Approximately 10%–15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA . One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA .

Patients treated with platinum compounds are subject to hypersensitivity reactions. Our study has highlighted the reactions related to oxaliplatin (OHP) infusion. One hundred and twenty-four patients affected by advanced colorectal cancer were treated with different schedules containing OHP, at the Institute of Haematology and Medical Oncology ‘L. and A. Seragnoli’ of Bologna and at the Medical Oncology Division of Livorno Hospital. Seventeen patients (13%) showed hypersensitivity reactions after a few minutes from the start of the OHP infusion. Usually, these reactions were seen after 2–17 exposures to OHP (Mean±s.e.: 9.4±1.07). No patient experienced allergic reactions at his/her first OHP infusion. Eight patients developed a mild reaction consisting of flushing and swelling of the face and hands, itching, sweating and lachrymation. The remaining nine patients showed a moderate–severe reaction with dyspnoea, wheezing, laryngospasm, psycho-motor agitation, tachycardia, precordial pain, diffuse erythema, itching and sweating. Six patients out of 17 were re-exposed to the drug with premedication of steroids and all except one developed the hypersensitivity reaction again. The cumulative dose, the time of exposure to OHP and the clinical features are variable and unpredictable. The risk of developing hypersensitivity reactions in patients treated with a short infusion of OHP cannot be underestimated.

Purpose:To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/ fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology Experimental Design:Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFb was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis (PCA). Results:All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 PR, 1 SD, 1 PD. Median PFS was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most up-regulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed up-regulation in genes involved in antigen processing and presentation, NK mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected. Conclusions:All metastatic cases were fibrosarcomatous. Most patients responded to IM but PFS was shorter than reported in published series which included both DFSP and FS/DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of naïve and post-treatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.