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Kunstlinger H.,University of Cologne | Huss S.,University of Cologne | Huss S.,University of Munster | Merkelbach-Bruse S.,University of Cologne | And 10 more authors.
American Journal of Surgical Pathology | Year: 2013

KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.Copyright © 2013 by Lippincott Williams &Wilkins.

Joensuu H.,University of Helsinki | Trent J.C.,University of Texas M. D. Anderson Cancer Center | Reichardt P.,Sarcoma Center Berlin Brandenburg
Cancer Treatment Reviews | Year: 2011

Patients diagnosed with advanced gastrointestinal stromal tumor (GIST) are currently treated with oral tyrosine kinase inhibitors (TKIs). Imatinib mesylate is the standard first-line treatment, and sunitinib malate is administered second-line for patients who are intolerant or progress on imatinib. Imatinib has recently been approved for adjuvant treatment of GIST patients who have a significant risk for relapse. In both the metastatic and adjuvant settings, patients may be on these TKIs for many years. Low plasma imatinib levels have been reported to be associated with a short median time to progression of advanced GIST, stressing the importance of maintaining optimal drug levels. We summarize management of the most frequent and clinically significant adverse effects of imatinib and sunitinib in the treatment of GIST in the context of current guidelines, published literature, and the experience of three large GIST referral centers. The adverse events reviewed include nausea and vomiting, diarrhea, skin rash, musculoskeletal complaints, fatigue, hemorrhage, edema, hand-foot skin reaction, skin and hair discoloration, mucositis, hypertension, cardiac toxicity, hypothyroidism, liver transaminase changes, and hematological toxicity of imatinib and sunitinib. Potential drug-drug interactions with each respective agent are also discussed. With prudent use of supportive care measures, many side effects can be managed without dose reduction or interruption of treatment. On the other hand, individualized tailoring of the dose is often required to manage severe toxicity, such as painful hand-foot skin reactions, fatigue, hepatotoxicity, or cardiac toxicity. Management of many TKI-related adverse effects require further evaluation in prospective clinical trials. © 2010 Elsevier Ltd.

Kasper B.,University of Mannheim | Reichardt P.,Sarcoma Center Berlin Brandenburg | Pink D.,HELIOS Klinikum Bad Saarow | Sommer M.,University of Mannheim | And 3 more authors.
Marine Drugs | Year: 2015

Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2 . Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies. © 2015 by the authors licensee MDPI Basel Switzerland.

Le Cesne A.,Institute Gustave Roussy | Blay J.-Y.,Center Leon Berard | Reichardt P.,Sarcoma Center Berlin Brandenburg | Joensuu H.,University of Helsinki
Oncologist | Year: 2013

Background. The oral tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), most of which harbor oncogenic mutation in genes thatencodethe receptor tyrosine kinases KIT orPDGFA. Imatinib is the standard of care for patients with advanced GIST and for patients with primary GIST at significant risk of recurrence after surgery. Design. This review discusses data supporting continuous kinase suppression with imatinib and key issues, including response to imatinib reintroduction, effect of treatment interruption on secondary resistance to imatinib, and prognostic factors associated with sustained response to imatinib. Results. Long-term follow-up results of the B2222 study and updated results of the BFR14 trial demonstrate that continuous imatinib treatment in patients with advanced GIST is associated with reduced risk of progression. For patients progressing on or intolerant of imatinib, continuing therapy with TKIs sunitinib followed by regorafenib is recommended. In the adjuvant setting, final results of the trial by the Scandinavian Sarcoma Group and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie demonstrate that 3 years of adjuvant imatinib,comparedwith 1 year, significantly reduces the risk of recurrence and improves overall survival of patients with KIT-positive GIST at high risk of recurrence. Conclusions. Maintenance of therapy with TKIs is the key to successful treatment of GIST. Results from recent studies provide a strong rationale for continuous imatinib treatment for 3 years following surgical resection and long-term continuous administration in advanced or metastatic GIST. © AlphaMed Press 2013.

Bauer S.,University of Duisburg - Essen | Hilger R.A.,University of Duisburg - Essen | Muhlenberg T.,University of Duisburg - Essen | Grabellus F.,University of Duisburg - Essen | And 11 more authors.
British Journal of Cancer | Year: 2014

Background:Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.Methods:Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.Results:Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).Conclusion:Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST. © 2014 Cancer Research UK.

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