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1.
Cancer Treat Rev ; 112: 102491, 2023 01.
Article in English | MEDLINE | ID: mdl-36502615

ABSTRACT

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.


Subject(s)
Giant Cell Tumor of Tendon Sheath , Quality of Life , Humans , Consensus , Giant Cell Tumor of Tendon Sheath/drug therapy , Giant Cell Tumor of Tendon Sheath/pathology
2.
Eur J Cancer ; 51(1): 75-83, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25466504

ABSTRACT

PURPOSE: Imatinib mesylate is the front-line targeted therapy for gastrointestinal stromal tumours (GISTs). Patient's eligibility to adjuvant imatinib after primary tumour resection is currently based on histological and clinical risk assessment. While therapeutic options are clear for the very-low, low and high-risk subpopulations, no standard is actually available for the tumours classified as intermediate. Since we recently validated genomic index (GI), a measure of the level of genomic alterations, as a strong predictor of clinical outcome in GIST, we asked whether it could also represent a novel prognostic factor for the intermediate subgroup. EXPERIMENTAL DESIGN: 82 intermediate risk patients were selected based on the Armed Forces Institute of Pathology (AFIP) classification for genomic profiling. RESULTS: Data revealed that even if studied samples generally harboured a combination of the typical genetic aberrations found in GIST, i.e. 1p, 14q 22q deletions and frequently lost CDKN2A locus on chromosome 9, they profoundly differed from each other on the total number of genomic changes and GI value. Kaplan-Meier analyses of metastatic-free survival unveiled that stratification of the tumours by the GI value at a cutoff of 10 separated the good from the poor prognosis patients, proven that metastatic-risk in GIST intermediate patients is strongly associated with high GI values and genome complexity. CONCLUSION: GI is validated here as a robust marker to predict intermediate-GIST clinical outcome. Applicable in numerous Pathology Laboratories already using array comparative genomic hybridisation (CGH) with formalin-fixed paraffin-embedded (FFPE) samples, this assay presently stands as an efficient tool for the clinical management of intermediate GIST-patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Gastrointestinal Stromal Tumors/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Antineoplastic Agents/administration & dosage , Benzamides/administration & dosage , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Imatinib Mesylate , Male , Neoplasm Metastasis , Piperazines/administration & dosage , Prognosis , Pyrimidines/administration & dosage , Treatment Outcome
3.
Am J Surg Pathol ; 37(3): 385-92, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23348204

ABSTRACT

Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.


Subject(s)
Cell Dedifferentiation , Gastrointestinal Stromal Tumors/metabolism , Gastrointestinal Stromal Tumors/pathology , Proto-Oncogene Proteins c-kit/metabolism , Adult , Aged , Antineoplastic Agents/therapeutic use , Benzamides , DNA Mutational Analysis , Female , Gastrointestinal Stromal Tumors/genetics , Gene Dosage , Genes, p53 , Humans , Imatinib Mesylate , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , Mutation , Phenotype , Piperazines/therapeutic use , Polymerase Chain Reaction , Proto-Oncogene Proteins c-kit/genetics , Pyrimidines/therapeutic use , Young Adult
4.
J Gastroenterol ; 46(5): 586-94, 2011 May.
Article in English | MEDLINE | ID: mdl-21286759

ABSTRACT

BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.


Subject(s)
Gastrointestinal Stromal Tumors/genetics , Laboratories/standards , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , DNA Mutational Analysis/methods , DNA, Neoplasm/analysis , Exons , Genotype , Humans , Mutation , Polymorphism, Genetic , Quality Control
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