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Background: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R)., Methods: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor., Results: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment., Conclusions: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Giant cell tumor of the tendon sheath (GCTTS) is one of the most common benign soft tissue tumors in the extremities, and is frequently associated with bone abnormalities. Although extrinsic bone erosion is the most common bone abnormality associated with GCTTS, intraosseous invasion of GCTTS occurs rarely and may mimic a primary bone tumor, making diagnosis more challenging. We report an unusual imaging presentation of GCTTS mimicking a primary intramedullary metatarsal tumor and review the literature on the frequency of bone involvement of GCTTS.

Giant cell tumor of bone (GCTB) is a locally aggressive tumor that shows predilection for the metaphysis/epiphysis of long bones, with an incidence of 4–5% of primary bone tumors. GCTB shows two main populations of cells: mononuclear cells and non-neoplastic multi-nucleated giant cells, with or without fibrous background. On the other hand, giant-cell-poor GCTB are rare with only few reports in the literature. These cases offer a diagnostic challenge, given the absence of giant cells and such cases have consistently been shown to harbor the H3F3A gene mutation by sequencing. The H3.3 G34W mutation-specific monoclonal antibody has shown high specificity in the diagnosis of GCTB. Two cases of giant-cell-poor GCTB are presented in this study, in which giant cells were absent or sparse and the diagnosis of GCTB was confirmed by the expression of H3.3 G34W monoclonal antibody in the mononuclear cells by immunohistochemistry. Whether this represents a histologic variant of GCTB or partial involution of GCTB is not yet fully understood; however, an immune response, infectious/inflammatory reaction, and/or anti-tumor cytokine production have been purported to be factors inciting disease regression in GCTB. [ABSTRACT FROM AUTHOR]

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) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Tenosynovial giant cell tumor (TGCT) is a rare neoplasm of the joint synovium that has a wide clinical spectrum including pain and stiffness in the affected joint, joint swelling, periarticular erosions, and cartilage loss, which can severely impact quality of life. The mainstay treatment for TGCT has been surgery involving partial or total synovectomy using arthroscopic or open techniques. However, surgical resection alone is associated with high recurrence rates, particularly in diffuse-TGCT (D-TGCT) cases. The 3 cases presented here summarize a combination approach (surgery+pexidartinib [tyrosine kinase inhibitor]) in patients with previously unresectable or inoperable D-TGCT. Case 1-Hip. A 29-year-old male was treated with pexidartinib prior to surgery, resulting in tumor reduction. A left total hip arthroplasty (THA) was then performed with a lack of recurrence in 12 months postoperative, and the patient currently on pexidartinib treatment. Case 2-Foot. A 35-year-old female, nearly a decade following a left foot mass resection, was treated with pexidartinib following disease recurrence. A decrease in soft tissue lesions at the midfoot and decreased marrow enhancement at the first metatarsal head were seen within 4–5 months of pexidartinib treatment; the patient is currently on pexidartinib (400 mg/day) with improved symptom control. Case 3-Knee. A 55-year-old male patient received pexidartinib pre- and postoperatively. A reduction in swelling and the size of the popliteal cyst was significant and maintained, with the synovial disease growing when pexidartinib was discontinued. Surgery and adjuvant therapy eliminated the disease as of the last follow-up visit (11 months postoperative). These cases provide a unique perspective based on tumor location, type/timing of treatment strategy, and patient outcomes. Optimal treatment strategies for this debilitating disease may entail utilizing a combination approach (surgery+systemic treatment) to reduce surgical morbidity and the risk of postoperative disease recurrence. [ABSTRACT FROM AUTHOR]

Pexidartinib is a novel oral small‐molecule tyrosine kinase inhibitor targeting the colony‐stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'‐diphospho‐glucuronosyl transferase enzymes, with ZAAD‐1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib. The objective of the two phase 1, open‐label studies was to determine the pharmacokinetics of pexidartinib after a single 200‐mg dose in subjects with mild and moderate HI, based on Child–Pugh classification (PL3397‐A‐U123: 8 mild HI and 8 moderate HI vs 16 matched healthy controls) and National Cancer Institute Organ Dysfunction Working Group (NCI‐ODWG) criteria (PL3397‐A‐U129: 8 moderate HI versus 8 matched healthy controls [NCT04223635]). Based on Child–Pugh classification, exposure to pexidartinib (maximum observed concentration [Cmax], area under the plasma concentration–time curve up to the last measurable concentration [AUClast], and extrapolated to infinity [AUCinf]) was similar in subjects with mild and moderate HI and in respective matched healthy controls, whereas ZAAD‐1006a exposure (AUC) was approximately 27% to 28% and 41% to 48% higher in mild and moderate HI, respectively. According to NCI‐ODWG criteria, total pexidartinib exposure was 42% to 46% higher in subjects with moderate HI, compared with healthy controls, and total ZAAD‐1006a exposure was 70% to 79% higher for subjects with moderate HI, compared with matched healthy controls with normal hepatic function. These findings were used to develop appropriate dose recommendations in patients with hepatic impairment. [ABSTRACT FROM AUTHOR]

Tenosynovial giant cell tumor (TCGT) is a rare neoplasm affecting the synovium of joints, bursae, and tendon sheaths. The overproduction of colony‐stimulating factor‐1 (CSF‐1) by a minority of the tumor population works in a paracrine fashion to drive tumor growth. Pathology of the reactive, monocytic component has been well elucidated, whereas the populations of neoplastic cells and all the sources of CSF‐1 overproduction are incompletely characterized. Podoplanin (PDPN), or gp38, is a cell surface glycoprotein that is expressed on fibroblast‐like synovial cells and upregulated in rheumatoid arthritis and many cancers; it governs cell mobility, epithelial–mesenchymal transition, and other functions and is associated with lymphangiogenesis and poor prognosis in many solid tumors, which underscores its local and possible systemic effects. We found higher PDPN expression in TGCT than in internal controls of patients' healthy synovium. Flow cytometry partitioned PDPNhigh cells into PDPNhighCD90+ and PDPNhighCD14+ populations. Quantitative real‐time polymerase chain reaction analysis of the PDPNhighCD90+ cells revealed that CSF‐1 expression was 10‐fold higher than in PDPNhighCD14+ cells. Therefore, we conclude that the lining fibroblast‐like synovial cells, which express PDPNhighCD90+, are responsible for the overproduction of CSF‐1 and for driving tumor growth. [ABSTRACT FROM AUTHOR]

Tenosynovial giant cell tumor (TGCT) is a neoplasm of the joint synovium that can have severe impacts on joint mobility, function, and quality of life. Traditionally, treatment modalities included partial or complete surgical synovectomy, radiotherapy (typically as an adjunct to surgery), and watchful monitoring (no medical or surgical intervention). However, these approaches have been met with varying degrees of success and high recurrence rates, as well as onerous complications and clinical sequelae. Pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, presents a promising molecular approach that targets a neoplastic driver of TGCT. While the introduction of pexidartinib allows clinicians to avoid the significant morbidity associated with traditional treatment options, there are also defined risks associated with pexidartinib treatment. Therefore, patient selection is critical in optimizing treatment modalities in TGCT. The purpose of this literature review is to identify the TGCT patient population that would derive maximal benefit with minimal risk from pexidartinib, and to determine the specific indications and contraindications for selecting pexidartinib over other therapeutic approaches. Specifically, this paper compares the efficacy and safety profile of pexidartinib across clinical and preclinical studies to that of surgery, radiotherapy, and watchful monitoring. Rates of improvement in joint mobility, pain, and recurrence-free survival across studies of pexidartinib have been encouraging. The most common adverse events are mild (hypopigmentation of the hair) or reversible (transient aminotransferase elevation). Severe or permanent adverse events (notably cholestatic hepatotoxicity) are rare. While the optimal treatment strategy remains highly dependent on a patient's clinical circumstances and treatment goals, pexidartinib has surfaced as a promising therapeutic in cases where the morbidity of surgery or radiotherapy outweighs the benefits. [ABSTRACT FROM AUTHOR]

This analysis was conducted to assess exposure–response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT‐related and AST‐related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT‐related and AST‐related AEs. These results support the US Food and Drug Administration–approved dose (400 mg two times/day without initial loading dose). [ABSTRACT FROM AUTHOR]

Background and purpose — The ENLIVEN trial showed that, after 25 weeks, pexidartinib statistically significantly reduced tumor size more than placebo in patients with symptomatic, advanced tenosynovial giant cell tumor (TGCT) for whom surgery was not recommended. Here, we detail the effect of pexidartinib on patient-reported physical function and stiffness in ENLIVEN. Patients and methods — This was a planned analysis of patient-reported outcome data from ENLIVEN, a double-blinded, randomized phase 3 trial of adults with symptomatic, advanced TGCT treated with pexidartinib or placebo. Physical function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function (PF), and worst stiffness was assessed using a numerical rating scale (NRS). A mixed model for repeated measures was used to compare changes in PROMIS-PF and worst stiffness NRS scores from baseline to week 25 between treatment groups. Response rates for the PROMIS-PF and worst stiffness NRS at week 25 were calculated based on threshold estimates from reliable change index and anchor-based methods. Results — Between baseline and week 25, greater improvements in physical function and stiffness were experienced by patients receiving pexidartinib than patients receiving placebo (change in PROMIS-PF = 4.1 [95% confidence interval (CI) 1.8–6.3] vs. –0.9 [CI −3.0 to 1.2]; change in worst stiffness NRS = –2.5 [CI −3.0 to −1.9] vs. –0.3 [CI −0.9 to 0.3]). Patients receiving pexidartinib had higher response rates than patients receiving placebo for meaningful improvements in physical function and stiffness. Improvements were sustained after 50 weeks of pexidartinib treatment. Interpretation — Pexidartinib treatment provided sustained, meaningful improvements in physical function and stiffness for patients with symptomatic, advanced TGCT. [ABSTRACT FROM AUTHOR]

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. Pexidartinib is approved in the U.S. for treatment of tenosynovial giant cell tumors (TGCT). This article assesses the hepatic safety profile of pexidartinib in TGCT cases and describes risk mitigation procedures designed to identify any instances of serious liver injury as early as possible to better inform prescribers and patients about this drug. [ABSTRACT FROM AUTHOR]

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. Most findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study prospectively explores the management of TGCT in tertiary sarcoma centers.Methods: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%) and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases. Name of registry: Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).Trial Registration Number: NCT02948088. Date of registration: 10 October 2016. URL of Trial registry record: https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2 . [ABSTRACT FROM AUTHOR]

Background: There is a lack of evidence regarding long-term outcomes of rotating-hinge knee prostheses with distal femoral replacement in a large oncologic patient series. In this study, we investigated the proportion of patients experiencing complications requiring surgery in the long term, as well as the cumulative incidence of implant removal/revision and amputation at 5, 10, 15, and 20 years through competing risk analyses.Methods: We retrospectively studied 214 patients treated with a Finn/Orthopaedic Salvage System (OSS) knee prosthesis (Zimmer Biomet) after distal femoral resection from 1991 to 2017. The study end points were postoperative complications requiring surgery. Reoperations were classified as major when there was (1) removal of the metal-body femoral component, the tibial component, or the bone-implant fixation; (2) major revision (exchange of the metal-body femoral component, the tibial component, or the bone-implant fixation); or (3) amputation. Minor reoperations were defined as all other reoperations. Competing risk analysis was used to estimate the cumulative incidence of implant removal/revision or amputation.Results: There were 312 reoperations in 113 patients (98 major reoperations in 68 patients and 214 minor reoperations). Seventeen patients (8%) required ≥5 additional operations, and 21 patients (10%) required >1 major reoperation. Although the number of reoperations decreased over time, major and minor reoperations continuously accrued after 10 years. The cumulative incidences of implant removal or revision for any reason at 5, 10, 15, and 20 years were 22.6%, 30.1%, 34.3%, and 42.5%, respectively. Although most implant removals/revisions occurred in the first 10 years, the risk persisted after 10 years, at a mean of 1.24%/year, mainly due to deep infection (1.06%/year).Conclusions: The long-term outcomes of treatment with a Finn/OSS distal femoral rotating-hinge knee prosthesis showed it to be a durable reconstruction technique. The rate of implant removal/revisions after 10 years was gradual (1.24%/year). Deep infection remains a major late-failure mechanism, and lifetime surveillance for prosthetic problems is needed.Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2‐compartment model with sequential zero‐ and first‐order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non‐Asian, weight = 80 kg, creatinine clearance ≥90 mL/min, aspartate aminotransferase ≤80 U/L, and total bilirubin ≤20.5 μmol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady‐state area under the curve values from 0 to 24 hours (AUC0‐24,ss). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC0‐24,ss were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC0‐24,ss than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles. [ABSTRACT FROM AUTHOR]

Background: Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage.Case Presentation: One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB.Conclusions: Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the study of the use cryotherapy of human giant cell tumor of bone. It states that the study analysis the extent of apoptosis in tumors subjected to cryotherapy in vitro. It mentions that the interest in cryotherapy has increased due to the understanding of the immune system and research into how tissues can autoimmunize.

Purpose: The goal of this study was to identify radiographic and anatomic features of Campanacci grade 3 distal radius giant cell tumors that are associated with an acceptable rate of local recurrence after intralesional treatment. Methods: We retrospectively reviewed 15 grade 3 distal radius giant cell tumors treated with intralesional curettage, cryosurgery, and cementation (CCC) (n = 9) or with wide en bloc excision and reconstruction (WEE) (n = 6). Success was defined as local control after CCC without conversion to wide excision, and as a recurrence rate comparable with rates in the scientific literature. Preoperative radiographic evaluation and intraoperative determination of tumor extension guided the choice of treatment. Tumor width on x-rays and tumor volume on magnetic resonance imaging were measured. Outcome was assessed with postoperative motion and grip strength, and the Disabilities of the Shoulder, Arm and Hand, the visual analog pain score, and a satisfaction questionnaire. Results: Local recurrence occurred in 2 of 9 patients after primary CCC, in none with repeat CCC, and in none of the 6 with WEE. No patient treated with secondary CCC had unresectable recurrence requiring conversion to WEE. Patients with a single site of cortical perforation who received CCC treatment achieved local control with intralesional treatment alone. Average tumor volume was 12 cm3 (range, 9–17 cm3) with CCC and 43 cm3 (range, 29–57 cm3) with WEE. Postoperative motion and strength, Disabilities of the Shoulder, Arm and Hand score, and visual analog pain scale score were acceptable in all and superior with CCC. All patients were highly satisfied. Conclusions: Tumor volume measured with magnetic resonance imaging and anatomically defined limits of soft tissue extension may help identify grade 3 lesions that can be treated with with CCC with an acceptable rate of local recurrence. We propose subclassification of Campanacci grade 3 lesions. Under this classification, tumors with extension assessed by preoperative imaging and confirmed by intraoperatively to be limited to a single site of palmar cortical perforation are classified as grade 3(p), where (p) denotes a single site bound by the pronator quadratus. Type of study/level of evidence: Therapeutic IV. [Copyright &y& Elsevier]

Background: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT. Methods: Patients were recruited for qualitative research interviews to identify predominant TGCT symptoms and impacts. Patients completed a checklist to evaluate the relevance of each PROMIS-PF item. The publicly available PROMIS-PF item response theory (IRT) parameters were used to select items representing the range of the latent PF trait. Results: Participants (n = 20) were 75% female, mean age 42.5 years. TGCTs were located in the knee (n = 15), hip (n = 3), and ankle (n = 2). Fifty-four PROMIS-PF items were identified as relevant by ≥20% of the participants. PF concepts discussed by participants during the qualitative interviews were also used to select relevant items. Selected items (n = 13) were used to create a physical function subscale specific to lower extremity tumors. Conclusions: We describe a novel method of combining qualitative research and IRT-based item information to select a relevant and content valid subset of PROMIS-PF items to assess heterogeneous impacts on PF in TGCT, a rare disease population. [ABSTRACT FROM AUTHOR]

Giant cell tumor of bone (GCTB) is a benign, locally destructive neoplasm, with tumors comprised of mesenchymal fibroblast-like stromal cells; monocytic, mononuclear cells of myeloid lineage; and the characteristic osteoclast-like, multinucleated giant cells. Hampering the study of the complex interaction of its constituent cell types is the propensity of longstanding, repeatedly passaged cell cultures to undergo phenotypic alteration and loss of osteoclast-inducing capacities. In this study, we employed a novel, single-step technique to purify freshly harvested stromal cells using a CD14-negative selection column. Using 9 freshly harvested GCTB specimens and the purified stromal cell component, we performed analyses for markers of osteoblast lineage and analyzed the capacity of the stromal cells to undergo osteoblastic differentiation and induce osteoclastogenesis in co-cultures with monocytic cells. Successful purification of the CD14-negative stromal cells was confirmed via flow cytometric analysis and immunocytochemistry. Osteogenic media upregulated the expression of osteocalcin, suggesting an osteoblastic lineage of the GCTB stromal cells. The effects of the Wnt pathway agonist, SB415286, and recombinant human bone morphogenetic protein (BMP)-2 on osteoblastogenesis varied among samples. Notably, osteogenic media and SB415286 reversed the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) expression ratio resulting in diminished osteoclastogenic capacity. Recombinant human BMP2 had the opposite effect, resulting in enhanced and sustained support of osteoclastogenesis. Targeting the giant cell tumor stromal cell may be an effective adjunct to existing anti-resorptive strategies. [ABSTRACT FROM AUTHOR]