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Abstract 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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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 GaBr3 or GaCl3 resulted in the mononuclear complexes [GaBr3 (btaH) 2](1) and [GaCl1 (btd) 2](2), respectively, while treatment of GaCl3 with L resulted in the anionic complex (LH) 2 [GaCl4](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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It is known that the presence of hemoglobin S (HbS) affects the determination of hemoglobin A2 (HbA2) levels in clinical samples. We quantitated this effect using the Menarini HA-8160 analyzer and compared with other instruments (HELENA beta-thal quik column, TOSOH HLC-723G7 and BIORAD Variant II) using the HELENA SAS-MX alkaline gel electrophoresis kit as the reference method. The %HbA2 values from the HA-8160 analyzer and the alkaline gel electrophoresis show a good linear correlation in the absence of HbS. A strong positive bias in the %HbA2 values from the HA-8160 is apparent in the presence of HbS in the samples, when compared with the alkaline electrophoresis. The analytical imprecision and bias of the three HPLC instruments are comparable both in the presence and absence of HbS. The manual column method shows a lower bias in the absence of HbS but is more affected when HbS is present in the samples. [ABSTRACT FROM AUTHOR]

The cytotoxicity of three resin-based root canal sealers (AH26, AH-plus, Topseal) was evaluated in vitro. The experiments included two cell lines, L929 mouse skin fibroblasts and RPC-C2A rat pulp cells. The cytotoxicity was assessed by sulforodamine B (SRB) colorimetric assay and hemocytometer viable cell counting after 24- and 48-h exposure. AH26 had a severe cytotoxic effect whilst Topseal and AH-Plus showed a markedly lower toxic influence on the cells during the experimental period. [ABSTRACT FROM AUTHOR]

Cell cultures of L929 and BHK21/C13 cells were used to evaluate the toxicity of a newly introduced bleaching agent (Colgate Platinum) compared to hydrogen peroxide, an established bleaching agent. The cell reaction was determined by a quantitative technique at 24 h and 72 h. Both bleaching materials had a dose-dependent effect on cell viability. Concentrations of hydrogen peroxide causing a 50% decrease in cell number (50% inhibition dose-ID[Sub50] were calculated as 0.00034% after 24 h and 0.0001% after 72 in L929 cells. The ID[Sub50] of hydrogen peroxide was found to be 0.00016% after 24 h and 0.00007% after 72 h in BHK21/C13 cells. The ID[Sub50] of Colgate Platinum was 0.00074% after 24 h and 0.00045% after 72 h in L929 cells and 0.00055% after 24 h and and 0.00024% after 72 h in BHK21/C13 cells. The results showed that, in vitro, both bleaching agents were cytotoxic to fibroblasts and the new bleaching agent was less toxic than hydrogen peroxide. [ABSTRACT FROM AUTHOR]

The cytotoxicity of three calcium hydroxide-containing root canal sealers (Sealapex, CRCS and Apexit) was tested by using L929 and BHK 21/C13 cells. After setting for 24h, the sealers were covered with cell suspension. Cytotoxicity was determined by a quantitative technique at 24h, 48h and 72h. All the sealers were found to be cytotoxic. Sealapex showed the highest cytotoxicity, causing a significant decrease in cell density. CRCS was less toxic than Sealapex and more toxic than Apexit. Apexit proved to be the least toxic material. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: : The analytical performance of the TOSOH HLC-723G7 hemoglobin HPLC analyzer and the effect of the presence of HbS in the determination of HbA2 using HPLC and manual column methods. Design and methods: : The performance characteristics of the TOSOH HLC-723G7 analyzer in the determination of HbA2 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 HbA2 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 %HbA2 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 %HbA2 determination when no HbS is detectable in the samples. When HbS is present, the gel electrophoresis method gives more accurate results. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

In this review we will provide a synopsis of the biological markers used in the care of breast cancer patients with emphasis on clinical application. The advent of molecular technology has incorporated new biomarkers along with the older immunohistochemical and serum ones. Serum tumor markers are proteins shed from breast cancer cells. Their levels have long been used as a measure of tumor burden and disease progression or recurrence. However, limitations exist that should be known to those involved in breast cancer management. Historically, immunohistochemical markers have been used to guide treatment decisions. These markers reveal characteristics of the cancer cells and have been used both as prognostic and predictive factors. Molecular markers give information on the expression of certain genes in tumor tissues related to proliferation, invasion, and metastasis and researchers try to correlate them with the use of mathematical modeling with clinical outcomes, hence those markers exhibit prognostic and predictive significance. All these tools can guide personalized treatment by estimating patient prognosis and risk of relapse and tailor accordingly therapeutic approaches.

New targeted agents have become the mainstream of treatment in metastatic renal cell carcinoma (mRCC) and substituted the previous cytokine-based therapies. Vascular endothelial growth factor (VEGF) pathway is the principle target for drugs like sunitinib, sorafenib and bevacizumab. As VEGF is regulating dendritic cell (DC) function, inhibition of VEGF results in activation of DCs and a shift towards cellular (type 1) immunity, which is believed to favor cancer rejection. Recent studies have established the immune-stimulating effects of sunitinib that may as well be a marker for effectiveness. On the other hand, sorafenib not only inhibits VEGF receptor (VEGFR) but is also a B-Raf inhibitor (a component of the ras - MAPK pathway) and this leads to downregulation of immune responses. Sorafenib has not yet shown benefit in first-line treatment of mRCC when compared to interferon (IFN)-alpha and sorafenib-mediated immunosuppression may partially account for that. Mammalian target of rapamycin (mTOR), the target of temsirolimus, is an element of the DC activation pathway. There are no data for in vivo effects of temsirolimus in the immune system. The addition of IFN-alpha to temsirolimus resulted in inferior outcomes than temsirolimus alone. IFN-alpha has however still a place in mRCC treatment, as bevacizumab has been approved in combination with IFN-alpha. New clinical trials address the effects of the combination of cytokines with targeted agents. The immune-modulating effects of targeted treatments may be important in pharmacodynamic outcomes, effectiveness or the development of adverse events.