CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells.

Stimulus-sensitive, nanomedicine-based photosensitizer delivery has an opportunity to target tumor tissues since oxidative stress and the expression of molecular proteins, such as CD44 receptors, are elevated in the tumor microenvironment. The aim of this study is to investigate the CD44 receptor- and reactive oxygen species (ROS)-sensitive delivery of nanophotosensitizers of chlorin e6 (Ce6)-conjugated hyaluronic acid (HA) against HeLa human cervical cancer cells. For the synthesis of nanophotosensitizers, thioketal diamine was conjugated with the carboxyl group in HA and then the amine end group of HA-thioketal amine conjugates was conjugated again with Ce6 (Abbreviated as HAthCe6). The HAthCe6 nanophotosensitizers were of small diameter, with sizes less than 200. Their morphology was round-shaped in the observations using a transmission electron microscope (TEM). The HAthCe6 nanophotosensitizers responded to oxidative stress-induced changes in size distribution when H2O2 was added to the nanophotosensitizer aqueous solution, i.e., their monomodal distribution pattern at 0 mM H2O2 was changed to dual- and/or multi-modal distribution patterns at higher concentrations of H2O2. Furthermore, the oxidative stress induced by the H2O2 addition contributed to the disintegration of HAthCe6 nanophotosensitizers in morphology, and this phenomenon accelerated the release rate of Ce6 from nanophotosensitizers. In a cell culture study using HeLa cells, nanophotosensitizers increased Ce6 uptake ratio, ROS generation and PDT efficacy compared to free Ce6. Since HA specifically bonds with the CD44 receptor of cancer cells, the pretreatment of free HA against HeLa cells decreased the Ce6 uptake ratio, ROS generation and PDT efficacy of HAthCe6 nanophotosensitizers. These results indicated that intracellular delivery of HAthCe6 nanophotosensitizers can be controlled by the CD44 receptor-mediated pathway. Furthermore, these phenomena induced CD44 receptor-controllable ROS generation and PDT efficacy by HAthCe6 nanophotosensitizers. During in vivo tumor imaging using HeLa cells, nanophotosensitizer administration showed that the fluorescence intensity of tumor tissues was relatively higher than that of other organs. When free HA was pretreated, the fluorescence intensity of tumor tissue was relatively lower than those of other organs, indicating that HAthCe6 nanophotosensitizers have CD44 receptor sensitivity and that they can be delivered by receptor-specific manner. We suggest that HAthCe6 nanophotosensitizers are promising candidates for PDT in cervical cancer.

Redox-Sensitive and Folate-Receptor-Mediated Targeting of Cervical Cancer Cells for Photodynamic Therapy Using Nanophotosensitizers Composed of Chlorin e6-Conjugated ß-Cyclodextrin via Diselenide Linkage.

The aim of this study was to fabricate a reactive oxygen species (ROS)-sensitive and folate-receptor-targeted nanophotosensitizer for the efficient photodynamic therapy (PDT) of cervical carcinoma cells. Chlorin e6 (Ce6) as a model photosensitizer was conjugated with succinyl ß-cyclodextrin via selenocystamine linkages. Folic acid (FA)-poly(ethylene glycol) (PEG) (FA-PEG) conjugates were attached to these conjugates and then FA-PEG-succinyl ß-cyclodextrin-selenocystamine-Ce6 (FAPEGbCDseseCe6) conjugates were synthesized. Nanophotosensitizers of FaPEGbCDseseCe6 conjugates were fabricated using dialysis membrane. Nanophotosensitizers showed spherical shapes with small particle sizes. They were disintegrated in the presence of hydrogen peroxide (H2O2) and particle size distribution changed from monomodal distribution pattern to multimodal pattern. The fluorescence intensity and Ce6 release rate also increased due to the increase in H2O2 concentration, indicating that the nanophotosensitizers displayed ROS sensitivity. The Ce6 uptake ratio, ROS generation and cell cytotoxicity of the nanophotosensitizers were significantly higher than those of the Ce6 itself against HeLa cells in vitro. Furthermore, the nanophotosensitizers showed folate-receptor-specific delivery capacity and phototoxicity. The intracellular delivery of nanophotosensitizers was inhibited by folate receptor blocking, indicating that they have folate-receptor specificity in vitro and in vivo. Nanophotosensitizers showed higher efficiency in inhibition of tumor growth of HeLa cells in vivo compared to Ce6 alone. These results show that nanophotosensitizers of FaPEGbCDseseCe6 conjugates are promising candidates as PDT of cervical cancer.

The Complex Relationship Between Lower Urinary Tract Symptoms and Sexual Health.

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) and sexual health have common links. Medical and surgical treatments for LUTS can significantly affect various domains of sexual health including erectile function, ejaculatory function, and libido. This review summarizes recent findings. RECENT FINDINGS: Current literature demonstrates a strong association between LUTS, sexual health, and metabolic syndrome. The role of miRNA is also being investigated. Combination medical therapy with phosphodiesterase 5 inhibitors (PDE5-I) shows promise but needs further investigation. Newer surgical therapies for benign prostatic hyperplasia (BPH) aim to preserve sexual function without sacrificing efficacy and durability. Although we are beginning to acknowledge the link between LUTS and sexual health, a better understanding of the underlying biochemistry is needed. Only then can more effective therapies be developed. Further prospective studies should focus on the long-term durability and safety of treatments for both conditions.

A comparison of analgesic prescribing among ED back and neck pain visits receiving physical therapy versus usual care.

OBJECTIVE: Physical therapy (PT) is commonly cited as a non-opioid pain strategy, and previous studies indicate PT reduces opioid utilization in outpatients with back pain. No study has yet examined whether PT is associated with lower analgesic prescribing in the ED setting. METHODS: This was a retrospective cohort study of discharged ED visits with a primary ICD-10 diagnosis relating to back or neck pain from 10/1/15 to 2/21/17 at an urban academic ED. Visits receiving a PT evaluation were matched with same-date visits receiving usual care. We compared the primary outcomes of opioid and benzodiazepine prescribing between the two cohorts using chi-squared test and multivariable logistic regression. RESULTS: 74 ED visits received PT during the study period; these visits were matched with 390 same-date visits receiving usual care. Opioid prescribing among ED-PT visits was not significantly higher compared to usual care visits on both unadjusted analysis (50% vs 42%, p = 0.19) and adjusted analysis (adjOR 1.05, 95% CI 0.48-2.28). However, benzodiazepine prescribing among ED-PT visits was significantly higher than usual care visits on both unadjusted (45% vs 23%, p < 0.001) and adjusted analysis (adjOR 3.65, 95% CI 1.50-8.83). CONCLUSIONS: In this single center study, ED back and neck pain visits receiving PT were no less likely to receive an opioid prescription and were more likely to receive a benzodiazepine than visits receiving usual care. Although prior studies demonstrate that PT may reduce opioid utilization in the subsequent year, these results indicate that analgesic prescribing is not reduced at the initial ED encounter.

Industrializing Autologous Adoptive Immunotherapies: Manufacturing Advances and Challenges.

Cell therapy has proven to be a burgeoning field of investigation, evidenced by hundreds of clinical trials being conducted worldwide across a variety of cell types and indications. Many cell therapies have been shown to be efficacious in humans, such as modified T-cells and natural killer (NK) cells. Adoptive immunotherapy has shown the most promise in recent years, with particular emphasis on autologous cell sources. Chimeric Antigen Receptor (CAR)-based T-cell therapy targeting CD19-expressing B-cell leukemias has shown remarkable efficacy and reproducibility in numerous clinical trials. Recent marketing approval of Novartis' Kymriah™ (tisagenlecleucel) and Gilead/Kite's Yescarta™ (axicabtagene ciloleucel) by the FDA further underscores both the promise and legwork to be done if manufacturing processes are to become widely accessible. Further work is needed to standardize, automate, close, and scale production to bring down costs and democratize these and other cell therapies. Given the multiple processing steps involved, commercial-scale manufacturing of these therapies necessitates tighter control over process parameters. This focused review highlights some of the most recent advances used in the manufacturing of therapeutic immune cells, with a focus on T-cells. We summarize key unit operations and pain points around current manufacturing solutions. We also review emerging technologies, approaches and reagents used in cell isolation, activation, transduction, expansion, in-process analytics, harvest, cryopreservation and thaw, and conclude with a forward-look at future directions in the manufacture of adoptive immunotherapies.

Intraoperative Neuromonitoring Alarms: Relationship of the Surgeon's Decision to Intervene (or Not) and Clinical Outcomes in a Subset of Spinal Surgical Patients with a New Postoperative Neurological Deficit.

BACKGROUND: The goal of intraoperative neurophysiologic monitoring (IONM) is to minimize neurologic injury during surgery, yet patients still emerge with postoperative deficits. Few studies focus on outcomes relative to IONM alarms and interventions in this population. The authors sought to analyze the influence of IONM alarms with and without surgical intervention on patient outcome in spinal surgical patients who suffered immediate postoperative neurologic deficits. METHODS: Of 62,038 spinal surgeries with multimodality IONM, 90 patients with new or worsened postoperative neurologic deficits and whose outcomes were reported immediate to the surgery and at discharge were analyzed. Outcomes at discharge were compared for surgeries in which an IONM alarm versus no alarm occurred. Outcomes where surgical intervention was performed versus not performed were also compared. RESULTS: By discharge, 48 (53.3%) of 90 patients had complete or partial recovery of their postoperative deficit. Patients with IONM alarms and surgical interventions had an 80% (39/49) recovery rate overall versus only 26% (7/27) recovery rate of patients with IONM alarms but no interventions, and only 14% (2/14) of patients without IONM alarms and without interventions (P < 0.001). CONCLUSIONS: These data showed significantly more patients recovered by the time of discharge when a surgical intervention was precipitated by an IONM alarm versus when it was not. The authors conclude that surgical interventions based on IONM alarms do improve patient outcomes despite immediate postoperative deficit.

Differential rates of false-positive findings in transcranial electric motor evoked potential monitoring when using inhalational anesthesia versus total intravenous anesthesia during spine surgeries.

BACKGROUND CONTEXT: False-positive loss of transcranial electrical motor evoked potentials (TCe-MEPs) limits the efficacy of motor tract monitoring during spine surgery. Although total intravenous anesthesia (TIVA) is widely regarded as the optimal regimen for TCe-MEPs, inhalational anesthesia is an alternative regimen. PURPOSE: To compare the rates of false-positive TCe-MEPs during spine surgery for patients anesthetized with TIVA and inhalation anesthesia. STUDY DESIGN: A retrospective analysis of data collected from consecutive patients undergoing TCe-MEP monitoring during spinal surgery. PATIENT SAMPLE: Consecutive adult patients from multiple surgical centers undergoing spine surgery inclusive of cervical or thoracic spinal levels during 2008-2009 who received TIVA or inhalation anesthesia. OUTCOME MEASURES: The primary outcome measure was the rate of false-positive alerts using TCe-MEPS, defined as a persistent loss of 90% or greater of the amplitude of TCe-MEP in one or more muscles not attributed to technical or transient systemic factors (hypotension or hypoxia) and not associated with any postoperative neurologic deficit. METHODS: Patients were divided into two groups according to anesthetic regimen: those anesthetized with one or more inhalational agents (n=1,303) and patients anesthetized with TIVA (n=511). The Fisher exact test and unpaired t test were used to compare group characteristics and false-positive rates. Each group was further subdivided by spinal region (cervical, thoracic, and thoracolumbar) and by presence of preoperative motor deficit. A Pearson chi-squared test was used to identify differences according to spinal region. This study was not supported by any financial sources nor do the authors have any financial relationships to disclose. RESULTS: Patient with inhaled anesthesia showed significantly higher rates of false-positive TCe-MEP changes (15.0% vs. 3.2%) compared with the TIVA group. These differences were significant across all surgical subgroups. The inhaled group had a larger number of patients with preoperative motor deficits compared with TIVA (45.0% vs. 37.4%), a potential confounder for false-positive results. However, a significantly higher rate of false-positive TCe-MEP changes was still observed in the inhaled group (11.4% vs. 0.6% for TIVA) when analyzing only those patients without preoperative motor deficits. CONCLUSIONS: Use of inhalation anesthesia during adult spinal surgery is associated with significantly higher rates of false-positive changes compared with TIVA during TCe-MEP monitoring. This relationship appears independent of preoperative motor status. Further study and multivariate analysis of anesthetic agents, diagnosis, and symptoms is necessary to elucidate the impact of these variables. The potential confounding effects of inhalational anesthesia on TCe-MEP monitoring should be considered when determining anesthetic regimen.

Bladder perforation secondary to primary systemic amyloidosis.

Amyloidosis is a disorder of protein folding characterized by extracellular aggregation and deposition of amyloid protein fibrils. Light-chain amyloidosis, also known as primary systemic amyloidosis, is the most common form of the disease. We present a case of an 84-year-old male with a history of systemic primary amyloidosis causing genitourinary, cardiac, and autonomic dysfunction who presented with hematuria and hypotension secondary to bladder perforation. He underwent open repair of a large extraperitoneal bladder defect. He ultimately died as a result of medical complications from his disease.

Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? It is known that both lactate inhibition and carbohydrate restriction inhibit tumour growth. What is unknown is whether the two work synergistically together. This study adds that though the combination of lactate inhibition and carbohydrate restriction did not synergistically slow tumour growth in our model, we confirmed that carbohydrate restriction started after tumour inoculation slowed tumour growth. Moreover, lactate inhibition resulted in changes in the tumour microenvironment that may have implications for future metabolic targeting of prostate cancer growth. OBJECTIVE: To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS: 120 nude athymic male mice (aged 6-8 weeks) were injected s.c. in the flank with 1.0 × 10(5) LAPC-4 prostate cancer cells. • Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh; or NCKD and MCT1 inhibition. • Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. • Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal-Wallis analysis of all four groups. Independent effects of treatment (NCKD vs WD and CHC vs Veh) on tumour volume were tested using linear regression analysis. • All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal-Wallis and linear regression analysis, respectively. RESULTS: There were no significant differences in tumour volumes among the four groups (P= 0.09). • When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P= 0.026), while CHC administration was not (P= 0.981). However, CHC was associated with increased necrotic fraction (P < 0.001). CONCLUSIONS: Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. • MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction.

Creating permissive microenvironments for stem cell transplantation into the central nervous system.

Traumatic injury to the central nervous system (CNS) is highly debilitating, with the clinical need for regenerative therapies apparent. Neural stem/progenitor cells (NSPCs) are promising because they can repopulate lost or damaged cells and tissues. However, the adult CNS does not provide an optimal milieu for exogenous NSPCs to survive, engraft, differentiate, and integrate with host tissues. This review provides an overview of tissue engineering strategies to improve stem cell therapies by providing a defined microenvironment during transplantation. The use of biomaterials for physical support, growth factor delivery, and cellular co-transplantation are discussed. Providing the proper environment for stem cell survival and host tissue integration is crucial in realizing the full potential of these cells in CNS repair strategies.

Effects of dibutyryl cyclic-AMP on survival and neuronal differentiation of neural stem/progenitor cells transplanted into spinal cord injured rats.

Neural stem/progenitor cells (NSPCs) have great potential as a cell replacement therapy for spinal cord injury. However, poor control over transplant cell differentiation and survival remain major obstacles. In this study, we asked whether dibutyryl cyclic-AMP (dbcAMP), which was shown to induce up to 85% in vitro differentiation of NSPCs into neurons would enhance survival of transplanted NSPCs through prolonged exposure either in vitro or in vivo through the controlled release of dbcAMP encapsulated within poly(lactic-co-glycolic acid) (PLGA) microspheres and embedded within chitosan guidance channels. NSPCs, seeded in fibrin scaffolds within the channels, differentiated in vitro to betaIII-tubulin positive neurons by immunostaining and mRNA expression, in response to dbcAMP released from PLGA microspheres. After transplantation in spinal cord injured rats, the survival and differentiation of NSPCs was evaluated. Untreated NSPCs, NSPCs transplanted with dbcAMP-releasing microspheres, and NSPCs pre-differentiated with dbcAMP for 4 days in vitro were transplanted after rat spinal cord transection and assessed 2 and 6 weeks later. Interestingly, NSPC survival was highest in the dbcAMP pre-treated group, having approximately 80% survival at both time points, which is remarkable given that stem cell transplantation often results in less than 1% survival at similar times. Importantly, dbcAMP pre-treatment also resulted in the greatest number of in vivo NSPCs differentiated into neurons (37±4%), followed by dbcAMP-microsphere treated NSPCs (27±14%) and untreated NSPCs (15±7%). The reverse trend was observed for NSPC-derived oligodendrocytes and astrocytes, with these populations being highest in untreated NSPCs. This combination strategy of stem cell-loaded chitosan channels implanted in a fully transected spinal cord resulted in extensive axonal regeneration into the injury site, with improved functional recovery after 6 weeks in animals implanted with pre-differentiated stem cells in chitosan channels.

A natural history of weight change in men with prostate cancer on androgen-deprivation therapy (ADT): results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

OBJECTIVES: • To better understand the natural history of weight change with androgen-deprivation therapy (ADT), we investigated the effect of ADT on body weight among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. • Men undergoing ADT lose lean muscle but gain fat mass, contributing to an overall gain in weight. PATIENTS AND METHODS: • We identified 132 men in SEARCH who received ADT after radical prostatectomy. • 'Weight change' was defined as the difference in weight before starting ADT (6 months before ADT) and the on-ADT weight (between 6 and 18 months after starting ADT). • In a subanalysis, baseline characteristics of weight-gainers and -losers were analysed using univariate and multivariate analysis to test association with weight change. RESULTS: • In all, 92 men (70%) gained weight, and 40 (30%) either lost or maintained a stable weight. • On average, weight on ADT was 2.2 kg higher than the weight before ADT, with the mean change for weight-gainers and -losers being +4.2 kg and -2.4 kg, respectively. • This compared with no significant weight change in the year before starting ADT (paired t-test, change -0.7 kg, P= 0.19) or in the second year on ADT (paired t-test, change -0.5 kg, P= 0.46) for 84 men in whom these additional weight values were recorded. • There was no significant association between any of the features examined and weight change on univariate and multivariate analysis. CONCLUSION: • In this longitudinal study, ADT was accompanied by significant weight gain (+2.2 kg). This change occurred primarily in the first year of therapy, with men neither losing nor gaining additional weight thereafter.

Microsurgical spermatocelectomy: technique and outcomes of a novel surgical approach.

PURPOSE: A microsurgical approach to spermatocelectomy theoretically minimizes the risk of injury to the epididymis and testicular blood supply. We present the technique of microsurgical spermatocelectomy and report our perioperative and recurrence outcomes. MATERIALS AND METHODS: In a 15-year period 23 men with a total of 36 epididymal cystic masses underwent microsurgical resection with confirmation of spermatocele diagnosis by intraoperative identification of sperm in the cyst fluid. We reviewed pathology reports for resected epididymal tissue in the spermatocele specimen. Postoperative outcome measures included complications, sperm count changes, improvement in pain and fertility, and cyst recurrence. RESULTS: Mean spermatocele size was 5.0 cm (range 1 to 15). Common indications for surgery included pain in 35% of cases, infertility in 30% and the 2 conditions in 13%. A total of 13 patients (57%) underwent simultaneous procedures for concomitant varicocele and/or hydrocele with a mean overall surgical time of 152 minutes. A single scrotal hematoma managed conservatively was the only postoperative complication. There was no case of infection. Avoidance of inadvertent epididymal resection was shown by absent epididymal tissue in each of the 36 spermatocele pathology specimens. Also, no patient with preoperative and postoperative semen analyses available experienced a decreased sperm count, confirming the avoidance of iatrogenic epididymal tubule obstruction. At a mean followup of 17.3 months no man had cyst recurrence or testicular atrophy and all with preoperative pain reported improvement. One patient with preoperative infertility achieved pregnancy 12 months after surgery. CONCLUSIONS: Microsurgical spermatocelectomy is safe and effective with a minimal risk of epididymal injury, testicular atrophy and recurrence.

Chitosan channels containing spinal cord-derived stem/progenitor cells for repair of subacute spinal cord injury in the rat.

OBJECTIVE: We evaluated the survival and differentiation capacity of neural stem/progenitor cells (NSPCs) derived from the adult rat spinal cord and seeded on intramedullary chitosan channels that were implanted in a subacute rat spinal cord injury model. METHODS: We implanted into the injured spinal cord a chitosan channel filled with NSPCs harvested from the spinal cord of adult transgenic rats expressing green fluorescent protein 3 weeks after extradural 35g clip compression injury at T8. The NSPC-chitosan channel group was compared with 2 control groups not receiving channels: 1 receiving a direct intramedullary injection of NSPCs into the lesion cavity and 1 receiving trauma alone. The survival and differentiation of NSPCs were evaluated with immunohistochemical and histopathological techniques, and functional improvement was assessed for 6 weeks with the Basso, Beattie, and Bresnahan locomotor score. RESULTS: The NSPC-chitosan channel group showed enhanced survival of NSPCs compared with NSPCs transplanted directly into the lesion cavity, although there was no significant difference in functional recovery between the treatment and control groups. In addition, the intramedullary implantation of the chitosan channel did not worsen the functional deficit after the 35g clip injury. CONCLUSIONS: Chitosan channels enhanced the survival of transplanted NSPCs in the subacutely injured spinal cord. Functional deficits were not exacerbated by the intramedullary transplantation of chitosan channels into the site of injury.

Male circumcision: Africa and beyond?

PURPOSE OF REVIEW: Male circumcision has become an important component of HIV prevention strategies in Africa. Results of recent trials have renewed interest in this ancient procedure and its potential application in the reduction of sexually transmitted infections (STIs). With renewed interest comes controversy, which has always been a close companion to circumcision. RECENT FINDINGS: Following the three randomized trials in Africa demonstrating the protective effects of male circumcision on HIV infection, studies have reported other benefits of circumcision including protection from certain STIs, including human papillomavirus and herpes simplex virus 2. With data accumulating on the public health benefits of circumcision and the endorsement of circumcision from WHO, investigators have begun to evaluate the feasibility, safety and cost of implementation of large-scale circumcision programs. Limitations of circumcision have also been explored. SUMMARY: Male circumcision will likely play an important role in HIV/STI prevention programs in Africa; the inclusion of circumcision in the health policy of developed countries will require further investigation.

Glycemic control and prostate cancer progression: results from the SEARCH database.

PURPOSE: Several studies have examined the association between diabetes mellitus (DM) and prostate cancer (PCa) risk and progression, however nearly all of these studies have compared diabetic versus non-diabetic men. We sought to investigate the role of glycemic control, as measured by HbA1c, on PCa aggressiveness and prognosis in men with DM and PCa from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. METHODS: We identified 247 men in SEARCH with DM and a recorded HbA1c value within the 12 months prior to radical prostatectomy between 1988 and 2009. We divided these men into tertiles by HbA1c level. The associations between HbA1c tertiles and risk of adverse pathology and biochemical recurrence were tested using multivariate logistic regression and Cox proportional hazards models, respectively. RESULTS: Median HbA1c level was 6.9. On multivariate analysis, HbA1c tertiles were predictive of pathological Gleason score (P-trend = 0.001). Relative to the first tertile, men in the second (OR 4.68, P = 0.003) and third tertile (OR 6.60, P < 0.001) were more likely to have Gleason score > or = 4 + 3. HbA1c tertiles were not associated with margin status, node status, extracapsular extension or seminal vesicle invasion (all P-trend > 0.2). In the multivariate Cox proportional hazards model, increasing HbA1c tertiles were not significantly related to risk of biochemical recurrence (P-trend = 0.56). CONCLUSION: Men with higher HbA1c levels presented with more biologically aggressive prostate tumors at radical prostatectomy. Although risk of recurrence was unrelated to HbA1c levels, further studies are needed to better explore the importance of glycemic control on long-term outcomes in diabetic men with PCa.

Androgen deprivation therapy in prostate cancer: anticipated side-effects and their management.

PURPOSE OF REVIEW: In men with metastatic or recurrent prostate cancer, androgen deprivation therapy (ADT) is the standard of care. Although effective in cancer control, ADT is associated with multiple adverse effects of which physicians and patients should be aware herein we review these side-effects and their potential management. RECENT FINDINGS: ADT reduces serum levels of testosterone and estrogen, resulting in changes in body composition, increased fracture risk, development of insulin resistance, and an unfavorable lipid profile. A number of studies have investigated the association of ADT with cardiovascular mortality; however, it is unclear whether such an association exists. Recently, two separate clinical trials have found that denosumab, a monoclonal antibody, and toremifene citrate, a selective estrogen receptor modulator, could be used to reduce the incidence of fracture in men on ADT. SUMMARY: By providing clinicians with a greater awareness of the literature on ADT, we may minimize the physical and psychological impact of its side-effects. Physicians should be aware of a recent statement by a multilateral advisory panel, stating that there is no indication for a cardiovascular evaluation before starting ADT. Finally, physicians should be informed of recent developments in the prevention of vertebral fractures in men on ADT.