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The surgical treatment of men with lower urinary tract symptoms (LUTS) and significantly enlarged symptomatic prostates on active surveillance (AS) for low-risk prostate cancer (PCa) is not well defined. We report our single-institution initial experience with holmium laser enucleation of the prostate (HoLEP) for LUTS in men with low-risk PCa being managed with AS.Men on AS who underwent HoLEP between 2013 and 2019 were identified. Data regarding preoperative cancer workup, prostate-specific antigen (PSA), perioperative outcomes, and voiding parameters were analyzed. Postoperative surveillance for PCa including PSA nadir, prostate magnetic resonance imaging, prostate biopsy (PBx), and PSA at last follow-up were evaluated.Twenty men met the inclusion criteria. Preoperative mean max flow 7.9 ml/s, median postvoid residual 101 cc, and mean transrectal ultrasound prostate size 99 cc. Patients had a median adjusted preoperative PSA of 8.5 (interquartile range [IQR]: 4.8-13.2) ng/ml. Mean resected tissue weight was 65.5 g with improved postoperative flow rate and significantly decreased residual. A total of 5/20 men had PCa in the specimen (all Gleason Grade Group 1). The median postoperative PSA nadir was 1.2 (IQR: 0.5-1.8) ng/ml at median of 5 months. At the last follow-up (median 18.5 months, IQR: 10.5-37.8), the median postoperative PSA was 1.4 (IQR: 0.63-2.48) ng/ml. Nine men underwent postoperative multiparametric magnetic resonance imaging (mpMRI) with the identification of a new prostate imaging reporting and data system 5 lesion in one patient who underwent negative fusion biopsy. Five men underwent post-HoLEP PBx with progression in two patients, who both successfully underwent radical prostatectomy.Men on AS for low-risk PCa can safely undergo HoLEP with significantly improved voiding parameters. Postoperative monitoring with PSA, mpMRI, and PBx can detect disease progression requiring definitive treatment. Further research is needed to optimize surveillance strategies and long-term cancer-specific outcomes.

Mesenchymal stem cell (MSC)-based cell therapy can provide opportunities for the treatment of various diseases. However, when used in vivo, these cells should be labelled and monitored by a non-invasive method during delivery to the desired locations within the body. This study describes a biomimicry method that effectively labels human Wharton's jelly-derived MSCs (hWJ-MSCs) with a photoacoustics (PA) contrast agent, gold nanorods (GNRs), without the need for transfection agents (TAs). In this method for cell labelling, the hWJ-MSCs were co-incubated with non-adherent cells isolated from fresh umbilical cord for 2 days immediately before incubation with GNRs. Next, hWJ-MSCs were labelled with the GNRs at a concentration of approximately 1010 nanorads/mL (NR/mL) followed by transmission electron microscopy (TEM) and inductively coupled plasma mass spectroscopy (ICP-MS) to verify their labelling effectiveness. The GNRs-labelled MSCs prepared by this method had an intracellular gold (Au) concentration of 3.4 ± 0.4 pg/cell, which is an acceptable amount for cell labelling.

Among autoimmune rheumatic diseases, systemic sclerosis (SSc) is especially challenging due to its clinical diversity, reflected by the extent of skin and internal organ involvement 1 . Besides the two major subsets, limited and diffuse SSc (lcSSc, dcSSc), a substantial number of SSc cases exhibit overlap features of another rheumatic disease, summarized as SSc-overlap syndromes. A few of these are already well characterized by their specific clinical course and circulating antibodies (e.g., mixed connective tissue disease, polymyositis-scleroderma syndrome).

Cloud computing has been a rising trend in the business world. In this study, we consider two most important pricing schemes offered to sustained customers by major service providers in the cloud industry: the reservation‐based scheme (the R‐scheme) by Amazon or Microsoft, and the utilization‐based scheme (the U‐scheme) by Google. We consider a duopoly model with heterogeneous customers characterized by the mean and the coefficient of variation of their usage. We show that under either pricing scheme, the effective price is essentially an increasing function of the coefficient of variation of usage, and thus both schemes aim for rewarding stability in usage. However, when the providers adopt different schemes, we show that customers with lower demand volatility would prefer the R‐scheme, while those with higher demand volatility would prefer the U‐scheme. Furthermore, we study the impact of evolving market characteristics, including the distributions of market preference, demand size, and demand volatility, as well as the impact of the providers’ service levels on their choices of schemes and decisions on the pricing parameters. We find that if the market has a stronger preference for a particular provider or that provider has a higher service level than its competitor, the provider is more likely to adopt the R‐scheme, while its competitor's adoption of a scheme depends on the extent of the price competition. Specifically, when the diversity of customer preference becomes higher (lower), the price competition becomes softened (intensified), and the competitor is more likely to adopt the R‐scheme (U‐scheme, respectively).

In recent years, Peer-to-Peer (P2P) networks have become an increasingly popular method for distributing digital content. In this paper, we consider the development of optimal contracts for a P2P network by a profit-seeking provider to support the operations of an online file exchange service. By utilizing the principal-agent model of incentive theory, we propose appropriate reward and pricing schemes for profit-seeking P2P content distribution networks. We show that when peers are homogeneous, upload compensation increases with propagation delay uncertainty, maximum uploading nodes allowed, peers’ provision cost and disutility of download delay, but decreases with the network size and content availability. We also characterize a general contracting model where there are a countable number of peer classes which are heterogeneous in their provisioning costs. For the case of two peer classes where optimal delays are separable, we derive the optimal upload compensations under different scenarios and show that the impact of operational parameters is quite similar to the case of homogeneous peers, lending support to the robustness of our analysis. This article is protected by copyright. All rights reserved.

We model a supply chain consisting of a supplier and multiple retailers facing deterministic demand. We denote some retailers as strategic in the sense that given the supplier inventory information, they will implement the optimal stocking policy by incorporating such information. On the other hand some retailers are denoted as naive in the sense that they ignore supply information and resort to a simplistic ordering policy. Naive retailers learn the optimal policy over time and adjust their orders accordingly. We study the dynamics of this game and investigate the impact of such strategic and naive retailers on the cost, ordering pattern and stocking policies of all parties. We analyze the supply chain under two scenarios: the centralized supply chain where the objective is to minimize the total supply chain cost, and the decentralized supply chain where each self-interested player minimizes its own cost in a Stackelberg game setting. We fully characterize the optimal policies under both centralized and decentralized scenarios and show that, surprisingly, the supply chain might be better off by virtue of naive retailers. The result is driven by the fact that strategic and naive players’ decisions shift the positioning of inventory in the supply chain with its final impact being determined by the relative costs of different retailer-types. Our results also offer managerial insights into how access to supply information can improve supply chain performance. This article is protected by copyright. All rights reserved.

Localized scleroderma designates a heterogeneous group of sclerotic skin disorders. Depending on the subtype, severity, and site affected, adjacent structures such as adipose tissue, muscles, joints, and bones may be involved. This is an update of the existing German AWMF (Association of the Scientific Medical Societies in Germany) guidelines (classification: S2k). These guidelines provide an overview of the definition, epidemiology, classification, pathogenesis, laboratory workup, histopathology, clinical scoring systems, as well as imaging and device-based workup of localized scleroderma. Moreover, consensus-based recommendations are given on the management of localized scleroderma depending on its clinical subtype. Treatment recommendations are presented in a therapeutic algorithm. No financial support was given by any pharmaceutical company. The guidelines are valid until July 2019.

What's known on the subject? and What does the study add? LumagelTM is a reverse thermosensitive polymer (RTP) that has previously been described in the literature as providing temporary vascular occlusion to allow for bloodless partial nephrectomy (PN) while maintaining blood flow to the untargeted portion of the kidney. At body temperature, LumagelTM has the consistency of a viscous gel but upon cooling rapidly converts to a liquid state and does not reconstitute thereafter. This property has allowed for it to be used in situations requiring temporary vascular occlusion. Previous experience with similar RTPs in coronary arteries proved successful, with no detectable adverse events. We have previously described our technique for temporary vascular occlusion of the main renal artery, as well as segmental and sub-segmental renal branches, to allow for bloodless PN in either an open or minimally invasive approach. These experiments were performed in the acute setting. This study is a two-armed survival trial to assess whether this RTP is as safe as hilar clamping for bloodless PN. Surviving animals showed normal growth after using the RTP, absence of toxicity, no organ dysfunction, and no pathological changes attributable to the RTP. We conclude that LumagelTM is as safe as conventional PN with hilar clamping, while adding the advantage of uninterrupted perfusion during renal resection. OBJECTIVE • To examine whether randomly selected regions of the kidney could undergo temporary flow interruption with a reverse thermosensitive polymer (RTP), LumagelTM (Pluromed, Inc., Woburn, MA, USA), followed by partial nephrectomy (PN), without adding risks beyond those encountered in the same procedure with the use of hilar clamping. MATERIALS AND METHODS • A two-armed (RTP vs hilar clamp), 6-week swine survival study was performed. • Four swine underwent PN using hilar clamps, while six underwent PN with flow interruption using the RTP. • The RTP, administered angiographically, was used for intraluminal occlusion of segmental or subsegmental arteries and was compared with main renal artery clamping with hilar clamps. The resection site was randomized for each swine. • Laboratory studies were performed preoperatively, and at weeks 1, 3 and 6. • Before killing the swine, repeat angiography was performed with emphasis on the site of previous flow interruption. • Gross and microscopic examination of kidney, liver, lung, heart, skeletal muscle was later performed, and the vessel that had supported the previous plug was examined. RESULTS • All animals survived. No abnormal chemistry or haematology results were encountered over the 6 weeks. There were no surgical complications in either group. • Using angiography we found 100% patency of vessels that had been occluded with the polymer 6 weeks previously for PN. The only gross or microscopic abnormalities were related to the renal resection and scar formation, and were similar in the two groups. CONCLUSION • Targeted flow interruption with the RTP added no additional risk to PN while allowing bloodless resection and uninterrupted flow to untargeted renal tissue.

Systemic sclerosis (scleroderma, SSc) is characterized as a severe and very heterogeneous disease with a bright variation of skin and organ manifestations in individual patients. The pathogenesis is still not fully elucidated; however, it is known that this disease starts with an initial vascular damage, which then leads to an inflammatory process and finally promotes the development of an accumulation of collagen and other extracellular matrix (ECM) components. As a result of the heterogeneous characteristics of this multisystem, autoimmune disease, it is always a challenge to identify high-risk patients and to monitor the fibrotic activity also in response to therapies. This can be achieved by several physical methods including the mRSS, the durometer and ultrasound determination of skin thickness. However, this also requires the use of laboratory biomarkers, which are easily detectable and that reflect the inflammatory and/or fibrotic activity. As skin correlates well with the extent of fibrosis also in other organs, we focused in this review on biomarkers which reflect skin involvement of scleroderma patients. These include growth factors, cytokines and proteases as well as their inhibitors. Moreover, several ECM proteins, especially the collagens have been determined in skin biopsies and in blood/serum samples. Determination of proteins has been supported by mRNA levels using PCR techniques and expression analysis of gene expression patterns. This review summarizes all non-invasive physical and laboratory examinations, which permit a better understanding of the fibrotic activity of the disease, can be effectively used to assess potential therapeutic response and help to find better treatment options.

Background: Fibrosis is characterized by an excessive accumulation of connective tissue because of an imbalance between synthesis and degradation of extracellular matrix proteins. Systemic sclerosis (SSc) is a prototypic chronic inflammatory disease leading to a severe fibrosis of the skin and many internal organs. Questions Addressed: We investigated whether serum MMP-7 levels reflect the activity of the fibrotic reaction in systemic sclerosis. Experimental Design: Serum samples were obtained from 123 patients with systemic sclerosis. MMP-serum levels of all patients with SSc were compared with age-matched healthy controls. Results: Significantly increased median serum MMP-7 levels were found in patients with SSc when compared with controls. The median MMP-7 serum level of patients with lung fibrosis (LF) was significantly higher compared with those without LF. Accordingly, patients with dyspnea and DLCO (diffusion capacity of the lung for carbon monoxide) levels below 60% showed significantly higher median MMP-7 levels. Conclusions: Elevated MMP-7 levels are associated with an advanced stage of SSc and LF. These data suggest that in SSc MMP-7 is involved in the process of fibrotic tissue remodelling.

Purpose Systemic sclerosis (SSc) is characterized by autoimmunity, vasculopathy and fibrosis. Fibrosis is due to an activation of fibroblasts by the transforming growth factor-s (TGF-s). This study investigates the proteomic response of SSc fibroblasts to TGF-s. Experimental design Skin fibroblasts from diffuse SSc patients and healthy controls (HC) are cultured with or without TGF-s. Two-dimensional differential in-gel electrophoresis and mass spectrometry (MS) combined with Ingenuity Pathway analysis (IPA) and Panther/David software analyze proteins differentially expressed between groups. Real-time cell analyzer (RTCA) assesses fibroblast proliferation and viability. Results Two-hundred-and-seventy-nine proteins are differentially expressed between groups. Principal component analysis shows significant differences between groups. IPA shows specific process networks such as actin cytoskeleton and integrin signaling. Panther and David software show predominant biological processes such as cellular and metabolic processes. TGF-s enhances protein synthesis and protein pathways. IPA and RTCA suggest the involvement of epidermal growth factor receptor (EGFR) and phosphatidylinositol 3 kinase (Pi3K). Conclusions and clinical relevance That the proteome of fibroblasts differs between SSc patients and HC is confirmed, and it is demonstrated that fibroblasts exacerbate their proteomic phenotype upon stimulation with TGF-s. EGFR and Pi3K are highlighted as proteins of interest in SSc fibroblasts.

OBJECTIVE To evaluate PP2 as a modulator of the cadherin/catenin complex in late-stage bladder carcinoma cells, and to assess its potential invasion-suppressor activity in this model. MATERIALS AND METHODS A panel of five human bladder carcinoma cells, characterizing late-stage disease, was used to determine the concentration for 50% inhibition of PP2 in cell-proliferation assays. Modulation of cadherin/catenin expression by PP2 was determined in Western blot analysis, with an assessment of the activation status of mitogen-activated protein kinase and Akt signalling pathways. Altered invasive capacity linked to these variables was determined in standard in vitro invasion assays. RESULTS PP2 elicited concentration-dependent growth inhibition in all bladder cell lines within the panel, with growth suppression recorded at 10–35 µmol/L PP2. Distinct morphological changes were recorded in cell lines exposed to PP2, accompanied by up-regulation of plakoglobin expression in a subset of lines. Exposure of cells to PP2 resulted in inactivation of Akt in all cells and a concomitant reduction in in vitro invasive capacity. CONCLUSIONS These results show that PP2 inhibits bladder carcinoma cell growth and can modulate plakoglobin expression in a subset of cell lines. In addition, PP2 can suppress the in vitro invasive capacity of bladder carcinoma cells by modulating the activation status of Akt.

It is a reflection of the many manuscripts submitted on urological oncology in general, and prostate cancer in particular, that I am publishing 10 papers in this section this month. Seven of these relate to the latter subject. The authors from the Lahey Clinic describe their technique of radial prostatectomy and include a novel method of posterior bladder plication. They report an early return to continence and conclude that the technique is important in achieving their excellent results. In another study the group from Stockport show that patients often make decisions about types of treatment for prostate cancer having been strongly influenced by their partner, who in turn may have had pre-existing conceptions about this. They recommend early involvement of the partner to help in this very important decision-making. The two papers on bladder cancer describe possible prognostic factors, both clinical and laboratory-based, from a large experience in Hamburg and Mansoura. OBJECTIVE To analyse the incidence of incontinence after radical retropubic prostatectomy (RRP) and the time to return of continence, using an RRP technique including a novel posterior bladder plication PATIENTS AND METHODS We retrospectively reviewed the medical records of 200 consecutive patients who underwent RRP between September 1995 and February 1997, by one surgeon, at our institution. Patient characteristics including age, preoperative prostate-specific antigen (PSA) level and Gleason grade, were assessed. Continence was assessed before and after RRP by either a third-party patient interview or a prospective validated questionnaire. Continence was defined as not requiring the use of any sanitary pads or diapers. The continence rate was determined immediately after catheter removal, and at 3, 6, 12 and 15 months after RRP. RESULTS The mean age of the patients was 59.4 years, the preoperative PSA level 8.5 ng/mL and the Gleason grade 6.1. The time to continence and percentage of continent patients was 63.5% immediately, 82% at 3 months, 91% at 6 months, and 98.5% at 12 months after RRP. At 15 months, 199 of 200 consecutive patients were continent (99.5%). CONCLUSION With our technique there was an early return to continence and only a minor incontinence rate at 15 months. The cumulative effect of sequential technical manoeuvres in our RRP technique, including posterior bladder plication, is critical for continence after RRP.

Loss of heterozygosity (LOH) on 10q is associated with late-stage events in urothelial neoplastic progression. The tumor suppressor gene PTEN, which is mutated or homozygously deleted in numerous cancers, maps to a region of 10q within the reported region of minimal loss in bladder tumors. In two recent studies alterations in the PTEN gene occur at a low frequency in bladder tumors displaying 10q LOH. We have screened 35 late-stage bladder tumors for mutations in PTEN and MXI1, both genes mapping to chromosome 10q. Using single-strand conformation polymorphism analysis, we identified 6 tumors harboring mutations in PTEN and 2 additional tumors displaying homozygous deletion at this locus. No MXI1 mutations were identified within the same tumor panel. Of 16 bladder tumor cell lines analyzed, 2 showed homozygous deletion of PTEN and 3 harbored point mutations resulting in an amino acid change. Two cell lines harbored missense mutations in MXI1. We report a significantly higher frequency of PTEN alterations in bladder carcinoma (23%) than was previously recorded, with no accompanying mutations in the MXI1 gene.