Effects of thyromimetic drugs on aldosterone-dependent sodium transport in the toad bladder.

Aldosterone increases transepithelial Na+ transport in the urinary bladder of Bufo marinus. The response is characterized by 3 distinct phases: 1) a lag period of about 60 min, ii) an initial phase (early response) of about 2 hr during which Na+ transport increases rapidly and transepithelial electrical resistance falls, and iii) a late phase (late response) of about 4 to 6 hr during which Na+ transport still increases significantly but with very little change in resistance. Triiodothyronine (T3, 6 nM) added either 2 or 18 hr before aldosterone selectively antagonizes the late response. T3 per se (up to 6 nM) has no effect on base-line Na+ transport. The antagonist activity of T3 is only apparent after a latent period of about 6 to 8 hr. It is not rapidly reversible after a 4-hr washout of the hormone. The effects appear to be selective for thyromimetic drugs since reverse T3 (rT3) is inactive and isopropyldiiodothyronine (isoT2) is more active than T3. The relative activity of these analogs corresponds to their relative affinity for T3 nuclear binding sites which we have previously described. Our data suggest that T3 might control the expression of aldosterone by regulating gene expression, e.g. by the induction of specific proteins, which in turn will inhibit the late mineralocorticoid response, without interaction with the early response.

Tumor-reactive, SSX-2-specific CD8+ T cells are selectively expanded during immune responses to antigen-expressing tumors in melanoma patients.

The SSX-2 gene encodes a tumor-specific antigen expressed in neoplasms of various histological types. By analyzing a tumor-infiltrated lymph node of a melanoma patient bearing an SSX-2-expressing tumor, we have recently identified the first SSX-2-derived CD8(+) T-cell epitope, that corresponds to peptide SSX-2(41-49), and is recognized by specific CTL in an HLA-A2 restricted fashion. Here, we have used fluorescent HLA-A2/SSX-2(41-49) peptide multimeric complexes to analyze the response to SSX-2(41-49) in melanoma patients and healthy donors. Multimer(+) CD8(+) T cells were readily detected in the majority of patients bearing SSX-2-expressing tumors and, at lower proportions, in patients with nonexpressing tumors and healthy donors. Importantly, isolated A2/SSX-2(41-49) multimer(+) CD8(+) T cells exhibited a large functional heterogeneity in terms of antigen recognition and tumor reactivity. SSX-2-specific CTLs isolated from tumor-infiltrated lymph node of antigen-expressing patients as well as from the corresponding peripheral blood mononuclear cells exhibited high functional avidity of antigen recognition and efficiently recognized antigen-expressing tumors. In contrast, SSX-2-specific CTLs isolated from patients with undetectable responses in the tumor-infiltrated lymph node, as well as from healthy donors, recognized the antigen with decreased functional avidity and were not tumor reactive. Together, these data indicate that CD8(+) T-cell responses to SSX-2(41-49) frequently occur in SSX-2-expressing melanoma patients and suggest that SSX-2(41-49)-specific CTLs of high avidity and tumor reactivity are selectively expanded during immune responses to SSX-2-expressing tumors in vivo.

Congenital tumors: imaging when life just begins.

BACKGROUND: The technical developments of imaging methods over the last 2 decades are changing our knowledge of perinatal oncology. Fetal ultrasound is usually the first imaging method used and thus constitutes the reference prenatal study, but MRI seems to be an excellent complementary method for evaluating the fetus. The widespread use of both techniques has increased the diagnosis rates of congenital tumors. During pregnancy and after birth, an accurate knowledge of the possibilities and limits of the different imaging techniques available would improve the information obtainable, thus helping the medical team to make the most appropriate decisions about therapy and to inform the family about the prognosis. CONCLUSION: In this review article, we describe the main congenital neoplasms, their prognosis and their imaging characteristics with the different pre- and postnatal imaging methods available.

A prospective randomised double-blind controlled trial evaluating the effect of trans-sacral magnetic stimulation in women with overactive bladder.

Overactive bladder (OAB) is a prevalent condition with 16% of adults having one or more symptoms that significantly affect quality of life. Transcutaneous electrical nerve stimulation and neuromodulators have had success in treating OAB but are expensive, invasive, and sometimes cumbersome. We developed an alternative neuromodulatory technique that involves electromagnetic stimulation of the sacral nerve roots with a portable electromagnetic device to produce trans-sacral stimulation of the S3 and S4 sacral nerve roots. The aim of this study was to evaluate the impact of this device on OAB symptoms in women with a prospectively randomised double-blind controlled study. Following a power analysis, women with symptoms of OAB were prospectively recruited with ethical approval for randomisation to an active treatment (n = 33) or placebo group (n = 30) in a double-blind trial. The patient, at home, used the belt device daily for 20 min over 12 weeks. Outcome measures included a 3-day voiding diary, 1 h pad test, visual analogue score (VAS) for symptom impact (0-100%), Kings Health Questionnaire (KHQ) and Australian Quality of Life questionnaire (AQOL) at baseline, 6 and 12 weeks. Overall, no difference was found between groups for any of the research questions. Specifically, we were unable to demonstrate any difference between the active and sham device groups in frequency, nocturia, urinary leakage, or quality of life, nor was there any evidence of a placebo effect. The quality of the data was high with the number of missing observations (especially for disease specific KHQ and general AQOL) being few. This attempt to promote trans-sacral electromagnetic neuromodulation with a specially created device was ineffective on the symptoms of OAB.

Testosterone: a specific competitive antagonist of aldosterone in the toad bladder.

Testosterone (100 nM to 40 microM) antagonized the effect of aldosterone (10 nM) on Na+ transport in the toad bladder measured in vitro as short-circuit current (SCC). Half-maximal inhibition occurred at an antagonist-agonist molar ratio of 150:1. The antagonist action of testosterone was reversed by addition of more aldosterone. The antagonism was specific in the sense that testosterone (20 microM) did not inhibit the response of the SCC to oxytocin (50 mU/ml). By itself, testosterone (up to 20 microM) had no agonist activity on base-line SCC. Finally, testosterone (500 nM to 20 microM) specifically displaced [3H]aldosterone (5 nm) from its cytoplasmic and nuclear binding sites in bladders incubated in vitro at 25 or 0 degrees C and labeled at steady state. There was a significant linear correlation between the effect of testosterone on the aldosterone-dependent SCC and its effect on [3H]aldosterone binding sites in the cytoplasm and in the nucleus. We conclude that 1) testosterone is a specific competitive antagonist of aldosterone, and 2) [3H]aldosterone nuclear and cytoplasmic binding sites could be mineralocorticoid receptors, mediating the action of aldosterone on Na+ transport.

MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951.

PURPOSE: O6-methylguanine-methyltransferase (MGMT) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy (RT). It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendroglial tumors (AOT). PATIENTS AND METHODS: In the European Organisation for the Research and Treatment of Cancer study 26951, 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV. From 165 patients of this study, formalin-fixed, paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis. This was investigated with methylation specific multiplex ligation-dependent probe amplification. RESULTS: In 152 cases, an MGMT result was obtained, in 121 (80%) cases MGMT promoter methylation was observed. Methylation strongly correlated with combined loss of chromosome 1p and 19q loss (P = .00043). In multivariate analysis, MGMT promoter methylation, 1p/19q codeletion, tumor necrosis, and extent of resection were independent prognostic factors. The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival. In tumors diagnosed at central pathology review as glioblastoma, no prognostic effect of MGMT promoter methylation was observed. CONCLUSION: In this study, on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy. The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma.

Connexins 43 and 26 are differentially increased after rat bladder outlet obstruction.

To evaluate the regulation of connexin expression by fluid pressure, we have studied the effects of elevated transmural urine pressure on Connexin43 (Cx43) and Cx26. We chose to focus on these two proteins out of the five connexins (Cx26, 43, 40, 37, and 45) which we found by RT-PCR to be expressed in the rat bladder, since in situ hybridization and immunofluorescence showed that Cx43 is the predominant connexin expressed by smooth muscle cells (SMC), whereas Cx26 is abundantly expressed only in the latter cell type. To evaluate whether these connexins are affected by changes in transmural urine pressure, we used a rat model of bladder outlet obstruction, in which a ligature is placed around the urethra. Under conditions of increased fluid pressure due to urine retention, we observed that the expression of both Cx43 and Cx26 increased at both transcript and protein levels, reaching a maximum 7-9 h after the ligature. Further analysis revealed that these changes were accounted for by a fourfold increase in Cx43 mRNA of SMC but not urothelial cell and by a fivefold increase in Cx26 mRNA of urothelium. Scrape-loading of propidium iodide showed that the latter change was paralleled by a twofold increase in coupling between urothelial cells. The data show that Cx43 and Cx26 are differentially regulated during bladder outlet obstruction and contribute to the response of the bladder wall to increased voiding pressure, possibly to control its elasticity.

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes-or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

A collagen-poly(lactic acid-co-ɛ-caprolactone) hybrid scaffold for bladder tissue regeneration.

Scaffold materials should favor cell attachment and proliferation, and provide designable 3D structures with appropriate mechanical strength. Collagen matrices have proven to be beneficial scaffolds for tissue regeneration. However, apart from small intestinal submucosa, they offer a limited mechanical strength even if crosslinking can enhance their mechanical properties. A more cell-friendly way to increase material strength is to combine synthetic polymer meshes with plastic compressed collagen gels. This work describes the potential of plastic compressed collagen-poly(lactic acid-co-ɛ-caprolactone) (PLAC) hybrids as scaffolds for bladder tissue regeneration. Human bladder smooth muscle and urothelial cells were cultured on and inside collagen-PLAC hybrids in vitro. Scaffolds were analyzed by electron microscopy, histology, immunohistochemistry, and AlamarBlue assay. Both cell types proliferated in and on the hybrid, forming dense cell layers on top after two weeks. Furthermore, hybrids were implanted subcutaneously in the backs of nude mice. Host cell infiltration, scaffold degradation, and the presence of the seeded bladder cells were analyzed. Hybrids showed a lower inflammatory reaction in vivo than PLAC meshes alone, and first signs of polymer degradation were visible at six months. Collagen-PLAC hybrids have potential for bladder tissue regeneration, as they show efficient cell seeding, proliferation, and good mechanical properties.

Pial and arachnoid welding for restoration of normal cord anatomy after excision of intramedullary spinal cord tumors.

A significant postoperative problem in patients undergoing excision of intramedullary tumors is painful dysesthesiae, attributed to various causes, including edema, arachnoid scarring and cord tethering. The authors describe a technique of welding the pia and arachnoid after the excision of intramedullary spinal cord tumors used in seven cases. Using a fine bipolar forcep and a low current, the pial edges of the myelotomy were brought together and welded under saline irrigation. A similar method was used for closing the arachnoid while the dura was closed with a running 5-0 vicryl suture. Closing the pia and arachnoid restores normal cord anatomy after tumor excision and may reduce the incidence of postoperative painful dysesthesiae.

Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse [Fluorescence diagnosis in patients with non-muscle invasive bladder cancer: results of a metaanalysis]

Purpose: Heterogeneous results of single studies with photodynamic diagnosis (PDD) in bladder cancer have been reported. A metaanalysis of prospective studies has now been performed. Material and Methods: The effect of PDD in addition to WLC on a) the diagnosis and b) the therapeutic outcome of primary or recurrent non-muscle invasive bladder cancer (NMIBC) investigated by cystoscopy or transurethral resection was analysed. An electronic database search was performed. Trials were included if they prospectively compared WLC with PDD in bladder cancer. Primary endpoints were additional detection rate, residual tumour at second resection and recurrence-free survival. Results: Significantly more tumour-positive patients were detected with PDD in all patients with non-muscle invasive tumours (= 20%) [95% confidence interval (CI): 8 to 35%] and in CIS patients (= 39%) (CI: 23 to 57%). Residual tumour was significantly less often found after PDD (odds ratio 0.28, CI: 0.15 to 0.52, p<0.0001). Recurrence-free survival was significantly higher at 12 and 24months in the PDD groups than in WLC only groups. Conclusions: More bladder tumour-positive patients are detected by PDD. Best results were found in CIS patients. Diagnosis with PDD results in a more complete resection and a longer recurrence-free survival.

Levetiracetam and pregabalin for antiepileptic monotherapy in patients with primary brain tumors. A phase II randomized study.

BACKGROUND: In patients with brain tumors, the choice of antiepileptic medication is guided by tolerability and pharmacokinetic interactions. This study investigated the effectiveness of levetiracetam (LEV) and pregabalin (PGB), 2 non-enzyme-inducing agents, in this setting. METHODS: In this pragmatic, randomized, unblinded phase II trial (NCT00629889), patients with primary brain tumors and epilepsy were titrated to a monotherapy of LEV or PGB. Efficacy and tolerability were assessed using structured questionnaires. The primary composite endpoint was the need to discontinue the study drug, add-on of a further antiepileptic treatment, or occurrence of at least 2 seizures with impaired consciousness during 1 year follow-up. RESULTS: Over 40 months, 25 patients were randomized to LEV, and 27 to PGB. Most were middle-aged men, with a high-grade tumor and at least one generalized convulsion. Mean daily doses were 1125 mg (LEV) and 294 mg (PGB). Retention rates were 59% in the LEV group, and 41% in the PGB group. The composite endpoint was reached in 9 LEV and 12 PGB patients-need to discontinue: side effects, 6 LEV, 3 PGB; lack of efficacy, 1 and 2; impaired oral administration, 0 and 2; add-on of another agent: 1 LEV, 4 PGB; and seizures impairing consciousness: 1 in each. Seven LEV and 5 PGB subjects died of tumor progression. CONCLUSIONS: This study shows that LEV and PGB represent valuable monotherapy options in this setting, with very good antiepileptic efficacy and an acceptable tolerability profile, and provides important data for the design of a phase III trial.

Traitement chirurgical des tumeurs palpebrales. [Surgical treatment of eyelid tumors]

After reviewing the general principles of eyelid reconstruction, the authors present reconstruction techniques with regard to the location and size of the eyelid defect. When the defect is less than one-quarter of lid length, direct suture is possible. When the defect is larger, reconstruction techniques differ for the upper and lower lid.

Distribution de la morphologie des tumeurs incidentes dans le canton de Vaud [Morphologic distribution of tumors occuring in the canton of Vaud].

After a short presentation of the methodological aspects of cancer registration and morphological coding, the results concerning cancer of the upper digestive tract, lung, testis and ovary were discussed. Some distributions of the main histological types are analysed by age, sex, site and multiple primaries. Known statistical associations are described between morphology and sex for lung cancer and between morphology and controlateral tumor for ovary.

Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process. [Authors]