Osteoporosis in men treated with androgen deprivation therapy for prostate cancer

PURPOSE: We surveyed the growing literature on osteoporosis secondary to androgen deprivation therapy and provide suggestions regarding its identification and treatment. MATERIALS AND METHODS: We reviewed pertinent studies of male osteoporosis, osteoporotic fracture incidence or bone mineral density loss as a possible side effect of prostate cancer treatment and potential therapies for this side effect. RESULTS: Hypogonadism is a well-known cause of secondary osteoporosis in men. There is evidence of decreased bone mineral density with all types of androgen deprivation therapy, presumably due to its anti-testosterone effect. Bone mineral density loss is 3% to 5% yearly in the first few years of androgen deprivation therapy with an increase in osteoporotic fracture incidence. There are little data on potential treatments, although bisphosphonates and intermittent androgen deprivation therapy may have salutary effects. CONCLUSIONS: Osteoporosis is an important and debilitating side effect of androgen deprivation therapy, although precise estimates of its incidence, degree and cost are not completely elucidated. Until more data are available, it is prudent for all men beginning androgen deprivation therapy to receive calcium and vitamin D, and maintain a moderate exercise regimen. Baseline and at least 1 followup bone density measurement seem appropriate with bisphosphonate treatment a possibility in those in whom osteoporosis develops. More research is needed to explore the effect of bisphosphonates, calcium and vitamin D supplementation, exercise, calcitonin, selective estrogen re-uptake inhibitors, estrogens and intermittent androgen deprivation therapy on the course of androgen deprivation therapy induced osteoporosis. The osteoporotic fracture incidence and bone mineral density should be regularly incorporated into studies involving the hormonal treatment of prostate cancer.     

Clinical Value of Neuroimaging in the Diagnosis of Dementia. Sensitivity and Specificity of Regional Cerebral Metabolic and Other Parameters for Early Identification of Alzheimer's Disease

Dementing illnesses such as Alzheimer's disease (AD) progressively devastate human brain tissue and consequently the health and lives of people afflicted by these disorders. One of the greatest clinical challenges posed by dementia is establishing an approach to ensure its early identification and accurate diagnosis-thus making it possible to treat and, potentially, arrest the development of disease before a substantial amount of brain tissue has been permanently destroyed. The data generated by neuroimaging studies conducted over the past two decades show PET with [(18)F]fluorodeoxyglucose (FDG) to be exceptionally well-suited to meeting this challenge. The regional metabolic patterns imaged with FDG-PET enable sensitive diagnosis of AD, and reveal pathophysiologic alterations even before they lead to symptomatic expression. The accuracy of PET in identifying early AD, and distinguishing it from other etiologies of cognitive impairment, exceeds that of CT, MRI (qualitative or quantitative), and SPECT, as well as that of expert clinical evaluation based on history, physical examination, cognitive testing, and blood laboratory values. Recent developments in instrumentation and radiopharmaceutical distribution have made obtaining scans of cerebral metabolism achievable in routine clinical settings, including most hospitals in which Nuclear Medicine services are provided, for less than the cost of a single year of anticholinesterase therapy or a single month of lost productivity. The need and opportunity are thus present for making a fundamental change in the current approach to evaluating patients for dementia.     

The impact of prior radical prostatectomy in men with metastatic castration recurrent prostate cancer: a pooled analysis of 9 Cancer and Leukemia Group B Trials

PURPOSE: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy. MATERIALS AND METHODS: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes. RESULTS: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9-16.7) and 14.5 months (95% CI 13.5-15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90-1.19, p = 0.65) in men with vs without prostatectomy. CONCLUSIONS: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer.     

Intravesical botulinum toxin type A in chronic interstitial cystitis: results of a pilot study.

AIM: To assess the efficacy of intravesical botulinum toxin type A (BTX-A) in interstitial cystitis (IC). METHODS: Eleven patients with IC were injected with BTX-A. Primary outcome measures were: Bristol Female Lower Urinary Tract Symptom Score, Kings Health Questionnaire and 24-hour frequency-volume chart. They had urodynamics done before and six weeks after injection. Detrusor contractility was assessed using the modified PIP1 (projected isovolumetric detrusor pressure).     

Expression of insulin-like growth factor-1 receptor in local and metastatic prostate cancer

PURPOSE: The insulin-like growth factor (IGF)-1 receptor is currently being targeted in clinical trials in prostate cancer. Despite this targeting, there are conflicting data on the presence of this receptor in human tumor samples, largely because of differences in technique. MATERIALS AND METHODS: Immunohistochemistry was used to determine the presence of IGF-1 receptor in frozen normal prostate and prostate cancer specimens. Clinical and pathologic parameters were correlated with IGF-1 receptor intensity and frequency of staining. Only 2-3+ staining on a scale of 0-3 was considered positive in this evaluation. RESULTS: IGF-1 receptor was expressed in normal prostate epithelium in 6 of 6 patients without cancer and in morphologically normal epithelium adjacent to tumor cells in 21 of 22 patients with cancer studied. IGF-1 receptor was present in the prostate tumor epithelium of 28 of 28 primary tumors, 3 of 5 locally recurrent androgen-independent tumors, and in 4 of 5 metastatic lymph nodes. Stromal staining patterns were positive in 2 of 28 specimens near benign epithelium compared to 19 of 30 specimens of stroma surrounding tumor epithelium (P < 0.0001, Fisher exact test). Stroma adjacent to Gleason grade >or=7 tumors showed higher intensity staining than that adjacent to lower grade tumors (P < 0.001). Expression of the closely related insulin receptor did not show expression in either normal or cancer epithelium, or in adjacent stroma. CONCLUSIONS: This study using frozen tissue shows widespread IGF-1 receptor expression in normal prostate, prostate cancers, and metastases. These data support investigations into IGF-1 receptor as a therapeutic target in prostate cancer.     

Unintended consequences of policy change to watchful waiting for asymptomatic inguinal hernias

Introduction

In 2009 the Department of Health instructed McKinsey & Company to provide advice on how commissioners might achieve world class National Health Service productivity. Asymptomatic inguinal hernia repair was identified as a potentially cosmetic procedure, with limited clinical benefit. The Birmingham and Solihull primary care trust cluster introduced a policy of watchful waiting for asymptomatic inguinal hernia, which was implemented across the health economy in December 2010. This retrospective cohort study aimed to examine the effect of a change in clinical commissioning policy concerning elective surgical repair of asymptomatic inguinal hernias.

Methods

A total of 1,032 patients undergoing inguinal hernia repair in the 16 months after the policy change were compared with 978 patients in the 16 months before. The main outcome measure was relative proportion of emergency repair in groups before and after the policy change. Multivariate binary logistic regression was used to adjust the main outcome for age, sex and hernia type.

Results

The period after the policy change was associated with 59% higher odds of emergency repair (3.6% vs 5.5%, adjusted odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03–2.47). In turn, emergency repair was associated with higher odds of adverse events (4.7% vs 18.5%, adjusted OR: 3.68, 95% CI: 2.04–6.63) and mortality (0.1% vs 5.4%, p<0.001, Fisher’s exact test).

Conclusions

Introduction of a watchful waiting policy for asymptomatic inguinal hernias was associated with a significant increase in need for emergency repair, which was in turn associated with an increased risk of adverse events. Current policies may be placing patients at risk.     

Reversible oxidant-induced increases in albumin transfer across cultured endothelium: alterations in cell shape and calcium homeostasis

To determine whether reactive oxygen molecules could directly and reversibly increase the transfer of albumin across an endothelial barrier, we measured albumin transfer across monolayers of endothelium cultured on micropore filters before and after exposure to xanthine and xanthine oxidase. Xanthine and xanthine oxidase increased endothelial albumin transfer in a dose-dependent fashion. Parallel phase contrast and fluorescence microscopy demonstrated retraction of adjacent cells from one another and disruption of the actin filaments. The oxidant- induced increases in albumin transfer and changes in cell shape were reversed by removing xanthine oxidase and then incubating the monolayers for 3 1/2 hours in tissue culture media enriched with fetal bovine serum. However, incubation in tissue culture media without serum resulted in progressive injury and cell death. Hence, the brief exposure to oxidants initiated a progressive injury process that was reversed by incubation in serum. Because intracellular and extracellular calcium are important determinants of cell shape, and because some oxidized membrane lipids act as calcium ionophores, we asked whether oxidants altered endothelial calcium homeostasis. Xanthine-xanthine oxidase increased release of 45Ca++ from preloaded cells. The calcium antagonist lanthanum chloride prevented xanthine- xanthine oxidase increases in endothelial albumin transfer and prevented the changes in cell shape; chelation of extracellular calcium inhibited lysis of endothelium by xanthine-xanthine oxidase; and the calcium ionophore A23187 increased endothelial albumin transfer and mimicked the oxidant-induced changes in cell shape. Lanthanum chloride inhibited these effects of A23187. These data suggest that oxygen radicals can reversibly increase endothelial permeability to macromolecules, that this is associated with reversible changes in endothelial cell shape and actin filaments, and that the changes in cell shape are related to oxidant-induced changes in endothelial calcium homeostasis.     

Computer-assisted distal radius osteotomy

PURPOSE: To establish the accuracy, precision, and clinical feasibility of a novel technique of computer-assisted distal radius osteotomy for the correction of symptomatic distal radius malunion. METHODS: Six patients underwent a computer-assisted distal radius osteotomy and were followed-up for an average of 25 months. Objective radiographic measurements and functional outcomes, as measured by clinical examination including grip strength and range of motion, and Disability of the Arm, Shoulder and Hand (DASH) questionnaires, were used. RESULTS: The mean radiographic parameters included an increase of radial inclination to 21 degrees from 12 degrees (normal, 23 degrees ). Dorsal and volar tilt (malunion) were corrected to 9 degrees from -30 degrees and 21 degrees, respectively (normal, 10 degrees ). Ulnar variance was corrected to 1.9 mm from 7.5 mm (normal, +1.5 mm). Normal is defined as the average of the contralateral limb radiographs. The mean clinical outcome measures at an average of 25 months included a DASH global score of 14, a DASH individual item average score of 1.6, and an average affected side grip strength of 79% when compared with the unaffected side. CONCLUSIONS: The results of the computer-assisted technique were comparable with published results of traditional non-computer-assisted opening wedge osteotomy techniques. This technique allows a surgeon to accurately and precisely recognize and correct 3-dimensional deformities of the distal radius including axial malalignment (supination). The technique has the added benefit of reducing radiation exposure to the patient and surgical team because fluoroscopy is not used during the procedure. Additional benefits of the computer-assisted technique include the ability to perform multiple surgical simulations to optimize the alignment plan, and it serves as an excellent teaching tool for less-experienced surgeons.