Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients. METHODS: We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma. RESULTS: From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log-rank test, p = 0.001). CONCLUSIONS: This is the first time that a potential "surrogate marker" has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice.

Synthesis, Structure, and Antiproliferative Activity of Three Gallium(III) Azole Complexes.

As part of our interest into the bioinorganic chemistry of gallium, gallium(III) complexes of the azole ligands 2,1,3-benzothiadiazole (btd), 1,2,3-benzotriazole (btaH), and 1-methyl-4,5-diphenylimidazole (L) have been isolated. Reaction of btaH or btd with GaBr(3) or GaCl(3) resulted in the mononuclear complexes [GaBr(3)(btaH)(2)] (1) and [GaCl(3)(btd)(2)] (2), respectively, while treatment of GaCl(3) with L resulted in the anionic complex (LH)(2)[GaCl(4)] (3). All three complexes were characterized by single-crystal X-ray crystallography and IR spectroscopy, while their antiproliferative activities were investigated against a series of human and mouse cancer cell lines.

Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers.

BACKGROUND: Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution. METHODS: We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA. RESULTS: At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression. CONCLUSION: Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.

Expression of the HER family mRNA in breast cancer tissue and association with cell cycle inhibitors p21(waf1) and p27(kip1).

BACKGROUND: The HER family of the receptor tyrosine kinases epidermal growth factor receptor (EGFR), HER2, HER3 and HER4 are involved in the pathogenesis of many human malignancies. Although there is extensive literature on the expression of single HER-2 and EGFR receptors in breast cancer, little is known concerning the simultaneous expression at the mRNA level of these four receptors in human breast tissue and their influence in downstream signaling pathways that control cell cycle and proliferation. MATERIALS AND METHODS: The mRNA expression pattern of the four HER-receptors has been investigated and correlated with the expression of the cyclin-dependent kinase (CDK) inhibitors p21(Waf1) and p27(Kip1) in 67 breast cancer specimens. RESULTS: A positive correlation between HER-3 and HER-4 mRNA levels and a negative correlation between HER-2 and HER-3 was found. Compared to normal breast tissue, all four receptors were overexpressed in breast tumors and the strongest overexpression was found for HER-3 (p = 0.001). HER-4 expression was inversely related to histopathological grading (HPG), suggesting that elevated HER-4 mRNA expressions could be a biological marker of a more differentiated phenotype. The expression of p21(Waf1) protein was higher in HER-2-negative tumors, compared to HER-2-positive breast carcinomas. Compared to normal breast tissue, p21delta, the 19 kDa degraded form of p21 protein, was markedly expressed in breast cancer (p < 0.001). Conversely, p27(Kip1) was positively associated with HER-2 receptor and inversely associated with HER-3. CONCLUSION: The HER family members are overexpressed in breast cancer. Complex patterns of HER family expression were observed and the effect on cell cycle regulation was dependent on that pattern.

Effect of HbS in the determination of HbA2 with the Biorad Variant II analyzer.

OBJECTIVES: The effect of the presence of HbS in the determination of HbA2 using the Biorad Variant II analyzer. DESIGN AND METHODS: The effect of HbS presence in the samples was quantified using the HELENA SAS-MX alkaline gel electrophoresis kit as the reference method. RESULTS: The %HbA2 values from the Variant II analyzer and the HELENA SAS-MX alkaline gel electrophoresis kit show a good linear correlation in the absence of HbS. A strong positive bias in the %HbA2 values from the Variant II is apparent in the presence of HbS in the samples, when compared to the alkaline electrophoresis gel. CONCLUSION: The Variant II analyzer gives reliable results for %HbA2 determination when no HbS is detectable in the samples. When HbS is present, the gel electrophoresis method gives more accurate results.

Effect of HbS in the determination of HbA(2) with the TOSOH HLC-723G7 analyzer and the HELENA Beta-Thal Quik column kit.

OBJECTIVES: The analytical performance of the TOSOH HLC-723G7 hemoglobin HPLC analyzer and the effect of the presence of HbS in the determination of HbA(2) using HPLC and manual column methods. DESIGN AND METHODS: The performance characteristics of the TOSOH HLC-723G7 analyzer in the determination of HbA(2) were compared to those of the HELENA Beta-Thal Quik column. The effect of HbS presence in the samples was quantified using the HELENA SAS-MX alkaline gel electrophoresis kit as the reference method. RESULTS: Within-run and between-run CVs for HbA(2) were better for the TOSOH HPLC analyzer than for the HELENA manual column method. The presence of HbS in the samples produces a strong positive bias in the %HbA(2) values when using both the HPLC and manual column methods, compared to the alkaline electrophoresis gel. CONCLUSION: Both the TOSOH HPLC and the manual column are reliable methods for %HbA(2) determination when no HbS is detectable in the samples. When HbS is present, the gel electrophoresis method gives more accurate results.

Acute effects of soccer training on white blood cell count in elite female players.

PURPOSE: To investigate the acute changes in leukocyte number and cortisol after a single bout of soccer training. METHODS: Ten elite female national-team soccer players and 8 nonathletes participated in the study. The duration of the exercise was 2 h, and it was performed at an intensity of 75% of maximal heart rate (HRmax). Blood samples were taken before, immediately after, and 4 h after a soccer training session to determine total white blood cells; the subsets of neutrophils, lymphocytes, monocytes, eosinophils, and basophils; and cortisol. At the same time, blood samples were obtained from nonathletes who refrained from exercise. RESULTS: Data analysis indicated a significant increase in total white blood cells in the athletes postexercise (P < .001). The leukocytosis was still evident after 4 h of recovery (78% higher than the preexercise values), and there was a significant difference between athletes and nonathletes (P < .001). This leukocytosis was primarily caused by neutrophilia-there were no significant differences in lymphocytes after the end of exercise or between the 2 groups (P > 0.05). In addition, there was a statistically significant difference in cortisol concentration between athletes and nonathletes after the exercise (P < .001). CONCLUSION: These findings revealed that the single bout of soccer training at an intensity of 75% of HRmax induced leukocytosis without affecting the lymphocyte count in elite female athletes and probably the effectiveness of cellular components of adaptive immunity. Coaches should provide adequate time (>4 h) until the next exercise session.

Synergistic effects of protein tyrosine kinase inhibitor genistein with camptothecins against three cell lines in vitro.

Genistein, a natural isoflavone product has been shown to induce cellular death and increase the apoptotic cell death induced by several DNA-damaging stimuli. We have explored the combined effect of genistein and camptothecins against three cell lines, HeLa (cervical cancer), OAW-42 (ovarian cancer) and L929 (normal fibroblasts). Combined effect was estimated in 96-well plates using the SRB method and median-effect analysis. Addition of genistein synergistically increased the antiproliferative affect of camptothecins, inhibiting the camptothecin-induced G2/M arrest and increasing the apoptotic cell population. In HeLa cells, genistein inhibited CDK1 phosphorylation after irinotecan treatment. Thus, abrogation of the G2/M checkpoint control by genistein may be a useful maneuver to increase cytotoxicity of agents that damage DNA and inhibit cell-cycle progression in the G2/M boundary.

Serum CYFRA 21-1 in patients with invasive bladder cancer and its relevance as a tumor marker during chemotherapy.

PURPOSE: Previous studies have shown that serum levels of the degradation products of cytokeratins could be used as surrogate markers in the diagnosis and followup of patients with solid tumors, including tumors of the bladder. MATERIALS AND METHODS: The soluble cytokeratin 19 fragment CYFRA 21-1 was measured by solid phase radioimmunoassay in the serum of 142 patients with invasive transitional cell cancer of the bladder. Of the patients 56 had clinical stage I to III locally confined disease (T1-4aN0M0) and 86 had stage IV metastatic disease with lymph node and/or distant metastases. A control group consisted of 33 healthy volunteers. In a subgroup of 49 patients with metastatic disease receiving combined platinum based chemotherapy serum CYFRA 21-1 was determined prior to the initiation of therapy and after the documentation of response. RESULTS: Abnormal CYFRA 21-1 was observed in 7% of patients with locally invasive disease and in 66% of those with metastatic disease (p < 0.0001). There was no correlation of CYFRA 21-1 with tumor differentiation. Patients with abnormal CYFRA 21-1 showed statistically significant worse median overall survival. Moreover, in the subgroup of patients with metastatic disease receiving chemotherapy CYFRA 21-1 levels correlated with the response to treatment. CONCLUSIONS: Patients with transitional cell cancer of the bladder with evidence of distant metastases showed a significant increase in serum CYFRA 21-1. During chemotherapy CYFRA 21-1 appears to be a potentially sensitive and useful indicator for monitoring treatment response.