Urine miR-93-5p is a promising biomarker for early detection of HBV-related hepatocellular carcinoma.

INTRODUCTION: The mortality rate of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)continues to increase because sensitive, early and readily available diagnostic tools are lacking. To address this problem, we aimed to identify diagnosticbio markers to be used for early detection of HCC. MATERIALS AND METHODS: miR-93-5p was selected as a candidate biomarker based on the analyses of relevant Gene Expression Omnibus (GEO) datasets; it was validated using qPCR to quantify its expression levels in tissue, plasma and saliva sample sets. RESULTS: miR-93-5p was significantly upregulated in HBV-related HCC tissue. Notably, miR-93-5p in plasma and urine was also significantly increased in patients with early HBV-related HCC. The expression of miR-93-5p was significantly and positively correlated in pairwise comparisons of samples (tissue vs. plasma, tissue vs. urine, plasma vs. urine). Moreover, after curative hepatectomy,miR-93-5p in plasma and urine decreased significantly over one month after the curative hepatectomy and returned to normal levels. Furthermore, receiver operating characteristic (ROC) analysis indicated that both plasma and urine miR-39-5p could detect be used to early, advanced and overall HBV-related HCC cases with more than 85% sensitivities and 93% of specificities. Finally, urine miR-93-5p could be used to predict progress-free survival for early HCC patients who received curative hepatectomy and overall survival for advanced HCC patients without curative treatments. CONCLUSIONS: Plasma and urine miR-93-5p show great promise as potential novel biomarkers for early detection of HBV-related HCC. Moreover, urine miR-93-5p could be used to predict the prognosis of patients with HBV-related HCC.

Detection of Hepatitis B Virus-Host Junction Sequences in Urine of Infected Patients.

Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral-host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy.

Exploratory Study Using Urinary Volatile Organic Compounds for the Detection of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) biomarkers are lacking in clinical practice. We therefore explored the pattern and composition of urinary volatile organic compounds (VOCs) in HCC patients. This was done in order to assess the feasibility of a potential non-invasive test for HCC, and to enhance our understanding of the disease. This pilot study recruited 58 participants, of whom 20 were HCC cases and 38 were non-HCC cases. The non-HCC cases included healthy individuals and patients with various stages of non-alcoholic fatty liver disease (NAFLD), including those with and without fibrosis. Urine was analysed using gas chromatography-ion mobility spectrometry (GC-IMS) and gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS). GC-IMS was able to separate HCC from fibrotic cases with an area under the curve (AUC) of 0.97 (0.91-1.00), and from non-fibrotic cases with an AUC of 0.62 (0.48-0.76). For GC-TOF-MS, a subset of samples was analysed in which seven chemicals were identified and tentatively linked with HCC. These include 4-methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (2TMS derivative), 2-butanone, 2-hexanone, benzene, 1-ethyl-2-methyl-, 3-butene-1,2-diol, 1-(2-furanyl)-, bicyclo(4.1.0)heptane, 3,7,7-trimethyl-, [1S-(1a,3ß,6a)]-, and sulpiride. Urinary VOC analysis using both GC-IMS and GC-TOF-MS proved to be a feasible method of identifying HCC cases, and was also able to enhance our understanding of HCC pathogenesis.

Urinary Metabolic Biomarkers in Cancer Patients: An Overview.

The pathogenesis of cancer involves multiple molecular alterations at the level of genome, epigenome, and stromal environment, resulting in several deregulated signal transduction pathways. Metabolites are not only end products of gene and protein expression but also a consequence of the mutual relationship between the genome and the internal environment. Considering that metabolites serve as a comprehensive chemical fingerprint of cell metabolism, metabolomics is emerging as the method able to discover metabolite biomarkers that can be developed for early cancer detection, prognosis, and response to treatment. Urine represents a noninvasive source, available and rich in metabolites, useful for cancer diagnosis, prognosis, and treatment monitoring. In this chapter, we reported the main published evidences on urinary metabolic biomarkers in the studied cancers related to hepatopancreatic and urinary tract with the aim at discussing their promising role in clinical practice.

Urine Neutrophil Gelatinase-Associated Lipocalin a Possible Diagnostic Marker for Egyptian Hepatocellular Carcinoma Patients.

BACKGROUND: Most effective method for reducing mortality from hepatocellular carcinoma (HCC) is early diagnosis. Despite its lack of adequate sensitivity, ultrasound is considered fundamental for HCC screening. AIM: to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) as non-invasive marker for HCC diagnosis in Egyptian patients. METHODS: One hundred and twenty patients were divided into three groups (40 patients each): patients with chronic viral hepatitis (HCV or HBV), cirrhotic patients and HCC patients and 40 healthy age and gender matched subjects were enrolled as control group. After clinical assessments, urinary NGAL was measured by enzyme-linked immunosorbent assay. RESULTS: Our results revealed that median level of urinary NGAL was 290, 834, 1090 and 1925 pg/ml in control, chronic hepatitis, cirrhotic and HCC groups respectively among studied groups (p<0.001). Receiver operating characteristics (ROC) analysis showed that urinary NGAL cutoff value of 1255 ng/ml could discriminate between HCC and cirrhosis. The area under curve (AUC) was 0.95 with 90% sensitivity, 87.5% specificity (p-value <0.001). In HCC group, urine NGAL level didn`t show significant correlation with Child Pugh score, MELD score or Barcelona Clinic Liver Cancer (BCLC) stage. CONCLUSION: Urinary NGAL could be a simple, non-invasive test for diagnosis of HCC in chronic liver disease patients.
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Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma.

BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.

Urine α-fetoprotein and orosomucoid 1 as biomarkers of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the sixth common malignant tumor worldwide, but current efficient and convenient screening methods remain lacking. This study aimed to discover a diagnostic or a screening biomarker from the urine of hepatitis B virus (HBV)-related HCC patients. We used iTRAQ coupled with mass spectrometry to identify candidate urinary proteins in a discovery cohort (n = 40). The selected proteins were confirmed using ELISA in a validation cohort (n = 140). Diagnostic performance of the selected proteins was assessed using receiver operating characteristic (ROC) and qualitative diagnostic analysis. A total of 96 differentially expressed proteins were identified. Urinary α-fetoprotein (u-AFP) and orosomucoid 1 (u-ORM1) were selected as target proteins by bioinformatics analysis and were significantly higher in HCC than in non-HCC patients, as validated by Western blot analysis and ELISA. u-AFP had a strong correlation with serum AFP-L3 (Pearson's r = 0.944, P < 0.0001), indicating that u-AFP may be derived from circulating blood. The area under the curve (AUC) of u-AFP was 0.795 with a sensitivity of 62.5% and a specificity of 95.4%, which showed no significantly difference with serum AFP (se-AFP). The AUC was 0.864 as u-AFP and u-ORM1 were combined, and they performed much better than u-AFP or u-ORM1 alone. Qualitative diagnostic analysis showed that the positive predictive value of u-AFP was 90.1% and the diagnostic sensitivity of parallel combination of u-AFP and u-ORM1 was 85.1%. Taken together, AFP and ORM1 in the urine may be used as a diagnostic or screening biomarker of HCC, and studies on large samples are needed to validate the result.NEW & NOTEWORTHY This study provides a novel way to find biomarkers of hepatocellular carcinoma (HCC) and a new perspective of α-fetoprotein clinical application. The urine reagent strips may be helpful in high epidemic areas of HCC and in low-resource settings.

Prediagnostic Level of Dietary and Urinary Isoflavonoids in Relation to Risk of Liver Cancer in Shanghai, China.

BACKGROUND: No epidemiologic studies have directly assessed the association between dietary and urinary isoflavonoids and risk of liver cancer in humans. METHODS: A nested case-control study, including 217 incident cases of liver cancer and 427 individually matched control subjects, was conducted in Shanghai, China. Dietary isoflavonoid intakes were assessed through a validated food-frequency questionnaire and the Chinese Food Composition Tables. Urinary excretion levels of four major isoflavonoids were measured by the reversed-phase high-performance liquid chromatography. ORs and 95% confidence intervals (CI) were derived using conditional logistic regression models. RESULTS: The adjusted ORs (95% CIs) for liver cancer across increasing quartiles of urinary genistein levels were 1.00 (reference), 0.55 (95% CI, 0.22-1.36), 0.57 (95% CI, 0.23-1.43), and 0.19 (95% CI, 0.06-0.59) (P trend = 0.008) in women and 1.00 (reference), 1.22 (0.52-2.86), 1.17(0.47-2.90), and 1.23 (0.55-2.76) in men, respectively. These associations were consistent by limiting the cases to primary malignant neoplasm of liver or malignant neoplasms of the intrahepatic bile ducts, or among participants without self-reported liver disease or cirrhosis at the baseline survey. No associations were found between dietary isoflavonoids and liver cancer risk. CONCLUSIONS: Our study suggests for the first time that urinary excretion of genistein may be associated with reduced risk of liver cancer in women. IMPACT: In this nested case-control study in China, we found that urinary excretion of genistein was associated with lower risk of liver cancer in women, and not in men.

Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma.

BACKGROUND: Proteinuria monitoring is required in patients receiving lenvatinib, however, current methodology involves burdensome overnight urine collection. METHODS: To determine whether the simpler urine protein:creatinine ratio (UPCR) calculated from spot urine samples could be accurately used for proteinuria monitoring in patients receiving lenvatinib, we evaluated the correlation between UPCR and 24-hour urine protein results from the phase 3 REFLECT study. Paired data (323 tests, 154 patients) were analysed. RESULTS: Regression analysis showed a statistically significant correlation between UPCR and 24-hour urine protein (R2: 0.75; P < 2 × 10-16). A UPCR cut-off value of 2.4 had 96.9% sensitivity, 82.5% specificity for delineating between grade 2 and 3 proteinuria. Using this UPCR cut-off value to determine the need for further testing could reduce the need for 24-hour urine collection in ~74% of patients. CONCLUSION: Incorporation of UPCR into the current algorithm for proteinuria management can enable optimisation of lenvatinib treatment, while minimising patient inconvenience. CLINICAL TRIAL REGISTRATION: NCT01761266.

Cancer metabolomic markers in urine: evidence, techniques and recommendations.

Urinary tests have been used as noninvasive, cost-effective tools for screening, diagnosis and monitoring of diseases since ancient times. As we progress through the 21st century, modern analytical platforms have enabled effective measurement of metabolites, with promising results for both a deeper understanding of cancer pathophysiology and, ultimately, clinical translation. The first study to measure metabolomic urinary cancer biomarkers using NMR and mass spectrometry (MS) was published in 2006 and, since then, these techniques have been used to detect cancers of the urological system (kidney, prostate and bladder) and nonurological tumours including those of the breast, ovary, lung, liver, gastrointestinal tract, pancreas, bone and blood. This growing field warrants an assessment of the current status of research developments and recommendations to help systematize future research.

Blood and urine analyses after radioembolization of liver malignancies with [166Ho]Ho-acetylacetonate-poly(l-lactic acid) microspheres.

BACKGROUND: [166Ho]Ho-acetylacetonate-poly(L-lactic acid) microspheres were used in radioembolization of liver malignancies by intra-arterial administration. The primary aim of this study was to assess the stability and biodistribution of these microspheres. MATERIALS AND METHODS: Peripheral blood and urine samples were obtained from two clinical studies. Patient and in vitro experiment samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS), gamma-ray spectroscopy, light microscopy, Coulter particle counting, and high performance liquid chromatography (HPLC). RESULTS: The median percentage holmium compared to the total amount injected into the hepatic artery was 0.19% (range 0.08-2.8%) and 0.32% (range 0.03-1.8%) in the 1 h blood plasma and 24 h urine, respectively. Both the blood plasma and urine were correlated with the neutron irradiation exposure required for [166Ho]Ho-AcAc-PLLA microsphere production (ρ = 0.616, p = 0.002). After a temporary interruption of the phase 2 clinical study, the resuspension medium was replaced to precipitate [166Ho]Ho3+ pre-administration using phosphate. The in vitro near-maximum neutron irradiation experiments showed significant [166Ho]Ho-AcAc-PLLA microsphere damage. CONCLUSION: The amount of holmium in the peripheral blood and urine samples after [166Ho]Ho-AcAc-PLLA microsphere intrahepatic infusion was low. A further decrease was observed after reformulation of the resuspension solution but minimization of production damage is necessary.

Forms of diagnostic material as sources of miRNA biomarkers in hepatocellular carcinoma: a preliminary study.

Aim: To assess the diagnostic value of selected miRNAs from various material collected from hepatocellular carcinoma (HCC) patients. Patients & methods: Tissue, serum, urine and fecal samples from HCC patients and healthy individuals were screened for associated miRNAs using microarray analysis; the selected miRNAs were then validated by real time-quantitative PCR on 65 patients. Results: Serum miR-122, a combination of serum miR-155 with miR-885-5p, a combination of urinary miR-532-3p with miR-765, and fecal miR-320a displayed 100% efficiency in discriminating patients from controls. A combination of urinary miR-532-3p and miR-765 allowed patients with neoplastic grade G3 to be distinguished from those with G1 and G2. Conclusion: Additionally to serum, urine and feces also appeared to be valuable source of potential HCC noninvasive miRNA biomarkers.

Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma.

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case-control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8-epi-PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8-epi-PGF2α were 2.55 (95% confidence interval = 1.62-4.01, Ptrend < 0.001). This positive 8-epi-PGF2α-HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes.

Evaluation of 5-hydroxyindoloacetic acid excretion in urine in patients with small intestine neuroendocrine neoplasm and carcinoid syndrome treated with somatostatin analogues.

BACKGROUND: The assessment of hormonal function of neuroendocrine neoplasm (NEN) is an important stage in the diagnosis and monitoring of these diseases treatment. Objective of this study was to analyze the results of urinary excretion of 5-hydroxyindoloacetic acid (5-HIAA) in patients with carcinoid syndrome treated with somatostatin analogues, depending on the histologic maturity, degree of liver involvement and stage of the disease. METHODS: The final group comprised of 41 patients. All patients were subject to surgical removal of the primary site. Presence of hepatic metastases was determined in all patients. All patients were treated with somatostatin analogues. The 5-HIAA urine excretion was determined using the ELISA immunoenzymatic method. RESULTS: The mean excretion of 5-HIAA in patients with histological maturity grade G1 was 45.64 mg/24h, while in the group G2 the mean excretion was 108.41 mg/24h and was higher than in the group G1 (p=0.003). In the analysis of 5-HIAA value depending on the degree of liver involvement, the mean value of 5-HIAA excretion in patients with 10% liver involvement was 38.99 mg/24h, whereas in patients with 25% liver involvement this value was considerably higher and amounted 131.00 mg/24h (p< 0.001). In patients with disease progression the mean excretion was 117.37 mg/24h compared to the group of patients with stabilization of the disease, where the mean value was lower and amounted to 39.39 mg/24h (p<0.001). CONCLUSION: Assessment of 5-HIAA excretion in patients with carcinoid syndrome is of considerable significance in the diagnostics and monitoring of the treatment.

Development of a simple, rapid and high-throughput fluorescence polarization immunoassay for glycocholic acid in human urine.

In this paper, a simple, rapid and high-throughput fluorescence polarization immunoassay (FPIA) based on polyclonal antibodies (PAb) is described for the determination of glycocholic acid (GCA) in human urine. Three fluorescein-labeled GCA (tracers) with different structures and spacer bridges were synthesized and purified by thin-layer chromatography (TLC). The structure effect of tracers on the assay was investigated and the sensitivity of best tracer in the optimized FPIA demonstrated an IC50 value of 306 ng/mL. The working range of FPIA was 36 ∼ 2 600 ng/mL and the limit of detection (LOD) was 9 ng/mL. The developed FPIA was time-saving that could be completed within 10 min. Human urine samples spiked with GCA were analyzed by this method, followed by confirmation with commercial enzyme immunoassay analysis (EIA). Excellent recoveries and correlation between these two methods were observed (R2 = 0.996), suggesting the developed FPIA could be applied to screening of GCA in human urine samples without complicated cleanup.

Pre-diagnostic urinary 15-F2t -isoprostane level and liver cancer risk: Results from the Shanghai Women's and Men's Health Studies.

Oxidative stress has been hypothesized to affect cancer development via various mechanisms, but the evidence from human is limited and inconclusive. 15-F2t -isoprostane (15-F2t -IsoP) is an accurate marker of oxidative stress in humans. Recent studies showed that the evidence of urinary 15-F2t -IsoP level correlating cancer risk is conflicting. We conducted a case-control study nested within two population-based cohort studies. Pre-diagnosis urine samples, collected at cohort enrollment, from 363 incident liver cancer cases and 725 individually matched controls, were used to determine the level of 15-F2t -IsoP by enzyme-linked immunosorbent assay. Conditional logistic regression model was used to estimate the odds ratio to measure the association between the urinary 15-F2t -IsoP level and liver cancer risk. We found that higher pre-diagnostic urinary 15-F2t -IsoP level was associated with an increased liver cancer risk, with an adjusted OR in males (OR4thvs.1st quartile = 8.84, 95% CI 2.74-28.60), which was significantly higher than those in females (OR4thvs.1st quartile = 1.75, 95% CI 0.70-4.42). HBsAg carriers with higher 15-F2t -IsoP had a significantly increased liver cancer risk (ORfemale = 59.04, 95% CI 12.26, 284.30; ORmale = 92.55, 95% CI 34.83, 245.96) compared to non-carriers with lower 15-F2t -IsoP. High urinary 15-F2t -IsoP level was associated with high liver cancer risk, suggesting that 15-F2t -IsoP may be a promising biomarker for liver cancer risk. The result suggests that people with sero-positive HBsAg and higher level of 15-F2t -IsoP might be given a higher priority on future surveillance program of liver cancer.

Development and Evaluation of Novel Statistical Methods in Urine Biomarker-Based Hepatocellular Carcinoma Screening.

Hepatocellular carcinoma is one of the fastest growing cancers in the US and has a low survival rate, partly due to difficulties in early detection. Because of HCC's high heterogeneity, it has been suggested that multiple biomarkers would be needed to develop a sensitive HCC screening test. This study applied random forest (RF), a machine learning technique, and proposed two novel models, fixed sequential (FS) and two-step (TS), for comparison with two commonly used statistical techniques, logistic regression (LR) and classification and regression trees (CART), in combining multiple urine DNA biomarkers for HCC screening using biomarker values obtained from 137 HCC and 431 non-HCC (224 hepatitis and 207 cirrhosis) subjects. The sensitivity, specificity, area under the receiver operating curve, and variability were estimated through repeated 10-fold cross-validation to compare the models' performances in accuracy and robustness. We show that RF and TS have higher accuracy and stability; specifically, they reach 90% specificity and 86%/87% sensitivity respectively along with 15% higher sensitivity and 10% higher specificity than LR in cross-validation. The potential of RF and TS to develop a panel of multiple biomarkers and the possibility for self-training, cloud-based models for HCC screening are discussed.

Urinary Excretion of Yttrium-90 after Radioembolization with Yttrium-90-Labeled Resin-based Microspheres.

In radioembolic therapy (RET) of hepatic malignancies using yttrium-90 (Y)-labeled resin microspheres, radiation protection is primarily concerned with avoiding contamination by radioactive spheres. However, as Y is bound to the microsphere surface by a potentially reversible ion-exchange process, the aim of this study was to assess the extent of the potential excreted activity in urine. After RET with Y-labeled resin-based microspheres, urinary excretion of free Y was prospectively analyzed in 51 interventions (n = 45 patients) by sampling urine over 48 h (two 24-h intervals) consecutively. The measured urinary concentration of Y, normalized to the administered microsphere activity, was a median of 58.5 kBq L GBq (range = 3.5-590.9 kBq L GBq) and 17.8 kBq L GBq (1.8-58.8 kBq L GBq) for the first and second 24-h periods after administration, respectively (p ≤ 0.0001, F = 28.4, result from ANOVA). The total excreted activity significantly decreased (p ≤ 0.0001) from a median of 72.5 kBq in the first 24-h period to a median of 22.1 kBq in the second 24-h period. Urinary excretion of free Y after resin-based RET occurs for a longer period and at a higher activity excretion than previously published, which has to be considered when patients are either hospitalized or return home after RET. Existing approaches for patient hospitalization, especially in temporary radiation protection areas, justified by the previously reported lower excretion rate, should be re-evaluated, and as a consequence, the current product safety information and handling recommendations for Y-labeled resin-based microspheres may need to be revised.

Sensitive detection of brucine an anti-metastatic drug for hepatocellular carcinoma at carbon nanotubes - nafion composite based biosensor.

A neoteric approach for the electrochemical analysis of brucine in biological environment has been developed. The glassy carbon electrode modified with single walled carbon nanotubes and nafion composite film is delineated for the first time to determine brucine employing square wave voltammetry. The quantification of brucine at physiological pH 7.2 manifests remarkable performance at the developed biosensor. The effect of several operational parameters has been studied in the present investigation. Under optimized conditions, a dynamic linear range from 1nM to 8µM with a high sensitivity of 340.8µAµM-1 and limit of detection corresponding to 0.11nM was achieved. The interfering effect of some coexisting metabolites on the current response of brucine has been reported. The method was successfully applied for the detection of brucine in traditional pharmaceutical formulations. The biological relevance of the present method has been demonstrated by the analysis of the alkaloid in human serum and urine samples. The analytical utility was further assessed by the selective determination of brucine in Strychnos nux-vomica seeds exhibiting considerable potential as a diagnostic tool.