Lubor Urbánek

Urinary Neopterin in Patients with Ovarian Cancer

Abstract Urinary neopterin, an indicator of systemic immune activation, is increased in most patients with epithelial ovarian carcinoma (EOC) and is an independent prognostic indicator. The data on prognostic significance of neopterin in EOC have been collected before the advent of paclitaxel that has changed the management and natural history of the disease. In the present study, we have evaluated the prognostic significance of urinary neopterin in 49 patients with primary and secondary ovarian neoplasms treated in the late 1990s and in 2000s. Urinary neopterin was measured by high-performance liquid chromatography. Compared to controls, urinary neopterin was significantly increased in patients with both primary ovarian cancer and ovarian metastases of other tumors (341 ± 343, and 328 ± 277 vs. 133 ± 40 μmol/mol creatinine; p <0.001 ). Serious toxicity of chemotherapy was observed in 8 out of 12 (67%) patients with urinary neopterin equal or above 338 μmol/mol creatinine (mean of all patients) compared to 2 of 19 ( 11%) of patients with urinary neopterin below 338 μmol/mol creatinine (Fisher exact test, p - 0.001). No significant changes were observed in urinary neopterin concentrations during the treatment with paclitaxel/platinum. A significant correlation was observed between urinary neopterin and percentage of xylose absorbed (rs = -0.58, p = 0.03), and positive correlations were observed between urinary neopterin and lactulose/ mannitol (rs = 0.63, p = 0.02), lactulose/xylose (rs = 0.79, p = 0.0007) and sucrose/xylose (rs = 0.60, p = 0.02) ratios. Survival was significantly longer in patients with urinary neopterin below 338 μιηοΐ/ιτιοί creatinine in the whole group of 49 patients with ovarian cancer, in 36 patients with primary ovarian cancer as well as in 13 patients in ovarian metastases of other primary tumors. A significant difference in survival was also observed when 37 pretreated patients or 24 pretreated EOC patients were evaluated (p = 0.05). In conclusion, neopterin remains a significant prognostic indicator in patients with recurrent ovarian cancer in the era of newer chemotherapeutic agents. Increased urinary neopterin was associated with chemotherapy toxicity.

Intestinal permeability and vitamin A absorption in patients with chemotherapy-induced diarrhea.

Objective:Gastrointestinal toxicity is one of the most common side effects of anticancer therapy. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity. The aim of the present study was to investigate intestinal permeability and vitamin A absorption in patients with chemotherapy-induced diarrhea (CID). Methods:We have assessed intestinal permeability, by measuring absorption of lactulose, mannitol, xylose, and vitamin A absorption, in 11 patients with CID, 10 healthy controls, and 24 untreated patients with gastrointestinal tumors. Urinary lactulose, mannitol and xylose were measured by capillary gas chromatography and serum retinol and retinyl esters were determined by high performance liquid chromatography. The results obtained in patients and controls were compared by Mann-Whitney U test. Results:Lactulose/mannitol and lactulose/xylose ratios were increased and retinol esters (retinyl palmitate and retinyl stearate) were decreased significantly in patients with CID. Conclusions:Measurements of intestinal permeability and vitamin A absorption may represent sensitive tools in the assessment of CID.

HPLC method for simultaneous determination of retinoids and tocopherols in human serum for monitoring of anticancer therapy

A simple and rapid HPLC method requiring small volumes (250 microL) of human serum after C18 SPE sample preparation was developed using monolithic technology for simultaneous determination of all-trans-retinoic acid, 13-cis-retinoic acid, retinol, gamma- and alpha-tocopherol. The monolithic column, Chromolith Performance RP-18e (100x4.6 mm), was operated at ambient temperature. The mobile phase consisted of a mixture of acetonitrile (ACN) and 1% ammonium acetate in water (AMC) at pH 7.0. The mobile phase started at 98:2 (v/v) ACN/AMC (column pre-treatment) at a flow rate of 2 mL/min, then changed to 95:5 (v/v) ACN/AMC for 4 min at a flow rate of 1.5 mL/min and a further 3 min at a flow rate of 3.2 mL/min. Detection and identification were performed using a photodiode array detector. Retinol, 13-cis- and all-trans-retinoic acid were monitored at 325 nm. Both alpha- and gamma-tocopherol were detected at 295 nm. The total analysis time was 7.2 min. Tocol (synthesized tocopherol, not occurring in humans) was used as internal standard. The method was linear in the range of 0.125-10.00 micromol/L for all-trans-retinoic acid, 0.125-5.00 micromol/L for 13-cis-retinoic acid, 0.25-10.00 micromol/L for retinol, 0.5-50.00 micromol/L for gamma-tocopherol, and 0.5-50.00 micromol/L for alpha-tocopherol. The present method may be useful for monitoring of retinoids and tocopherols in clinical studies.

Serial Urinary Neopterin Measurements Reflect the Disease Course in Patients with Epithelial Ovarian Carcinoma Treated with Paclitaxel/Platinum Chemotherapy

Abstract Increased concentrations of urinary neopterin, an indicator of systemic immune activation, have been reported in patients with cancer, including epithelial ovarian carcinoma (EOC). We have assessed urinary neopterin before the treatment and then daily during the therapy with paclitaxel/platinum combination in 5 EOC patients. A correlation was observed between the clinical course and serial urinary neopterin concentrations. We conclude that the determination of serial urinary neopterin concentrations may be useful for monitoring of EOC patients during chemotherapy.

Urinary Neopterin in Patients with upper Gastrointestinal, Biliary and Pancreatic Carcinomas

Abstract Increased urinary neopterin has been associated with advanced disease and poor prognosis in patients with colorectal carcinoma, but less is known about urinary neopterin in other gastrointestinal tumors. We have investigated urinary neopterin in 53 patients with carcinomas of the upper gastrointestinal tract, pancreas and biliary tract. Conipared to controls, urinary neopterin was increased in patients with gastric carcinoma, pancreatic Carcinoma, cholangiocarcinoma and gallbladder carcinoma. Urinary neopterin was a significant prognostic indicator of survival in univariate as well as multivariate analyses. No significant change in urinary neopterin concentrations was observed during the short follow-up, but increased urinary neopterin concentration at the end of followup was associated with poor prognosis. In conclusion, significantly increased urinary neopterin concentrations were observed in the present cohort of patients. Urinary neopterin is an independent prognostic indicator in patients with carcinomas of the upper gastrointestinal tract, biliary tree and pancreas.

Urinary neopterin in patients with liver tumors.

Aims and background Primary and secondary liver tumors are associated with poor prognosis. Neopterin is an indicator of systemic immune activation, and increased neopterin concentrations have been associated with poor prognosis in a wide range of malignant tumors. Methods Urinary neopterin was determined by high-performance liquid chromatography in 154 patients with primary and secondary liver tumors. The survival of different groups of patients was compared by log-rank test, and Cox regression was used for multivariate analysis. Results Urinary neopterin was significantly increased in patients compared to controls. A statistically significant correlation was observed between urinary neopterin and age of the patients, hemoglobin concentration, mean erythrocyte volume and peripheral blood leukocyte or platelet count. In univariate analysis, urinary neopterin below 214 μmol/mol creatinine, peripheral blood leukocytes below 8 x 109/L, hemoglobin equal to or above 125 g/L, no extrahepatic tumor, stage of liver involvement, and colorectal, breast or ovarian primary were significant prognostic factors for survival. In multivariate analysis, Bengtsson stage, presence of extrahepatic involvement, primary other than colorectal, breast or ovarian carcinoma, peripheral blood leukocyte count and urinary neopterin were independent prognostic factors. Increased urinary neopterin during and at the end of follow-up was also associated with poor prognosis. Conclusions Urinary neopterin is increased in patients with liver tumors. Neopterin is an independent prognostic indicator in patients with liver tumors along with Bengtsson stage, presence of extrahepatic disease, primary site and peripheral blood leukocyte count.

Intestinal permeability, vitamin A absorption and serum alpha-tocopherol during therapy with gefitinib.

Abstract Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity of anticancer therapy. We have assessed intestinal permeability (by measuring absorption of lactulose, mannitol, and xylose), vitamin A absorption and serum alpha-tocopherol in patients with non-small cell lung carcinoma or head and neck carcinomas treated with gefitinib. Lactulose, mannitol and xylose were determined by capillary gas chromatography, and retinol, alpha-tocopherol, retinyl stearate and retinyl palmitate were determined by high-performance liquid chromatography. Compared to healthy controls, patients had significantly increased lactulose/mannitol ratio and lower postprandial retinyl palmitate and retinyl stearate concentrations. Compared with pre-treatment values, xylose absorption was decreased and lactulose/mannitol and lactulose/xylose ratios were increased during the therapy. A significant decrease of serum alpha-tocopherol was evident throughout the course of therapy. In contrast, only minor alterations of vitamin A absorption were observed. In conclusion, an alteration in intestinal permeability reflected in increased lactulose/mannitol and lactulose/xylose ratios was observed during gefitinib therapy. Potential association between decreased serum alpha-tocopherol concentrations and the toxicity of gefitinib therapy should be further investigated.

Gastrointestinal Permeability - a Parameter of Possible Prognostic Importance in Metastatic Colorectal Carcinoma

Abstract Recently, we have observed in patients with ovarian carcinoma an association between intestinal permeability and prognosis and a correlation between urinary neopterin and parameters of intestinal permeability. In order to examine prognostic significance of intestinal permeability in a different group of patients, we have retrospectively analyzed pretreatment parameters of gastrointestinal permeability and urinary neopterin in 21 consecutive patients with metastatic colorectal carcinoma treated with the combination of cetuximab, irinotecan, leucovorin and 5-fluorouracil. Neopterin was determined by high-performance liquid chromatography, and gastrointestinal permeability was assessed by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose, mannitol and sucralose after oral challenge. Pretreatment sucrose/mannitol ratio equal or above 0.04 (median survival 10.6 vs. 18.4 months; p = 0.03), sucrose/xylose equal or above 0.02 (12.1 vs. 19 months; p = 0.04) and urinary neopterin equal or above 220 μmol/mol creatinine (10.6 vs. 18.4 months; p = 0.02) were indicative of poor survival. A significant correlation was observed between urinary neopterin and sucrose/xylose ratio (rs = 0.57, p = 0.007), while correlation between urinary neopterin and sucrose/mannitol ratio (rs = 0.38, p = 0.096) was of borderline significance. In conclusion, present data demonstrate that gastrointestinal permeability is associated with systemic immune activation and may be of prognostic significance in patients with metastatic colorectal carcinoma.

Effect of comorbidity on urinary neopterin in patients with breast carcinoma

Urinary neopterin is increased in less than 20% of patients with breast carcinoma. Moderately increased neopterin concentrations are also known to accompany comorbid conditions commonly observed in patients with breast carcinoma, for example, diabetes mellitus or complications of atherosclerosis. In the present study, we evaluated the effect of the presence of comorbid conditions on urinary neopterin. A trend for higher neopterin concentrations was observed in patients with most of the comorbid conditions, but significantly higher neopterin was observed only in patients aged 70 years or older and in a heterogeneous group of patients with comorbidity other than diabetes mellitus, thyroid disorder, hyperlipidaemia, cardiac disorder or other malignancy. Significantly higher neopterin levels were noted in patients with two or more comorbid conditions. In conclusion, present data demonstrate an association between systemic immune activation reflected in increased urinary neopterin concentrations and age or presence of comorbid diseases in patients with breast carcinoma. A cumulative effect was observed with the presence of two or more comorbid conditions resulting in significantly increased urinary neopterin. These observations should be taken into account when interpreting the changes of parameters of systemic immune and inflammatory response in patients with breast carcinoma.

Urinary Neopterin in Patients Treated with Gefitinib

Abstract Inhibitors of epidermal growth factor receptor (EGFR), including low molecular weight inhibitor erlotinib and gefitinib, have been demonstrated to be active antitumor agents in patients with non-small cell lung carcinoma and head and neck carcinomas. Increased concentrations of urinary neopterin, an indicator of systemic immune activation, have also been reported in patients with lung carcinoma and head and neck carcinomas. EGFR blockade has been reported to induce immune activation. We have measured, using high performance liquid chromatography, urinary neopterin in patients with non-small cell lung carcinoma and head and neck carcinomas treated with gefitinib. Intestinal permeability was also investigated at baseline by measuring, using capillary gas chromatography, urinary xylose, mannitol and lactulose after oral challenge. Compared to controls, urinary neopterin was significantly increased in patients with non-small cell lung carcinoma. No significant change in urinary neopterin was observed during the therapy with gefitinib. A significant correlation was observed between urinary neopterin and xylose absorption (rs = -0.58, p <0.05), lactulose/mannitol (rs = 0.75, p <0.01), and lactulose/ xylose (rs = 0.62, p <0.05) ratios. In conclusion, EGFR blockade had no effect on systemic immune activation, evaluated with urinary neopterin. A significant correlation has been observed between urinary neopterin and parameters of intestinal permeability and absorption.