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.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

Diagnosis of chondrosarcoma in a noninvasive way using volatile organic compounds in exhaled breath: a pilot study.

Aim: Aim of this explorative pilot study was to evaluate the capability of an electronic nose (aeoNose, the eNose Company) to classify healthy individuals and patients with chondrosarcoma, based on their volatile organic compound profiles in exhaled breath. Materials & methods: Fifty-seven patients (25 healthy controls, 24 chondrosarcoma and 8 different benign lesions) were included in the study from 2018 to 2023. An artificial neural network was used as classifier. Results: The developed model had a sensitivity of 75%, and a specificity of 65% with an AUC of 0.66. Conclusion: Results show that there is not enough evidence to include the aeoNose as diagnostic biomarker for chondrosarcoma in daily practice. However, the aeoNose might play an additional role alongside MRI, in questionable chondrosarcoma cases.

Evaluation of response to neoadjuvant chemotherapy in osteosarcoma using dynamic contrast-enhanced MRI: development and external validation of a model.

OBJECTIVE: To identify which dynamic contrast-enhanced (DCE-)MRI features best predict histological response to neoadjuvant chemotherapy in patients with an osteosarcoma. METHODS: Patients with osteosarcoma who underwent DCE-MRI before and after neoadjuvant chemotherapy prior to resection were retrospectively included at two different centers. Data from the center with the larger cohort (training cohort) was used to identify which method for region-of-interest selection (whole slab or focal area method) and which change in DCE-MRI features (time to enhancement, wash-in rate, maximum relative enhancement and area under the curve) gave the most accurate prediction of histological response. Models were created using logistic regression and cross-validated. The most accurate model was then externally validated using data from the other center (test cohort). RESULTS: Fifty-five (27 poor response) and 30 (19 poor response) patients were included in training and test cohorts, respectively. Intraclass correlation coefficient of relative DCE-MRI features ranged 0.81-0.97 with the whole slab and 0.57-0.85 with the focal area segmentation method. Poor histological response was best predicted with the whole slab segmentation method using a single feature threshold, relative wash-in rate <2.3. Mean accuracy was 0.85 (95%CI: 0.75-0.95), and area under the receiver operating characteristic curve (AUC-index) was 0.93 (95%CI: 0.86-1.00). In external validation, accuracy and AUC-index were 0.80 and 0.80. CONCLUSION: In this study, a relative wash-in rate of <2.3 determined with the whole slab segmentation method predicted histological response to neoadjuvant chemotherapy in osteosarcoma. Consistent performance was observed in an external test cohort.

A novel colony-stimulating factor 1 (CSF1) translocation involving human endogenous retroviral element in a tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TSGCTs) are rare tumors arising in tendons or the synoviae of joints and bursae. The localized type is benign while the diffuse type shows expansive growth leading to greater morbidity and is therefore considered locally aggressive. Typical recurrent chromosomal aberrations are found in the majority of TSCGT and the CSF1 gene is frequently involved. In this article, we describe a newly identified gene fusion mediated by an inversion in a case of diffuse TSGCT. Multicolor-fluorescence in situ hybridization (FISH) molecular karyotyping identified a pericentric inversion of chromosome 1 in 7 out of 17 analyzed cells 46,XX,inv(1)(p13.3q24.3) [7]/46,XX [10], and with interphase FISH the involvement the CSF1 locus was detected. After performing transcriptome sequencing analysis for fusion detection, only one out of five fusion gene algorithms detected a fusion involving the CSF1 gene product. The resulting chimera fuses a sequence from a human endogenous retrovirus (HERV) gene to CSF1 Exon 6 on chromosome 1, abrogating the regulatory element of the 3' untranslated region of the CSF1 gene. This new translocation involving Exon 6 of the CSF1 gene fused to 1q24.1, supports the hypothesis that a mutated CSF1 protein is likely to play a vital role in the pathogenesis of TSGCT. The role of the HERV partner identified as a translocation partner, however, remains unclear. Our data add to the complexity of involved translocation partners in TSGCT and point to the potential difficulty of identifying fusion partners in tumor diagnostics using transcriptome sequencing when HERV or other repeat elements are involved.

Impaired social functioning in adolescent and young adult sarcoma survivors: Prevalence and risk factors.

BACKGROUND: Sarcomas account for almost 11% of all cancers in adolescents and young adults (AYAs; 18-39 years). AYAs are increasingly recognized as a distinct oncological age group with its own psychosocial challenges and biological characteristics. Social functioning has been shown to be one of the most severely affected domains of health-related quality of life in AYA cancer survivors. This study aims to identify AYA sarcoma survivors with impaired social functioning (ISF) and determine clinical and psychosocial factors associated with ISF. METHODS: AYAs from the population-based cross-sectional sarcoma survivorship study (SURVSARC) were included (n = 176). ISF was determined according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 social functioning scale, and age- and sex-matched norm data were used as reference. RESULTS: The median time since diagnosis was 6.2 years (range, 1.8-11.2). More than one-quarter (28%) of AYA sarcoma survivors experienced ISF. Older age, higher tumor stage, comorbidities, lower experienced social support, uncertainty in relationships, feeling less attractive, sexual inactivity, unemployment, and financial difficulties were associated with ISF. In a multivariable analysis, unemployment (OR, 3.719; 95% CI, 1.261-10.967) and having to make lifestyle changes because of financial problems caused by one's physical condition or medical treatment (OR, 3.394; 95% CI, 1.118-10.300) were associated with ISF; better experienced social support was associated with non-ISF (OR, 0.739; 95% CI, 0.570-0.957). CONCLUSION: More than one-quarter of AYA sarcoma survivors experience ISF long after diagnosis. These results emphasize the importance of follow-up care that is not only disease-oriented but also focuses on the psychological and social domains. PLAIN LANGUAGE SUMMARY: Sarcomas account for almost 11% of all cancers in adolescents and young adults (AYAs; 18-39 years). The AYA group is increasingly recognized as a distinct oncological age group with its own psychosocial challenges and biological characteristics. Social functioning has been shown to be severely affected in AYA cancer survivors. A population-based questionnaire study to identify AYA sarcoma survivors with impaired social functioning (ISF) and determine factors associated with ISF was conducted. More than one-quarter of AYA sarcoma survivors experience ISF long after diagnosis. These results emphasize the importance of follow-up care that is not only disease-orientated but also focuses on the psychological and social domains.

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).

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.

The treatment of aneurysmal bone cysts.

PURPOSE OF REVIEW: Aneurysmal bone cysts are rare, locally aggressive bone tumors. Optimal treatment of ABCs is still matter of debate as therapies including sclerotherapy, selective arterial embolization and systemic treatment with denosumab are increasingly utilized, in addition to or instead of traditional curettage. The purpose of this review is to discuss current concepts and difficulties in diagnosing and treating primary ABCs, based on latest available literature. RECENT FINDINGS: In diagnostics, multiple new fusion partners of USP-6 have been described on next-generation sequencing specifically for primary ABCs. In a recent systematic review, failure rates of percutaneous injections and surgery were comparable. In a literature review, the use of denosumab seemed effective but resulted in multiple cases of severe hypercalcemia in children. SUMMARY: Accurately diagnosing primary ABC is crucial for treatment decisions. Curettage remains a valid treatment option, especially with adjuvant burring, autogenous bone grafting and phenolization. Percutaneous sclerotherapy represents a solid alternative to surgery, with polidocanol showing good results in larger studies. Systematic therapy with denosumab exhibits favorable results but should be reserved in the pediatric population for unresectable lesions, as it may result in severe hypercalcemia in children. When selecting a treatment option, localization, stability and safety should be considered.

Noninvasive detection of soft tissue sarcoma using volatile organic compounds in exhaled breath: a pilot study.

Aim: The aim of this pilot study was to assess whether an electronic nose can detect patients with soft tissue sarcoma (STS) based on volatile organic compound profiles in exhaled breath. Patients & methods: In this cross-sectional pilot study, patients with primary STS and healthy controls, matched on sex and age, were included for breath analysis. Machine learning techniques were used to develop the best-fitting model. Results: Fifty-nine breath samples were collected (29 STS and 30 control) from March 2018 to March 2022. The final model yielded a c-statistic of 0.85 with a sensitivity of 83% and specificity of 60%. Conclusion: This study suggests that exhaled volatile organic compound analysis could serve as a noninvasive diagnostic biomarker for the detection of STS with a good performance.

Diagnosing soft tissue sarcoma (STS) among the large number of benign soft tissue tumors is challenging. There is a serious need for a novel and easy tool that could accurately detect patients with STS. This study aimed to assess how well an easy-to-use electronic nose could differentiate between patients with STS and those without STS based on their exhaled breath. This is the first pilot study to reveal that an electronic nose could serve as a diagnostic tool for the detection of STS with a good performance. Future studies are needed to validate the findings in larger cohorts.

Pexidartinib Provides Modest Pain Relief in Patients With Tenosynovial Giant Cell Tumor: Results From ENLIVEN.

BACKGROUND: The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described. QUESTIONS/PURPOSES: (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief? METHODS: The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups. RESULTS: A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib). CONCLUSION: Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief. LEVEL OF EVIDENCE: Level II, therapeutic study.

Do's and Don'ts in Primary Aneurysmal Bone Cysts of the Proximal Femur in Children and Adolescents: Retrospective Multicenter EPOS Study of 79 Patients.

BACKGROUND: Aneurysmal bone cysts (ABC) are rare benign cystic bone tumors, generally diagnosed in children and adolescents. Proximal femoral ABCs may require specific treatment strategies because of an increased pathologic fracture risk. As few reports are published on ABCs, specifically for this localization, consensus regarding optimal treatment is lacking. We present a large retrospective study on the treatment of pediatric proximal femoral ABCs. METHODS: All eligible pediatric patients with proximal femoral ABC were included, from 11 tertiary referral centers for musculo-skeletal oncology (2000-2021). Patient demographics, diagnostics, treatments, and complications were evaluated. Index procedures were categorized as percutaneous/open procedures and osteosynthesis alone. Primary outcomes were: time until full weight-bearing and failure-free survival. Failure was defined as open procedure after primary surgery, >3 percutaneous procedures, recurrence, and/or fracture. Risk factors for failure were evaluated. RESULTS: Seventy-nine patients with ABC were included [mean age, 10.2 (±SD4.0) y, n=56 male]. The median follow-up was 5.1 years (interquartile ranges=2.5 to 8.8).Index procedure was percutaneous procedure (n=22), open procedure (n=35), or osteosynthesis alone (n=22). The median time until full weight-bearing was 13 weeks [95% confidence interval (CI)=7.9-18.1] for open procedures, 9 weeks (95% CI=1.4-16.6) for percutaneous, and 6 weeks (95% CI=4.3-7.7) for osteosynthesis alone ( P =0.1). Failure rates were 41%, 43%, and 36%, respectively. Overall, 2 and 5-year failure-free survival was 69.6% (95% CI=59.2-80.0) and 54.5% (95% CI=41.6-67.4), respectively. Risk factors associated with failure were age younger than 10 years [hazard ratios (HR)=2.9, 95% CI=1.4-5.8], cyst volume >55 cm 3 (HR=1.7, 95% CI=0.8-2.5), and fracture at diagnosis (HR=1.4, 95% CI=0.7-3.3). CONCLUSIONS: As both open and percutaneous procedures along with osteosynthesis alone seem viable treatment options in this weight-bearing location, optimal treatment for proximal femoral ABCs remains unclear. The aim of the treatment was to achieve local cyst control while minimizing complications and ensuring that children can continue their normal activities as soon as possible. A personalized balance should be maintained between undertreatment, with potentially higher risks of pathologic fractures, prolonged periods of partial weight-bearing, or recurrences, versus overtreatment with large surgical procedures, and associated risks. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Carbon-fibre plates for traumatic and (impending) pathological fracture fixation: Where do we stand? A systematic review.

BACKGROUND: Carbon-fibre (CF) plates are increasingly used for fracture fixation. This systematic review evaluated complications associated with CF plate fixation. It also compared outcomes of patients treated with CF plates versus metal plates, aiming to determine if CF plates offered comparable results. The study hypothesized that CF plates display similar complication rates and clinical outcomes as metal plates for fracture fixation. METHODS: The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were searched from database inception until June 2023: PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare, Academic Search Premier and Google Scholar. Studies reporting on clinical and radiological outcomes of patients treated with CF plates for traumatic fractures and (impending) pathological fractures were included. Study quality was assessed, and complications were documented as number and percentage per anatomic region. RESULTS: A total of 27 studies of moderate to very low quality of evidence were included. Of these, 22 studies (800 patients, median follow-up 12 months) focused on traumatic fractures, and 5 studies (102 patients, median follow-up 12 months) on (impending) pathological fractures. A total of 11 studies (497 patients, median follow-up 16 months) compared CF plates with metal plates. Regarding traumatic fractures, the following complications were mostly reported: soft tissue complications (52 out of 391; 13%) for the humerus, structural complications (6 out of 291; 2%) for the distal radius, nonunion and structural complication (1 out of 34; 3%) for the femur, and infection (4 out of 104; 4%) for the ankle. For (impending) pathological fractures, the most frequently reported complications were infections (2 out of 14; 14%) for the humerus and structural complication (6 out of 86; 7%) for the femur/tibia. Comparative studies reported mixed results, although the majority (7 out of 11; 64%) reported no significant differences in clinical or radiological outcomes between patients treated with CF or metal plates. CONCLUSION: This systematic review did not reveal a concerning number of complications related to CF plate fixation. Comparative studies showed no significant differences between CF plates and metal plates for traumatic fracture fixation. Therefore, CF plates appear to be a viable alternative to metal plates. However, high-quality randomized controlled trials (RCTs) with long-term follow-up are strongly recommended to provide additional evidence supporting the use of CF plates. LEVEL OF EVIDENCE: III, systematic review.

Validation of a novel risk score to predict early and late recurrence in solitary fibrous tumour.

BACKGROUND: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. METHODS: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. RESULTS: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. CONCLUSIONS: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.

Updated concepts in treatment of giant cell tumor of bone.

PURPOSE OF REVIEW: Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy including denosumab and bisphosphonates over the last decade. RECENT FINDINGS: In diagnostics, focus has been on H3F3A (G34) driver mutations present in GCTB. The most frequent mutation (G34W) can be detected using immunohistochemistry and is highly specific in differentiating GCTB from other giant cell containing tumors. PD-L1 expression can be used as biological marker to predict higher recurrence risks in GCTB patients.The use of bisphosphonate-loaded bone cement is under investigation in a randomized controlled trial. A new technique consisting of percutaneous microwave ablation and bisphosphonate-loaded polymethylmethacrylate cementoplasty was proposed for unresectable (pelvic) GCTB.Increased experience with use of denosumab raised concern on elevated recurrence rates. However, conclusions of meta-analyses should be interpreted with risk of indication bias in mind. Several small studies are published with short-course denosumab (varying from 3 to 6 doses). One small trial directly compared denosumab and zoledronic acid, with no statistical differences in radiological and clinical outcome, and nonsignificantly higher recurrence rate after denosumab. As bisphosphonates directly target neoplastic stromal cells in GCTB, larger directly comparative trials are still warranted. SUMMARY: Neoadjuvant denosumab is highly effective for advanced GCTB, and a short-course is advised to facilitate surgery, whereas increased recurrence rates remain of concern. Randomized controlled trials are conducted on bisphosphonate-loaded bone cement and on optimal dose and duration of neoadjuvant denosumab. PD-L1 could be a potential new therapy target in GCTB.

Surgical management of 144 diffuse-type TGCT patients in a single institution: A 20-year cohort study.

BACKGROUND AND OBJECTIVES: Surgery is the mainstay of treatment for tenosynovial giant cell tumors (TGCTs). However, achieving a cure through surgery alone remains challenging, especially for the diffuse-type (D-TGCT). METHODS: Our goal was to describe the surgical management of patients with D-TGCT related to large joints, treated between 2000 and 2020. We analyzed the effect of (in)complete resections and the presence of postoperative tumor (POT) on magnetic resonance imaging (MRI) on radiological and clinical outcomes. RESULTS: A total of 144 patients underwent open surgery for D-TGCT, of which 58 (40%) had treatment before. The median follow-up was 65 months. One hundred twenty-five patients underwent isolated open surgeries, in which 25 (20%) patients' D-TGCT was intentionally removed incompletely. POT presence on the first postoperative MRI was observed in 64%. Both incomplete resections and POT presence were associated with higher rates of radiological progression (73% vs. 44%; Kaplan-Meier [KM] analysis p = 0.021) and 59% versus 7%; KM analysis p < 0.001), respectively. Furthermore, patients with POT presence clinically worsened more often than patients without having POT (49% vs. 24%; KM analysis p = 0.003). CONCLUSIONS: D-TGCT is often resected incompletely and tumor presence is commonly observed on the first postoperative MRI, resulting in worse radiological and clinical outcomes. Therefore, surgeons should try to remove D-TGCT in toto and consider other multimodal therapeutic strategies.

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.

Intraosseous hibernoma of the appendicular skeleton.

Hibernomas are rare lipomatous tumors composed of brown adipocytes. The relative paucity of reported cases involving the bones accounts for the poor understanding of this entity, which is known to affect almost exclusively the axial skeleton. We present a case of intraosseous hibernoma of the humerus, which was found incidentally in a 52-year-old woman and initially misinterpreted as a cartilaginous tumor on magnetic resonance imaging (MRI). The lesion was unchanged in size and morphology at short interval follow-up but increased in size during follow-up over 6 years with an 11 mm increase in the largest diameter. Given the patient's concerns and lesion growth, curettage was performed. Pathology analysis revealed brown fat in keeping with the diagnosis of intraosseous hibernoma. Radiological and pathological findings and pitfalls are herein highlighted to enforce knowledge on this lesion rarely affecting the long bones. Radiologists should think of intraosseous hibernoma if they come across a sclerotic lesion on X-ray or computed tomography, which contains macroscopic fat and shows enhancement on contrast-enhanced MRI. In addition, an intraosseous hibernoma may be picked up incidentally on positron emission tomography-computed tomography due to high fluorodeoxyglucose avidity.

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.

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.