Diffuse-type tenosynovial giant cell tumor (dt-TGCT) is a benign clonal neoplastic proliferation arising from the synovium. Patients are often symptomatic, require multiple surgical procedures during ...their lifetime, and have reduced quality of life (QoL). Surgery is the main treatment with relapse rates ranging from 14 to 55%. The treatment strategy for patients with dt-TGCT is evolving. The purpose of this review is to describe current treatment options, and to highlight recent developments in the knowledge of the molecular pathogenesis of dt-TGCT as well as related therapeutic implications.
TGCT cells overexpress colony-stimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumor, has led to clinical trials with CSF1R inhibitors. These inhibitors include small molecules such as pexidatinib, imatinib, nilotinib, DCC-3014 (vimseltinib), and the monoclonal antibody RG7155 (emactuzumab).
In conclusion, D-TGCT impairs patients' QoL. The evidence that the pathogenetic loop of D-TGCT can be inhibited has changed the therapeutic armamentarium for this condition. Clinical trials of agents that target CSF1R are currently ongoing. All this new evidence should be taken into consideration within multidisciplinary management.
Abstract At present, the optimal treatment strategy in patients with diffuse-type tenosynovial giant cell tumour (D-TGCT) is unclear. The purpose of this review was to describe current treatment ...options, and to highlight recent developments in the knowledge of the molecular pathogenesis of D-TGCT as well as related therapeutic implications. Epidemiology, clinical features, and the pathogenesis of D-TGCT and the most widely used treatment modalities are described. D-TGCT is a benign clonal neoplastic proliferation arising from the synovium. Patients are often symptomatic and require multiple surgical procedures during their lifetime. Currently, surgery is the main treatment for patients with D-TGCT, with relapse rates ranging from 14% to 55%. Radiosynovectomy and external beam radiotherapy have been used in combination with surgical excision or as single modalities. The finding that D-TGCT cells overexpress colony-stimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumour, has led to clinical trials with CSF1R inhibitors. These inhibitors include small molecules such as imatinib, nilotinib, PLX3397, and the monoclonal antibody RG7155. In conclusion, D-TGCT impairs patients’ quality of life significantly. The evidence that the pathogenetic loop of D-TGCT can be inhibited could potentially change the therapeutic armamentarium for this condition. Clinical trials of agents that target D-TGCT are currently ongoing. In the meantime, international registries should be activated in order to provide useful information on this relatively rare tumour.
Rare Primary Malignant Bone Sarcomas Palmerini, Emanuela; Righi, Alberto; Staals, Eric L.
Cancers,
11/2020, Letnik:
12, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Rare primary malignant bone sarcomas (RPMBS), other than osteosarcoma, chondrosarcoma, chordoma, and Ewing sarcoma, account for about 5–10% of primary bone tumors and represent a major diagnostic ...challenge. These tumors include spindle cell and round cell sarcoma entities, hemangiopericytoma-like and vascular tumors. Additionally, several histotypes, traditionally described in the soft tissues, such as myxofibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor of bone, have been reported in patients with primary bone tumors. While wide surgical resection is the mainstay of local treatment, systemic therapy of these rare entities is controversial. Patients with undifferentiated spindle cell or pleomorphic high-grade tumors of bone, are usually treated with osteosarcoma-like chemotherapy, while patients with round cell and undifferentiated round cell tumors (URCTs), may respond to sarcoma treatment regimens for Ewing sarcoma patients. Studies on analogies and differences among these ultra-rare tumors have seldom been reported. This review describes relevance, clinical aspects, diagnostic procedures, staging, treatment recommendations, and current research in this composite tumor group.
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.
This analysis further illustrates that systemic therapy targeting the CSF1/CSF1R pathway is an effective therapeutic strategy in patients with tenosynovial giant cell tumor. Because of the limited availability of long‐term prospective data for tenosynovial giant cell tumor, these findings are encouraging and demonstrate the overall long‐term benefit of continued treatment with pexidartinib.
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.
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.
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.
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).
NCT02948088. Date of registration: 10 October 2016. URL of Trial registry record: https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2 .
Purpose
To evaluate the health-related quality of life and associated risk factors for Multiple Osteochondromas patients.
Methods
A cross-sectional, observational study was conducted from May to ...December 2022 during the routine visit to the referral center for rare skeletal disorders. All patients with Multiple Osteochondromas aged ≥ 3 years were included. EuroQol 5-dimension questionnaires, and demographic, clinical, and surgical history data were collected. Descriptive statistics, Fisher’s exact test, One-sample
t
-test, Spearman’s correlation, and multiple linear and logistic regression were performed to analyze the data. Results are reported following STROBE guidelines.
Results
A total of 128 patients were included in the study, with a mean age of 14 SD, 10 years. The mean EQ-5D Index Value was 0.863 SD, 0.200 and the EQ-VAS was 84 SD, 19 with a positive correlation between two scores
r
= 0.541,
p
< 0.001. Patients frequently referred problems in pain/discomfort 78.8%, anxiety/depression 50%, and usual activities 38.8% dimensions. Increasing age was the common risk factor for health-related quality of life
p
< 0.000, as well as Index Value and VAS scores were significantly lower in surgical patients
p
= 0.001 and
p
< 0.001, respectively.
Conclusion
Increasing age and surgical procedures were found highly associated with reduced health-related quality of life in Multiple Osteochondromas patients. Our findings provide relevant information to support the establishment of patient-centered healthcare pathways and pave the way for further research into medical and non-medical therapeutic strategies for these patients.
Malignancy in giant cell tumor of bone Bertoni, Franco; Bacchini, Patrizia; Staals, Eric L.
Cancer,
15 May 2003, Letnik:
97, Številka:
10
Journal Article
The optimal treatment for synovial sarcoma remains controversial. Treatment, outcome, and prognostic factors in patients treated in a single institution were examined.
Synovial sarcoma patients who ...underwent surgery at the Rizzoli Institute between 1976 and 2006 were identified and analyzed.
Characteristics of the 250 patients (128 female; 122 male) included: median age, 37 years (range, 7-83 years); 177 (71%) with tumors in the lower extremity, 40 (16%) with tumors in the upper extremity, and 33 with tumors in the trunk (13%); primary lesion size >5 cm in 121 patients (55%); and 204 (82%) patients with localized disease and 46 (18%) with metastatic disease at the time of presentation. All patients with localized disease underwent surgery. Twenty-four percent of patients underwent amputation. Adequate surgical margins were achieved in 88% patients. In patients with localized disease, radiotherapy was administered to 103 (50%) patients, and chemotherapy to 98 (48%). With a median follow-up of 5.5 years (range, 1-30 years), the 5-year overall survival rate was 10% for patients with metastatic disease and 76% for patients with localized disease (P = .0001). The 5-year event-free survival was 58% in patients with localized disease. Multivariate analysis indicated that size, age, histologic subtype, and the use of radiotherapy were independent factors for event-free survival.
In those patients with localized disease, a good rate of cure can be achieved. Age, size, histology, and use of radiotherapy influence prognosis, whereas to the authors' knowledge, the role of adjuvant chemotherapy remains unproven.
Background
Reconstruction of the distal femur after resection for malignant bone tumors in skeletally immature children is challenging. The use of megaprostheses has become increasingly popular in ...this patient group since the introduction of custom-made, expandable devices that do not require surgery for lengthening, such as the Repiphysis
®
Limb Salvage System. Early reports on the device were positive but more recently, a high complication rate and associated bone loss have been reported.
Questions/purposes
We asked: (1) what are the clinical outcomes using the Musculoskeletal Tumor Society (MSTS) scoring system after 5-year minimum followup in patients treated with this prosthesis at one center; (2) what are the problems and complications associated with the lengthening procedures of this implant; and (3) what are the specific concerns associated with revision of this implant?
Methods
At our institute, between 2002 and 2007, the Repiphysis
®
expandable prosthesis was implanted in 15 children (mean age, 8 years; range, 6–11 years) after distal femoral resection for malignant bone tumors. During this time, the general indication for use of this implant was resection of the distal femur for localized malignant bone tumors in pediatric patients. Alternative techniques used for this indication were modular prosthetic reconstruction, massive (osteoarticular or intercalary) allograft reconstruction, or rotationplasty. Age and tumor extension were the main factors to decide on the surgical indication. Of the 15 patients who had this prosthesis implanted during reconstruction surgery, five died with the implant in situ or underwent amputation before 5 years followup and the remaining 10 were evaluated at a minimum of 5 years (mean, 104 months; range, 78–140 months). No patients were lost to followup. These 10 patients were long-term survivors and underwent the lengthening program. They were included in our study analysis. The first seven lengthening procedures were attempted in an outpatient setting; however, owing to pain and burning sensations experienced by the patients, the procedures failed to achieve the desired lengthening. Therefore, other procedures were performed with the patients under general anesthesia. We reviewed clinical data at index surgery for all 15 patients. We further analyzed the lengthening procedures, implant survival, radiographic and functional results, for the 10 long-term survivors. Functional results were assessed according to the MSTS scoring system. Complications were classified according to the International Society of Limb Salvage (ISOLS) classification system.
Results
Nine of the 10 survivors underwent revision of the implant for mechanical failure. They had a mean MSTS score of 64% (range, 47%–87%) before revision surgery. At final followup the 10 long-term surviving patients had an average MSTS score of 81% (range, 53%–97%). In total, we obtained an average lengthening of 39 mm per patient (range, 17–67 mm). Exact expansion of the implant was unpredictable and difficult to control. Nine of 10 of the long-term surviving patients underwent revision surgery of the prosthesis—eight for implant breakage and one for stem loosening. At revision surgery, six patients had another type of expandable prosthesis implanted and three had an adult-type megaprosthesis implanted. In five cases, segmental bone grafts were used during revision surgery to compensate for loss of bone stock.
Conclusions
We could not comfortably expand the Repiphysis
®
prosthesis in an outpatient setting because of pain experienced by the patients during the lengthening procedures. Furthermore, use of the prosthesis was associated with frequent failures related to implant breakage and stem loosening. Revisions of these procedures were complex and difficult. We no longer use this prosthesis and caution others against the use of this particular prosthesis design.
Level of Evidence
Level IV, therapeutic study.
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