Adjuvant vs. progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial.

BACKGROUND: Cisplatin-based chemotherapy (ChT) is the preferred perioperative treatment in muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Nevertheless, a certain number of patients are ineligible for platinum-based ChT. This trial compared immediate adjuvant vs. delayed gemcitabine ChT at progression in platinum-ineligible patients with high-risk UCUB. METHODS: High-risk platinum-ineligible UCUB patients (n = 115) were randomized 1:1 to adjuvant gemcitabine (n = 59) or gemcitabine at progression (n = 56). Overall survival was analyzed. Additionally, we analyzed progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: After a median follow-up of 3.0 years (inter quartile range [IQR]: 1.3-11.6), adjuvant ChT did not significantly prolong overall survival (OS) (HR: 0.84; 95% CI: 0.57-1.24; P = 0.375), with 5-year OS of 44.1% (95% CI: 31.2-56.2) and 30.4% (95% CI: 19.0-42.5), respectively. We noted no significant difference in PFS (HR: 0.76; 95% CI: 0.49-1.18; P = 0.218), with 5-year PFS of 36.2% (95% CI: 22.8-49.7) in the adjuvant group and 22.2% (95% CI: 11.5%-35.1%) when treated at progression. Patients with adjuvant treatment showed a significantly worse QoL. The trial was prematurely closed after recruitment of 115 of the planned 178 patients. CONCLUSIONS: There was no statistically significant difference in terms of OS and PFS for patients with platinum-ineligible high-risk UCUB receiving adjuvant gemcitabine compared to patients treated at progression. These findings underline the importance of implementing and developing new perioperative treatments for platinum-ineligible UCUB patients.

Oral batyl alcohol supplementation rescues decreased cardiac conduction in ether phospholipid-deficient mice.

Plasmalogens (Pls) are a class of membrane phospholipids which serve a number of essential biological functions. Deficiency of Pls is associated with common disorders such as Alzheimer's disease or ischemic heart disease. A complete lack of Pls due to genetically determined defective biosynthesis gives rise to rhizomelic chondrodysplasia punctata (RCDP), characterized by a number of severe disabling pathologic features and death in early childhood. Frequent cardiac manifestations of RCDP include septal defects, mitral valve prolapse, and patent ductus arteriosus. In a mouse model of RCDP, reduced nerve conduction velocity was partially rescued by dietary oral supplementation of the Pls precursor batyl alcohol (BA). Here, we examine the impact of Pls deficiency on cardiac impulse conduction in a similar mouse model (Gnpat KO). In-vivo electrocardiographic recordings showed that the duration of the QRS complex was significantly longer in Gnpat KO mice than in age- and sex-matched wild-type animals, indicative of reduced cardiac conduction velocity. Oral supplementation of BA for 2 months resulted in normalization of cardiac Pls levels and of the QRS duration in Gnpat KO mice but not in untreated animals. BA treatment had no effect on the QRS duration in age-matched wild-type mice. These data suggest that Pls deficiency is associated with increased ventricular conduction time which can be rescued by oral BA supplementation.

Characterization of Atypical Off-Flavor Compounds in Natural Cork Stoppers by Multidimensional Gas Chromatographic Techniques.

Natural cork stoppers with sensory deviations other than the typical cork taint were subgrouped according to their sensory descriptions and compared with unaffected control cork stoppers. The assessment of purge and trap extracts obtained from corresponding cork soaks was performed by heart-cut multidimensional gas chromatography-olfactometry (MDGC-O). The identification of compounds responsible for atypical cork taint detected in MDGC-O was further supported with additional multidimensional GC analysis in combination with mass spectrometric detection. Geosmin and 2-methylisoborneol were mainly found in cork stoppers described as moldy and cellarlike; 3-isopropyl-2-methoxypyrazine and 3-isobutyl-2-methoxypyrazine were found in cork stoppers described with green attributes. Across all cork subgroups, the impact compound for typical cork taint, 2,4,6-trichloroanisole (TCA), was present and is therefore a good marker for cork taint in general. Another potent aroma compound, 3,5-dimethyl-2-methoxypyrazine (MDMP), was also detected in each subgroup, obviously playing an important role with regard to the atypical cork taint. Sensory deviations possibly affecting the wine could be generated by MDMP and its presence should thus be monitored in routine quality control.

How does the 'ancient' asexual Philodina roseola (Rotifera: Bdelloidea) handle potential UVB-induced mutations?

Like other obligate asexuals, bdelloid rotifers are expected to suffer from degradation of their genomes through processes including the accumulation of deleterious mutations. However, sequence-based analyses in this regard remain inconclusive. Instead of looking for historical footprints of mutations in these ancient asexuals, we directly examined the susceptibility and ability to repair point mutations by the bdelloid Philodina roseola by inducing cyclobutane-pyrimidine dimers (CPDs) via exposure to UVB radiation (280-320 nm). For comparison, we performed analogous experiments with the facultative asexual monogonont rotifer Brachionus rubens. Different strategies were found for the two species. Philodina roseola appeared to shield itself from CPD induction through uncharacterized UV-absorbing compounds and, except for the genome reconstruction that occurs after desiccation, was largely unable to repair UVB-induced damage. By contrast, B. rubens was more susceptible to UVB irradiation, but could repair all induced damage in ~2 h. In addition, whereas UV irradiation had a significant negative impact on the reproductive output of P. roseola, and especially so after desiccation, that of B. rubens was unaffected. Although the strategy of P. roseola might suffice under natural conditions where UVB irradiation is less intense, the lack of any immediate CPD repair mechanisms in this species remains perplexing. It remains to be investigated how typical these results are for bdelloids as a group and therefore how reliant these animals are on desiccation-dependent genome repair to correct potential DNA damage given their obligate asexual lifestyle.

Nutritional aspects of primary prostate cancer prevention.

There are three well-known and indisputable risk factors for development of prostate cancer, namely heredity, ethnic origin, and increasing age. Geographic variations in incidence rates are considerable and, therefore, it has been suggested that environmental factors may also play a role. Data from migration studies clearly show that men with the same genetic background raised in different environments present the risk of the disease associated with their country of residency. Prostate cancer is a good candidate for studies on primary prevention due to several specific features such as high prevalence, long latency, hormonal dependency, serum markers for monitoring (prostate specific antigen), and histological precursor lesions (prostatic intraepithelial neoplasia). Nutritional factors that may influence the disease include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D and E), fruit and vegetable intake, minerals (calcium, selenium), and phytoestrogens (isoflavonoids, flavonoids, lignans). Most studies reported to date are case-control analysis. The selenium and vitamin E cancer prevention trial (SELECT), however, is a population-based, prospective, randomized clinical trial to examine the effect of selenium and vitamin E alone or in combination on prostate cancer risk reduction. The trial was discontinued recently as there was no evidence of a benefit from either agent. Nevertheless, lifestyle changes could be recommended to men at risk for developing clinical prostate cancer.

An EMF cell with a nitrogen solid electrolyte--on the transference of nitrogen ions in yttria-stabilized zirconia.

The mobility and electrochemical activity of nitrogen inside and/or at the surface of ionic compounds is of fundamental, as well as of possibly practical, relevance. In order to better understand the role of nitrogen anions in solid electrolytes, we measured the transference number of nitrogen in yttria-stabilized zirconia (YSZ) by a concentration cell technique as a function of oxygen activity at different temperatures in the range of 1023 ≤T/K≤ 1123. YSZ doped with 1.9 wt% of N (YSZ:N) turned out to have an appreciable nitrogen transference number, which increased from 0 to 0.1 with decreasing oxygen activity in the range of -20 < log a(O(2)) < -14. The stability of N in YSZ:N, however, has yet to be elucidated under oxidizing conditions.

Nephron sparing surgery in renal cancer--individual decision or standard procedure?

Organ-preserving surgery has gained widespread acceptance within the international urological community through the last decade. In consequence, the question of radical vs. nephron sparing surgery for the treatment of renal cancer is increasingly discussed in a controversial way. Today, even advocates of a radical nephrectomy must admit that long-term results obtained through nephron sparing surgery are excellent. In consequence, heminephrectomy has become a standard treatment in patients with impaired renal function. However, in patients with a normal contralateral kidney, national and international guidelines still favor radical nephrectomy. An increased morbidity and doubts on the efficacy of heminephrectomy concerning tumor control are the key reasons behind this strategy. Within this analysis the authors stress the hypothesis that the actual differences between organ-preserving surgery and radical nephrectomy concerning survival are marginal if the requirements for heminephrectomy are met. Therefore, the actual controversy appears to be rather based upon assumptions and convictions than on actual facts. To definitively answer this question a prospective randomized trial is suggested, however, the problems of this study may not be underestimated.

Cirugía conservadora de la nefrona en el cáncer de riñón - ¿decisión individual oprocedimiento normalizado? / Nephron sparing surgery in renal cancer individual decision or standard procedure?

A lo largo de la última década, la cirugía conservadora del órgano ha alcanzado reconocimiento generalizado dentro de la comunidad urológica internacional. En consecuencia, la cuestión de la cirugía radical frente a la cirugía conservadora del órgano está siendo cada vez más debatida de forma polémica. A día de hoy, incluso los defensores de la nefrectomía radical deben admitir que los resultados a largo plazo obtenidos con la cirugía conservadora de la nefrona son excelentes. Por consiguiente, la heminefrectomía se ha convertido en un tratamiento habitual en pacientes con función renal comprometida. Sin embargo, en pacientes cuyo riñón contralateral es normal, las directrices nacionales e internacionales siguen mostrándose favorables a la nefrectomía radical. El aumento de la morbilidad y las dudas sobre la eficacia de la heminefrectomía en relación con el control tumoral son los motivos clave tras esta estrategia. Como parte de este análisis, los autores destacan la hipótesis de que las diferencias actuales entre cirugía conservadora del órgano y nefrectomía radical en relación con la supervivencia son marginales siempre que se cumplan los requisitos para la heminefrectomía. Así pues, la polémica actual parece basarse sobre todo en suposiciones y convicciones más que en hechos reales. Para responder definitivamente a esta pregunta se ha sugerido la realización de un ensayo clínico prospectivo y aleatorizado, aunque sin subestimar los problemas que conlleva dicho estudio. (AU)

Interaction of antibodies to proteinase 3 (classic anti-neutrophil cytoplasmic antibody) with human renal tubular epithelial cells: impact on signaling events and inflammatory mediator generation.

Among the anti-neutrophil cytoplasmic Abs (ANCA), those targeting proteinase 3 (PR3) have a high sensitivity and specificity for Wegener's granulomatosis (WG). A pathogenetic role for these autoantibodies has been proposed due to their capacity of activating neutrophils in vitro. Recently, PR3 was also detected in human renal tubular epithelial cells (TEC). In the present study, the effect of murine monoclonal anti-PR3 Abs (anti-PR3) and purified c-ANCA targeting PR3 from WG serum on isolated human renal tubular cell signaling and inflammatory mediator release was characterized. Priming of TEC with TNF-alpha resulted in surface expression of PR3, as quantified in immunofluorescence studies and by flow cytometry. Moreover, PR3 was immunoprecipitated on surface-labeled TEC. Primed TEC responded to anti-PR3 with a dose- and time-dependent activation of phosphoinositide hydrolysis, resulting in a remarkable accumulation of inositolphosphates. Control IgG was entirely ineffective, whereas PR3-ANCA reproduced the phosphoinositide response. The signaling response was accompanied by a pronounced release of superoxidanion into the cell supernatant. Moreover, large amounts of PGE(2) and, to a lesser extent, of thromboxane B(2), the stable metabolite of TxA(2), were secreted from anti-PR3-stimulated TEC. In parallel, a rise in intracellular cAMP levels was observed, which was blocked by the cyclooxygenase inhibitor indomethacin. We conclude that anti-PR3 Abs directly target renal TECs, thereby provoking pronounced activation of the phosphoinositide-related signal transduction pathway. Associated metabolic events such as the release of reactive oxygen species and lipid mediators may directly contribute to the development of renal lesions and loss of kidney function in WG.