Analyses of biomarkers of exposure to nephrotoxic mycotoxins in a cohort of patients with renal tumours.

The Czech Republic occupies the first place in the world in the frequency of renal and other urinary tract tumours, but their aetiology is unknown. To explore whether carcinogenic and nephrotoxic mycotoxins may contribute to kidney diseases in the Czech population, biomarkers of ochratoxin A (OTA) and citrinin (CIT) exposure were determined in biological specimens from a cohort of 50 patients with malignant renal tumours. Biomarker analyses in blood and urine samples used validated targeted methods for measuring OTA and CIT plus dihydrocitrinone (DH-CIT) after enrichment of analytes by specific immunoaffinity clean-up. OTA and CIT plus its metabolite DH-CIT were frequently detected in patient urine samples (OTA 62%; CIT 91%; DH-CIT 100%). The concentration ranges in urine were 1-27.8 ng/L for OTA, 2-87 ng/L for CIT and 2-160 ng/L for DH-CIT. The analyses of blood samples revealed also a frequent co-occurrence of OTA and CIT, in the ranges of 40-870 ng/L serum for OTA and 21-182 ng/L plasma for CIT. This first analysis of biomarkers in blood and urine samples of Czech patients revealed no major differences in comparison with published data for the general healthy Czech and European populations. Nonetheless, a frequent co-occurrence of CIT and OTA biomarkers in patient samples may be of interest with regard to potential interactions with other risk factors for renal disease.

Analysis of preoperative serum levels of MMP1, -2, and -9 in patients with site-specific head and neck squamous cell cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) includes tumors of various anatomical sites sharing common etiological factors. Serum levels of MMP1, MMP2, and MMP9 were analyzed in patients with oropharyngeal, laryngeal, and hypopharyngeal carcinomas in an effort to elucidate the pathobiology and in order to find useful biomarkers of site-specific HNSCC. PATIENTS AND METHODS: The study group comprised of 46 patients with HNSCC (21 with oropharyngeal, 21 with laryngeal and 4 with hypopharyngeal cancer). Serum levels of MMP1, -2, and -9 were determined by the MAGPIX multiplex method. P16 protein was detected by immunohistochemistry. Serum levels of matrix metalloproteinases (MMPs) were correlated with clinicopathological features of carcinomas and were compared with respect to tumor site. RESULTS: Significant correlations were confirmed between p16 positivity and oropharyngeal cancer, MMP1 and p16 positivity, and recurrence and smoking. Statistically significant differences in serum levels of MMPs between cancer of different locations were not found. CONCLUSION: MMP1 expression is significantly affected by smoking habit and by p16 and might mediate etiopathogenetical process in cancerogenesis of HNSCC. Our pilot study did not establish any utility of MMP1, -2, or -9 in clinical practice as diagnostic/prognostic markers.

Urinary neopterin concentrations during combination therapy with cetuximab in previously treated patients with metastatic colorectal carcinoma.

BACKGROUND/AIM: Increased concentrations of neopterin, a biomarker of systemic immune response, have been reported after administration of cytokines, cytotoxic chemotherapy or external-beam radiation, but little is known about the effects of targeted-agents on neopterin. PATIENTS AND METHODS: Urinary neopterin was studied in pre-treated patients with metastatic colorectal carcinoma during therapy with cetuximab, administered mostly in combination with irinotecan, 5-fluorouracil and leucovorin. Urinary neopterin was determined by high-performance liquid chromatography. RESULTS: High initial urinary neopterin concentrations predicted poor prognosis. A significant correlation was observed between urinary neopterin and peripheral blood leukocyte count, hemoglobin and carcinoembryonic antigen concentrations. Urinary neopterin concentrations significantly increased during therapy only in patients with initially low neopterin concentrations. CONCLUSION: Urinary neopterin concentrations predict prognosis in patients with metastatic colorectal carcinoma treated with cetuximab. Rising neopterin concentrations indicate an activation of systemic immune response that could be responsible for the antitumor activity of cetuximab.

Hepatic arterial infusion of irinotecan, 5-Fluorouracil and leucovorin in patients with liver metastases from colorectal carcinoma.

AIM: The aim of the present study was to evaluate single center experience with hepatic arterial infusion (HAI) of irinotecan, 5-fluorouracil and leucovorin in patients with liver metastases from colorectal carcinoma (CRC). PATIENTS AND METHODS: A retrospective analysis of 68 patients treated between 1998 and 2007 was performed. RESULTS: Among 60 patients who had no simultaneous liver-directed procedure (LDP), the best results obtained were complete response in two patients (3%), partial response in 18 patients (30%), and stable disease in 23 patients (38%), for an overall disease control rate of 72%. Median progression-free survival was 11 months, and median survival was 24 months. Overall survival was significantly better in patients with simultaneous LDP or secondary resection. Steatosis was present in all secondary resection specimens. CONCLUSION: Our data demonstrate the efficacy of HAI of irinotecan combined with 5-fluorouracil and leucovorin for liver metastases from CRC, specifically in patients also treated with LDP.

Hypomagnesaemia in patients with metastatic colorectal carcinoma treated with cetuximab.

BACKGROUND/AIMS: Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Among the side-effects of cetuximab hypomagnesaemia has been described, but the information is still limited. METHODOLOGY: We have evaluated retrospectively serum magnesium, potassium, calcium, creatinine and albumin in 51 consecutive patients with metastatic colorectal carcinoma treated with cetuximab, mostly combined with irinotecan-based combination chemotherapy. RESULTS: A significant decrease of serum magnesium, potassium, calcium and corrected serum calcium, creatinine and albumin concentrations was already evident one week after the start of treatment. Hypomagnesaemia of any grade was detected in 56% of evaluable patients, but grade 3 or grade 4 hypomagnesaemia was observed in 6% and 4% of patients, respectively. Grade 1 hypokalemia was detected in 47%, grade 3 in 17% and grade 4 hypokalemia was detected in 6% of the patients. Among evaluable patients grade 1 hypocalcaemia was detected in (36%), grade 2 hypocalcaemia in 42%, grade 3 in 4% and grade 4 in 13% of patients. Baseline hypocalcaemia of grade 1 or higher was associated with significantly inferior survival. CONCLUSIONS: Asymptomatic hypomagnesaemia, hypokalemia and hypocalcaemia are common in metastatic colorectal carcinoma patients treated with cetuximab. Hypocalcaemia is a predictor of poor prognosis.

Confirmatory testing in primary aldosteronism: extensive medication switching is not needed in all patients.

OBJECTIVE: Confirmatory testing of suspected primary aldosteronism (PA) requires an extensive medication switch that can be difficult for patients with severe complicated hypertension and/or refractory hypokalemia. For this reason, we investigated the effect of chronic antihypertensive medication on confirmatory testing results. To allow the results to be interpreted, the reproducibility of confirmatory testing was also evaluated. DESIGN AND METHODS: The study enrolled 114 individuals with suspected PA who underwent two confirmatory tests. The patients were divided into two groups. In Group A, both tests were performed on the guidelines-recommended therapy, i.e. not interfering with the renin-angiotensin-aldosterone system. In Group B, the first test was performed on chronic therapy with the exclusion of thiazides, loop diuretics, and aldosterone antagonists; and the second test was performed on guidelines-recommended therapy. Saline infusion, preceded by oral sodium loading, was used to suppress aldosterone secretion. RESULTS: Agreement in the interpretation of the two confirmatory tests was observed in 84 and 66% of patients in Groups A and B respectively. For all 20 individuals in Group A who ever had end-test serum aldosterone levels ≥240 pmol/l, aldosterone was concordantly nonsuppressible during the other test. Similarly, for all 16 individuals in Group B who had end-test serum aldosterone levels ≥240 pmol/l on modified chronic therapy, aldosterone remained nonsuppressible with guidelines-recommended therapy. CONCLUSION: Confirmatory testing performed while the patient is on chronic therapy without diuretics and aldosterone antagonists can confirm the diagnosis of PA, provided serum aldosterone remains markedly elevated at the end of saline infusion.

Universal screening detects two-times more thyroid disorders in early pregnancy than targeted high-risk case finding.

OBJECTIVE: Screening of thyroid disorders in pregnancy has been controversial. Recent recommendations favour targeted high-risk case finding, though this approach may miss a significant number of those affected. We aimed to assess the prevalence of accepted high-risk criteria in women with autoimmune thyroiditis and/or hypothyroidism detected from universal screening in an iodine-sufficient population. DESIGN: In 400 non-selected women in the 9-11th gestational week, thyroid-related tests were performed, and those with abnormalities were offered consultation. METHODS: TSH was determined by IRMA, and the upper cut-off value for screening was set at 3.5 mIU/l. For free thyroxine (FT(4)) and thyroperoxidase antibodies (TPO-Ab), RIAs were used, with cut-offs of <10 pmol/l and >50 IU/ml respectively. Endocrinological consultation included Doppler ultrasonography and was aimed to confirm autoimmune thyroiditis and/or hypothyroidism. The prevalence of consensus high-risk criteria was assessed. RESULTS: Among the 400 women, 65 (16.3%) had ≥1 abnormality: higher TSH was found in 10.3%, lower FT(4) in 2% and positive TPO-Ab in 8.3%. Fifty-one women were examined and followed up. Levo-T(4) treatment was initiated in 49 women for autoimmune thyroiditis (in 42), hypothyroidism (in 34) or both (in 27). Only 22 (45%) of 49 treated women fulfilled ≥1 high-risk criterion: most commonly family history (31%), history of miscarriage or preterm delivery (14%) and personal history (8%). CONCLUSIONS: Over half (55%) of pregnant women with abnormalities suggestive of autoimmune thyroiditis and/or hypothyroidism would be missed if only those with high-risk criteria were examined. A more extensive screening of thyroid autoimmunity and dysfunction seems warranted.

Adrenal venous sampling: where is the aldosterone disappearing to?

Adrenal venous sampling (AVS) is generally considered to be the gold standard in distinguishing unilateral and bilateral aldosterone hypersecretion in primary hyperaldosteronism. However, during AVS, we noticed a considerable variability in aldosterone concentrations among samples thought to have come from the right adrenal glands. Some aldosterone concentrations in these samples were even lower than in samples from the inferior vena cava. We hypothesized that the samples with low aldosterone levels were unintentionally taken not from the right adrenal gland, but from hepatic veins. Therefore, we sought to analyze the impact of unintentional cannulation of hepatic veins on AVS. Thirty consecutive patients referred for AVS were enrolled. Hepatic vein sampling was implemented in our standardized AVS protocol. The data were collected and analyzed prospectively. AVS was successful in 27 patients (90%), and hepatic vein cannulation was successful in all procedures performed. Cortisol concentrations were not significantly different between the hepatic vein and inferior vena cava samples, but aldosterone concentrations from hepatic venous blood (median, 17 pmol/l; range, 40-860 pmol/l) were markedly lower than in samples from the inferior vena cava (median, 860 pmol/l; range, 460-4510 pmol/l). The observed difference was statistically significant (P < 0.001). Aldosterone concentrations in the hepatic veins are significantly lower than in venous blood taken from the inferior vena cava. This finding is important for AVS because hepatic veins can easily be mistaken for adrenal veins as a result of their close anatomic proximity.

Serum homocysteine, cholesterol, retinol, alpha-tocopherol, glycosylated hemoglobin and inflammatory response during therapy with bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin.

BACKGROUND: Targeted agents present with a new spectrum of side-effects, including toxicities that negatively impact the risk of atherosclerosis. The aim of the present study was to evaluate the effect of the combination of targeted therapy and chemotherapy on serum homocysteine and other laboratory parameters of cardiovascular risk in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Thirty-one patients with metastatic colorectal carcinoma treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin were studied before and during the therapy. RESULTS: Serum homocysteine decreased significantly throughout the course of treatment. Total cholesterol and low-density lipoprotein cholesterol also decreased significantly during the first month of therapy. In contrast, serum retinol significantly increased during the second and third months of treatment. A significant increase in glycosylated hemoglobin was also observed. After an initial rise, serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were significantly lower compared to baseline throughout the course of treatment. Serum ferritin increased throughout most of the course of treatment. A significant correlation was observed between CRP and high-density lipoprotein cholesterol, retinol, ferritin, and CEA. CEA correlated with hemoglobin, retinol, and ferritin. Retinol correlated significantly with hemoglobin. CONCLUSION: Tumor control, reflected in lower CEA, resulted in suppression of the acute phase response and generally in favorable effects on laboratory parameters indicative of risk factors of atherosclerosis, including lower homocysteine concentrations, and lower total and LDL cholesterol.

Endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration with cyst fluid analysis in pancreatic cystic neoplasms.

BACKGROUND/AIMS: Pancreatic cystic neoplasms represent a heterogeneous group of tumors with varied malignant potential. The aim of this prospective study was to evaluate EUS, EUS-FNA and cyst fluid analysis in distinguishing serous cystadenomas (SCA) and mucinous cystic neoplasms (MCN). METHODOLOGY: Twelve patients with SCA (4 men, 8 women, mean age 58), 16 with MCN (3 men, 13 women, mean age 53) and 10 pancreatic non-tumorous cysts as controls (1 man, 9 women, mean age 43) were investigated by EUS-FNA from January 2003 to February 2006. Cyst fluid evaluation was done for cytology, amylase, CEA, CA 19-9, CA 72-4 and CA 15-3 (RIA). The final diagnosis was based on surgery & histology (14 patients) and/or follow-up after EUS-FNA (mean 15 months). RESULTS: In the MCN-group 13 mucinous cystadenomas, 2 cystadenocarcinomas and 1 malignant IPMT were found. EUS-FNA results: cytology (including staining for mucin) was diagnostic in 2/12 SCA (17%), 10/16 MCN (63%) and negative in all controls. Fluid CEA in MCN-group (mean 9487, 95%CI 0-23637) was significantly higher compared both with SCA-group (mean 22, 95%CI 0-54, p<0.001) and controls (mean 4, 95%CI 0.5-8, p<0.001). Similar results were found in fluid CA72-4 and fluid CA19-9. Accuracy of EUS-FNA with final diagnosis was 93%. CONCLUSIONS: EUS-FNA with cyst fluid CEA, CA72-4, CA19-9 and cytology are useful tools in differentiating SCA, MCN and non-tumorous cysts.

Urinary neopterin, hemoglobin and peripheral blood cell counts in breast carcinoma patients treated with dose-dense chemotherapy.

BACKGROUND: Among other actions, chemotherapy may induce an activation of systemic inflammatory and immune response. PATIENTS AND METHODS: Urinary neopterin was evaluated, using high-performance liquid chromatography, before and during dose-dense combination chemotherapy with doxorubicin, cyclophosphamide and sequential paclitaxel (neoadjuvant or adjuvant) in 194 patients with breast carcinoma. Hemoglobin, peripheral blood cell count and, in a subgroup of patients, iron metabolism were also evaluated. RESULTS: Urinary neopterin increased significantly during the chemotherapy. The increase in urinary neopterin was accompanied by a gradual decrease of hemoglobin. A marked increase in serum ferritin concentration was observed during the chemotherapy, along with fluctuations of iron concentrations. Among 161 patients treated with primary chemotherapy, the pathological response was evaluable in 150. Pathological complete response was observed in 37 cases (25%). In patients with pathological complete response, significantly lower serum ferritin concentrations were observed. CONCLUSION: Present data demonstrate the presence of systemic immune activation, reflected in increased urinary neopterin concentrations, in breast carcinoma patients treated with dose-dense chemotherapy. Lower ferritin concentrations were predictive of pathological complete response.

Successful management of infusion reaction accompanying the start of cetuximab therapy.

INTRODUCTION: Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma after failure of standard chemotherapy. Rare infusion reactions that resulted in the cessation of therapy have been described after cetuximab administration. CASE DESCRIPTION: We have observed severe infusion reactions accompanied by a loss of consciousness in two patients. The patients were transferred to intensive care unit, and the treatment was continued after administration of corticosteroids under careful monitoring of vital signs without any further serious reactions. In both cases, benefit of therapy with cetuximab could be demonstrated. CONCLUSION: This experience indicates that cetuximab can be continued in patients who experience infusion reactions. Surveillance in the intensive care unit is mandatory during readministration of the drug.

Serum alpha-tocopherol, retinol and neopterin during paclitaxel/carboplatin chemotherapy.

BACKGROUND: Disorders of antioxidant balance are considered to be involved in the toxicity associated with radiotherapy or chemotherapy. PATIENTS AND METHODS: Serum alpha-tocopherol and retinol were determined, by high performance liquid chromatography, before and during therapy with a combination of paclitaxel and carboplatin in 28 patients with breast and ovarian cancer. Serum neopterin and cholesterol were measured using a radioimmunoassay and enzymatic colorimetric method, respectively. RESULTS: Compared to pretreatment concentrations, a significant increase was observed in serum alpha-tocopherol and retinol concentrations during therapy that was associated with decreased serum neopterin concentrations. Serum alpha-tocopherol concentrations were significantly higher during therapy in patients who did not experience serious toxicity. CONCLUSION: An increase in alpha-tocopherol and retinol during therapy with combination paclitaxel/carboplatin may be explained by inhibition of systemic immune activation secondary to control of the tumor with effective chemotherapy. Lower alpha-tocopherol concentrations were associated with the toxicity of therapy.