Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the US. The majority (~85%) of GISTs possess gain-of-function mutations in KIT or PDGFRA, causing constitutive activation of the kinase receptor. GIST management has been transformed by the identification of tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite IM’s efficacy, most patients experience primary and/or secondary resistance within 2 y of treatment. Additional therapies and methods to optimize screening of novel approaches in preclinical studies are warranted. Clinically, treatment efficacy is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines or Choi criteria. Both require a period of time on therapy before changes indicative of response can be observed. In addition, neither informs directly about cell death. We evaluated the use of molecular imaging technology in an animal model using near-infrared (NIR) imaging probes together with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determined the potential of NIR probes (PSVue(TM)794 and cell-penetrating KcapQ647) for detecting distinct markers of apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. Our studies revealed statistically significant increases in apoptosis due to IM treatment using both probes as early as 24 h post IM treatment which was confirmed by IHC. Molecular imaging will allow for faster and more effective screening of novel therapies in preclinical GIST models

Surgical options for localized and advanced gastrointestinal stromal tumors

The development of imitinab has led to a revolution in the management of gastrointestinal stromal tumors (GIST), but surgical resection remains the cornerstone of treatment for patients with localized disease. The principles to surgical treatment of GIST include careful handling of tissues to prevent tumor rupture and resection to negative margins without the need for wide excision. Minimally invasive techniques have proven equally efficacious provided appropriate oncologic resections are performed. J. Surg. Oncol. 2011; 104:882–887. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88036/1/21892_ftp.pd

Imatinib Mesylate: Past Successes and Future Challenges in the Treatment of Gastrointestinal Stromal Tumors

Just over a decade ago, gastrointestinal tumours were a poorly understood mesenchymal neoplasm unsuccessfully treated with chemotherapy. Cytotoxic therapy for advanced disease yielded response rates of 10% and median survival of just 18 months. However, the discovery of KIT and platelet derived growth factor receptor alpha (PDGFRA) mutations as oncogenic drivers of most gastrointestinal tumours, paved the way for targeted therapy. Imatinib mesylate, a tyrosine kinase inhibitor, produces a clinical benefit rate (complete response, partial response, and stable disease) of more than 80% in metastatic setting and a median survival of 57 months. Imatinib is now also approved in adult patients following resection of KIT-positive GIST. Major insights into the mechanism of action of imatinib, unique pharmacokinetics, drug resistance, and management of low grade but chronic adverse effects continue to be made

Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up

Gastrointestinal stromal tumours (GISTs) are malignant mesenchymal tumours with a variable clinical behaviour, marked by differentiation towards the interstitial cells of Cajal. GISTs belong to the family of soft tissue sarcomas (STSs) but are treated separately due to their peculiar histogenesis, clinical behaviour and specific therapy. This European Society for Medical Oncology (ESMO)–European Reference Network for Rare Adult Solid Cancers (EURACAN)–European Reference Network for Genetic Tumour Risk Syndromes (GENTURIS) Clinical Practice Guideline (CPG) will cover GISTs while other STSs are covered in the ESMO–EURACAN–European Reference Network for Paediatric Oncology (ERN PaedCan)–GENTURIS STS CPG

Gastrointestinal Stromal Tumor: A Rare Abdominal Tumor

Gastrointestinal stromal tumors (GISTs) are rare abdominal tumors which arise from the interstitial cells of Cajal in the gastrointestinal tract. Gastric GISTs are the most commonly seen GIST tumors and may grow to a very large size. They are often associated with abdominal pain, anorexia and weight loss. Most of them can be detected by CT. These tumors have been found to harbor mutations in CD117 which causes constitutional activation of the tyrosine kinase signaling pathway and is considered to be pathognomic. Tyrosine kinase inhibitors such as imatinib have revolutionized the treatment of these tumors, which are otherwise resistant to conventional chemotherapy and radiotherapy. Although surgical resection is the mainstay of treatment, tyrosine kinase inhibitors have been useful in prolonging the recurrence-free survival of these patients. Resistance to imatinib has been reported in GISTs with specific mutations. We present a case of gastric GIST which grew to a very large size and was associated with abdominal pain and weight loss. It was successfully resected and the patient was commenced on imatinib therapy

Gastrointestinal Stromal Tumours: Consensus Statement on Diagnosis and Treatment

In the multidisciplinary management of gastrointestinal stromal tumours (GISTs), there is a need to coordinate the efforts of pathology, radiology, surgery and oncology. Surgery is the mainstay for resectable nonmetastatic GISTs, but virtually all GISTs are associated with a risk of metastasis. Imatinib 400 mg/day with or without surgery is the recommended first-line treatment for recurrent or metastatic GIST; a higher dose may be considered in patients who progress, develop secondary resistance or present with specific genotypic characteristics. Adjuvant or neoadjuvant imatinib is not advised for resectable non-metastatic GISTs. Neoadjuvant imatinib may be considered when surgery would result in significant morbidity or loss of organ function. Follow-up computed tomography imaging is recommended every three to six months for at least five years. Patients with metastatic disease should be continued on imatinib due to the high risk of recurrence on discontinuation of therapy. Treatment should be continued until there is progression or intolerable adverse effects. If dose escalation with imatinib fails, a clinical trial with novel agents alone or in combination may be considered. The present recommendations were developed at a surgical subcommittee meeting and a subsequent full Advisory Committee meeting held in Toronto, Ontario, in April 2005, under the sponsorship of Novartis Pharmaceuticals Canada Inc

Efficacy of Imatinib Mesylate Neoadjuvant Treatment for a Locally Advanced Rectal Gastrointestinal Stromal Tumor

Surgery is the standard treatment for a primary gastrointestinal stromal tumor (GIST); however, surgical resection is often not curative, particularly for large GISTs. In the past decade, with imatinib mesylate (IM), management strategies for GISTs have evolved significantly, and now IM is the standard care for patients with locally advanced, recurrent or metastatic GISTs. Adjuvant therapy with imatinib was recently approved for use, and preoperative imatinib is an emerging treatment option for patients who require cytoreductive therapy. IM neoadjuvant therapy for primary GISTs has been reported, but there is no consensus on the dose of the drug, the duration of treatment and the optimal time of surgery. These are critical because drug resistance or tumor progression can develop with a prolonged treatment. This report describes two cases of large rectal malignant GISTs, for which a abdominoperineal resection was initially anticipated. The two patients received IM preoperative treatment; we followed-up with CT or magnetic resonance imaging to access the response. After 9 months of treatment, a multi-disciplinary consensus that maximal benefit from imatinib had been achieved was reached. We determined the best time for surgical intervention and successfully performed sphincter-preserving surgery before resistance to imatinib or tumor progression occurred. We believe that a multidisciplinary team approach, considerating the optimal duration of therapy and the timing of surgery, is required to optimize treatment outcome

Gastric GIST

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The stomach is considered the most common site of GIST, and the most common histopathological type of GISTs is spindle cell. Mutational analysis may help in defining the management of GIST. Multiple stratification modules are available for the estimation of GISTs’ prognosis. Surgery is considered the only curative option for GISTs. The discovery of KIT protein has allowed better identification of GISTs and has allowed creation of selective tyrosine kinase inhibitors which dramatically affected GIST management. Results of trials on neoadjuvant imatinib therapy are promising. Adjuvant imatinib therapy is recommended for 3 years and has proven to improve outcome in high-risk GISTs. New therapeutic agents are now available in case of imatinib resistance. Follow-up of patients with GISTs depends on the type of GIST