure mechanisms to outline to discuss current controversies in management. RESULTS: Five mechanisms of failure have been identified: soft-tissue failure, aseptic loosening, structural failure, infection, and tumor progression. Infection was the most common mode of failure in our series, accounting for 34% of cases. Soft-tissue failure occurred most commonly in the joints that depend heavily on periarticular muscles and ligaments for stability due to their high degree of functional range of motion. We observed a 28% soft-tissue failure rate about the shoulder and hip, aseptic loosening accounted for 19% of implant failures, and structural failure was seen in 17% of cases. Seventeen percent of cases failed due to tumor progression, an etiology that is defined by biological factors, surgical technique, and adjuvant therapies. CONCLUSIONS: Surgical techniques and megaprosthesis designs are constantly changing in order to meet the challenge of increasing functional demands and longevity in this unique patient population. A classification system defined by treatment failure etiologies provides the framework for discussion of current controversies in limb salvage therapy as well as a guide for advancement and potential solutions in this challenging arena.

Enhancing soft tissue ingrowth in proximal femoral arthroplasty with aortograft sleeve: a novel technique and early results.

Hip abductor function is critical to joint stability after proximal femoral arthroplasty. Normal soft tissue relationships are often violated during this procedure for complete tumor resection. Abductor insufficiency leads to abnormal gait mechanics and poor function. To improve soft tissue stability about a metallic proximal femoral endoprosthesis, we devised a novel use of vascular graft material. Two patients received a proximal femoral arthroplasty using this technique. These patients were followed for an average of 26.5 months. They demonstrated mean active hip abduction of 48°, hip flexion of 90°, mean Musculoskeletal Tumor Society score of 24 (80%), and Toronto Extremity Salvage Score of 80. We believe that this technique may be useful in achieving soft tissue stability about a metal endoprosthesis and may facilitate better function in patients undergoing this surgery.

Ischial osteoid osteoma: A cause of persistent hip pain in an adolescent patient with bilateral femoroacetabular impingement.

A 15-year-old boy presented with left-sided hip pain and imaging consistent with the diagnosis of femoroacetabular impingement. Following hip arthroscopy, which included an osteochondroplasty, labral repair, and capsular repair, the patient's anterior hip pain improved. However, his deep aching hip pain persisted until an ischial osteoid osteoma was identified and treated with radiofrequency ablation. At 3 years follow-up, the patient reports high satisfaction and minimal pain. We present this case to illustrate the importance of considering all potential causes of persistent hip pain following hip arthroscopy, including benign bone tumors which may be difficult to visualize on plain radiographs.

Nonmechanical Revision Indications Portend Repeat Limb-Salvage Failure Following Total Femoral Replacement.

BACKGROUND: There is scant evidence to guide decision-making for patients considering total femoral replacement (TFR). We aimed to identify the indication, patient, disease, and surgical technique-related factors associated with failure. We hypothesized that failure occurs more frequently in the setting of revision surgical procedures, with infection as the predominant failure mode. METHODS: We performed a retrospective cohort study of patients receiving total femoral endoprostheses for oncological and revision arthroplasty indications; 166 patients met these criteria. Our primary independent variable of interest was TFR for a revision indication (arthroplasty or limb salvage); the primary outcome was failure. Analyses were performed for patient variables (age, sex, diagnosis group, indication), implant variables (model, decade, length, materials), and treatment variables. We analyzed TFR failures with respect to patient factors, operative technique, and time to failure. We conducted bivariate logistic regressions predicting failure and used a multivariate model containing variables showing bivariate associations with failure. RESULTS: Forty-four patients (27%) had treatment failure. Failure occurred in 24 (23%) of 105 primary TFRs and in 20 (33%) of 61 revision TFRs; the difference was not significant (p = 0.134) in bivariate analysis but was significant (p = 0.044) in multivariate analysis. The mean age at the time of TFR was 37 years in the primary group and 51 years in the revision group (p = 0.0006). Of the patients who had mechanical failure, none had reoccurrence of their original failure mode, whereas all 8 patients from the nonmechanical cohort had reoccurrence of the original failure mode; this difference was significant (p = 0.0001). CONCLUSIONS: TFR has a high failure rate and a propensity for deep infection, especially in the setting of revision indications and prior infection. All failed TFRs performed for revision indications for infection or local recurrence failed by reoccurrence of the original failure mode and resulted in amputation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Reconstruction After Tumor Resection in the Growing Child.

Limb preservation surgery has gained acceptance as a viable alternative to amputation for the treatment of extremity bone tumors in the growing child. There are several options for reconstructing the potential loss of a physis and the defect created by tumor excision. Metallic endoprosthesis, massive allograft, and allograft-prosthesis composites have been described in the skeletally immature population. With the development of expandable prostheses, even those far from skeletal maturity may be candidates for limb salvage. However, improvements in the literature are needed, including reporting surgical and functional outcomes in a rigorous manner, specific to age, anatomic location, and reconstruction.

Surgical and Functional Outcomes After Limb-Preservation Surgery for Tumor in Pediatric Patients: A Systematic Review.

BACKGROUND: Limb-salvage surgery and segmental reconstruction for the treatment of lower extremity osseous tumors in the pediatric population have been described in the literature, but there is little consensus regarding the optimal surgical treatment for this patient population. METHODS: A systematic review of the literature was performed to identify studies focusing on limb-salvage procedures in pediatric patients who were managed with one of three reconstructions with use of a metallic endoprosthesis, allograft, or allograft-prosthesis composite. Data were segregated according to the excised and reconstructed anatomical location (proximal part of the femur, total femur, distal part of the femur, proximal part of the tibia) and were collated to assess modes of failure and functional outcomes of each reconstruction type for each anatomic location. RESULTS: Sixty articles met the inclusion criteria; all were Level-IV evidence, primarily consisting of small, retrospective case series. Infection was a primary mode of failure across all reconstruction types and locations, whereas allograft reconstructions were susceptible to structural failure as well. The rate of failure in the pediatric population correlated well with previously published results for adults. The incidence of subsequent amputation was lower in the pediatric population (5.2%) than has been reported in adults (9.5%) (p = 0.013). Meaningful growth of expandable metallic endoprostheses was reported in the literature, with an overall rate of leg-length discrepancy of 13.4% being noted at the time of the latest follow-up. The Musculoskeletal Tumor Society (MSTS) questionnaire was the most consistently used outcome measure in the literature, with average scores ranging from 71.0% to 86.8%, depending on reconstruction type and anatomic location. CONCLUSIONS: The current state of the literature detailing the surgical and functional outcomes of segmental reconstruction for the treatment of pediatric bone tumors is limited to Level-IV evidence and is complicated by under-segregation of the data by age and anatomical location of the reconstruction. Despite these limitations, pediatric limb-salvage surgery demonstrates satisfactory initial surgical and functional outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Failure mode classification for tumor endoprostheses: retrospective review of five institutions and a literature review.

BACKGROUND: Massive endoprostheses provide orthopaedic oncologists with many reconstructive options after tumor resection, although failure rates are high. Because the number of these procedures is limited, failure of these devices has not been studied or classified adequately. This investigation is a multicenter review of the use of segmental endoprostheses with a focus on the modes, frequency, and timing of failure. METHODS: Retrospective reviews of the operative databases of five institutions identified 2174 skeletally mature patients who received a large endoprosthesis for tumor resection. Patients who had failure of the endoprosthesis were identified, and the etiology and timing of failure were noted. Similar failures were tabulated and classified on the basis of the risk of amputation and urgency of treatment. Statistical analysis was performed to identify dependent relationships among mode of failure, anatomic location, and failure timing. A literature review was performed, and similar analyses were done for these data. RESULTS: Five hundred and thirty-four failures were identified. Five modes of failure were identified and classified: soft-tissue failures (Type 1), aseptic loosening (Type 2), structural failures (Type 3), infection (Type 4), and tumor progression (Type 5). The most common mode of failure in this series was infection; in the literature, it was aseptic loosening. Statistical dependence was found between anatomic location and mode of failure and between mode of failure and time to failure. Significant differences were found in the incidence of failure mode Types 1, 2, 3, and 4 when polyaxial and uniaxial joints were compared. Significant dependence was also found between failure mode and anatomic location in the literature data. CONCLUSIONS: There are five primary modes of endoprosthetic failure, and their relative incidences are significantly different and dependent on anatomic location. Mode of failure and time to failure also show a significant dependence. Because of these relationships, cumulative reporting of segmental failures should be avoided because anatomy-specific trends will be missed. Endoprosthetic design improvements should address failure modes specific to the anatomic location.