Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression

OBJECTIVE: Few studies have examined pathological changes in serotonergic neurons in depression, particularly in elderly patients and in elderly patients in which depression occurs in dementia. The authors hypothesized that greater neurofibrillary pathology and fewer serotonergic neurons would be found in the dorsal raphe nuclei in depressed elderly subjects, compared with nondepressed elderly subjects, and in Alzheimer's disease patients with depression, compared to Alzheimer's disease patients without depression. METHOD: In a postmortem study, immunocytochemistry and two-dimensional image analysis were used to measure neuronal density and neuritic pathology in serotonergic neurons in the dorsal raphe nuclei of elderly subjects with primary major depression (N=14), elderly Alzheimer's disease patients with (N=8) and without (N=7) comorbid depression, and nondepressed elderly comparison subjects (N=10). RESULTS: No differences in neuritic pathology or neuronal density were found between the subjects with primary major depression and the nondepressed comparison subjects. The Alzheimer's disease subjects showed markedly fewer serotonergic neurons and associated higher levels of neuritic pathology, compared with the subjects with primary depression and the nondepressed comparison subjects, but the Alzheimer's disease subjects with comorbid major depression did not differ from the Alzheimer's disease subjects without depression on these measures. CONCLUSIONS: The study found no evidence of a loss of serotonergic neurons or of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid Alzheimer's disease. These findings suggest that if serotonergic dysfunction occurs in older depressed subjects, it is not due to neuronal loss in the brainstem. Pathophysiological changes may lie elsewhere, such as in the frontal-subcortical circuits.     

Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer

Objectives  To study the time-to-recurrence and duration of response in non-muscle invasive bladder cancer (NMIBC) patients, with a complete ablative response after intravesical apaziquone instillations. Methods  Transurethral resection of bladder tumour(s) (TURBT) was performed in patients with multiple pTa-T1 G1-2 urothelial cell carcinoma (UCC) of the bladder, with the exception of one marker lesion of 0.5–1.0 cm. Intravesical apaziquone was administered at weekly intervals for six consecutive weeks, without maintenance instillations. A histological confirmed response was obtained 2–4 weeks after the last instillation. Routine follow-up (FU) was carried out at 6, 9, 12, 18 and 24 months from the first apaziquone instillation. Results  At 3 months FU 31 of 46 patients (67.4%) had a complete response (CR) to ablative treatment. Side-effects on the long-term were only mild. Two CR patients dropped out during FU. On intention-to-treat (ITT) analysis 49.5% of the CR patients were recurrence-free at 24 months FU, with a median duration of response of 18 months. Of 15 no response (NR) patients, only two received additional prophylactic instillations after TURBT. On ITT-analysis 26.7% of the NR patients were recurrence-free (log rank test, P = 0.155). The overall recurrence-free survival was 39% (18 of 46 patients) at 24 months FU. Conclusions  The CR of the marker lesion in 67% of patients was followed by a recurrence-free rate of 56.5% at 1-year FU, and 49.5% at 2-year FU. These long-term results are good in comparison with the results of other ablative studies.     

Experimental rat bladder urothelial cell carcinoma models

Bladder cancer is a major public health problem. Currently available therapeutic options seem to be unable to prevent bladder cancer recurrence and progression. To enable preclinical testing of new intravesical therapeutic agents, a suitable bladder tumor model that resembles human disease is highly desirable. The aim of this topic paper was to discuss the problems associated with current in vivo animal bladder tumor models, focusing on the orthotopic syngeneic rat bladder tumor model. In the second part of the paper the development of a potential new orthotopic rat bladder tumor model is described.     

Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer

Background

Cigarette smoking is the most well-established risk factor for developing bladder cancer.

Objective

To investigate the role of smoking status on the clinical outcome of patients with non-muscle-invasive bladder cancer.

Design, setting, and participants

Data obtained during a prospective phase 3 study with three schedules of epirubicin were used for statistical analysis. Smoking status (obtained when entering the study), other prognostic variables, and clinical outcome measures of 718 patients were analyzed. Mean follow-up was 2.5 yr.

Measurements

The primary outcome measure was recurrence-free survival (RFS).

Results and limitations

Demographics were similar for nonsmokers versus ex-smokers and current smokers, except for gender (p < 0.001) and grade (p = 0.022). In univariate analyses, RFS was significantly shorter in male patients (p = 0.020), in patients with a history of recurrences (p < 0.003), in patients with multiple tumors (p < 0.004), in patients with a history of intravesical therapy (p = 0.037), and in ex-smokers and current smokers (p = 0.005). In multivariate analyses, a history of recurrences, multiplicity, and smoking status remained significant factors for predicting RFS. Gender and initial therapy were no longer a significant influence on RFS.Because progression was uncommon (n = 25) and follow-up was short and focused only on recurrences, no conclusion can be drawn on progression-free survival. A limitation of the study were the questionnaires. They were only used when entering the study, and there were no questions about passive smoking and other causal factors.

Conclusions

In this prospective study, the significance of known factors (history of recurrences and number of tumors) in predicting RFS was confirmed. Another significant factor that appears to predict RFS is smoking status: ex-smokers and current smokers had a significantly shorter RFS compared with nonsmokers.     

Conditional analyses of recurrence and progression in patients with TaG1 non–muscle-invasive bladder cancer

Objective

To determine conditional recurrence-free survival (RFS) and progression-free survival (PFS) and improve decision-making toward surveillance protocols and scheduling. Furthermore, evaluating the evolution of predictors for disease recurrence over time, because TaG1 non–muscle-invasive bladder cancer harbors a risk of disease recurrence and progression.

Implementing the MOLST (medical orders for life-sustaining treatments): Challenges faced by nursing home staff

This study examined how the Medical Orders for Life-sustaining Treatment (MOLST) is implemented in two nursing homes in Massachusetts; one had primarily long-term care residents and high hospice utilization, the other had low hospice utilization and a high proportion of post-acute care residents. Qualitative in-person interviews with 21 staff members who had a role implementing the MOLST explored their experiences using the form in their daily work routines. Staff at both nursing homes described benefits of the MOLST such as providing guidance for staff and family. Yet, they also gave detailed accounts of challenges they face in implementing the form. They reported problems with the form itself such as confusing language and conflicting categories as well as a set of procedural challenges that undermined the timely completion of the form. The nursing home with more post-acute care residents faced more challenges with transferability of the MOLST to and from hospitals.     

Current strategies for first and second line intravesical therapy for nonmuscle invasive bladder cancer

PURPOSE OF REVIEW: Nonmuscle invasive bladder cancer is a common malignancy, usually treated by transurethral resection and adjuvant intravesical instillations of chemotherapy or immunotherapy. Appropriate adjuvant treatment can be selected based on several prognostic factors that determine risk for recurrence or progression. We discuss options for first-line and second-line adjuvant therapy for nonmuscle invasive bladder cancer. RECENT FINDINGS: Mitomycin-C and epirubicin are the mostly used adjuvant chemotherapeutic drugs for tumours of low and intermediate risk. Bacillus Calmette-Guérin remains first-choice therapy in high-risk nonmuscle invasive bladder cancer. Gemcitabine and apaziquone are especially promising for treatment of intermediate risk nonmuscle invasive bladder cancer but require further study. Device-assisted therapies, such as thermochemotherapy and electromotive drug administration, have yielded good results in high-risk nonmuscle invasive bladder cancer and could be considered second-line therapy in this setting. SUMMARY: Primary problems in nonmuscle invasive bladder cancer are its tendency to recur and its elusiveness (especially high-risk nonmuscle invasive bladder cancer) of progression to muscle invasive disease. First-line adjuvant therapies are well established but suboptimal. Some second-line therapies are promising but should be used cautiously, because in some patients the best option is not always the conservative one.