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tient was given a multi kinase inhibitor that did not target BRAF,or a MEK inhibitor.Nevertheless,it really should be noted that both of these agents were experimental,and as a result their therapeutic value has not however been totally validated.Treaent with dabrafenib,which targets BRAF directly,resulted in tumor regression Combretastatin A-4 soon after 6 weeks,and continued decreasing in size until week 24,followed by a plateau and after that progression at 8 months.Entire exome sequencing did not reveal secondary BRAF or RAS mutations but did demonstrate a somatic gain of function PIK3CA mutation,that has previously been reported in other human cancers.We speculate that the PIK3CA mutation may be the cause of the acquired BRAF inhibitor resistance in lesion 1.This obtaining is notable,due to the fact to the greatest of our information this really is only the second PIK3CA mutation ever reported in GIST.
Furthermore,despite the fact that PIK3CA mutations have not previously been reported as a cause of acquired resistance to BRAF inhibitors in melanoma or other malignancies,low PTEN Combretastatin A-4 expression as well as other PTEN alterations are associated with reduce response rate and shorter progression cost-free survival in BRAF mutant melanoma individuals treated with BRAF inhibitors.We further speculate that dysregulation of cell cycle control by the homozygous CDKN2A mutation in lesion 2 may possibly also be a molecular basis for resistance of this lesion.No apparent explanation for resistance to BRAF inhibitor treaent was seen in lesion 3.We further tested RNA from all three lesions and were unable to detect aberrant BRAF splicing as a basis for drug resistance.
The differences in sequencing among the three lesions highlight the prevalence of intratumor OAC1 heterogeneity and also the possible relevance to treaent outcomes.In conclusion,we present the very first patient with GIST and also a V600E BRAF mutation whose tumor showed regression even though receiving treaent with a BRAF inhibitor.To our information,the efficacy of BRAF inhibitors in BRAF mutant GIST has not been reported,but our case suggests that extra studies and perhaps a international clinical trial are warranted.Entire exome capture was performed with a SeqCap EZ Human Exome v2.0 kit,and sequencing was carried out on a HiSeq 2000 instrument.Sequence alignment and variant calling were performed with DNAnexus software program.Tumor distinct variants were identified based on a minimum variant allele ratio of 20%,a minimum read depth of 20,and absence of the variant in a matched normal specimen.
Nucleotide variants were translated,and non synonymous variants were identified working with Extispicy SIFT,PolyPhen2,and Mutation Assessor.Variants of interest were confirmed by Sanger sequence analysis.Gastrointestinal stromal tumor OAC1 is often a malignancy of mesenchymal origin that arises within the gastrointestinal tract and is resistant to conventional cytotoxic chemotherapy agents.KIT and platelet derived growth aspect receptor mutations are present in 80% and 8% of GISTs,respectively.Approximately 13% of KIT and PDGFRA wild type GISTs contain BRAF mutations.Though receptor tyrosine kinase inhibitors,such as imatinib or sunitinib,are therapeutically active antagonists of KIT and PDGFRA in KIT or PDGFRA mutated GIST,efficient treaents for individuals with advanced BRAF mutant GIST have not been reported.
Clinical trials of Combretastatin A-4 tyrosine kinase inhibitors that are highly selective for V600 BRAF mutations have demonstrated high response rates in BRAF mutant melanoma,also as improvement in general survival and OAC1 progression cost-free survival.Lately,we've shown that the BRAF inhibitor dabrafenib is also active in many non melanoma BRAF mutated cancers.Herein,we report antitumor activity within the initial patient with BRAF mutated GIST who was treated with a BRAF inhibitor.Entire exome sequencing of tumor obtained at time of progressive disease did not reveal secondary BRAF or RAS mutations,but did demonstrate a somatic gain of function PIK3CA mutation also as a CDKN2A aberration,which may have been responsible for dabrafenib resistance.
A 60 year old man initially presented in September 2007 with abdominal pain and also a palpable mass.Computed tomography revealed Combretastatin A-4 a 10 cm heterogeneous mass,and also a subsequent biopsy demonstrated GIST,spindled cell histology,optimistic for CD34 and CD117 by immunohistochemistry with 6 mitoses per 10 high powered fields.The patient underwent surgical resection revealing a 15 cm mass.DNA was extracted from formalin fixed paraffin embedded tumor tissue and subjected to polymerase chain reaction amplifications of KIT exons 9,11,13,and 17 also as PDGFRA exons 12 and 18.Sanger sequencing did not determine mutations in either the KIT or PDGFRA genes.The patient OAC1 presented with a new 14 cm mass at the dome of the bladder soon after 10 months of adjuvant imatinib therapy.The imatinib dose was elevated to 800 mg daily,followed by surgical resection of the mass.The patient received adjuvant sunitinib,a a number of tyrosine kinase inhibitor,at a dose of 50 mg on a schedule of as soon as daily for four weeks,then off for two weeks.Nineteen mont