scholarly journals Novel case of a scleroderma-mimicking syndrome associated with gastrointestinal stromal tumour

2021 ◽  
Vol 14 (3) ◽  
pp. e240211
Author(s):  
Zaran Ahmad Butt ◽  
Wan Lin Ng ◽  
Kamal Osman ◽  
Donough Howard
Keyword(s):  
Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumour ◽  
Symptomatic Improvement ◽  
Stromal Tumour ◽  
Newly Diagnosed ◽  
Rapid Improvement ◽  
Potential Efficacy ◽  
Surveillance Imaging ◽  
Gastric Mass ◽  
Fibrotic Disorders

We report a case of a 54-year-old man who developed an atypical systemic syndrome involving Raynaud’s phenomenon, pulmonary fibrosis and skin thickening. These features were initially suggestive of newly diagnosed scleroderma. However, he displayed atypical clinical features of same, antinuclear antibody was negative and symptoms were refractory to various immunosuppressive therapies. CT imaging revealed a gastric mass, which later proved to be a gastrointestinal stromal tumour (GIST). Resection of the GIST leads to minimal symptomatic improvement. Surveillance imaging 1 year later revealed metastatic deposits. He was subsequently initiated on imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. While there have been previous descriptions of paraneoplastic fibrotic disorders, this is the first description of a scleroderma mimic in the setting of a GIST. It highlights an important potential overlap in the pathogenesis of these disease processes and the potential efficacy of tyrosine kinase inhibitors for scleroderma-like fibrotic disorders.

A New Monoclonal Antibody that Blocks KIT Dimerisation and Inhibits Gastrointestinal Stromal Tumour Growth

2020 ◽  
Author(s):  
Chen Guang Bai ◽  
Yi Xu ◽  
Cen Qiu
Keyword(s):  
Monoclonal Antibody ◽  
Cell Growth ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumour ◽  
Signalling Pathway ◽  
Stromal Tumour ◽  
Growth Responses ◽  
Kit Mutation

Abstract Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the gastrointestinal tract, and arises owing to oncogenic mutations in c-kit that result in constitutive auto-phosphorylation of KIT in the absence of ligand binding. Small-molecule tyrosine kinase inhibitors have shown good clinical activity by inhibiting ATP binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. Here, we demonstrate c-kit mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Treatment of KIT-dimer-expressing cells with the KITMAb slowed down cell growth. Furthermore, KITMAb reduced the proportion of cells in the proliferative phase (S+G2-M). Finally, we also demonstrate that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.

Imatinib-induced haematuria necessitating drug discontinuation

2020 ◽  
Vol 4 (3) ◽  
pp. 121-123
Author(s):  
Anandu Hemakumar ◽  
Keechilat Pavithran
Keyword(s):  
Kinase Inhibitors ◽  
Advanced Disease ◽  
Gastrointestinal Stromal Tumour ◽  
Stromal Tumour ◽  
Drug Discontinuation ◽  
Gastrointestinal Stromal Tumours ◽  
Old Adult ◽  
History Of ◽  
Improvement In Survival ◽  
Gross Haematuria

Gastrointestinal stromal tumours are rare neoplasms of the gastrointestinal tract that are mesenchymal in origin. The introduction of tyrosine kinase inhibitors resulted in significant improvement in survival of patients with gastrointestinal stromal tumour even in advanced disease conditions. A 43-year-old adult male who is a known case of gastrointestinal stromal tumour of the stomach, on adjuvant therapy with imatinib, presented with a history of gross haematuria of several episodes as well as persistent microhaematuria and was evaluated for the same. He was investigated for all possible causes, but all were negative. The patient was advised to withhold imatinib. Haematuria resolved 1 month after stopping imatinib. Then it was rechallenged. He had recurrence of symptoms, so it was discontinued. In view of the temporal relation of haematuria and administration of imatinib, a diagnosis of imatinib-induced haematuria was made.

scholarly journals Outstanding Response to Sorafenib in a Patient with Metastatic Gastrointestinal Stromal Tumour

2021 ◽  
pp. 1567-1573
Author(s):  
Charlotte Brinch ◽  
Marie Dehnfeld ◽  
Estrid Hogdall ◽  
Tim Svenstrup Poulsen ◽  
Anders Toxvaerd ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Primary Tumour ◽  
Growth Factor Receptor ◽  
Gastrointestinal Stromal Tumour ◽  
Stromal Tumour ◽  
Correct Treatment ◽  
Imatinib Resistance ◽  
Term Survival ◽  
Mutation Analyses

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (<i>PDGFRA</i>). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at <i>PDGFRA</i> exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

scholarly journals P033 Scleroderma-like fibrotic disorder associated with a gastro-intestinal stromal tumour which responded only to imatinib

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Zaran A Butt ◽  
Wan Lin NG ◽  
Donough Howard ◽  
Kamal Osman
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Negative Symptoms ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Gastric Fundus ◽  
Stromal Tumour ◽  
Platelet Derived Growth Factor ◽  
Rapid Improvement ◽  
Metastatic Recurrence

Abstract Background/Aims  Gastro-intestinal stromal tumour (GIST) is recognised as the most prevalent mesenchymal tumour of the gastro-intestinal (GI) tract. The vast majority of GIST display activating mutations in receptor tyrosine kinases, such as platelet-derived growth factor receptor alpha (PDGFRA) and c-kit. This characteristic has lead to the development and approval of targeted therapies such as Imatinib for metastatic GIST. Scleroderma is an idiopathic fibrotic syndrome which involves excess collagen deposition in multiple tissues and organs. There is emerging evidence that dysfunctional fibroblasts are central to the underlying pathogenesis of this disease. An increasing awareness of the complex interplay of these fibroblasts with other cells and inflammatory mediators, such as platelet-derived growth factor (PDGF), is being recognised. This novel case serves to further develop our understanding of these pathological interactions, and to highlight a prospective role for Imatinib in disrupting them. Methods  We present a case report below. Results  A 54-year-old Caucasian male was referred to our rheumatology clinic due to worsening Raynaud's syndrome, arthralgia, and dry cough. He subsequently developed weight loss, pyrosis and skin thickening. This clinical picture was suggestive of a new diagnosis of systemic sclerosis. However, fibrotic skin changes did not extend to the distal finger, and anti-nuclear antibody (ANA) was negative. Symptoms were also refractory to various vasodilator and immunosuppressive therapies, including nifedipine, repeated iloprost infusions, azathioprine, mycophenolic acid, prednisolone, and sildenafil. Computed tomography (CT) imaging revealed interstitial pulmonary fibrosis and a mass within the gastric fundus. Histopathologic features and immunological staining of this mass were consistent with a GIST. Resection of the tumour did not improve fibrotic symptoms. Surveillance imaging one-year later was highly concerning for metastatic recurrence, which was later confirmed with tissue biopsy. He was subsequently initiated on Imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. Conclusion  While there have been previous descriptions of para-neoplastic fibrotic syndromes, this is the first reported case of a scleroderma-mimicking disorder associated with GIST. It hints at an important potential overlap in the pathogenesis of these disease processes, and a potential role for tyrosine-kinase inhibitors in the treatment of scleroderma-like fibrotic disorders. Disclosure  Z.A. Butt: None. W. Ng: None. D. Howard: None. K. Osman: None.

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