Purpose: Gastrointestinal stromal tumors (GIST) are a distinctive group of mesenchymal neoplasms of the gastrointestinal tract. The oncogene KIT has a central role in the pathogenesis of GIST, with c-kit receptor tyrosine kinase (KIT) protein expression being the gold standard in its diagnosis. The identification of GIST patients has become crucial, because the tyrosine kinase inhibitor Imatinib is effective in the treatment of this malignancy. However, a small set of GISTs remain unrecognized, because KIT protein expression is not always evident. The aim of this study was the identification of new markers for the differential diagnosis of GIST.Experimental Design: By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C (PKC-), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies.Results: We found that all of the GISTs expressed PKC-, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KITpositive tumors. PKC-immunoreactivity was also observed in interstitial cells of Cajal.Conclusions: Our results show that PKC-is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.

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Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.

BACKGROUNDIn the current study, the authors set out to determine the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD) associated with a combination of gemcitabine and dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (ASTS), to obtain preliminary information on the activity of this combination, and to explore possible pharmacodynamic interactions between gemcitabine and DTIC.METHODSEvery 2 weeks, 22 patients with refractory ASTS received fixed–dose rate gemcitabine (10 mg/m2/min) at escalating doses, which ranged from 800 mg/m2 to 2160 mg/m2, plus 500 mg/m2 DTIC. Plasma concentrations of gemcitabine and 2′,2′‐difluorodeoxyuridine, along with gemcitabine triphosphate (dFdCTP) levels in peripheral blood mononuclear cells (PBMCs), were evaluated during the course of treatment.RESULTSGrade 3 elevation of transaminase and γ‐glutamyltransferase levels represented the DLT associated with the administration of 2160 mg/m2 gemcitabine plus 500 mg/m2 DTIC. This side effect was reversible, rather than cumulative, and did not exceed Grade 3 in its severity. The doses recommended for use in subsequent Phase II studies are 1800 mg/m2 gemcitabine (administered over the course of 3 hours) and 500 mg/m2 DTIC. Hematologic toxicity was moderate, and nonhematologic side effects that did not exceed Grade 2 in severity included the following: asthenia (75% of patients), fever (59%), nausea (52%), stomatitis (48%), anorexia (44%), emesis (40%), flulike syndrome (37%), and erythematous rash (26%). Alopecia was common. Intracellular dFdCTP levels, which were evaluated in 6 patients, reached a mean maximum value of 209 pmol per 106 cells (standard deviation, 59 pmol per 106 cells) at the conclusion of gemcitabine administration. DTIC had a limited effect on the elimination of dFdCTP from PBMCs. Objective responses were observed in 5 of the 19 patients who were evaluable for treatment efficacy.CONCLUSIONSThe combination of gemcitabine and DTIC possesses an acceptable toxicity profile and may warrant further investigation in patients with ASTS. Cancer 2004. © 2004 American Cancer Society.