Skeletal-related events in metastatic prostate cancer and the number needed to treat: a critical consideration.

PURPOSE: With stage migration induced by early diagnosis of prostate-specific antigen, the course of disease for prostate cancer (PCa) patients has changed. Increasingly, patients undergo long-term androgen ablation with consecutive risks including osteoporosis and pathologic fractures. A recent randomized trial found that the RANK ligand inhibitor denosumab was more effective preventing skeletal-related events in patients with metastatic PCa as compared to treatment with the bisphosphonate zoledronic acid. This improved efficacy was linked to an increase of side effects. METHODS: The present analysis compares results reported for both substances using a number needed to treat analysis approach. Based upon these findings, risk-benefit calculations were performed. RESULTS: The results demonstrate that for patients with bone metastatic castration-resistant PCa, decision for or against treatment with either denosumab or zoledronic acid must not only consider efficacy but needs to balance the desired effects versus potential side effects. This is of specific relevance since life expectancy is limited in this patient cohort with end-stage disease. CONCLUSIONS: Further scientific efforts are necessary to identify optimal dosing and application intervals for denosumab and zoledronic acid as well as to answer the question of optimal duration of treatment. These findings will directly impact the risk versus benefit relations for both therapeutic options.

Immunocytology in the assessment of patients with painless gross haematuria.

OBJECTIVE: To evaluate, in a prospective study, the role of immunocytology in assessing patients with gross haematuria. Due to the high prevalence of urothelial cancer in this population, a thorough assessment is mandatory to identify all patients with tumours. PATIENTS AND METHODS: We used Ucyt (DiagnoCure Inc., Quebec, Canada), a commercially available immunocytological assay based on the microscopic detection of tumour-associated antigens on the membrane of urothelial cells by immunofluorescence. Between October 2000 and March 2007, 61 consecutive patients with a first episode of painless gross haematuria, but no previous transitional cell carcinoma, were included. Urine samples were obtained from all patients and examined cytologically and immunocytologically. RESULTS: Clinically (by physical examination, laboratory tests, endoscopy and imaging) there was bladder cancer in 17 patients (28%); further diagnoses were benign prostatic enlargement (20, 33%), urinary tract infection (seven, 12%), urolithiasis (two, 3%), and 'further conditions' (seven, 12%). In 10 patients (16%) the reasons for haematuria were not disclosed. Of the 61 samples, 59 (97%) were assessable by cytology and immunocytology. For cystoscopy, immunocytology and conventional urine cytology the sensitivity was 76%, 88% and 47%, and the specificity 100%, 77% and 95%, respectively. Two bladder tumours were not detected by cystoscopy and immunocytology (one each), and two upper urinary tract tumours were diagnosed by imaging and immunocytology. CONCLUSIONS: The combination of cystoscopy and immunocytology gave 100% sensitivity, while combining cystoscopy and cytology only marginally improved the sensitivity of cystoscopy alone. As sensitivity appears to be of key relevance in assessing patients with gross haematuria, we suggest adding immunocytology to the diagnostic protocol in this situation.

Structural basis of neurogenic bladder dysfunction. II. Myogenic basis of detrusor hyperreflexia.

PURPOSE: We describe the ultrastructure of detrusor smooth muscle in long-standing neurogenic bladder dysfunction in the human. MATERIALS AND METHODS: Detrusor biopsies were obtained from (15 female and 31 male) patients 7 to 96 years old with neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 spinal cord injury and 12 brain disorder. Urodynamically, all patients had detrusor hyperreflexia (neurogenic detrusor overactivity) in addition to bladder outlet obstruction in 4, impaired detrusor contractility in 19, decreased bladder compliance in 4, and detrusor-sphincter dyssynergia in 24. Ultrastructural changes in detrusor, including those associated with detrusor overactivity, impaired detrusor contractility and bladder outlet obstruction, were evaluated qualitatively and quantitatively. RESULTS: Intermediate junctions of muscle cells were absent or reduced in 45 biopsies, which instead had dominant intimate cell appositions with much narrower junctional gaps. A greater than 2 intimate cell apposition-to-intermediate junction ratio was present in 45 biopsies (98%), and intimate cell apposition linked chains of 5 muscle cells or greater in all biopsies (100%). Muscle cell degeneration was observed in 34 biopsies from 20 of 27 patients (74%) with normal contractility and 14 of 19 (74%) with impaired detrusor contractility. No particular changes were associated with functional bladder outlet obstruction due to detrusor-sphincter dyssynergia. CONCLUSIONS: The ultrastructural complete dysjunction pattern is a feature of hyperreflexia as well as nonneuropathic detrusor overactivity of various etiology. A greater than 2 intimate cell apposition-to-intermediate junction ratio had 98% sensitivity but its specificity remains to be determined. The lack of relationship between muscle cell degeneration and detrusor contractility probably reflects limitations of urodynamic measurement of contractility in patients with spinal cord injury and meningomyelocele.

Structural basis of neurogenic bladder dysfunction. I. Methods of prospective ultrastructural study and overview of the findings.

PURPOSE: We standardize procedures for ultrastructural study of detrusor smooth muscle and intrinsic nerves in neurogenic bladder dysfunction in the human, and present an overview of the findings. MATERIALS AND METHODS: The study included 18 female and 33 male patients 7 to 96 years old. They had neurogenic bladder dysfunction with hyperreflexia for less than 1 to 43 years, resulting from upper motoneuron lesions (spinal cord injury 25, brain disorder 17) or combined upper and lower motoneuron deficit (meningomyelocele 9). Endoscopic or open bladder biopsies were processed for ultrastructural study of detrusor smooth muscle and intrinsic neural elements. Qualitative morphologic criteria of muscle cell arrangement, degeneration and cell-cell contacts, as well as those of degeneration and regeneration of intrinsic neural elements are defined. RESULTS: Five biopsies from the brain disorder group had insufficient smooth muscle and were excluded from study. The remaining 46 biopsies were evaluated by electron microscopy, and all displayed the complete dysjunction pattern of detrusor overactivity. Most displayed degeneration and regeneration of intrinsic axons but disproportionately limited muscle cell degeneration, irrespective of detrusor contractility. The brain disorder group biopsies displayed many more ultrastructurally normal axons than the meningomyelocele and spinal cord injury group biopsies (median 33% versus 8% or less). CONCLUSIONS: Upper motoneuron neurogenic bladder dysfunction in humans is associated with intrinsic neuromuscular defects in the detrusor. Ultrastructural features of these defects suggest morphologic markers that not only may distinguish neuropathic from nonneuropathic bladder dysfunction, but also may point to the anatomical level of the neurogenic deficit.

Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation.

PURPOSE: We studied the ultrastructure of intrinsic detrusor innervation in long-standing neurogenic bladder dysfunction in the human. MATERIALS AND METHODS: Endoscopic or open detrusor biopsies were obtained from 15 female and 31 male patients 7 to 96 years old who had hyperreflexic neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 had spinal cord injury and 12 had a brain disorder. Changes in intrinsic detrusor nerves were evaluated by electron microscopy qualitatively and quantitatively according to predefined criteria. RESULTS: Axonal degeneration was observed in 44 of the 45 biopsies with discernible intrinsic nerves. Structurally normal axons were 5(1/2) or 4 times more common in brain disorder than meningomyelocele or spinal cord injury group biopsies (median 33%, 6%, 8%, respectively). Axonal regeneration, not encountered in nonneuropathic dysfunctional detrusors, was observed in restricted distribution in most biopsies (76%) and was independent of the duration of neurogenic bladder dysfunction. Axon sprouts were observed in 17 biopsies (38%), and copeptidergic axons formed 20% (median per biopsy) of discernible axon profiles in contrast to less than 1% in normal detrusor. Activated Schwann cells were observed in all but 1 biopsy. The axonal changes were not associated with the level or degree of spinal cord lesion in patients with meningomyelocele or spinal cord injury. CONCLUSIONS: Combined degeneration and regeneration is the characteristic change in intrinsic nerves of detrusor in upper motoneuron neurogenic bladder dysfunction. The observed changes offer the possibility of clinically recognizing neuropathic contribution to a dysfunctional detrusor, as well as the potential to distinguish its spinal versus supraspinal etiology.