Small cell carcinoma of the urinary bladder: a 15‐year retrospective review of treatment and survival in the Anglian Cancer Network

OBJECTIVE

To report the clinical experience and management of patients with small cell carcinoma (SCC) of the bladder, treated in the Anglia Cancer network from 1992 to 2007, and to review published studies, as SCC is a rare condition, accounting for <1% of all bladder tumours, and there is no established treatment strategy for managing these patients.

PATIENTS AND METHODS

We analysed retrospectively data from all patients diagnosed with SCC of the urinary bladder between 1992 and 2007, with an emphasis on stage, treatment and overall survival.

RESULTS

Twenty patients were identified with primary bladder SCC (male: female ratio 3:1; mean age 68 years; mean follow‐up 15.8 months). Nine patients (45%) had extensive‐stage disease at diagnosis. Four patients received best supportive care, three had a radical cystectomy, one radical radiotherapy and six sequential chemo‐radiotherapy. In all, 13 patients were treated with chemotherapy, with six receiving cyclophosphamide, doxorubicin and vincristine, three receiving carboplatin and etoposide, and the remainder receiving alternative platinum‐based regimens. For 12 patients with assessable disease, six had a complete response, three a partial response and three had progressive disease after chemotherapy. No patient received prophylactic cranial irradiation (PCI). At the time of analysis, 14 (70%) patients had died, with one (5%) developing brain metastasis. The median survival was 33 months for patients receiving chemotherapy, vs 3 months with no chemotherapy.

CONCLUSIONS

SCC of the bladder tends to occur in an older population, more commonly in men. It is an aggressive tumour with a propensity for early metastasis. The response rate to chemotherapy is high but the overall prognosis is poor. Brain secondaries are less common than for SCC of the lung and currently the role of PCI is unclear. As there is no standard of care for these patients, they are treated according to local protocols. Further efforts should be made to develop more effective treatments and the role of PCI should be assessed in the setting of a clinical trial, in conjunction with other extrapulmonary SCCs.     

Further characterization of the spatial learning deficit in the human immunodeficiency virus-1 transgenic rat

Human immunodeficiency virus (HIV)-associated dementia (HAD) encompasses a spectrum of cognitive and motor deficits resulting from the progression of central nervous system abnormalities caused by the HIV-1 virus. With the advent of highly active antiretroviral therapy (HAART), these deficits have become milder, but more prevalent as the population of HIV-positive individuals ages. Mild impairment in cognition has also been identified in asymptomatic HIV-1 patients. The noninfectious HIV-1 transgenic (Tg) rat recently developed to study the pathogenesis of acquired immunodeficiency syndrome (AIDS) may also be useful for the study of the early and chronic effects of HIV-1 on learning and cognition. In a previous study, we demonstrated that HIV-1Tg rats show a deficit in learning how to swim to a hidden platform in a modified water maze task compared to normal and transgenic controls. In the present study, we replicate this result and demonstrate that HIV-1Tg rats also show a significant deficit in reversal learning and new strategy learning. These results indicate that the HIV-1Tg rat is a promising model in which to study the neuropathogenic mechanisms that can cause cognitive deficits in patients with HAD as well as asymptomatic HIV-positive individuals.     

Safety and tolerability of once-daily versus twice-daily memantine: a randomised, double-blind study in moderate to severe Alzheimer's disease

OBJECTIVE: To assess the safety and tolerability of three different dosing schedules of memantine in patients with moderate to severe Alzheimer's disease (AD). METHOD: This 12-week, randomised, double-blind study, investigated three dosing schedules of memantine: OD1 (20 mg once daily with a 1-step up-titration); OD3 (20 mg once daily with a 3-step up-titration); and BID3 (10 mg twice daily with a 3-step up-titration as currently recommended in the memantine labelling). The study comprised 78 patients with moderate to severe AD (DSM-IV-TR criteria; MMSE score < or = 18), 70% of whom were on stable dosing of acetylcholinesterase inhibitor (AChEI) initiated > or = 3 months prior to study start. Safety and tolerability were assessed by the number of withdrawals, adverse events (AEs) and monitoring of vital signs. RESULTS: The number of patient withdrawals was low: 3 of 27 in OD1, 1 of 25 in OD3 and 2 of 26 in BID3. One or more AEs were reported in 9 patients in OD1, 7 patients in OD3 and 12 patients in BID3. Most AEs were mild or moderate, and typical for the population studied; no clinically important differences in AEs or vital signs were observed between the different dosing schedules. There were no between-group differences in efficacy, as assessed by clinical global severity and clinical global change. These results are consistent with the good safety profile of memantine observed in larger studies. CONCLUSIONS: Although relatively small in size, the study indicates that once-daily dosing and twice-daily dosing of memantine are similar in terms of safety and tolerability.     

JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition

Histamine 3 (H₃) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H₃ receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H₃ receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H₃ receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.     

Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization

Phenol contamination of soil and water has raised concerns among people living near phenol-producing factories and hazardous waste sites containing the chemical. Phenol, particularly in high concentrations, is an irritating and corrosive substance, making mucosal membranes targets of toxicity in humans. However, few data on the effects of phenol after oral exposure exist.We used an in vitro model employing human intestinal epithelial cells (SK-CO15) cultured on permeable supports to examine effects of phenol on epithelial barrier function. We hypothesized that phenol disrupts epithelial barrier by altering tight junction (TJ) protein expression. The dose-response effect of phenol on epithelial barrier function was determined using transepithelial electrical resistance (TER) and FITC-dextran permeability measurements. We studied phenol-induced changes in cell morphology and expression of several tight junction proteins by immunofluorescence and Western blot analysis. Effects on cell viability were assessed by MTT, Trypan blue, propidium iodide and TUNEL staining.Exposure to phenol resulted in decreased TER and increased paracellular flux of FITC-dextran in a dose-dependent manner. Delocalization of claudin-1 and ZO-1 from TJs to cytosol correlated with the observed increase in permeability after phenol treatment. Additionally, the decrease in TER correlated with changes in the distribution of a membrane raft marker, suggesting phenol-mediated effects on membrane fluidity. Such observations were independent of effects of phenol on cell viability as enhanced permeability occurred at doses of phenol that did not cause cell death. Overall, these findings suggest that phenol may affect transiently the lipid bilayer of the cell membrane, thus destabilizing TJ-containing microdomains.