BACKGROUND:Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive neoplasm that affects otherwise healthy adults. There are few systemic treatment options, highlighting an unmet need. We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT. METHODS:MANEUVER is a randomised, placebo-controlled, phase 3 study done in 40 specialised hospitals in Asia, Europe, and North America. Patients aged 18 years and older with unresectable, symptomatic TGCT (patient-reported worse stiffness or worst pain of at least 4 on a scale of 0-10) were randomly assigned (2:1, double-blind) to oral, once-daily pimicotinib 50 mg or placebo for 24 weeks (part 1). An independent statistician used a central interactive web response system to generate the randomisation schedule; stratification was by region (China vs non-China). Masking was achieved by using placebo identical in appearance to pimicotinib. In part 1, patients, all investigators, and study funders were masked to treatment assignments. All patients who completed part 1 were allowed to continue to open-label part 2: pimicotinib-treated patients could continue the same dosage and placebo-treated patients could cross over to receive pimicotinib for 24 weeks. Eligible patients who completed part 2 were allowed to continue once-daily pimicotinib long-term in part 3. The primary endpoint was objective response rate (ORR) at week 25 by blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population (all randomised patients). Safety was analysed in patients who received at least one dose of study drug. Missing data were not imputed and only observed data were analysed. Trial enrolment is complete; the study is registered at ClinicalTrials.gov (NCT05804045) and is ongoing. FINDINGS:Between April 27, 2023, and March 29, 2024, 126 patients were screened and 94 patients (China [n=45], non-China [n=49]) were randomly assigned to, and received, pimicotinib (n=63) or placebo (n=31). 30 (32%) patients were male and 64 (68%) were female. ORR at week 25 was 54% (34 of 63) in the pimicotinib group and 3% (one of 31) in the placebo group (absolute difference 51% [95% CI 33-63], p<0·0001). Pimicotinib was associated with mainly mild treatment-emergent adverse events, including mostly manageable asymptomatic laboratory abnormalities and clinical events, such as pruritus, facial oedema, rash, periorbital oedema, and fatigue. The only grade 3 or 4 treatment-emergent adverse event occurring in more than 10% of pimicotinib-treated patients was increase in blood creatine phosphokinase, in eight (13%) of 63 patients. The most common treatment-emergent adverse events in the placebo group were fatigue and arthralgia. Dose reductions occurred in five (8%) of 63 pimicotinib-treated patients and treatment discontinuations in one (2%) of 63 pimicotinib-treated patients. There was no cholestatic hepatotoxicity, drug-induced liver injury, or hypopigmentation of skin or hair. INTERPRETATION:Pimicotinib showed robust antitumour activity with clinically meaningful improvements in TGCT-related functional limitations and symptom burden, offering an effective treatment option with a manageable safety profile for this underserved condition. FUNDING:Abbisko Therapeutics.
Introduction: Accurate knowledge of the external carotid artery (ECA) anatomy is essential for head and neck surgery, interventional procedures, and imaging interpretation. Although its branching pattern is classically described as relatively constant, clinically relevant anatomical variations are frequently encountered. Cadaveric dissection remains fundamental for identifying rare vascular configurations. Materials and Methods: During an anatomical teaching dissection of a 72-year-old male cadaver, a right-sided lateral cervicotomy was performed to expose the carotid sheath. After mobilisation of the sternocleidomastoid muscle, the ECA and its proximal branches were skeletonised, allowing detailed three-dimensional assessment of their origin, calibre, and neurovascular relationships. Results: The superior thyroid artery originated from the proximal segment of the external carotid artery, in close proximity to the carotid bifurcation. The main anatomical finding was a lingual artery of relatively small initial calibre exhibiting an atypical superior trajectory: after its origin, it crossed superior to the hypoglossal nerve before continuing toward the tongue. This configuration differs from classical descriptions and modified the anatomical arrangement of Beclard’s and Pirogoff’s triangles, creating a potential site of close neurovascular contact. Conclusions: This cadaveric study describes a rare trajectory-based variant of the external carotid artery characterised by a lingual artery crossing superior to the hypoglossal nerve. Awareness of such rare patterns is essential for improving anatomical interpretation and enhancing surgical safety in the head and neck region.
11544 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive tumor originating in the synovial lining of the joint, bursa, and tendon sheath. Since TGCT typically impacts individuals 20-50 years of age, pediatric TGCT is ultra-rare. However, pediatric patients are often not included in clinical trials or prospective data. Real-world data are needed to understand the impact of TGCT on pediatric patients’ quality of life and any differences between adults with TGCT. Methods: The TGCT Support Registry is an international, prospective registry initiated in 2022 by TGCT Support, a program of The Life Raft Group. The registry is the largest registry of patients with TGCT and records patient-reported demographic, pathologic, clinical information. This cross-sectional analysis presents data of patients ≤ 18 years of age at time of enrollment with Diffuse (D)-TGCT, Localized (L)-TGCT, or unknown subtype. Results: A total of 122 pediatric patients (9.5%) were included from a 1,278-patient registry (Table). Most patients were female (67.2%), had D-TGCT (73.0%), in the knee (83.6%), and a median age at diagnosis of 14.5 years. Symptoms reported were pain (94.3%), limited joint range of motion (89.3%), and swelling (84.4%). >50% of pediatric patients were initially misdiagnosed and were more likely to be misdiagnosed than adults (62.3% vs 49.9%, p < 0.01). 64.8% of pediatric patients were diagnosed by orthopedic surgeons, and 52.5% were diagnosed ≥1 years after symptom onset. Half of pediatric patients had joint aspirations to manage symptoms (47.5%) and non-steroidal anti-inflammatories were common (76.2%). Surgery was the predominant treatment modality and 61.5% reported that surgery occurred ≤ 3 months of diagnosis. Pediatric patients with D-TGCT underwent an average of 3.4 surgeries, compared to 1.8 surgeries for those with L-TGCT. 66.3% of pediatric patients with D-TGCT had ≥1 post-operative recurrence compared to 15.0% of L-TGCT pediatric patients. Most pediatric patients were referred to general orthopedic surgeons (80.3%), only a third consulted an oncology specialist, and 35.3% were also treated by pediatricians. Systemic therapies (i.e., imatinib, nilotinib, pexidartinib) were prescribed infrequently to pediatric patients with D-TGCT (17.2%). Pediatric patients reported that pain often interfered with daily activities and enjoyment of life. Conclusions: This real-world analysis highlights the significant disease burden of pediatric TGCT, as compared to adults, which severely affecting their quality of life. The reliance on surgical treatment and underuse of multidisciplinary care emphasizes the unmet need for provider education and treatment advancements tailored to this population. Greater efforts to develop systemic therapies specific to pediatrics are warranted to reduce recurrence rates and improve quality of life. Characteristics of patients stratified by subtype (localized, diffuse, or unknown), including sex, age, region, location of disease, misdiagnosis, duration from symptom onset to diagnosis, average surgeries, recurrences, and use of systemic therapies. Diffuse(n=89, 73.0%) Localized(n=20, 16.4%) Unknown(n=13, 10.6%) Total(N=122) Female sex, n (%) 59 (66.3) 14 (70.0) 9 (69.2) 82 (67.2) Median age at Diagnosis, years (range) 14 (3 - 17) 15 (4 - 17) 14.5 (7 - 15) 14.5 (3 - 17) Median age at Enrollment, years (range) 16 (4-18) 17 (6-18) 15 (10-18) 16 (4-18) Located in the US, n (%) 47 (52.8) 11 (55.0) 4 (30.8) 62 (50.8) Location of disease, n (%) Knee 76 (85.4) 16 (80.0) 10 (76.9) 102 (83.6) Hip 8 (9.0) 4 (20.0) 1 (7.7) 13 (10.7) Ankle 5 (5.6) 0 (0.0) 0 (0.0) 5 (4.1) Other a 0 (0.0) 0 (0.0) 2 (15.4) 2 (1.6) Misdiagnosis, n (%) 56 (62.9) 10 (50.0) 10 (76.9) 76 (62.3) Time from Symptom Onset to Diagnosis, n (%) <12 months 42 (47.1) 8 (40.0) 4 (30.8) 54 (44.3) 12–24 months 24 (27.0) 5 (25.0) 3 (23.1) 32 (26.2) 25–60 months 14 (15.7) 4 (20.0) 3 (23.1) 21 (17.2) >60 months 6 (6.7) 3 (15.0) 2 (15.4) 11 (9.0) Diagnosed during Surgery 3 (3.4) 0 (0.0) 1 (7.7) 4 (3.3) Average surgeries, (SD) Median 3.4 (2.8)2 1.8 (1.5)1 1 (1.2)1 2.9 (2.5)2 Systemic Therapy, Check all that apply Pexidartinib Imatinib Nilotinib 20 (22.5)7 (7.9)12 (13.5)1 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7)1 (7.7)0 (0.0)0 (0.0) 21 (17.2)8 (7.4)12 (9.8)1 (0.8) Local Recurrences, n (%) Yes 1 Recurrence ≥ 2 Recurrences 59 (66.3)19 (21.3)40 (44.9) 3 (15.0)2 (10.0)1 (5.0) 4 (3.8)1 (7.7)3 (23.1) 66 (54.1)22 (18.0)44 (36.1) No I have not had surgery I am unsure 30 (33.7)12 (13.5)8 (9.0) 17 (85.0)2 (10.0)4 (20.0) 9 (69.2)5 (38.5)1 (7.7) 56 (45.9)19 (15.6)13 (10.7)
Background: Mesenchymal chondrosarcoma (MCS) is an ultra-rare sarcoma, molecularly defined by the HEY1::NCOA2 fusion, and characterized by a poor prognosis in the advanced phase. Data on the activity of systemic agents in MCS are only retrospective and limited to case reports or heterogeneous series. We report the results of an Italian, multicentric, retrospective study on the activity of cytotoxic chemotherapy in patients with MCS. Patients and methods: This retrospective, multicentre Italian Sarcoma Group study included patients with molecularly confirmed MCS, treated with anthracycline-based chemotherapy, high-dose ifosfamide (HD-IFX), or trabectedin between 2000 and 2022. Response to treatment was assessed retrospectively through imaging review. Survival outcomes were estimated by the Kaplan-Meier method. Results: Thirty-five patients were identified (19 = localized disease, 16 = advanced disease). Anthracycline-based regimens yielded an overall response rate (ORR) of 26% [95% confidence interval (CI) 15% to 50%]. Among patients with localized disease, Ewing-like regimens showed an ORR of 33.3% (95% CI 9.9% to 65.1%), median relapse-free survival (mRFS) of 86.9 months, and 5-year overall survival of 95%; other anthracycline combinations had an ORR of 40% (95% CI 5.3% to 85.3%) and mRFS of 32.6 months. In advanced disease, Ewing-like regimens yielded an ORR of 16.7% (95% CI 0.4% to 64.1%) and median progression-free survival (mPFS) of 13.2 months, while other anthracycline regimens resulted in an ORR of 22.2% (95% CI 15% to 50%) and mPFS of 9.3 months. HD-IFX showed no responses, with early progression in all cases. Trabectedin achieved stable disease in all four treated patients, with a median PFS of 16.9 months. Conclusions: This multicentre study confirms that anthracycline-based regimens show activity in MCS, with responses more in line with soft tissue sarcoma than Ewing sarcoma. Their benefit in localized disease remains uncertain, but (neo)adjuvant chemotherapy with Ewing-like regimens should be considered for patients eligible for surgery. In advanced disease, trabectedin may provide prolonged disease control after anthracyclines.
