Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study.

INTRODUCTION: Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU. METHODS: Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range. RESULTS: The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting. CONCLUSIONS: The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Putative probiotics decrease cell viability and enhance chemotherapy effectiveness in human cancer cells: role of butyrate and secreted proteins.

Recent advances have highlighted probiotic role in preventing colorectal cancer, by promoting differentiation, inhibiting proliferation, and inducing apoptosis in colonocytes. Here, three ascertained probiotics (L. rhamnosus GG ATCC 53103, L. reuterii DSM 17938 and L. johnsonii LC1) and four food-isolated putative probiotics (L. plantarum S2, L. plantarum O2, L. pentosus S3, L. rhamnosus 14E4) were investigated for their ability to adhere to HT29 cancer cells and to inhibit their and the chemoresistant counterpart (HT29-dx cells) proliferation. Three putative probiotics (S2, S3 and 14E4) were able to decrease viability of both sensitive and chemo-resistant HT-29 cells. Supposing this effect related to secreted metabolites (namely short chain fatty acids (SCFA), exopolysaccharides (EPS) and extracellular proteins) we tested the efficacy of extracellular extracts and butyrate with or without the chemotherapeutic agent doxorubicin (DOXO) (10 µM, 4 h). Increased production of mitochondrial reactive oxygen species (ROS) in HT29 and HT29-dx cells was observed. Moreover, cell exposure to DOXO (10 µM, 24 h) and extracellular extracts (48 h) reduced cell viability. Comparative phenotypic and secretome analyses on the effective/non effective strains, revealed quantitative/qualitative differences in EPS content and protein profiles, suggesting that P40, phage-tail-like and capsid-like proteins may be also involved. These results suggest that food-isolated bacteria releasing bioactive compounds (butyrate, EPS and peculiar proteins) may control cancer cell proliferation and improve their response to chemotherapy.

Selenium effects on the metabolism of a Se-metabolizing Lactobacillus reuteri: analysis of envelope-enriched and extracellular proteomes.

Selenium (Se) has received great attention in the last few years, as it is considered to be essential for human health (prevention of viral infections, heart diseases and ageing-related diseases). Se deficiency can be counteracted by the administration of selenium-enriched probiotics that are able to convert inorganic selenium into less toxic and more bio-available organic forms. This study was performed on Lactobacillus reuteri Lb2 BM DSM 16143, a probiotic LAB previously demonstrated to be able to fix Se into selenocysteines. The aim was to assess Se influence on its metabolism, by a 2-DE proteomic approach, on two different cellular districts: envelope-enriched and extracellular proteomes. While in the envelope-enriched fraction 15 differentially expressed proteins were identified, in the extracellular proteome no quantitative difference was detected. However, at a molecular level, we observed the insertion of Se into selenocysteine, exclusively under the stimulated conditions. The obtained results confirmed the possibility to use L. reuteri Lb2 BM DSM 16143 as a carrier of organic Se that can be easily released in the gut becoming available for the human host.

Quantification of copper phases, their reducibility and dispersion in doped-CuCl2/Al2O3 catalysts for ethylene oxychlorination.

The comprehensive understanding of the composition, behaviour and reactivity of a catalyst used inside industrial plants is an extremely hard task that is rarely achieved. It requires the use of different spectroscopic techniques, applied under in situ or in operando conditions, and combined with the investigation of the catalyst activity. Often the operating experimental conditions are different from technique to technique and the different results must be compared with care. In the present contribution, we combined in situ XANES/EXAFS, IR spectroscopy of adsorbed CO, CO chemisorption and catalytic tests performed using a pulse reactor in depletive mode. This multitechnical approach resulted in the understanding of the role that dopants (LiCl, KCl, CsCl, MgCl(2) LaCl(3)) have in the nature, relative fraction, reducibility and dispersion of Cu-phases on CuCl(2)/gamma-Al(2)O(3) catalysts for oxychlorination reaction, a key step of the PVC chemistry. In the undoped catalyst two Cu phases coexist: Cu-aluminate and supported CuCl(2), being the latter the only active one [J. Catal., 2000, 189, 91]. EXAFS and XANES highlighted that all dopants contribute more or less efficiently in increasing the fraction of the active copper species, that reaches a value of almost 100% in the case of MgCl(2) or LaCl(3). EXAFS directly, and IR indirectly, proved that the addition of KCl or CsCl (and less efficiently of LiCl) results in the formation of mixed CuK(x)Cl(2+x) or CuCs(x)Cl(2+x) phases, so altering the chemical nature of the active phase. XANES spectroscopy indicates that addition of MgCl(2) or LaCl(3) does not affect the reducibility by ethylene (under static conditions) of the active CuCl(2) phase and that the reducibilility of the new copper-dopant mixed chloride are in the order CuCl(2) > CuLi(x)Cl(2+x) > CuK(x)Cl(2+x) > CuCs(x)Cl(2+x). However, when reduction is done inside a pulse reactor, a more informative picture comes out. The last technique is able to differentiate all samples, and their ability to be reduced by ethylene resulted in the order: La- > Mg- > Li-doped > undoped > K- > Cs-doped catalyst. To understand this apparent discrepancy the dispersion of the active phase, measured by CO chemisorption, was needed: it has been found that addition of LiCl increases enormously the dispersion of the active phase, LaCl(3) significantly and MgCl(2) barely, while addition of both KCl and CsCl results in a decrease of the surface area of the active phase. The mechanism of the enhancing effect of La and Mg on catalytic activity is still not clear, but it could be associated to the modification that they induce to the support surface: the Cu is so highly dispersed that almost all is in direct contact with support surface. It is finally worth noticing that the previous EXAFS and XANES study allowed us to refer the chemisorption data to the active phase only, while the IR study allowed us to fix the Cu(+)/CO surface stoichiometry. Summarizing the use of a multidisciplinary approach has been the conditio sine qua non (mandatory condition) to understand the complex role that the different additives have on the active phase of the CuCl(2)/gamma-Al(2)O(3) catalysts for ethylene oxychlorination.

Metal content and toxicity of produced formation water (PFW): study of the possible effects of the discharge on marine environment.

A preliminary chemical and ecotoxicological assessment was performed on the produced formation water (PFW) and superficial sediment around a gas platform (Fratello Cluster), located in the Adriatic Sea (Italy), in order to evaluate the effects of PFW discharged from the installation. The ecotoxicological bioassays, with the marine bacterium Vibrio fischeri and the sea urchin Paracentrotus lividus, were associated with chemical data to estimate the possible effects on living organisms. PFW collected on the platform was toxic, but no significant effect was recorded on marine sediment. Only the sediment station nearest to the discharge point showed higher values of some contaminants (zinc and arsenic) in comparison to other sites and only some stations showed low toxicity.

Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer.

INTRODUCTION: High microsatellite instability (MSI-H) occurs in about 15% of colorectal cancers (CRC) and clinical as well as pathological features differ from tumours exhibiting low microsatellite instability (MSI-L) or microsatellite stability (MSS). Conflicting data exists about the relevance of MSI in predicting the prognosis and benefit of 5-fluorouracil (5-FU) based chemotherapy in patients with CRC. We investigated the usefulness of MSI as a predictor of distinct clinical attributes influencing recurrence rate and disease-free survival (DFS) subject to the use of adjuvant or palliative chemotherapy with 5-FU in stage II- stage IV CRC. METHODS: We collected data and tumours of 416 consecutive stage I to IV CRC patients from 2000 to 2002, and followed them for a median time of 33 months. Microsatellite loci recommended by the National Cancer Institute were analysed. Cox proportional hazard modelling was used to compare clinical data and survival as well as associations for MSI and 5-FU treatment status of patients with MSI-H, MSI-L or MSS CRC. RESULTS: We identified 52 MSI-H (13%), 21 MSI-L (5%) and 343 MSS (82%) tumours. CRC with MSI-H tended to have a decreased likelihood of metastasising to regional lymph nodes (p=0.055), whilst age of diagnosis and tumour location did not differ. In an analysis that did not take into account the use of chemotherapy, univariate and multivariate analyses failed to show a difference between MSI-H and MSS groups with respect to disease-free and overall survival. Furthermore, survival under application of 5-FU did not correlate with MSI status. CONCLUSION: No clear influence of MSI status on overall survival and response to 5-FU chemotherapy was found.

Direct IR observation of vibrational properties of carbonyl species formed on Pd nano-particles supported on amorphous carbon: comparison with Pd/SiO2-Al2O3.

By diluting optically opaque carbon-supported Pd particles in silica Aerosil we succeeded in observing the IR bands of adsorbed carbonyls and extracting information on the particle dispersion. Comparison with literature single crystal data and with silica-alumina supported Pd allowed us to make an assignment in terms of linear and 2-fold bridged carbonyls formed on Pd(111) and Pd(100) faces. Two Pd/C samples have been investigated. The relative intensities of the two carbonyl families observed on the two samples are consistent with the Pd dispersion independently measured with CO chemisorption, TEM and EXAFS analysis.

[Adjuvant and palliative chemotherapy of colorectal cancer in Germany outside controlled trials]. / Adjuvante und palliative Chemotherapie des kolorektalen Karzinoms in Deutschland ausserhalb kontrollierter Studien.

BACKGROUND AND OBJECTIVE: Colorectal cancer is the second most common malignant tumour in Germany with an unfavorable prognosis especially in a locally advanced or metastasizing stage. Although adjuvant and palliative chemotherapy significantly improve 5-year survival, consensus recommendations have in the past been inadequately transformed into clinical practice. It was the aim of this study to analyse the implementation of existing guidelines in a cohort from a defined area of Germany. PATIENTS AND METHODS: In a multicentre study done between January 2000 and January 2002, tumour stage, primary care, adjuvant or palliative chemotherapy and follow-up of 444 patients (216 males, 228 females) with newly diagnosed colorectal cancer were recorded. RESULTS: 301 patients had colonic and 143 patients rectal cancer. The median age at diagnosis was 65 11.3 years. 36 of 96 (38%) patients with stage II colon cancer and 66 of 87 (76%) with stage III disease received adjuvant chemotherapy. 8 of 51 (16%) patients with rectal cancer stage II and 22 of 38 (58%) patients with stage III underwent adjuvant radio- and chemotherapy. The 68 of 84 (81%) patients with stage IV CRC who received palliative chemotherapy were given almost exclusively 5-FU monotherapy. Initial or sequential combination chemotherapy with oxaliplatin or irinotecan were performed in only 24 of 84 (29%) patients. CONCLUSIONS: Stage III colon cancer was predominantly treated according to the existing standard guidelines. In contrast combined radio- and chemotherapy for rectal cancer stage II and III was only performed in one third of the patients, another third receiving neither adjuvant radiation nor chemotherapy. Initial combined or sequential combined chemotherapy for metastasizing colorectal cancer was rarely performed.

Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis.

The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.

Nitric oxide influences the release of histamine and glutamate in the rat hypothalamus.

To investigate the influence of nitric oxide (NO) on the release of histamine and glutamate, the anterior hypothalamus of anaesthetized rats was superfused through a push-pull cannula either with artificial cerebrospinal fluid (CSF) or with various drugs dissolved in CSF. Hypothalamic superfusion with the NO-donating compounds linsidomine (200 mumol/l) or diethylamine-NO (DEANO, 100 mumol/l) led to a pronounced and sustained decrease in the histamine release rate, whereas the release rate of glutamate was enhanced. Superfusion with the inhibitor of NO synthase L-NG-nitro-L-arginine methyl ester (L-NAME, 200 mumol/l) increased the histamine release rate. The inhibitory effect of 200 mumol/l linsidomine was abolished by atropine (10 mumol/l). Superfusion with the glutamate receptor agonists glutamate (100 mumol/l) or N-methyl-D-aspartate (NMDA, 50 mumol/l) enhanced the histamine release rate. In the presence of linsidomine, the releasing effect of NMDA was not changed. These findings demonstrate that the release of histamine in the hypothalamus is diminished by endogenous NO. This effect of NO on histamine release seems to be due to enhanced release of acetylcholine from vicinal cholinergic neurons via stimulation of muscarinic acetylcholine receptors located presynaptically on histaminergic neurons. The NO-induced glutamate release seems to exert a subordinate stimulatory effect on histamine release. Finally, the inhibition of histamine release by NO is not due to blockade of NMDA receptors.