Showing papers by "Salomon M. Stemmer published in 2011"

Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib.

Abstract: Imatinib mesylate is the first of a novel group of drugs that specifically target protein tyrosine kinases, which are central to the pathogenesis of human cancer. It has been approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumor and has been found efficacious in other neoplastic diseases. Nilotinib and dasatinib, a second-generation of tyrosine kinase inhibitors (TKIs), were developed in response to findings of emerging imatinib resistance or intolerance to the drug. Cutaneous reactions are the most common nonhematologic side effect of these drugs, and their management is challenging especially in the absence of alternative anticancer agents. The present review focuses on the clinical characteristics and the hypothesized molecular pathogenesis of these first- and second-generation TKIs' cutaneous side effects, and approaches to their treatment. The wide range of adverse effects clarifies the difficulty in designing a truly antitumoral TKI.

CF102 an A3 adenosine receptor agonist mediates anti‐tumor and anti‐inflammatory effects in the liver

Abstract: The Gi protein-associated A(3) adenosine receptor (A(3) AR) is a member of the adenosine receptor family. Selective agonists at the A(3) AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 µg/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3β, NF-κB, and TNF-α and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro-apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K-NF-κB signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions.

In vivo bioimaging as a novel strategy to detect doxorubicin-induced damage to gonadal blood vessels.

Abstract: Introduction Chemotherapy may induce deleterious effects in normal tissues, leading to organ damage. Direct vascular injury is the least characterized side effect. Our aim was to establish a real-time, in vivo molecular imaging platform for evaluating the potential vascular toxicity of doxorubicin in mice. Methods Mice gonads served as reference organs. Mouse ovarian or testicular blood volume and femoral arterial blood flow were measured in real-time during and after doxorubicin (8 mg/kg intravenously) or paclitaxel (1.2 mg/kg) administration. Ovarian blood volume was imaged by ultrasound biomicroscopy (Vevo2100) with microbubbles as a contrast agent whereas testicular blood volume and blood flow as well as femoral arterial blood flow was imaged by pulse wave Doppler ultrasound. Visualization of ovarian and femoral microvasculature was obtained by fluorescence optical imaging system, equipped with a confocal fiber microscope (Cell-viZio). Results Using microbubbles as a contrast agent revealed a 33% (P<0.01) decrease in ovarian blood volume already 3 minutes after doxorubicin injection. Doppler ultrasound depicted the same phenomenon in testicular blood volume and blood flow. The femoral arterial blood flow was impaired in the same fashion. Cell-viZio imaging depicted a pattern of vessels' injury at around the same time after doxorubicin injection: the wall of the blood vessels became irregular and the fluorescence signal displayed in the small vessels was gradually diminished. Paclitaxel had no vascular effect. Conclusion We have established a platform of innovative high-resolution molecular imaging, suitable for in vivo imaging of vessels' characteristics, arterial blood flow and organs blood volume that enable prolonged real-time detection of chemotherapy-induced effects in the same individuals. The acute reduction in gonadal and femoral blood flow and the impairment of the blood vessels wall may represent an acute universal doxorubicin-related vascular toxicity, an initial event in organ injury.

Different schedules of granulocyte growth factor support for patients with breast cancer receiving adjuvant dose-dense chemotherapy: a prospective nonrandomized study.

Abstract: PURPOSE This prospective, nonrandomized study evaluates 4 schedules of granulocyte colony-stimulating factor (G-CSF) for patients with breast cancer receiving adjuvant dose-dense chemotherapy regarding febrile neutropenia, treatment delays, and costs. PATIENTS AND METHODS Two hundred and thirty-one patients were enrolled to receive adjuvant dose-dense chemotherapy with 4 G-CSF schedules: filgrastim (300 mcg) days 3 to 10 [n = 84 (36.4%) group A]; days 3 to 7 [n = 26 (11.3%) group B]; days 5, 7, 9, and 11 [n = 64 (27.7%) group C], or pegfilgrastim (6 mg) on day 2 [n=57 (24.6%) group D]. RESULTS Thirteen patients were hospitalized due to 14 episodes of febrile neutropenia; 3 in group A, 3 in group B, 1 in group C, and 6 in group D. No statistically significant difference was observed among the 4 groups. Fewer febrile neutropenic events were observed in group C than in group D (P=0.041). No statistically significant differences were observed in treatment delays or other hematological toxicities. Average overall G-CSF cost per patient in groups A and D was $8500 versus $4400 in groups B and C. CONCLUSIONS We found a trend in favor of the shorter G-CSF schedule. A larger, prospective randomized trial should be carried out to evaluate shorter versus standard filgrastim and pegfilgrastim schedules with regard to clinical outcomes, hematological and nonhematological toxicities, and impact in costs.

The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: a prospective, randomized, phase II trial.

Abstract: Objective: This study reports the efficacy and safety of zoledronic acid (ZOL) in preventing bone loss in postmenopausal patients receiving an aromatase inhibitor (AI) following tamoxifen. Methods: Postmenopausal patients with stage I–III hormone receptor-positive breast cancer who received tamoxifen for 2.5–3 years were randomized to receive letrozole (2.5 mg/day) with (n = 47) or without (n = 43) ZOL (4 mg i.v. every 6 months) for 2 years. The primary endpoint was percent change from baseline in lumbar spine (LS) bone mineral density (BMD) up to 60 months. Results: Ninety patients (86 evaluable) with a median age of 59 years (42.9–83.6), 50/86 of whom had previously been treated with chemotherapy, were followed for a median time of 41.4 months. While the control group showed a significant decrease in LS T-score (p = 0.0005), the ZOL group presented an increase over time (p = 0.0143). Change over time in LS T-score was significantly different between groups, favoring ZOL (p Conclusion: The addition of ZOL to letrozole was safe and efficacious in maintaining LS BMD in postmenopausal patients with hormone receptor-positive breast cancer and who were receiving letrozole following 2.5–3 years of tamoxifen.

The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: 36-month follow-up.

Abstract: e11111 Background: Adjuvant treatment with aromatase inhibitors (AIs) in postmenopausal women (PMW) with early breast cancer (EBC) can be associated with bone loss. Update of BIG-98 suggests that sequential TAM and Letrozole (LET) have similar efficacy to 5 years of LET. This study evaluates whether addition of zoledronic acid (ZOL) to LET, switched from TAM, can prevent bone loss. Methods: This is an open-label, randomized phase II study of PMW with hormone receptor positive EBC previously treated with TAM for 2.5 years, with bone mineral density (BMD) T-score ≥ -2.5. Patients were randomly assigned to receive 2.5mg/day LET +/- ZOL. Patients on treatment arm receive 5 intravenous administrations of 4 mg ZOL every 6 months. All patients are evaluated with blood chemistry and BMD test every 6 months in the first 3 years and yearly in the next 2 years. All patients receive vitamin D and calcium supplements. A comparison between groups and between time points was performed by one-way ANOVA with repeated meas...

OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.

Abstract: Background A number of phase III studies have shown significant progression-free survival (PFS) benefits with the combination of bevacizumab (Bev) and either first-line capecitabine (X) or taxane therapy in LR/MBC. The ongoing open-label, randomized, phase III CECOG-sponsored TURANDOT study (CECOG/BC.1.3.005) is investigating the efficacy and safety of first-line Bev plus paclitaxel (P) versus Bev plus X in this setting. Materials and methods: Eligible patients (pts) are aged ≥18 years with HER2−negative, chemonaive LR/MBC, an ECOG performance status of 0–2 and a life expectancy >12 weeks. Prior chemotherapy and concomitant hormonal therapy for LR/MBC are not permitted, but prior (neo)adjuvant chemotherapy is allowed if completed ≥6 months before randomization or ≥12 months if taxane based. Pts are randomized to receive Bev 10mg/kg days 1, 15 plus P 90mg/m2 days 1, 8, 15, q28d (Arm A) or Bev 15mg/kg day 1 plus X 1,000mg/m2 bid days 1–14, q21d (Arm B) until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to demonstrate non-inferiority in overall survival (OS) with Bev plus P versus Bev plus X (upper limit ≤1.33 for the two-sided confidence interval for hazard ratio [HR]). Secondary objectives are: comparison of overall response rate (RECIST criteria); PFS; time to response; duration of response; time to treatment failure; safety (CTCAE version 3); and quality of life (EORTC QLQ-30). The recruitment target is 560 pts. A sample size of 490 pts in the per-protocol population will be required to provide 80% power to reject the null hypothesis of inferiority at a one-sided significance level of 0.025, assuming a 24-month median OS with Bev plus P and an alternative hypothesis of HR=1. Data cut-off for adverse event reports was 12 Apr 2010. Interim and final efficacy analyses will be triggered after 175 and 389 events, respectively. Results: Recruitment to the study began in Sep 2008 and was completed in Aug 2010, with 561 pts randomized. Follow-up is ongoing. Conclusions: TURANDOT is the first study to examine the efficacy and safety of Bev plus P versus Bev plus X as first-line treatment for pts with LR/MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-02.