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Purpose: Salvage radical prostatectomy is rare due to the risk of postoperative complications. We compare salvage Retzius-sparing robotic assisted radical prostatectomy (SRS-RARP) with salvage standard robotic assisted radical prostatectomy (SS-RARP)., Materials and Methods: A total of 72 patients across 9 centers were identified (40 SRS-RARP vs 32 SS-RARP). Demographics, perioperative data, and pathological and functional outcomes were compared using Student's t-test and ANOVA. Cox proportional hazard models and Kaplan-Meier curves were constructed to assess risk of incontinence and time to continence. Linear regression models were constructed to investigate postoperative pad use and console time., Results: Median followup was 23 vs 36 months for SRS-RARP vs SS-RARP. Console time and estimated blood loss favored SRS-RARP. There were no differences in complication rates or oncologic outcomes. SRS-RARP had improved continence (78.4% vs 43.8%, p <0.001 for 0-1 pad, 54.1% vs 6.3%, p <0.001 for 0 pad), lower pads per day (0.57 vs 2.03, p <0.001), and earlier return to continence (median 47 vs 180 days, p=0.008). SRS-RARP was associated with decreased incontinence defined as >0-1 pad (HR 0.28, 95% CI 0.10-0.79, p=0.016), although not when defined as >0 pad (HR 0.56, 95% CI 0.31-1.01, p=0.053). On adjusted analysis SRS-RARP was associated with decreased pads per day. Lymph node dissection and primary treatment with stereotactic body radiation therapy were associated with longer console time., Conclusions: SRS-RARP is a feasible salvage option with significantly improved urinary function outcomes. This may warrant increased utilization of SRS-RARP to manage men who fail nonsurgical primary treatment for prostate cancer.

Competing Interests: None

Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease-relevant mechanisms. Building on our recent work showing the association of clinical disease course with post-mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology-associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T-allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis., (© 2019 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Inter-individual differences in cortisol production by the hypothalamus-pituitary-adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.

Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. This analysis shows for the first time that (1) in progressive MS, with a mean disease duration of 28.6 ± 13.3 years (mean ± SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; (2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e-06) and a higher lesion load (p = 2e-04) at the time of death, (3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, (4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients.

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1 , and ANO4 . Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16 , and OLR1 , and lipid uptake, such as CHIT1, GPNMB , and CCL18 . Except CCL18 , these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.

Background: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy., Objective: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy., Design, Setting, and Participants: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months., Outcome Measurements and Statistical Analysis: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis., Results and Limitations: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation., Conclusions: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential., Patient Summary: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

HLA-DR, Iba1 and CD68 are widely used microglia markers in human tissue. However, due to differences in gene regulation, they may identify different activation stages of microglia. Here, we directly compared the expression of HLA-DR, Iba1 and CD68 in microglia with different phenotypes, ranging from ramified to amoeboid, to foamy phagocytizing macrophages, in adjacent sections immunocytochemically double stained for two of the markers. Material was used from patients diagnosed with multiple sclerosis (MS) and Alzheimer's disease (AD) patients and control subjects because together they contain all the microglia activation stages in an acute and a chronic inflammatory setting. We found a similar, yet not identical, overall expression pattern. All three markers were expressed by ramified/amoeboid microglia around chronic active MS lesions, but overlap between HLA-DR and Iba1 was limited. Foamy macrophages in the demyelinating rims of active MS lesions of MS expressed more HLA-DR and CD68 than Iba1. All markers were expressed by small microglia accumulations (nodules) in MS NAWM. Dense core AD plaques in the hippocampus were mostly associated with microglia expressing HLA-DR. Diffuse AD plaques were not specifically associated with microglia at all. These results indicate that microglia markers have different potential for neuropathological analysis, with HLA-DR and CD68 reflecting immune activation and response to tissue damage, and Iba1 providing a marker more suited for structural studies in the absence of pathology., (Copyright © 2017. Published by Elsevier B.V.)

Objective: To investigate the results of performing laparoscopic radical prostatectomy (LRP) in patients with high-risk prostate cancer (HRPC): PSA level of ≥20 ng/mL ± biopsy Gleason ≥8 ± clinical T stage ≥2c., Patients and Methods: Of a total of 1975 patients having LRP during a 159-month period from 2000 to 2013, 446 (22.6%) had HRPC; all patients were staged by preoperative magnetic resonance imaging or computed tomography and isotope bone scanning. The median (range) patient age was 64.0 (36-79) years; body mass index 27.0 (18-43) kg/m(2) ; PSA level 8.1 (0.1-93) ng/mL and biopsy Gleason 8 (6-10). All patients had a pelvic lymphadenectomy, which was done using an extended template after April 2008 (53.3%). Neurovascular bundle (NVB) preservation was done in 41.5% (bilateral 26.3%; unilateral 15.2%) of patients; an incremental or partial nerve-sparing technique was used in 99 of the 302 (32.8%) NVBs preserved., Results: The median (range) gland weight was 58.5 (20-161) g; operating time 180 (92-330) min; blood loss 200 (10-1400) mL; postoperative hospitalisation 3.0 (2-7) nights; catheterisation time 14 (2-35) days; complication rate 7.6%; lymph node (LN) count 16 (2-51); LN positivity 16.2%; LN involvement 2 (1-8); positive surgical margin (PSM) rate 26.0%; up-grading 2.5%; down-grading 4.3%; up-staging from T1/2 to T3, 24.7%; down-staging from T3 to T1/2, 6.1%. No cases were converted to open surgery and three patients were transfused (0.7%) after surgery. At a mean (range) follow-up of 24.9 (3-120) months, 79.2% of patients were free of biochemical recurrence, 91.8% were continent and 64.4% of previously potent non-diabetic men aged <70 years were potent after bilateral nerve preservation., Conclusion: The low morbidity, 55.4% specimen-confinement rate, 26.0% PSM rate, 79.2% biochemical disease-free survival, 91.8% continence rate and 64.4% potency rate, at 35.2 months in the present study serve as evidence firstly that surgery is an effective treatment for patients with HRPC, curing many and representing the first step of multi-modal treatment for others, and that LRP for HRPC appears to be as effective as open RP in this context., (© 2014 The Authors. BJU International © 2014 BJU International.)

Objectives: To investigate the long-term outcomes of laparoscopic radical prostatectomy (LRP)., Patients and Methods: In all, 1138 patients underwent LRP during a 163-month period from 2000 to 2008, of which 51.5%, 30.3% and 18.2% were categorised into D'Amico risk groups of low-, intermediate- and high-risk, respectively. All intermediate- and high-risk patients were staged by preoperative magnetic resonance imaging or computed tomography and isotope bone scanning, and had a pelvic lymph node dissection (PLND), which was extended after April 2008. The median (range) patient age was 62 (40-78) years; body mass index was 26 (19-44) kg/m(2) ; prostate-specific antigen level was 7.0 (1-50) ng/mL and Gleason score was 6 (6-10). Neurovascular bundle was preservation carried out in 55.3% (bilateral 45.5%; unilateral 9.8%) of patients., Results: The median (range) gland weight was 52 (14-214) g. The median (range) operating time was 177 (78-600) min and PLND was performed in 299 patients (26.3%), of which 54 (18.0%) were extended. The median (range) blood loss was 200 (10-1300) mL, postoperative hospital stay was 3 (2-14) nights and catheterisation time was 14 (1-35) days. The complication rate was 5.2%. The median (range) LN count was 12 (4-26), LN positivity was 0.8% and the median (range) LN involvement was 2 (1-2). There was margin positivity in 13.9% of patients and up-grading in 29.3% and down-grading in 5.3%. While 11.4% of patients had up-staging from T1/2 to T3 and 37.1% had down-staging from T3 to T2. One case (0.09%) was converted to open surgery and six patients were transfused (0.5%). At a mean (range) follow-up of 88.6 (60-120) months, 85.4% of patients were free of biochemical recurrence, 93.8% were continent and 76.6% of previously potent non-diabetic men aged <70 years were potent after bilateral nerve preservation., Conclusions: The long-term results obtainable from LRP match or exceed those previously published in large contemporary open and robot-assisted surgical series., (© 2014 The Authors. BJU International © 2014 BJU International.)

High-risk prostate cancer (HRPC) currently comprises 17-35% of newly diagnosed cases and has the highest rate of metastasis and cancer-related death, making its management a top priority for improving prostate cancer outcomes. The definition of HRPC is not consensual and several risk stratification criteria have been used, which hinders the interpretation of data and the comparison of different studies. All classifications include prostate-specific antigen (PSA) level, biopsy Gleason score and clinical stage as criteria, but others have been added in an attempt to make stratification more accurate and clinically useful, to enable identification of the patients that can be cured by local treatment of the disease. HRPC was traditionally treated with radiotherapy (RT) and/or androgen deprivation therapy (ADT), but radical prostatectomy (RP) has slowly gained more importance in this context. This article aims to discuss the role of surgery in HRPC, highlighting the advantages of RP as primary treatment option: the ability to provide a definitive stage and grade of the cancer; allowing an early detection of treatment failure by having an undetectable PSA as treatment target; providing excellent local control of the disease; reducing the risk of metastatic progression to a greater extent than does RT. We will try to show the benefits and risks of a "surgery first" approach, keeping in mind that, despite the curative intent, a significant number of patients will still need adjuvant or salvage RT and/or ADT.

There has been a recent and near exponential increase in the use of hemostatic agents and sealants to supplement the rapidly evolving methods in the surgical management of urologic patients. This article reviews the use of hemostatic agents and sealants in current urologic practice.

Background: Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume., Objective: To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates., Design, Setting, and Participants: Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011., Outcome Measurements and Statistical Analyses: The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort., Results and Limitations: Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload., Conclusions: This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases., Patient Summary: In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The basis of gender differences in the prevalence and clinical progression of multiple sclerosis (MS) is not understood. Here, we identify gender-specific responses in steroid synthesis and signaling in the brains of MS patients as possible contributors to these differences. We investigated gene expression changes in these pathways and of inflammatory cytokines in MS lesions and normal-appearing white matter (NAWM) of male and female patients (n=21) and control NAWM (n=14) using quantitative polymerase chain reaction (25 MS lesions, 21 MS NAWM, and 14 control NAWM) and immunohistochemistry (3-4 sections per group). In MS lesions in males, there was local upregulation of aromatase (an enzyme involved in estrogen biosynthesis), estrogen receptor-β (ERβ), and tumor necrosis factor (TNF) mRNA; whereas in females, there was local upregulation of 3β-hydroxysteroid-dehydrogenase, a progesterone synthetic enzyme, and of progesterone receptor. Astrocytes in the rim and center of MS lesions were found to be the primary source of steroidogenic enzyme and receptor expression. Aromatase and ERα mRNA levels were positively correlated with that of TNF in primary cultures of human microglia and astrocytes; TNF caused increased ERα, suggesting that inflammatory signals stimulate estrogen signaling in this cell type. Together, these findings suggest that there are gender differences in the CNS of MS patients that may affect lesion pathogenesis, that is, in males, estrogen synthesis and signaling are induced; whereas in females, progestogen synthesis and signaling are induced. These differences may represent contributing factors to gender differences in the prevalence and course of MS.

Immune surveillance of the central nervous system (CNS) by T cells is important to keep CNS-trophic viruses in a latent state, yet our knowledge of the characteristics of CNS-populating T cells is incomplete. We performed a comprehensive, multi-color flow-cytometric analysis of isolated T cells from paired corpus callosum (CC) and peripheral blood (PB) samples of 20 brain donors. Compared to PB, CC T cells, which were mostly located in the perivascular space and sporadically in the parenchyma, were enriched for cells expressing CD8. Both CD4(+) and CD8(+) T cells in the CC had a late-differentiated phenotype, as indicated by lack of expression of CD27 and CD28. The CC contained high numbers of T cells expressing chemokine receptor CX3CR1 and CXCR3 that allow for homing to inflamed endothelium and tissue, but hardly cells expressing the lymph node-homing receptor CCR7. Despite the late-differentiated phenotype, CC T cells had high expression of the IL-7 receptor α-chain CD127 and did not contain the neurotoxic cytolytic enzymes perforin, granzyme A, and granzyme B. We postulate that CNS T cells make up a population of tissue-adapted differentiated cells, which use CX3CR1 and CXCR3 to home into the perivascular space, use IL-7 for maintenance, and lack immediate cytolytic activity, thereby preventing immunopathology in response to low or non-specific stimuli. The presence of these cells in this tightly regulated environment likely enables a fast response to local threats. Our results will enable future detailed exploration of T-cell subsets in the brain involved in neurological diseases.

Objective: To investigate the learning curve for performing extended pelvic lymphadenectomy (ePLND) during laparoscopic radical prostatectomy (LRP) in patients with intermediate- and high-risk prostate cancer., Patients and Methods: In all, 500 patients underwent ePLND for intermediate- or high-risk prostate cancer by one surgeon during a 48-month period. A transperitoneal laparoscopic approach was used in all patients to allow adequate access to the internal iliac vessels. The variables chosen as being the most important discriminators of the quality of ePLND were operating time, complication rate and lymph node (LN) yield. The learning curves for ePLND were calculated using the cumulative sum and cumulative average methods and the number of procedures performed until attainment of acceptable failure rates (competence levels) was calculated. LN parameters were compared with the results from the preceding 311 cases where limited PLND was undertaken., Results: The median (range) preoperative PSA level was 8.0(1-62.5) ng/mL and biopsy Gleason score was 7(6-10). In all, 64% of patients had intermediate-risk and 36% had high-risk prostate cancer. There were no intraoperative blood transfusions and no conversions to open surgery. The median (range) blood loss was 200(10-1400) mL and the postoperative transfusion rate was 1.6%. The operating time fell at a steady rate of 2.7% after the 15th case and plateaued after 130 patients. At competence levels of 5% and 10%, the learning curve for all complications ended after 346 and 136 patients, respectively. At a 5% competence level the learning curve for PLND-specific complications was 40 cases and there was no learning curve at a 10% competence level. The overall complication rate was 7.2% of which almost half (47%) were deemed to be PLND-specific. The cumulative average of the LN counts plateaued after 150 procedures. Furthermore, the median LN count after ePLND was more than double that of the authors' historical standard PLND controls (14 vs 6, P < 0.001) and increased with experience up to the end of the series (9 to 20). The likelihood of LN involvement (LNI) correlated with biopsy and pathological Gleason grade, clinical and pathological stage and d'Amico risk group., Conclusions: This study suggests a learning curve of ≈130 cases for operating time, 136 cases for all complications, 40 cases for PLND-specific complications and 150 cases for LN yield. The risk of LNI for patients with intermediate- and high-risk prostate cancer was 8.4% and 19.4%, respectively, which suggests that a significant proportion would benefit from ePLND. It also shows that ePLND can be safely incorporated into LRP, and therefore also into robot-assisted RP, in a high-volume setting., (© 2013 BJU International.)

The hypothalamus-pituitary-adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.

Autoantibodies and complement opsonization have been implicated in the process of demyelination in the major human CNS demyelinating disease multiple sclerosis (MS), but scavenger receptors (SRs) may also play pathogenetic roles. We characterized SR mRNA and protein expression in postmortem brain tissue from 13 MS patients in relation to active demyelination. CD68, chemokine (C-X-C motif) ligand 16 (CXCL16), class A macrophage SR (SR-AI/II), LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1), FcγRIII, and LRP-1 (low-density lipoprotein receptor-related protein 1) mRNA were upregulated in the rims of chronic active MS lesions. CD68 and CXCL16 mRNA were also upregulated around chronic active MS lesions. By immunohistochemistry, CD68, CXCL16, and SR-AI/II were expressed by foamy macrophages in the rim and by ramified microglia around chronic active MS lesions. CXCL16 and SR-AI/II were also expressed by astrocytes in MS lesions and by primary human microglia and astrocytes in vitro. These data suggest that SRs are involved in myelin uptake in MS, and that upregulation of CD68, CXCL16, and SR-AI/II is one of the initial events in microglia as they initiate myelin phagocytosis. As demyelination continues, additional upregulation of LOX-1, FcγRIII, and LRP-1 may facilitate this process.

Purpose: To investigate the results of laparoscopic radical prostatectomy (LRP) beyond the learning and discovery curves of 700 patients previously reported by the authors for potency., Patients and Methods: Five hundred consecutive patients underwent LRP during a 28-month period with a minimum follow-up of 12 months. Median age (with range) = 61.0 (33-76) years; prostate-specific antigen level = 7.0 (1-37); biopsy Gleason sum = 7 (4-10). Clinical stage was T1 in 41.0%, T2 in 54.2%, and T3 in 4.8%. Nerve preservation (NP) was performed bilaterally in 57.9%, unilaterally in 15.3%, and on neither side in 26.8%., Results: Median operative time was 157 (91-331) minutes, with no conversions or intraoperative blood transfusions; 0.4% of patients received a transfusion postoperatively, and 4.2% had complications. There were no rectal injuries. The overall positive margin rate was 13.0% and correlated with pathologic parameters. At a minimum of 1 year follow-up (mean=13.5 (12-36) mos), overall survival was 100%, and biochemical disease-free survival was 98.8%. The pad-free rate was 97.4%. Potency (International Index of Erectile Function-5 score ≥17) at a mean follow-up of 13.5 months in previously potent men in their 4th, 5th, 6th, and 7th decades after bilateral NP was 100.0%, 91.8%, 82.9%, and 60.0% and after unilateral NP was 100%, 66.7%, 50.1%, and 0.0%. Overall potency after bilateral neurovascular bundle NVB preservation was 86.9%., Conclusion: LRP is capable of matching or exceeding the best results for open radical prostatectomy and robot-assisted radical prostatectomy when performed by an experienced surgeon in a high-volume setting. These results suggest that the method used to perform radical prostatectomy is a less important determinant of success than surgical experience.

With the increasing prevalence of prostate cancer and evolving methods for the definitive treatment of OCPCa, health economic analyses will be critically important, albeit difficult to carry out. Preliminary studies point to RPP as the most cost-effective treatment for OCPCa. The quickest postoperative recovery, in experienced hands, occurs in RARP and RPP, with ORPP having a slightly, but statistically in significant, shorter hospital stay. It should be stressed that initial treatment costs are not the only important factor in healthcare costs. Readmission for early and late complications and the loss of productivity resulting from variation in time to return to work, need also to be considered. Loss of productivity may also vary in cost between different institutions and countries depending upon the proportion of patients employed. Further large-scale multicentre studies are necessary to assess this.

Objective: To investigate the effect of extended vs standard pelvic lymphadenectomy (sPLND) for patients with intermediate- and high-risk prostate cancer undergoing laparoscopic radical prostatectomy (LRP)., Patients and Methods: Of a total of 1269 patients who underwent LRP during a 109 month period, 374 (30%) had a PLND; 253 men had a sPLND (2000 to March 2008) and 121 had an extended PLND (ePLND; after April 2008) for intermediate- or high-risk prostate cancer. An extraperitoneal approach was used in all patients having sPLND and a transperitoneal approach in patients having ePLND., Results: Patient age, body mass index, gland weight, prostate-specific antigen level and Gleason grade were similar in the two groups. The ePLND group had a greater proportion of patients with cT3 disease (9.9% vs 4.2%, P = 0.046) and was associated with a longer operating time of 206.5 vs 180.0 min (P < 0.001) and a higher node count of 17.5 vs 6.1 (P = 0.002). Blood loss, hospital stay, transfusion and complication rates were similar in the two groups. Lymph node positivity was significantly greater (P = 0.018) in patients with pathological Gleason grade 7 tumours who had ePLND (9.6% vs 1.0%) but was similar for other grades of tumour., Conclusion: Based on these findings, and the results of other studies which show a reduction of prostate cancer-specific mortality of 23% if lymph nodes are positive and 15% if they are negative after ePLND, and the correlation between surgical experience, lymph node yield and positivity, we recommend that all patients undergo ePLND if they are being treated with curative intent for intermediate- and high-risk prostate cancer; ePLND should replace sPLND and surgeons performing <35 cases of RP a year should stop performing RP.

Background: The biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), controls the daily rhythms in physiology and behavior. Early studies demonstrated that light exposure not only affects the phase of the SCN but also the functional activity of peripheral organs. More recently it was shown that the same light stimulus induces immediate changes in clock gene expression in the pineal and adrenal, suggesting a role of peripheral clocks in the organ-specific output. In the present study, we further investigated the immediate effect of nocturnal light exposure on clock genes and metabolism-related genes in different organs of the rat. In addition, we investigated the role of the autonomic nervous system as a possible output pathway of the SCN to modify the activity of the liver after light exposure., Methodology and Principal Findings: First, we demonstrated that light, applied at different circadian times, affects clock gene expression in a different manner, depending on the time of day and the organ. However, the changes in clock gene expression did not correlate in a consistent manner with those of the output genes (i.e., genes involved in the functional output of an organ). Then, by selectively removing the autonomic innervation to the liver, we demonstrated that light affects liver gene expression not only via the hormonal pathway but also via the autonomic input., Conclusion: Nocturnal light immediately affects peripheral clock gene expression but without a clear correlation with organ-specific output genes, raising the question whether the peripheral clock plays a "decisive" role in the immediate (functional) response of an organ to nocturnal light exposure. Interestingly, the autonomic innervation of the liver is essential to transmit the light information from the SCN, indicating that the autonomic nervous system is an important gateway for the SCN to cause an immediate resetting of peripheral physiology after phase-shift inducing light exposures.

Objective: To address concerns about the impact of training on patient outcomes during the 'learning curve' for laparoscopic radical prostatectomy (LRP), we compare the results of our patients undergoing LRP with and without trainees performing a substantial proportion of the cases., Patients and Methods: In all, 771 consecutive cases of LRP were performed or supervised by one surgeon during a 7.5-year period, of which 114 (15%) were training cases. A five-port transperitoneal technique was used in the first 111 patients and an extraperitoneal approach in the remaining 660. Patient, operative and oncological outcome variables were compared using an independent samples t-test if continuous or with Fisher's exact test for rates., Results: There were no differences in preoperative patient or cancer characteristics with the exception of body mass index (BMI) which was lower in the training cases (medians 25 and 26 kg/m(2), P = 0.02) and patient age which was higher (medians 64 and 62 years, P < 0.001). Operative time, which was longer in training cases (medians 200 and 175 min, P < 0.001) was the only significantly different operative variable between the groups. There were no statistically significant differences in postoperative (duration of catheterization, hospitalization time, complication rates, biochemical recurrence and pad-free rates at 1 year) or pathological (gland weight, positive surgical margin rate) outcomes between the groups. As Fellows did not perform the posterior or apical dissection steps in nerve-sparing cases, no evaluation of potency outcomes is included., Conclusions: Training cases took a median of 25 min longer to complete than non-training cases. However, other perioperative measures, complications rates and cancer outcomes were similar. Adequately supervised training in LRP does indeed take additional time but is essential for the dissemination of surgical skills and preservation of acceptable outcomes.

Objective: To report the initial experience of one surgeon, with contemporary experience of both open radical prostatectomy (ORP) and reconstructive laparoscopy, in laparoscopic radical prostatectomy (LRP) in 1000 patients, and to investigate the rate of change of various outcome variables for this procedure with time., Patients and Methods: Between March 2000 and December 2007, 1000 consecutive patients with clinical stage T < or = 3aN0M0 prostate cancer underwent LRP, either supervised (17%) or performed (83%), by one surgeon. The median prostate-specific antigen (PSA) level was 7.0 (1-50) ng/mL and median Gleason sum 6 (4-10); the clinical stage was T1 in 46.9%, T2 in 49.8% and T3 in 3.3%., Results: The median (range) operative duration was 177 (78-600) min. There was one conversion (patient 8) to open surgery. The median blood loss was 200 (10-1300) mL and four patients were transfused (0.4%). The median postoperative hospital stay was 3.0 (3-28) nights. The median catheterization time was 10.0 (0.8-120) days. There were 48 complications (4.8%) requiring surgical intervention in 33 (3.3%) patients, 58% of these as a day-case admission. The positive margin rates according to d'Amico risk groups were: low, 9.1%; intermediate, 20.3%; and high, 36.8%. The overall positive margin rate was 13.3%. The PSA level was < or =0.1 mg/L at 3 months in 99.1% of patients. At a mean follow-up of 27.7 (3-72) months, 96.1% of patients were free of biochemical recurrence. In patients with a follow-up of > or =24 months potency rates peaked in the series at 86% for all men and 94% for men aged < or =65 years, and continence rates at 98% before declining thereafter in men with a shorter follow-up., Conclusion: The learning curve for operating time and blood loss was overcome within the first 100-150 cases, but complication and continence rates took 150-200 cases to reach a plateau. The longest learning curve was for potency, which did not stabilize until 700 cases. These learning curves are likely to be considerably shorter when surgeons are taught in departments with a high throughput of cases but both surgeons and patients should be aware of them. In view of these findings, the authors recommend that LRP should not be self-taught and should be learned within an immersion teaching programme. Even then, a large surgical volume is likely to be needed to maintain clinical outcomes at the highest level.

Unlabelled: Cyclooxygenase-2 (COX-2) is associated with tumour promotion, inhibition of apoptosis, angiogenesis and metastasis. Celecoxib, a selective COX-2 inhibitor was investigated, in patients with clinically localized prostate cancer using immunohistochemistry., Patients and Methods: Patients with cT1-2 prostate cancer (n=45) were randomized to celecoxib 400mg b.d. or no treatment for four weeks prior to radical prostatectomy. Histological sections of preoperative biopsy and matched radical prostatectomy specimens were stained for markers of cell proliferation (MIB-1/Ki-67), microvessel density (CD-31 with Weidner scoring), COX-2, apoptosis (TUNEL analysis), angiogenic factors (VEGF and KDR) and HIF-1., Results: Celecoxib decreased tumour cell proliferation, microvessel density, angiogenesis and HIF-1 whilst enhancing apoptosis. These effects approached statistical significance in a multivariate model and the cell proliferation index approached statistical significance on univariate analysis., Conclusion: In this pilot study a 4 week regimen of celecoxib resulted in measurable biological effects in prostate cancer tissue. These findings warrant further investigation.

Purpose: To determine the impact of a variety of intraoperative parameters that may affect blood loss during laparoscopic radical prostatectomy (LRP)., Patients and Methods: Intraoperative blood loss was calculated for 757 consecutive LRPs performed by the same surgeon (CE) over a 6-year period. The impact of a number of intraoperative factors that may affect blood loss was studied. These factors include the operative approach (transperitoneal or extraperitoneal), neurovascular bundle (NVB) preservation, lateral prostatic fascia preservation, prostate weight, and the impact of the learning curve for the primary surgeon and trainees. Multivariate and univariate analyses were performed to determine the significance of these factors on intraoperative blood loss during LRP., Results: Mean (+/-standard deviation) blood loss in the 757 patients was 263 +/- 206 mL. Five (0.7%) patients received transfusions. There was a statistically significant difference between extraperitoneal (256 +/- 207 mL) and transperitoneal (308 +/- 199 mL) LRP in terms of blood loss. Nerve preservation [standard or with preservation of the lateral prostatic fascia (LPF)] resulted in a statistically significantly increase in blood loss (205 mL vs 321 mL, respectively, P < 0.001). It also appears that lateral prostatic fascia dissection, as part of a modified NVB preservation, increases blood loss with statistical significance (295 mL vs 353 mL, respectively P < 0.001). There was no statistically significant increase in blood loss with increasing prostate weight (<30 g, 30-50 g, 50-80 g, >80 g). The learning curve also had no impact on blood loss. Trainees were able to perform LRP without an increase in blood loss when mentored by the primary surgeon (CE)., Conclusion: There was a low requirement for transfusion in this cohort of patients undergoing LRP, and the average blood loss is comparable with the most recently reported minimally invasive prostatectomy series. Blood loss during LRP is mainly affected by nerve preservation, with an average increase of 90 mL for a standard NVB and 150 mL when the lateral prostatic fascia is preserved. It is clear, however, that although NVB preservation may increase blood loss, it does not increase the risk of transfusion for patients or impact on postoperative recovery.

Pelvic arteriovenous malformations (AVM) are rare, usually congenital, lesions, which can pose significant difficulties for pelvic surgeons. We present a case of an AVM complicating laparoscopic radical prostatectomy. Unexpected failure of preoperative control led to significant intraoperative difficulty. The advantages of an antegrade approach and optimal magnification afforded by the laparoscopic approach led to successful completion of the operation with minimal morbidity.

Objective: To assess the effect on potency recovery of incorporating a high incision of the lateral prostatic fascia (LPF) or curtain dissection (CD) into our technique of laparoscopic nerve-sparing radical prostatectomy (LNSRP)., Patients and Methods: In all, 137 bilateral neurovascular bundle (NVB) preserving LNSRPs were performed, incorporating curtain dissection (CD) of the LPF. Potency was assessed at 1, 3, 6 and 12 months using validated questionnaires and compared with a control group (CG) of standard NVB preservation., Results: There were no conversions to open surgery in either group. The median operative duration in the CD group and the CG was 178 min and 174 min (P = 0.04), blood loss was 300 mL and 200 mL (P = 0.01), and the positive margin rate was 16.1% and 24.1% (P = 0.04), respectively. At a mean follow-up of 5.8 months in the CD group and 28.2 months in the CG, potency rates were 21.1% and 8.8% at 1 month (P = 0.01), and 68.4% and 67.2% at 12 months (P = 1.00), respectively., Conclusion: The potency rate was significantly higher in the CD group at 1 month than in the CG, thereafter the rates were similar between the groups. We think that the merit of this technique is in improved visualization of the basal prostatic contour during antegrade NVB dissection, rather than preserving important nerve fibres. This may explain the lower basal positive margin rate in the CD group of 0% vs 5.8% in the CG (P = 0.007).

Objectives: To analyse the indications and long-term results of endoscopic and minimal access approaches for the treatment of ureteropelvic junction (UPJ) obstruction and to compare them to open surgery., Methods: A review of the literature from 1950 to January 2007 was conducted using the Ovid Medline database., Results: A lack of standardisation of techniques used to diagnose UPJ obstruction and to follow up treated patients introduces a degree of inaccuracy in interpreting the success rates of the various modalities of treatment. However, there is no indication that any one of these techniques is affected by this to a greater or lesser extent than another. Open pyeloplasty achieves very good (90-100% success) results, endopyelotomy and balloon disruption of the UPJ fail to match these results by 15-20%, and minimal access pyeloplasty produces results that are at least as good as those of open surgery but with the advantages of a minimal access approach., Conclusions: Minimal access pyeloplasty is likely to gradually replace endopyelotomy and balloon disruption of the UPJ for the treatment of UPJ obstruction. The much higher cost of robotic pyeloplasty and greater availability of laparoscopic expertise in teaching centres are likely to limit the dissemination of robotic pyeloplasty.

Objective: To report the guidelines of the British Association of Urological Surgeons (BAUS), commissioned by the National Institute for Health and Clinical Excellence (NICE) in response to safety concerns about the rapid uptake of new, complex laparoscopic procedures., Methods: A combination of expert opinion and review of published studies was used to produce a consensus document., Results: Patient demand and excellent published reports have prompted many consultant urologists with little previous laparoscopic training to learn laparoscopic procedures. Laparoscopic urological surgery involves some of the most complex procedures in all of surgery and there has been a lack of formal training for consultants. The guidelines produced by BAUS are designed to help consultant urologists gain experience safely, by a combination of didactic learning and mentorship. We recommend that urologists work with a mentor and master ablative laparoscopic surgery before attempting more complex procedures such as prostatectomy, cystectomy, pyeloplasty and partial nephrectomy. These guidelines were approved by BAUS Council in October 2006., Conclusions: These guidelines are intended to be complementary to the NICE guidelines on specific procedures (available at http://www.nice.org.uk).

The ideal treatment for ureteropelvic junction (UPJ) obstruction should have the highest success rate, enable treatment of all types of obstruction, allow removal coexisting renal stones, and be minimally invasive. Open pyeloplasty offers all these features except the last (minimal invasiveness), whereas endourology techniques guarantee only the last one. Different techniques of pyeloplasty can be applied laparoscopically, although the best results are seen with dismembered pyeloplasty (Anderson-Hynes technique). Various methods of tissue approximation have been devised to avoid the difficult-to-master, time-consuming conventional suturing technique. Laparoscopic (antegrade) stenting is preferred by some surgeons, but we consider retrograde stenting is superior, as this rules out the presence of associated distal-ureteral obstruction. The transperitoneal approach has the advantages of a larger working space and readily identifiable anatomic landmarks. However, access to the renal pelvis requires considerable mobilization and retraction of the overlying loops of bowel. The retroperitoneal approach has the perceived disadvantage of a somewhat limited working space and absence of readily identifiable intra-abdominal anatomic structures such as the liver and spleen. However, the retroperitoneal approach has the advantage of greater familiarity, better detection of crossing vessels, direct and rapid access to the UPJ, and less risk of ileus. The robot-assisted technique has made suturing easier and may allow expansion of advanced laparoscopic procedures to surgeons without expertise in advanced laparoscopic surgery. The optimal length of follow-up after pyeloplasty is still unclear. Although most failures occur within the first 2 years, failures continue to appear after 5 and 10 years.

Objective: To examine, in a pilot study, the feasibility of laser dissection of the neurovascular bundle (NVB) during nerve-sparing laparoscopic radical prostatectomy (NSLRP). NSLRP demands precise NVB mobilization with minimal collateral tissue trauma and optimal haemostasis. Unlike other methods of delivering energy, lasers have the potential to provide rapid, precise dissection with good haemostasis and minimal adjacent tissue injury., Patients and Methods: Five patients were treated with NSLRP; in patient 1 the right NVB was dissected using clips and scissors and the left NVB using the 1064 nm Nd:YAG laser (8 W, continuous-wave mode). In the subsequent four patients, the NVB was dissected bilaterally using the laser. The NVBs were excised for histological analysis., Results: In patient 1, the estimated blood loss for the left (laser) NVB dissection was 20 mL, while the estimated blood loss for the right NVB was 100 mL. The maximum depth of laser necrosis was 327 microm. For the next four patients the mean (range) total operative duration was 214 (166-245) min, the mean NVB dissection time 22 (8-33) min, the mean total blood loss 213 (100-300) mL, the mean estimated NVB blood loss 28 (10-45) mL and the mean depth of tissue injury was 687 microm. There were no complications. There was no recurrence, as assessed by prostate-specific antigen levels, at a mean follow-up of 12 months and all patients were continent., Conclusion: Laser NSLRP was relatively straightforward and caused minimal blood loss, allowed a rapid dissection and minimal adjacent tissue injury. It is a promising technique that warrants further evaluation.

Objectives: To investigate the effect of previous bladder outlet surgery (BOS) on the peri-operative variables of patients having laparoscopic radical prostatectomy (LRP), as reported evidence as to whether BOS affects the outcome of RP is contradictory., Patients and Methods: Of 600 consecutive patients attending for LRP from March 2000 to January 2006, 558 had had no surgery (NS) and 42 (7.0%) had a history of BOS (transurethral prostatectomy in 35, 5.8%; bladder neck incision in seven, 1.2%). All patients had clinical stage < or = T3aN0M0 prostate cancer and had their procedure performed or supervised by the same surgeon., Results: Patients with previous BOS had a significantly greater age (mean 64.6 vs 61.8 years, P = 0.008), duration of catheterization (mean 13.7 vs 10.5 days, P = 0.003), proportion of pT3a tumours (16.7% vs 4.5%, P = 0.009) and potency rates at > or = 24 months (P < 0.001). Patients with previous BOS had a significantly lower body weight (mean 79.7 vs 83.0 kg, P = 0.05) and prostate weight (mean 46.7 vs 58.6 g, P = 0.01). Although patients with previous BOS had poorer continence at 3 months (61% vs 91%, P < 0.001), continence rates were similar in the two groups after this., Conclusion: Previous BOS does not affect the medium-term outcomes after LRP.

Objective: To investigate the effect of obesity on the operative variables of patients undergoing laparoscopic radical prostatectomy (LRP)., Patients and Methods: The database entries and case-notes of 532 consecutive patients undergoing LRP from March 2000 to August 2005 were examined retrospectively. Complete data were available on 505 (95%) patients, 108 (21%) of whom were obese (body mass index, BMI, > or = 30 kg/m2). All patients had clinical stage T < or = 3aN0M0 prostate cancer and had their procedure done or supervised by the same surgeon., Results: The patients' prostate-specific antigen level, Gleason score, clinical stage and prostate weight were similar. The mean values for patients deemed not obese and obese were: for operative duration (182 and 197 min, P = 0.01), blood loss (310 and 250 mL, P = 0.66), hospital stay (3.0 and 3.3 nights, P = 1.00), complications (3.5% and 4.6%, P = 0.77), positive margins (15.4% and 20.6%, P = 0.26) and biochemical recurrence (3.8% and 3.7%, P = 1.00) at a mean follow-up of 9.7 and 12.0 months, respectively., Conclusion: The operation was significantly longer for obese patients, by a mean of 15 min; all other variables were comparable in the two groups. The results from this study suggest that obese patients can expect a similar outcome to their non-obese counterparts after LRP, when operated on by an experienced surgeon.