Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

Tenosynovial Giant Cell Tumor Observational Platform Project (TOPP) Registry: A 2-Year Analysis of Patient-Reported Outcomes and Treatment Strategies.

BACKGROUND: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. MATERIAL AND METHODS: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). RESULTS: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. CONCLUSION: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088).

The microbial profile of infected endoprosthetic reconstructions after wide excision for patients with musculoskeletal tumors: A call for pathogen-based practices.

BACKGROUND AND OBJECTIVES: Periprosthetic infection is a devastating complication following endoprosthetic reconstruction. This study utilized a large database of endoprostheses to describe the incidence, risk factors, and microbial profile of such infections to better catalogue and understand these catastrophic events. METHODS: A retrospective review of endoprosthetic reconstructions for an oncologic indication from January 1, 1981 to December 31, 2020 was performed. Demographic, oncologic, procedural and outcome data was analyzed. Multivariable logistic regression was used to identify potential risk factors for infection with significance defined as p < 0.05. RESULTS: Forty four out of 712 (6.2%) reconstructions resulted in infection at a mean time of 39.9 ± 44.5 months. Revision surgery (odds ratio [OR] 6.14, p < 0.001) or having a postoperative wound complication (OR 7.67, p < 0.001) were significantly associated with infection. Staphylococcus aureus and Staphylococcus epidermidis were the most commonly cultured organisms at a rate of 34.1% (15/44) and 22.7% (10/44), respectively. Ten infections resulted in amputation; five due to antimicrobial-resistant infections and three due to polymicrobial infections. CONCLUSION: Understanding the microbial profile of patients undergoing endoprosthetic reconstruction is paramount. This study demonstrates a relatively high rate of polymicrobial and antibiotic-resistant infections that portend worse outcomes, thus suggesting that pathogen-specific infectious practices may be warranted. LEVEL OF EVIDENCE: Retrospective cohort study, level III.

Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets.

Tenosynovial giant cell tumor (TGCT) is a rare, benign, locally aggressive synovial based neoplastic process that can result in functional debilitation and end-stage arthrtitis. Although surgical resection is the primary treatment modality, novel systemic therapies are emerging as part of the multimodal armamentarium for patients with unresectable or complex disease burden. This review discusses the pathogenesis of TGCT, potential druggable targets and therapeutic approaches. It also evaluates the safety and efficacy of different systemic therapies.

What are the indications and survivorship of tumor endoprosthetic reconstructions for patients with extremity metastatic bone disease?

BACKGROUND AND OBJECTIVES: Given advances in therapies, endoprosthetic reconstruction (EPR) in metastatic bone disease (MBD) may be increasingly indicated. The objectives were to review the indications, and implant and patient survivorship in patients undergoing EPR for MBD. METHODS: A review of patients undergoing EPR for extremity MBD between 1992 and 2022 at two centers was performed. Surgical data, implant survival, patient survival, and implant failure modes were examined. RESULTS: One hundred fifteen patients were included with a median follow-up of 14.9 months (95% confidence interval [CI]: 9.2-19.3) and survival of 19.4 months (95% CI: 13.6-26.1). The most common diagnosis was renal cell carcinoma (34/115, 29.6%) and the most common location was proximal femur (43/115, 37.4%). Indications included: actualized fracture (58/115, 50.4%), impending fracture (30/115, 26.1%), and failed fixation (27/115, 23.5%). Implant failure was uncommon (10/115, 8.7%). Patients undergoing EPR for failed fixation were more likely to have renal or lung cancer (p = 0.006). CONCLUSIONS: EPRs were performed most frequently for renal cell carcinoma and in patients with a relatively favorable survival. EPR was indicated for failed previous fixation in 23.5% of cases, emphasizing the importance of predictive survival modeling. EPR can be a reliable and durable surgical option for patients with MBD.

Most Patients With Bone Sarcomas Seek Emotional Support and Information About Other Patients' Experiences: A Thematic Analysis.

BACKGROUND: Online discussion forums allow individuals who otherwise may be strangers to create a community where they can seek and share information. Patients with bone sarcomas and their support networks use discussion forums dedicated to cancer support. There is a paucity of published reports regarding the care experience of patients with bone sarcomas because studies on online discussion groups have primarily focused on some of the more common cancers, including breast and prostate cancer. Understanding commonly discussed themes among patients with bone sarcomas would allow treating physicians to have a better understanding of patient concerns when providing patient education and counseling. QUESTION/PURPOSE: We performed this study to review posts from bone sarcoma internet discussion boards to establish common themes related to the care experience of patients with sarcomas. METHODS: Online discussion forums were identified using the search term "sarcoma discussion forum." After identifying 12 websites, we excluded closed forum groups, websites with missing or invalid links to forums, and nonpublic forums, such as groups on Facebook. These websites include profiles and photos that are personal, and sufficient author anonymity could not be achieved for this study. Posts written between January 1, 2012, and May 1, 2022, posted on five discussion boards were reviewed and collected until we reached a point of data saturation in which we agreed that the collection of additional posts would not reveal new themes. Discussion threads were filtered to identify posts pertaining to the most common bone sarcomas: chondrosarcoma, Ewing sarcoma, and osteosarcoma. Grounded theory-the methodology of repeated analyses of qualitative data to identify recurring themes or concepts-was used to analyze posts. Caregiver posts were delineated from patient posts and categorized separately for subgroup analysis. Grounded theory, although a qualitative method, endeavors to integrate the strengths inherent in quantitative methods with qualitative approaches. Grounded theory categorizes words, language, and the meanings these imply and seeks to organize and reduce the data gathered into themes or essences, which, in turn, can be fed into descriptions, models, or theories. Our analysis used three reviews of text to assign and group codes based on repeating ideas or concepts. The first review (open coding) aims to assign codes based on the verbatim text included by the author to capture the specific thoughts and ideas of the post. The second review (axial coding) aims to consolidate the ideas of posts by applying broader concepts to each post. The third and final review (selective coding) aims to further consolidate the themes of each post by trying to embody the main message contained in a post. A total of 570 posts from 139 threads were collected and analyzed using grounded theory. Twenty-five axial codes and four selective codes were created. We defined data saturation by the absence of a new open code in the analysis of a block of 50 posts to ensure that signals of saturation were not accepted too early in the analysis. RESULTS: The four selective codes included emotional aspects or connecting with others, information support: diagnosis, information support: treatment, and information support: recovery. Of these four codes, emotional aspects and connecting with others was the most prevalent theme (78% [445 of 570] of posts) followed by information support: treatment (49% [282 of 570] of posts). Information support: diagnosis and information support: recovery were each captured in 15% of posts. CONCLUSION: Analysis of posts reveals that the two most common themes involve seeking out emotional support and information about the experiences of others with various treatment modalities. Although most of the posts we assessed contained experiential information and emotional support rather than directed medical advice, future studies should assess the accuracy of information shared among online sarcoma forums. CLINICAL RELEVANCE: Physicians caring for patients with sarcomas should not only address patient concerns related to medical care, but also provide emotional support directly and assist patients by providing resources to peer support outlets, including online discussion forums. Although we cannot ascertain the proportion of patients who use online sites given the anonymity of posts included, these findings suggest common experiential themes across patients with sarcomas outside their doctors' offices. It is important that providers be aware of reputable forums to provide as resources for their patients. The Musculoskeletal Tumor Society may further benefit from endorsing one or more of these forums and providing physician oversight to monitor misinformation.

Proximal Femur Replacements for an Oncologic Indication Offer a Durable Endoprosthetic Reconstruction Option: A 40-year Experience.

BACKGROUND: Proximal femur replacements (PFRs) are an effective surgical option to treat primary and metastatic tumors causing large bony defects in the proximal femur. Given the relative rarity of these indications, current studies on PFR for oncologic indications are generally limited by patient volume or relatively short-term follow-up. Because recent advances in systemic therapy have improved the prognosis of patients who undergo limb salvage surgery for musculoskeletal tumors, data on the long-term durability of endoprosthetic reconstructions have become increasingly important. QUESTIONS/PURPOSES: (1) How does the long-term survival of cemented bipolar PFRs compare with patient survival in patients who underwent PFR for benign, aggressive, and metastatic tumors? (2) What are common reasons for revisions of primary PFRs? (3) Which factors are associated with survival of primary PFRs? (4) What is the survivorship free from conversion of bipolar PFRs to THA? METHODS: Between January 1, 1980, and December 31, 2020, we treated 812 patients with an endoprosthetic reconstruction for an oncologic indication. All patients who underwent a primary PFR for an oncologic indication were included in this study. The study cohort consisted of 122 patients receiving a primary PFR. Eighteen patients did not reach a censored endpoint such as death, revision, or amputation within 2 years. Thirty-three patients died within 2 years of their surgery. Of the 122 patients with primary PFRs, 39 did not reach a censored endpoint and have not been seen within the past 5 years. However, the mean follow-up time for these patients was longer than 10 years. The Social Security Death Index was queried to identify any patients who may have died but might not have been captured by our database To allow for adequate follow-up, endoprosthetic reconstructions performed after December 31, 2020 were excluded. The mean age at the time of the index surgery was 48 ± 22 years. The mean follow-up time of surviving patients was 7 ± 8 years. All PFRs were performed using a bipolar hemiarthroplasty with a cemented stem, and all implants were considered comparable. Demographic, oncologic, procedural, and outcome data including prosthesis survival, patient survival, complication rates, and rates of conversion to THA were analyzed. Patient, prosthesis, and limb salvage survival rates were generated, with implant revision as the endpoint and death as a competing risk. Statistical significance was defined as p < 0.05. RESULTS: Generally, patients with benign or low-grade (Stage I) disease outlived their implants (100% patient survival through 30 years; p = 0.02), whereas the opposite was true in patients with high-grade, localized Stage II disease (64% patient survival at 5 years [95% CI 49% to 76%]; p = 0.001) or widespread Stage III metastatic disease (6.2% patient survival at 5 years [95% CI 0.5% to 24%]; p < 0.001). Primary PFR implant survival at 5, 10, 20, and 30 years was 97% (95% CI 90% to 99%), 81% (95% CI 67% to 90%), 69% (95% CI 46% to 84%), and 51% (95% CI 24% to 73%), respectively. Eight percent (10 of 122) of primary PFRs were revised for any reason. The most common causes of revision were aseptic loosening (3% [four of 122]), infection (3% [three of 122]), breakage of the implant (2% [two of 122]), and tumor progression (1% [one of 122]). Follow-up time was the only factor that was associated with revision of primary PFRs. Neither segment length nor stem length were associated with revision of primary. Six percent (seven of 122) of PFRs were converted to THA at a mean 15 ± 8 years from the index procedure. Survivorship free from conversion to THA (accounting for death as a competing risk) was 94% (95% CI 85% to 99%), 86% (95% CI 68% to 94%). and 77% (95% CI 51% to 91%) at 10, 20, and 30 years, respectively. CONCLUSION: Cemented bipolar PFRs for an oncologic indication are a relatively durable reconstruction technique. Given the relative longevity and efficacy of PFRs demonstrated in our study, especially in patients with high-grade or metastatic disease where implant survival until all-cause revision was longer than patient survival, surgeons should continue to seriously consider PFRs in appropriate patients. The relative rarity of these reconstructions limits the number of patients in this study as well as in current research; thus, further multi-institutional collaborations are needed to provide the most accurate prognostic data for our patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Is the Long-term Survivorship of Primary and Revision Cemented Distal Femoral Replacements for Limb Salvage of Patients With Sarcoma?

BACKGROUND: Cemented endoprosthetic reconstruction after resection of primary bone sarcomas has been in common use for decades. Although multiple studies have reported the survivorship of primary endoprostheses, implant survivorship after revision surgery is less well established. Given that earlier advances in systemic therapy improved survival of patients with sarcoma, the usage of revision endoprostheses can be expected to increase and, as such, understanding revision implant survivorship will help to inform patient and surgeon expectations. Additionally, as new implants are developed that allow alternative reconstruction options, a normative dataset establishing accurate expectations for revision cemented endoprostheses is a critical benchmark by which to measure progress. QUESTIONS/PURPOSES: (1) What is the implant survivorship free of all-cause revision for primary and revision cemented distal femoral replacements (DFRs) used in the treatment of malignant or benign tumors? (2) What are the most common indications for revision of primary and revision DFRs in an oncology population with mean follow-up of more than 10 years? (3) How does the indication for revision of a primary DFR affect the subsequent risk for and type of revision DFR complication? (4) What patient, tumor, or implant characteristics are associated with improved survivorship free of revision in cemented DFRs used in patients treated initially for primary malignant or benign tumors? METHODS: This was a retrospective, comparative study using our institution's longitudinally-maintained database of 806 cemented endoprostheses starting in 1980 and assessed through December 31, 2018. In all, 365 DFRs were inserted during this time, but 14% (51 of 365) were placed for nonprimary bone tumors and 1% (5 of 365) were cementless reconstructions, leaving 309 cemented DFRs. Seventy-one percent (218 of 309) were primary implants and 29 percent (91 of 309) were revision implants (used to revise a prior DFR in all patients). During this time period, our strong bias was to use cemented stems and, thus, nearly all of our patients had cemented stems. Six percent (13 of 218) of primary DFRs were implanted more than 2 years before the study end; however, they lacked 2 years of follow-up data and, thus, were considered lost to follow-up, leaving 205 implants in the primary DFR analysis group. Only the first revision after primary DFR revision surgery was included in the revision cohort analysis. Thirty-two percent (29 of 91) of revision DFRs were second or more revision patients and were excluded, leaving 62 implants in the revision analysis group. Most patients in both groups were men (57% [117 of 205] for primary and 71% [44 of 62] for revision) who had been diagnosed with osteosarcoma (75% [153 of 205] and 73% [45 of 62] for primary and revision, respectively). The primary cohort had mean age of 26 ± 16 years with a mean follow-up of 136 ± 122 months, and the revision cohort had mean age of 31 ± 13 years (p = 0.02) with 141 ± 101 months of follow-up. Study endpoints included all-cause implant revision and cause-specific revision for soft tissue complications, aseptic loosening, structural complications (defined as periprosthetic or implant fracture), infection, or tumor progression. Planned surgery for implant lengthening procedures was excluded. Implant survivorship free from all-cause revision was calculated using a competing risk (cumulative incidence) estimator with death as a competing risk. A log-rank test using chi-square analysis was used to evaluate the differences in implant survivorship between primary DFRs and first revisions. The cause-specific incidences of implant revision were tabulated for primary and revision DFRs. Cox regression analysis investigated the odds of subsequent all-cause revision surgery for revision cemented DFRs based on the primary implant complication. A binary logistic regression analysis using age, gender, indication for revision, tumor type, infection, perioperative chemotherapy, and radiation was performed to identify factors associated with a second DFR reoperation. Relative effect sizes are reported as ORs. RESULTS: The revision DFR cohort had a shorter mean survival to all-cause revision than the primary cohort (mean 10 years [95% CI 7 to 12] versus 18 years [95% CI 15 to 20]; p < 0.001). The most common complications necessitating revision for revision implants were periprosthetic or implant fracture in 37% (23 of 62) and aseptic loosening in 15% (9 of 62), and the type of primary implant complication was not associated with risk of subsequent all-cause revision surgery for revision implants. Stem diameter less than 15 mm was associated with repeat all-cause revision in cemented revision DFRs after controlling for resection length, stem length, implant fabrication (custom or modular), and presence of a porous collar (OR 4 [95% CI 1 to 17]; p = 0.03). No other parameters that we explored, including patient age, gender, chemoradiation history, or primary tumor diagnosis, were associated with repeat revision surgery. CONCLUSION: Understanding modifiable factors that can improve revision DFR survival is critical to achieving long-term limb salvage for patients with tumors around the knee. Our data suggest that utilizing implants with the largest possible stems-or at a minimum increasing the stem size over the primary implant-is important to revision cemented DFR survivorship and is an important part of our revision practice. Improving revision implants' resistance to aseptic loosening through designs that resist torsion (a common mode of cemented fixation failure)-such as with the use of custom cross-pin fabrication-may be one method to improve survivorship. Another will be improved implant metallurgy that is resistant to fatigue fracture. Next steps may include understanding the optimal ratio of femoral diaphyseal width to implant diameter in patients where anatomic constraints preclude the insertion of cemented stems 15 mm or more in diameter. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Is High-dose Radiation Therapy Associated With Early Revision Due to Aseptic Loosening in Patients With a Sarcoma of the Lower Extremities Reconstructed With a Cemented Endoprosthesis?

BACKGROUND: The durability of endoprostheses after limb salvage surgery is influenced by surgical factors (resection length, implant location, and residual bone quality), implant design (modular versus custom design, rotating versus fixed hinge, coating, collars, and the use of cross pins), and host factors (patient's immune status, activity levels, and age). In general, radiation therapy increases the risk of fractures, infection, delayed wound healing, and impaired osseointegration. Several studies have shown exposure to radiation to be associated with higher endoprosthesis revision rates and higher periprosthetic infection rates, but results are inconsistent. Although radiation therapy is not routinely used in the treatment of many bone sarcomas in current practice, it is still used in high doses after resection and prosthetic reconstruction in patients who have Ewing sarcoma with close or positive margins and in patients with soft tissue sarcoma. It is also used in varying doses after prosthetic reconstruction in patients with myeloma or bone metastasis after resection of periarticular destructive tumors. These patients may be at an increased risk of complications due to their radiation exposure, but this is a difficult question to study given the rarity of these diagnoses and poor overall survival of these patients. We therefore leveraged a large, longitudinally collected, 40-year endoprosthesis database that included patients who received radiation to the extremity for many bone and soft tissue sarcomas to investigate the association between preoperative or postoperative radiation therapy and endoprosthesis survival. QUESTIONS/PURPOSES: (1) Is receiving preoperative or postoperative radiation therapy in low or high doses for the treatment of bone or soft tissue malignancy of the lower extremities associated with decreased implant survivorship free from amputation or revision due to any cause? (2) Is receiving preoperative or postoperative radiation therapy in low or high doses for the treatment of bone or soft tissue malignancy of the lower extremities associated with decreased implant survivorship free from revision specifically due to aseptic loosening? (3) Is receiving preoperative or postoperative radiation therapy for the treatment of Ewing sarcoma of the femur specifically associated with decreased implant survivorship free from revision specifically due to aseptic loosening? METHODS: This was a retrospective, comparative study using our institution's database of 822 endoprostheses. Between 1980 and 2019, we treated 541 patients with primary cemented endoprostheses of the extremities. Of those patients, 8% (45 of 541) were excluded due to unknown radiation status, 3% (17 of 541) because of prior failed allograft, 15% (83 of 541) due to metastatic disease from a carcinoma, 1% (6 of 541) due to a nononcologic diagnosis, 4% (20 of 541) due to benign tumor diagnosis, 16% (87 of 541) due to upper extremity tumor location, 9% (49 of 541) due to not receiving chemotherapy, and 3% (14 of 541) due to expandable prostheses. Of the remaining 220 patients, 6% (13) were considered missing because they did not have 2 years of follow-up and did not reach a study endpoint. No patients had surgery within the last 2 years of the study end date. In all, 207 patients met inclusion criteria and were eligible for analysis. Patients who had received radiation to the lower extremities at any point in their treatment course were included in the radiation group and were compared with patients who did not receive radiation. For patients where radiation dose was available, the radiation group was subdivided into a low-dose (≤ 3000 cGy) and high-dose (> 3000 cGy) group. Revision surgery was defined as any surgery necessitating removal or replacement of the tibial or femoral stem. The complications necessitating revision or amputation were poor wound healing, aseptic loosening, implant breakage, deep infection, and tumor progression. The primary outcome of interest was implant survival free from revision or amputation due to any cause. The secondary outcome of interest was implant survival free from revision or amputation specifically due to aseptic loosening. The Kaplan-Meier survivorship curves were generated with implant survival free from revision or amputation as the endpoint and patient death as a competing risk. A log-rank test was used to identify differences in survivorship between the patients who received radiation and those who did not. Multivariate regression was used to identify factors associated with decreased implant survival. An odds ratio was used to determine relative effect size among the factors associated with decreased implant survival. RESULTS: The mean implant survival time for patients who did not receive radiation was 18.3 years (95% confidence interval [CI] 15.4 to 21.3) whereas the mean implant survival time for patients who received low- and high-dose radiation were 19.1 years (95% CI 14.5 to 23.7; p = 0.59) and 13.8 years (95% CI 8.2 to 19.5; p = 0.65), respectively. The mean implant survival free from revision for aseptic loosening for patients who did not receive radiation was 27.1 years (95% CI 24.1 to 30.1) whereas the mean implant survival for patients who received low- and high-dose radiation were 24.1 years (95% CI 19.1 to 29.1; p = 0.34) and 16.4 years (95% CI 10.6 to 22.2; p = 0.01), respectively. Patients who received high-dose radiation had decreased 5-year implant survivorship free from amputation or revision due to aseptic loosening (73% [95% CI 44% to 89%]) compared with patients who did not receive radiation (95% [95% CI 90% to 99%]; p = 0.01). For patients treated for Ewing sarcoma of the femur, the 5-year implant survival free from amputation or revision due to aseptic loosening for patients who did not receive radiation (100% [95% CI 100% to 100%]) was no different compared with patients who received radiation (71% [95% CI 35% to 90%]; p = 0.56). CONCLUSION: The results of this study may apply to scenarios where radiation is used, such as Ewing sarcoma with positive margins or local recurrence and after prosthetic reconstruction in patients with myeloma or bone metastasis after resection of periarticular destructive tumors. Surgeons may consider closer monitoring for early clinical and radiographic signs of aseptic loosening in patients who received high-dose radiation. These patients may also benefit from constructs that have increased resistance to aseptic loosening such as cross-pin or side plate fixation. The association between radiation and aseptic loosening should be further studied with larger studies with homogeneity in tumor diagnosis and prosthesis. The dose-dependent relationship between radiation and bone-related complications may also benefit from controlled, laboratory-based biomechanical studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. LEVEL OF EVIDENCE: Level III, therapeutic study.

The Role of Denosumab in the Treatment of Primary Tumors of Bone.

Many hand surgeons treat benign bone tumors without referral to orthopedic oncologists. However, there have been considerable advances in medical therapy for some of these tumors, with which hand surgeons may not be as familiar. This review focuses on the mechanism and uses of denosumab in the treatment of benign tumors of bone. Although the hand surgeon may not be directly prescribing this therapy, they are often the only physician treating the patient for these conditions. As such, awareness regarding the use of this therapy in reducing pain, decreasing tumor volume, and treatment of potential lung metastases is critical to those taking on these cases without the support of an orthopedic oncologist. This article aims to familiarize hand surgeons with denosumab to help promote knowledge of this therapeutic option and the potential role of this medication in the treatment of primary bone tumors in the hand.

Pedicled vastus lateralis myocutaneous flap for sacropelvic defects after wide oncologic resection: Wound complications and outcomes.

BACKGROUND AND OBJECTIVES: Adequate coverage of the soft tissue defects from wide resection of sacropelvic malignancies remains challenging. The vastus lateralis flap has been described for coverage in the setting of trauma and infection. This flap has not been described for coverage of sacropelvic tumor defects. METHODS: This is a retrospective cohort study of adult patients who underwent wide resection of a primary sacropelvic malignancy with reconstruction employing a pedicled vastus lateralis flap at two tertiary care centers. Patient demographics, tumor staging, and rate of complications were assessed. RESULTS: Twenty-eight patients were included, with a median age of 51 years. The most common primary tumor was chondrosarcoma followed by chondroblastic osteosarcoma. The median follow-up was 1.1 years. There were 10 cases of wound infection requiring re-operation and three cases of flap failure. CONCLUSIONS: We describe a pedicled vastus lateralis flap for coverage of defects after wide resection of sacropelvic malignancies. A large proportion of our cohort had independent risk factors for wound complications. Even with a cohort with high baseline risk for wound complications, we show that the use of a pedicled vastus lateralis flap is a safe reconstructive option with a wound complication rate in line with the literature.

A prospective real-world study of the diffuse-type tenosynovial giant cell tumor patient journey: A 2-year observational analysis.

BACKGROUND AND OBJECTIVES: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up. METHODS: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits. RESULTS: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD ± 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options. CONCLUSIONS: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy.

What Are the Long-term Surgical Outcomes of Compressive Endoprosthetic Osseointegration of the Femur with a Minimum 10-year Follow-up Period?

BACKGROUND: Endoprosthetic reconstruction after oncologic resection of bone tumors requires stable fixation between the prosthesis and residual host bone. Compressive osseointegration has been developed as an alternative to traditional stemmed implants to address the challenges and complications of achieving this fixation. Sufficient time has now passed from the advent of compressive implants to allow for an assessment of the intermediate-term and long-term results of this form of fixation. QUESTIONS/PURPOSES: At a minimum follow-up of 10 years after implantation of a compressive osseointegration device for oncologic reconstruction: (1) What is the risk of periprosthetic fracture, aseptic loosening, or implant breakage resulting in revision surgery for endoprosthesis removal? (2) What is the long-term cortical response at the host-endoprosthesis interface as visualized on plain radiographs? METHODS: A single-center, retrospective study was performed between 2002 and 2010, in which 110 patients with primary bone sarcoma of the proximal or distal femur were considered for oncologic resection and reconstruction. Patients were considered for a compressive osseointegration endoprosthesis if they were 50 years of age or younger, had not previously received femoral radiation, had no metabolic disease impairing bone healing, were not diagnosed with metastatic disease, and had life expectancy greater than six months. Of the 110 patients, 25 were treated with a compressive osseointegration implant of the proximal or distal femur, and 85 patients were treated with conventional stemmed implants or amputation because of older age, advanced disease, metabolic comorbidities, inability to tolerate a nonweightbearing postoperative period, or in the case of rotationplasty, patient preference. All patients who received this device during the period of study were considered eligible for inclusion in this review. The median (range) age was 18 years (7 to 50), and 13 of 25 patients were men. Five patients died of disease before the minimum follow-up duration of 10 years; two underwent amputation due to local recurrence and three died with the implant in situ, leaving 20 patients for complete analysis. Median follow-up was 144 months, and all 20 surviving patients had a minimum follow-up of 10 years (121 to 230 months). The primary endpoint was reoperation and implant removal for periprosthetic fracture, aseptic loosening, or mechanical breakage of any component of the compressive device in the endoprosthesis. In final analysis, death was considered a competing event to revision surgery, and cumulative incidence was reported after competing-event analysis. A secondary aim was radiographic evaluation of the host-implant interface to assess the long-term cortical response to compressive osseointegration. RESULTS: Spindle fracture or loosening was noted in three patients, and the remaining 17 patients maintained the compression device until the final follow-up. The risk of reoperation for aseptic loosening, periprosthetic fracture, or mechanical breakage of the implant using a competing risks estimator was 12% at 10 years (95% CI 0% to 26%). These complications occurred within 29 months of the index surgery; no patients had implant loosening or mechanical breakdown after this initial period. On radiographic assessment, 14 patients demonstrated cortical hypertrophy of the bone-implant interface, six patients had maintenance of the native cortical contour, and no patients had cortical atrophy or narrowing at the implant interface.Conclusion Long-term follow-up in patients with compressive osseointegrative endoprosthetic devices demonstrated no late revisions because of periprosthetic fracture, aseptic loosening, or implant breakage in this cohort with a minimum 10-year follow-up. There was no evidence of late-onset cortical atrophy or stress shielding at the host-implant interface. This study supports the long-term stability of the interface between host bone and the endoprosthesis in compressive osseointegration devices. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Low-Dose Aspirin for Venous Thromboembolism Prophylaxis is Associated With Lower Rates of Periprosthetic Joint Infection After Total Joint Arthroplasty.

BACKGROUND: Aspirin as a venous thromboembolism (VTE) prophylactic agent has been shown to have antistaphylococcal and antibiofilm roles. Optimal acetylsalicylic acid (ASA) dosage would facilitate antimicrobial effects while avoiding over-aggressive inhibition of platelet antimicrobial function. Our purpose was to determine the periprosthetic joint infection (PJI) rate after total joint arthroplasty in patients receiving low-dose ASA (81 mg twice a day), in comparison to high-dose ASA (325 mg twice a day). METHODS: We conducted a retrospective cohort study between 2008 and 2020. Eligible patients were older than 18 years, underwent primary total joint arthroplasty, both total knee arthroplasty and total hip arthroplasty, had a minimum 30-day follow-up, and received a full course ASA as VTE prophylaxis. Patients' records were reviewed for PJI, according to Musculoskeletal Infection Society criteria. Patients were excluded if they underwent revision arthroplasty, had a history of coagulopathy, or had an ASA regimen that was not completed. In total 15,825 patients were identified, 8,761 patients received low-dose ASA and 7,064 received high-dose ASA. RESULTS: The high-dose cohort had a higher PJI rate (0.35 versus 0.10%, P = .001). This relationship was maintained when comparing subgroups comprising total knee arthroplasty (0.32 versus 0.06%, P = .019) or total hip arthroplasty (0.38 versus 0.14%, P = .035) and accounting for potentially confounding demographic and surgical variables (odds ratio = 2.59, 95% CI = 1.15-6.40, P = .028). CONCLUSION: Comparing low-dose to high-dose ASA as a VTE prophylactic agent, low-dose ASA had a lower PJI rate. This may be attributable to a balance of anti-infective properties of ASA and antiplatelet effects.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

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.

Metaphyseal Stem Tip Location is a Risk Factor for Aseptic Loosening of Cemented Distal Femoral Replacements.

BACKGROUND: The objective of this study was to describe the incidence of aseptic loosening (AL) of cemented stem distal femoral replacements (DFR) and to identify modifiable risk factors for its development. METHODS: A retrospective review was performed of 245 consecutive primary, cemented stem DFRs implanted at a single institution over a 40-year period. The primary outcome was revision surgery for AL. A multivariate analysis was performed to identify risk factors for AL. Radiographs were reviewed to identify stem tip location, which was defined as diaphyseal or metaphyseal. Implant survival to AL was compared using Kaplan-Meier analysis. RESULTS: AL and structural failure were the most common causes of implant failure (incidence 11.8%, 29/245). Younger age (P = .002), male sex (P = .01), longer resection length (P = .04), and nonmodular implants (P = .002) were all significantly associated with AL. After 1:1 matching, stem tip location in metaphyseal bone was independently associated with AL (P = .04). 36% (9/25) of implants that loosened had a stem tip located in the metaphysis vs only 8% (2/25) of implants that did not fail. 30-year survival to AL was lower for implants with a metaphyseal stem tip than implants with a diaphyseal stem tip (22.7% vs 47.6%; P = .11). CONCLUSION: A stem tip location in metaphyseal bone is associated with diminished survival to AL. When templating before DFR, stem tip location can assist in identifying high-risk reconstructions that may benefit from alternative or supplemental fixation techniques to prevent the development of AL.

Long term outcomes of total humeral replacement for oncological reconstructions: A single institution experience.

BACKGROUND: There is a paucity of data on long-term survivorship and outcomes for total humerus replacements (THR) with only two series reporting 10-year survival. PATIENTS AND METHODS: A review of 769 consecutive, prospectively collected endoprosthetic reconstructions for oncological diagnoses at a single-center between 1980 and 2019 was performed. Patients with THRs were isolated and analyzed for outcomes, complications, and modes of failure. RESULTS: Eighteen patients with 20 THR implants were identified. The median follow-up for surviving patients was 148 months (interquartile range [IQR] = 74-194) and 60 months (IQR = 17-155 months) for all patients. Two prostheses required revision for failure, both for symptomatic shoulder dislocation. There were three local recurrences. Revision-free survival at 5, 10, and 15 years was 100%, 86% and 86%, respectively. There were no cases of ulnar component failure, radial nerve palsy, or periprosthetic infection. CONCLUSIONS: THR prosthesis survivorship is comparable to the previous series, with a longer follow-up than has previously been reported. Symptomatic shoulder instability was common (25%), and was the only cause of revision. Reverse total shoulder could be an important way to address this in the future. Local recurrence rates were high, as has been reported elsewhere for THR.