[Show abstract][Hide abstract] ABSTRACT: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm.
Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months.
From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects.
The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.
[Show abstract][Hide abstract] ABSTRACT: This study assesses the efficacy, toxicity and pharmacokinetic profile of trabectedin with or without prophylactic dexamethasone co-treatment in patients with recurrent advanced soft tissue sarcoma (STS).
Patients were randomized to receive trabectedin as a 3-h infusion every 3 weeks with dexamethasone or placebo in the first cycle, with the alternate in the second cycle and with the patient's choice subsequently. Due to toxicity, the randomized design was modified to open-label to make dexamethasone mandatory and the initial dose (1,650 μg/m(2)) was reduced to 1,500 μg/m(2) and then to 1,300 μg/m(2).
Forty-one patients were enrolled and 35 were evaluable for efficacy. One partial response and 18 disease stabilizations were found. The median PFS and OS were 2.1 and 10.2 months, respectively, with the 3- and 6-month PFS rates indicating activity in pretreated STS. Twenty-three and 27 patients developed transient asymptomatic grade 3/4 AST and ALT elevation, respectively, and 21 patients had grade 3/4 neutropenia. Dose reduction from 1,650 μg/m(2) to 1,300 μg/m(2) decreased the incidence of grade 3/4 thrombocytopenia (26% vs. 0%), neutropenia (51% vs. 25%) and AST increase (76% vs. 25% of patients). Four patients died due to drug-related toxicities (3 with placebo). The total body clearance of trabectedin was 28% higher and half-life was 21% lower with dexamethasone compared to placebo, with no differences in volume of distribution.
Trabectedin has confirmed activity in patients with pretreated STS. This study shows that co-treatment with dexamethasone improves the safety of trabectedin by reducing drug-induced hepatotoxicity and myelosuppression.
Investigational New Drugs 10/2010; 30(2):729-40. DOI:10.1007/s10637-010-9561-9 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma.
Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m(2) per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m(2) delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B).
Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14).
Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.
[Show abstract][Hide abstract] ABSTRACT: Studies with the gemcitabine/vinorelbine (GV) or the gemcitabine/docetaxel (GD) combinations have shown similar efficacy and less toxicity compared to platinum-based chemotherapies, in patients with advanced non-small-cell lung cancer (NSCLC). The present trial was designed to test the efficacy and safety of both, GV and GD, combinations. Chemotherapy-naïve patients (n=39)<or=75 years of age, KPS>or=60% and adequate hematological, renal and hepatic function were randomly assigned to receive G 1,000 mg/m2+either V 25 mg/m2 or D 35 mg/m2 (all of which were administered i.v.) on days 1 and 8 every 21 days. Baseline characteristics were comparable in GV (n=20) and GD (n=19) groups. Results indicated objective response of 7 (35%) vs 6 (31%) patients and median time-to-treatment failure of 120 versus 90 days in the GV and GD arms, respectively. The most common non-hematological toxicities were (GV vs GD): grade 2-4 pulmonary toxicity in 1 (5%) vs 7 (37%); grade 2-3 diarrhea 0 versus 4 (21%) and edema 1 (5%) vs 3 (16%); grade 3-4 hematological toxicities occurred in 3 (15%) vs 1 (5%) patients. Our results indicate that the combination of gemcitabine/docetaxel does not have a favorable safety profile with this schedule of administration, particularly in terms of pulmonary toxicity.
Investigational New Drugs 02/2008; 26(1):67-74. DOI:10.1007/s10637-007-9073-4 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Forty-four of 50 adult patients with advanced soft-tissue sarcoma who had received previous chemotherapy were evaluable for response after treatment with DTIC. The therapeutic schedule consisted of DTIC 1.2 g/m2 infused over 20 minutes, and repeated every 3 weeks. There were 1 complete and 7 partial remissions (objective activity 18%, 95% C.I. 7%-29%), with a median duration of 8 weeks (range 5–19), with the complete remission lasting 1 yr. Hematologic toxicity was dose-limiting; W.H.O. 3 values were observed for WBC in 36%, and for platelets in 26% of patients. The non-hematologic toxicity included nausea and vomiting (90%), a flu-like syndrome (49%), diarrhea (35%), pain in the infused vein (28%) and hypotensive episodes (4%). Intermittent high-dose DTIC is active in advanced soft-tissue sarcoma and should be considered for inclusion in combination regimens.
[Show abstract][Hide abstract] ABSTRACT: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen.
Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions.
Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine.
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.
Cancer Chemotherapy and Pharmacology 02/2007; 59(2):251-9. DOI:10.1007/s00280-006-0263-0 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A reverse-phase HPLC method based on ion-pair formation with UV detection was set up for the simultaneous determination of gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) in human cells. The separation was achieved on a Tracer Excel ODSA column (100 mm x 4.6mm i.d., 3 microm particle size) at room temperature. Nine nucleotides were separated by isocratic elution in 26 min. Accuracy, linearity, sensitivity and precision studies for dFdCDP, dFdCTP, adenosine diphosphate (ADP) and triphosphate (ATP) validated this method. This assay was used to provide data from gemcitabine treated patients and in vitro grown human cancer cells.
Journal of Chromatography B 09/2006; 840(1):44-9. DOI:10.1016/j.jchromb.2006.04.036 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Materials and methods Results Discussion References Acknowledgements Figures and TablesThe aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60 mg m-2 by i.v. bolus on day 1 followed by gemcitabine at 800 mg m-2 over 80 min on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2',2'-difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8 h after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3–4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9–35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration.Keywords: doxorubicin, gemcitabine, soft tissue sarcoma, gemcitabine triphosphate
British Journal of Cancer 05/2006; 94(12):1797-1802. DOI:10.1038/sj.bjc.6603187 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to assess whether adding cisplatin to gemcitabine/vinorelbine combination improves the clinical outcome in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-naïve patients with advanced NSCLC; age < or = 75 years: Karnofsky performance status > or = 60%, and with adequate hematological, renal and hepatic function, were randomized into 2 treatment groups to receive Gemcitabine 1250 mg/m2 + vinorelbine 30 mg/m2 (GV group), or cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 (CGV group). All drugs were administered on days 1 and 8 every three weeks: From September 1999 to March 2003, 114 patients were enrolled. No statistically significant difference was observed in GV vs CGV group in objective response (37 versus 47%, respectively; P = 0.5), median time to progression (5 versus 5.8 months; P = 0.6), overall survival (9 versus 10 months; P = 0.9) and 1-year survival (26 versus 28%; P = 0.9). Conversely, toxicities were significantly higher for CGV, including grade 3-4 neutropenia (24 versus 45%); neutropenic fever (4 versus 14%, including one toxic death); grade 3-4 thrombocytopenia (2 versus 14%); and grade 3-4 emesis (2 versus 14%). Our results suggest that the combination of gemcitabine and vinorelbine is less toxic than three-drug combination with cisplatin while showing similar efficacy.
Investigational New Drugs 05/2006; 24(3):241-8. DOI:10.1007/s10637-005-2478-z · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. To explore the tolerance and the activity of high-dose ifosfamide (IFOS) combined with doxorubicin (DXR) at 50 mg/m2 every 4 weeks in patients with soft tissue sarcomas. Methods. DXR was given IV bolus and IFOS by continuous infusion at 2 g/m2/day. Initial IFOS dose (12
g/m2) was adjusted to 10, 13, or 14 g/m2 according to toxicity. Results. Seventy patients received 277 cycles (median 3 cycles, range 1–10), 34% with IFOS dose increased, 30% decreased, and 48% delivered at 12 g/m2. Toxicity grade 4 occurred on granulocytes (67% of patients) or platelets (19%), 54% had febrile neutropenia, 31% grade 3/4 asthenia, and 26% abandoned the study due to toxicity. Three toxic deaths occurred. In 57 non-GIST patients objective activity was 45.6% (95% CI, 32 to 58%). Conclusion. At least 4 cycles were tolerated by 71% of patients, most receiving DXR 50 mg/m2 plus IFOS 10–12 g/m2, with substantial toxicity.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to evaluate the activity and toxicity of temozolomide given as an extended schedule in patients with advanced sarcoma.
Forty-nine patients with pretreated soft tissue sarcoma (the STS arm) and 18 patients with previously untreated gastrointestinal stromal tumor (the GIST arm) were enrolled onto a 2-arm, multicenter, Phase II study between November 1999 and July 2001. Temozolomide was administered on a 6-week, continuous, oral schedule at a dose of 75 mg/m2 per day in 41 patients and, after an amendment, at a dose of 100 mg/m2 per day in 22 patients.
Among 45 eligible patients in the STS arm, there were 7 partial responses, for an overall response rate of 15.5% (95% confidence interval [95% CI], 5-26%). Responses were seen in 5 of 11 patients who had gynecologic leiomyosarcoma. The median response duration was 12.5 months (range, 3.9-58.0 mos). In 4 patients, response lasted > 1 year, and 2 of those patients remained progression free for > 3 years. The median time to progression was 2.2 months (95% CI, 1.8-2.5 mos), and the median overall survival was 8.1 months (95% CI, 5.6-10.6 mos). Progression-free survival rates at 3 months and 6 months were 39.5% and 26%, respectively. In the GIST arm, no responses were noted. Grade 3-4 granulocytopenia, thrombocytopenia, and anemia were observed in 6 patients, 5 patients, and 7 patients, respectively. The most common nonhematologic toxicities were emesis and fatigue.
Temozolomide at the extended schedule was tolerated well and had activity in patients with pretreated soft tissue sarcomas, and especially among patients with gynecologic leiomyosarcoma.
Cancer 10/2005; 104(8):1706-12. DOI:10.1002/cncr.21384 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the prognostic value of mutations in c-KIT and PDGFR-alpha genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST.
For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT-positive immunostaining; and no other primary tumors.
The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-alpha. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients.
Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
[Show abstract][Hide abstract] ABSTRACT: Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR. Patients and methods: Patients with measurable and progressive STS received PLD at 35 mg/m2 every 3 weeks. Quality of life before and during treatment was assessed with EORTC QLQ-C30. Results: Twenty-eight patients, 22 DXR-pretreated, were given 140 cycles (median 3, range 1-18). Activity in 27 patients (5 GIST): one complete and one partial remission (both non-GIST and without prior DXR), 12 stabilizations and 13 progressions (response rate 7.4%, 95% CI: 0-17%). Grade 3 toxicity: palmar-plantar erythrodysesthesia (19% of patients), stomatitis (4%) or cutaneous (4%). Neutropenia grade ≥3 was detected in 16% of patients. Median relative dose intensity was 95%. Progression-free rate at 3 and 6 months was, respectively, 48 and 22%, median progression-free survival 5.8 months and median overall survival 8.7 months. QLQ-C30 at baseline and at weeks 6-11 in 23 and 13 patients, respectively, showed good reliability and validity. Quality of life did not seem to worsen during therapy. Conclusions: PLD did not induce objective remissions in 22 STS patients pretreated with DXR, but progression-free rate figures support the use of this agent in patients who have not progressed under a DXR-containing regimen. The toxicity observed was comparable to that of other PLD schedules.
[Show abstract][Hide abstract] ABSTRACT: In man, neurotoxicity associated to ifosfamide treatment can be reversed by intravenous thiamine administration. Trying to explain this clinical finding, we decided to study possible changes in thiamine availability and activation in patients exposed to ifosfamide. Free thiamine and its phosphate esters levels were measured in plasma, erythrocytes and urine by an ion-pair HPLC method with pre-column derivatization, which allowed separation of the fluorescent compounds in less than 10 min. The method was validated by linearity, sensitivity and reproducibility studies, whose values met the demands for bioanalytical assays. This method was applied to assess thiamine status in cancer patients exposed to ifosfamide therapy for advanced disease.
Journal of Pharmaceutical and Biomedical Analysis 05/2005; 37(5):1025-9. DOI:10.1016/j.jpba.2004.08.038 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A reverse phase HPLC method based on ion-pair formation was set up for the simultaneous determination of gemcitabine and its metabolite 2′,2′-difluoro-2′-deoxyuridine (dFdU) in plasma samples obtained from cancer patients. The separation was performed on a μBondapack C18 (300 mm × 3.9 mm i.d., 10 μm particle size) column at room temperature. The mobile phase, 5 mM pentane-1-sulfonic acid pH 3.1/methanol (96:4), was pumped at a flow rate of 1.5 mL min−1. Gemcitabine and dFdU eluted in less than 16 min. Linearity, sensitivity, and reproducibility studies, which actual values met the demands for bioanalytical assays, validated the method. This assay provided pharmacokinetic data from patients treated with intravenous gemcitabine.
[Show abstract][Hide abstract] ABSTRACT: In 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.
Every 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.
Grade 3 elevation of transaminase and gamma-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 10(6) cells (standard deviation, 59 pmol per 10(6) 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.
The combination of gemcitabine and DTIC possesses an acceptable toxicity profile and may warrant further investigation in patients with ASTS.
Cancer 12/2004; 101(10):2261-9. DOI:10.1002/cncr.20612 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the impact of different factors on response rate (RR), time to tumor progression (TTP), and overall survival time (OS) in patients with locally advanced or metastatic soft tissue sarcoma (ASTS), included in three protocols with high-dose ifosfamide (HDIF).
One hundred fifty six ASTS patients included in three consecutive phase II trials with HDIF (>10 g/m(2)), alone or in combination with doxorubicin (DX), were analyzed. Cofactors were institution, trial, gender, age, performance status, histologic type, grade of malignancy, prior radiotherapy, presence of locoregional disease, metastatic site, salvage surgery, number of organs involved, and disease-free interval.
By multivariate analysis performance status >0 and lack of salvage surgery correlated with a poorer survival. A good-risk and a poor-risk group were identified, with median survival time (OS) of 29, 5, and 10 months, respectively (P = 0.00001). The 1-, 2-, and 3-year OS for 83 good-risk patients (either with PS = 0 or receiving salvage surgery) was 83, 44, and 29%, respectively, those figures being 37, 7, and 3% for 73 poor-risk patients.
The design of randomized trials in ASTS including HDIF should consider those prognostic factors as stratification variables.
[Show abstract][Hide abstract] ABSTRACT: 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.
By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C theta (PKC-theta), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-theta expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-theta was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies.
We found that all of the GISTs expressed PKC-theta, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KIT-positive tumors. PKC-theta immunoreactivity was also observed in interstitial cells of Cajal.
Our results show that PKC-theta is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.
Clinical Cancer Research 07/2004; 10(12 Pt 1):4089-95. DOI:10.1158/1078-0432.CCR-04-0630 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Combinations of high-dose ifosfamide (IF; 10-12 g/m2) plus doxorubicin (DX; 50-90 mg/m2) have been administered to patients with advanced soft tissue sarcoma (ASTS) in an attempt to improve therapeutic efficacy. Although these combination regimens appear to yield higher response rates than do standard-dose regimens, they also are associated with significant hematologic toxicity, despite the administration of hematopoietic growth factor support. As a potentially less toxic alternative, the authors designed a sequential, dose-dense schedule of DX and IF and explored its feasibility and toxicity, as well as patient compliance with the schedule, in a Phase II trial.
Chemotherapy-naive patients with unresectable locally advanced or metastatic ASTS were to receive DX at 30 mg/m2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by IF at 12.5 g/m2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles. Granulocyte-colony-stimulating factor was administered subcutaneously for 7 days beginning 24 hours after the completion of each DX or IF cycle. Additional IF cycles were allowed if an objective response was achieved.
Sixty patients were enrolled in the trial. Three were ineligible, 9 had locally advanced disease, and 48 had metastatic disease. At the completion of therapy, the mean dose intensities for DX and IF were 40 mg/m2 per week and 3.87 g/m2 per week, respectively. Sixty-six percent of patients completed the regimen projected by the protocol. Grade 3 or 4 granulocytopenia, febrile neutropenia, and stomatitis occurred in 46%, 24%, and 27% of patients, respectively. Twenty of 53 assessable patients (38%; 95% confidence interval [CI], 25-51%) achieved objective responses, with a median time to progression of 24 weeks (95% CI, 18-30 weeks).
Sequential administration of dose-dense DX and high-dose IF is feasible and exhibits an acceptable hematologic toxicity profile and a level of activity that is within the range described for schedules that combine high-dose IF with an anthracycline.
Cancer 05/2004; 100(7):1498-506. DOI:10.1002/cncr.20115 · 4.89 Impact Factor