Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial.

BACKGROUND AND OBJECTIVE: The transrectal biopsy approach is traditionally used to detect prostate cancer. An alternative transperineal approach is historically performed under general anesthesia, but recent advances enable transperineal biopsy to be performed under local anesthesia. We sought to compare infectious complications of transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis. METHODS: We assigned biopsy-naïve participants to undergo transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis (rectal culture screening for fluoroquinolone-resistant bacteria and antibiotic targeting to culture and sensitivity results) through a multicenter, randomized trial. The primary outcome was post-biopsy infection captured by a prospective medical review and patient report on a 7-d survey. The secondary outcomes included cancer detection, noninfectious complications, and a numerical rating scale (0-10) for biopsy-related pain and discomfort during and 7-d after biopsy. KEY FINDINGS AND LIMITATIONS: A total of 658 participants were randomized, with zero transperineal versus four (1.4%) transrectal biopsy infections (difference -1.4%; 95% confidence interval [CI] -3.2%, 0.3%; p = 0.059). The rates of other complications were very low and similar. Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal, adjusted difference 2.0%; 95% CI -6.0, 10). Participants in the transperineal arm experienced worse periprocedural pain (0.6 adjusted difference [0-10 scale], 95% CI 0.2, 0.9), but the effect was small and resolved by 7-d. CONCLUSIONS AND CLINICAL IMPLICATIONS: Office-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making. PATIENT SUMMARY: In this multicenter randomized trial, we compare prostate biopsy infectious complications for the transperineal versus transrectal approach. The absence of infectious complications with transperineal biopsy without the use of preventative antibiotics is noteworthy, but not significantly different from transrectal biopsy with targeted antibiotic prophylaxis.

Getting over the hump with KAMEL-LOBE: Kernel-averaging method to eliminate length-of-bin effects in radial distribution functions.

Radial distribution functions (RDFs) are widely used in molecular simulation and beyond. Most approaches to computing RDFs require assembling a histogram over inter-particle separation distances. In turn, these histograms require a specific (and generally arbitrary) choice of discretization for bins. We demonstrate that this arbitrary choice for binning can lead to significant and spurious phenomena in several commonplace molecular-simulation analyses that make use of RDFs, such as identifying phase boundaries and generating excess entropy scaling relationships. We show that a straightforward approach (which we term Kernel-Averaging Method to Eliminate Length-Of-Bin Effects) mitigates these issues. This approach is based on systematic and mass-conserving mollification of RDFs using a Gaussian kernel. This technique has several advantages compared to existing methods, including being useful for cases where the original particle kinematic data have not been retained, and the only available data are the RDFs themselves. We also discuss the optimal implementation of this approach in the context of several application areas.

Protocol of a multicentre randomised controlled trial assessing transperineal prostate biopsy to reduce infectiouscomplications.

INTRODUCTION: Approximately one million prostate biopsies are performed annually in the USA, and most are performed using a transrectal approach under local anaesthesia. The risk of postbiopsy infection is increasing due to increasing antibiotic resistance of rectal flora. Single-centre studies suggest that a clean, percutaneous transperineal approach to prostate biopsy may have a lower risk of infection. To date, there is no high-level evidence comparing transperineal versus transrectal prostate biopsy. We hypothesise that transperineal versus transrectal prostate biopsy under local anaesthesia has a significantly lower risk of infection, similar pain/discomfort levels and comparable detection of non-low-grade prostate cancer. METHODS AND ANALYSIS: We will perform a multicentre, prospective randomised clinical trial to compare transperineal versus transrectal prostate biopsy for elevated prostate-specific antigen in the first biopsy, prior negative biopsy and active surveillance biopsy setting. Prostate MRI will be performed prior to biopsy, and targeted biopsy will be conducted for suspicious MRI lesions in addition to systematic biopsy (12 cores). Approximately 1700 men will be recruited and randomised in a 1:1 ratio to transperineal versus transrectal biopsy. A streamlined design to collect data and to determine trial eligibility along with the two-stage consent process will be used to facilitate subject recruitment and retention. The primary outcome is postbiopsy infection, and secondary outcomes include other adverse events (bleeding, urinary retention), pain/discomfort/anxiety and critically, detection of non-low-grade (grade group ≥2) prostate cancer. ETHICS AND DISSEMINATION: The Institutional Review Board of the Biomedical Research Alliance of New York approved the research protocol (protocol number #18-02-365, approved 20 April 2020). The results of the trial will be presented at scientific conferences and published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04815876.

TADA: The Topology-Accommodating Direction Assignment Algorithm for Liquid Crystals.

Despite the fact that topological defects are a hallmark of liquid crystalline materials, current computational techniques for identifying topological defects in particle-based simulations of these materials─which rest upon Q-tensor theory─do not leverage topological features of the system. In this work, we describe the topology-accommodating direction assignment (TADA) algorithm, a novel approach for identifying disclination cores in liquid crystalline materials, which is sensitive to topology: this method assigns to each mesogen a unique vector, thereby extending the concept of the liquid crystal director field down to the scale of mesogens. In systems containing disclination cores, TADA identifies line segments along which this assigned vector field is discontinuous, with cores located at the interior termination points of these line segments. The mere presence of defects can be identified by searching far away from them. We validate this approach by comparing its results to those obtained using the scalar order parameter for a variety of liquid crystalline assemblies sourced from molecular-dynamics simulations. We also discuss several benefits of the TADA algorithm over existing approaches for identifying topological defects in liquid crystalline materials.

Excess Entropy Scaling in Active-Matter Systems.

Active-matter systems feature discrete particles that can convert stored or ambient free energy into motion. To realize the engineering potential of active matter, there is a strong need for predictive and theoretically grounded techniques for describing transport in these systems. In this work, we perform molecular-dynamics (MD) simulations of a model active-matter system, in which we vary the total fraction of active particles (0.01 ≤ ϕ ≤ 0.5) as well as the degree of activity of the active particles. These simulations reveal a fascinating array of transport phenomena, including activity-enhanced diffusion coefficients. By adapting an existing result for binary (inactive) fluids, we demonstrate the existence of an excess entropy scaling relation in an active system. This relationship is well supported by our MD results and establishes a new connection between transport (dynamics) and structure (statics) in active matter, a promising step for predictive and generalizable models of other transport phenomena in such systems.

How to produce confidence intervals instead of confidence tricks: Representative sampling for molecular simulations of fluid self-diffusion under nanoscale confinement.

Ergodicity (or at least the tantalizing promise of it) is a core animating principle of molecular-dynamics (MD) simulations: Put simply, sample for long enough (in time), and you will make representative visits to states of a system all throughout phase space, consistent with the desired statistical ensemble. However, one is not guaranteed a priori that the chosen window of sampling in a production run is sufficiently long to avoid problematically non-ergodic observations; one is also not guaranteed that successive measurements of an observable are statistically independent of each other. In this paper, we investigate several particularly striking and troublesome examples of statistical correlations in MD simulations of nanoconfined fluids, which have profound implications on the quantification of uncertainty for transport phenomena in these systems. In particular, we show that these correlations can lead to confidence intervals on the fluid self-diffusion coefficient that are dramatically overconfident and estimates of this transport quantity that are simply inaccurate. We propose a simple approach-based on the thermally accelerated decorrelation of fluid positions and momenta-that ameliorates these issues and improves our confidence in MD measurements of nanoconfined fluid transport properties. We demonstrate that the formation of faithful confidence intervals for measurements of self-diffusion under nanoscale confinement typically requires at least 20 statistically independent samples, and potentially more depending on the sampling technique used.

Social distancing slows down steady dynamics in pedestrian flows.

Amidst the ongoing pandemic, social distancing has been broadly adopted as an effective front-line defense strategy for mitigating disease transmission. Viewed through the lens of particle-based simulations of flow, the practice of social distancing corresponds to a (significant) increase in an internal length scale of the flow, namely, the radius within which particles (pedestrians) strongly repel fellow particles. In this study, we report the results of two-dimensional pedestrian dynamics simulations modeling pedestrian counter-flows under confinement, in which individual pedestrians are described as active particles that aim to maintain a target speed while avoiding collisions. By systematically varying two quantities-the pedestrian density and the degree of social distancing-we compute fundamental diagrams for confined and socially distanced pedestrian flows, which show average pedestrian speed as a function of density and social distancing. These results reveal the sensitive dependence of average velocity on both independent variables, including a social distancing-induced jamming transition. These results highlight the need for both deliberate planning and careful public-health messaging regarding social distancing as shared indoor spaces return to appreciable levels of occupation.

Variation in Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy Outcomes in Asian American Men: A Multicenter Study.

PURPOSE: Asian American men have distinctly different prostate cancer epidemiology than other men. To our knowledge the role of multiparametric magnetic resonance imaging and targeted biopsy for elevated prostate specific antigen in this population has not been assessed. We sought to define imaging and targeted biopsy outcomes in Asian American men compared to other men. MATERIALS AND METHODS: We accrued a multicenter, prospective cohort of men who underwent magnetic resonance imaging targeted and systematic biopsy for elevated prostate specific antigen. The outcome of interest was a diagnosis of clinically significant prostate cancer (Gleason Grade Group 2 or greater) stratified by the PI-RADS™ (Prostate Imaging-Reporting and Data System) score and a history of negative biopsy. Multivariable logistic regression was used to assess the effect of Asian American race on cancer detection. RESULTS: Of the 2,571 men 275 (11%) were Asian American. Clinically significant prostate cancer was detected in 37% of Asian American men compared to 48% of men of other races (p <0.001). Asian American men were also less likely to be diagnosed with Grade Group 1 cancer (12% vs 18%, p=0.007). Additionally, there was significantly lower detection of significant cancer using PI-RADS 3 in Asian American men vs men of other races (12% vs 21%, p=0.032). On adjusted analysis Asian American men were less likely to be diagnosed with significant cancer (OR 0.57, 95% CI 0.42-0.79, p <0.001) and Grade Group 1 cancer (OR 0.57, 95% CI 0.38-0.84, p=0.005) than nonAsian men. CONCLUSIONS: Asian American men are less likely to be diagnosed with clinically significant prostate cancer on targeted biopsy, illustrating the different performance of PI-RADS in this population. Conventional risk assessment tools should be modified when selecting Asian American men for biopsy.

Layered Fluid Structure and Anomalous Diffusion under Nanoconfinement.

Molecular diffusion under nanoconfinement can differ significantly from diffusion in bulk fluids. Using molecular dynamics simulations and molecular mechanics arguments, we elucidate the effect of layering at the confining boundaries on the self-diffusion of a simple, single-phase, confined fluid. In particular, we show that anomalous diffusion due to layering is controlled by the degree of layering as quantified by the recently proposed Wall number ( Wa), which compares the strength of the wall-fluid interaction to the thermal energy. For low Wall numbers, layering is not sufficiently pronounced so as to have a significant effect, whereas for Wa ≳ 1, layering is sufficiently important to have a significant effect on diffusion dynamics. In the latter regime, we find that fluid in the fluid-solid interfacial region tends to exhibit restricted dynamics and may only leave this region via a thermally activated hopping process. We also identify conditions under which diffusivity under confinement can be estimated, to a good approximation level, as a weighted average of the bulk and first-layer region diffusivities, leading to direct expressions quantifying the deviation from bulk behavior in terms of the confinement length scale.

Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells.

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non-small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24- pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC.Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986-99. ©2018 AACR.

Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T-cell Infiltration.

Purpose: A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222).Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFNγ in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor-associated antigens (TAA). Tumor CD8+ T-cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression.Conclusions: Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen-specific immune responses; (ii) enhanced tumor CD8+ T-cell infiltration; and (iii) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination. Clin Cancer Res; 23(16); 4556-68. ©2017 AACR.

Association of Aromatase With Bladder Cancer Stage and Long-Term Survival: New Insights Into the Hormonal Paradigm in Bladder Cancer.

BACKGROUND: Hormonal factors may play a role in bladder cancer (BCa). We investigated the expression of aromatase and estrogen receptor (ER)ß and its association with pathological variables and survival outcomes. PATIENTS AND METHODS: BCa specimens from 40 patients were evaluated. Immunohistochemistry was performed for aromatase and ERß. Descriptive statistics and univariate analyses assessed the association of these markers with pathologic variables and survival outcomes. RESULTS: Aromatase expression was significantly associated with tumor stage; muscle-invasive disease was found in 15 of 19 (79%) patients with positive staining and in 7 of 18 (39%) patients with negative staining (P = .02). Node-positive disease was found in 8 of 19 (42%) patients with positive staining and 1 of 18 (6%) patients with negative staining (P = .01). After a median follow-up of 112 months, Cox regression analysis demonstrated that aromatase expression was associated with a more than 2-fold risk of cancer recurrence (hazard ratio, 2.37; confidence interval, 0.92-6.08; P = .07) and an almost 4-fold higher risk of cancer-specific death (hazard ratio, 3.66; 95% confidence interval, 1.19-12.06; P = .02). Muscle-invasive disease was found in 15 of 18 (83%) ERß-positive specimens and 4 of 12 (33%) ERß-negative specimens (P = .0009). Hierarchical clustering analysis demonstrated a 4-fold up-regulation of ERß gene expression in tumor versus adjacent, non-tumor urothelium (P < .05). However, no significant association with survival outcomes was found. CONCLUSION: Aromatase expression in BCa may be associated with advanced tumor stage and poorer survival outcomes. ERß is upregulated in malignant tissue, and its expression is associated with muscle-invasive disease. These findings provide further evidence for the hormonal paradigm in BCa.

Risk stratification of patients undergoing pulmonary metastasectomy for soft tissue and bone sarcomas.

OBJECTIVES: Our objective was to identify risk factors associated with survival in patients who underwent pulmonary metastasectomy for soft tissue or bone sarcoma and to create a risk stratification model. METHODS: A retrospective review of the prospectively maintained University of California Los Angeles Sarcoma Database was performed. Clinical, pathologic, and treatment variables were analyzed for overall survival and disease-free survival. Univariate and multivariate analyses were performed, and variables that were identified as significant were included to create a risk model. A total of 155 patients who underwent pulmonary metastasectomy for soft tissue sarcoma (n = 108 patients) or bone sarcoma (n = 47 patients) from 1994 to 2010 were identified. RESULTS: Multivariate analysis identified 7 factors associated with poor overall survival: age more than 45 years, disease-free interval less than 1 year, thoracotomy, synchronous disease, location and type of sarcoma (soft tissue vs bone sarcoma), and performance of a lobectomy. The number of factors present was associated with poor overall survival, which varied widely from 64% in patients with 2 factors to 3% in those with 5 factors. CONCLUSIONS: We have identified prognostic variables associated with overall survival after lung metastasectomy. Our model may be used as a risk stratification model to guide treatment decisions on the basis of the number of risk factors present. Although prospective studies are warranted to determine the benefit of surgical intervention in all cohorts compared with other local therapies or medical therapy, given the attendant dismal prognosis in patients with 5 or more risk factors, the benefit of surgical resection in this group is questioned.

Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway.

BACKGROUND: The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway. OBJECTIVE: The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling. METHODS AND RESULTS: Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, ß-and γ-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment. CONCLUSION: Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in human lung cancer cells through a STAT1 dominant pathway.

IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer.

BACKGROUND: Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. METHODS: STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. RESULTS: Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27-treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. CONCLUSION: IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1-dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27.

CCL21 Chemokine Therapy for Lung Cancer.

Lung cancer remains a challenging health problem with more than 1.1 million deaths worldwide annually. With current therapy, the long term survival for the majority of lung cancer patients remains low, thus new therapeutic strategies are needed. One such strategy would be to develop immune therapy for lung cancer. Immune approaches remain attractive because although surgery, chemotherapy, and radiotherapy alone or in combination produce response rates in all histological types of lung cancer, relapse is frequent. Strategies that harness the immune system to react against tumors can be integrated with existing forms of therapy for optimal responses toward this devastating disease. Both antigen presenting cell (APC) and T cell activities are reduced in the lung tumor microenvironment. In this review we discuss our experience with efforts to restore host APC and T cell activities in the lung cancer microenvironment by intratumoral administration of dendritic cells (DC) expressing the CCR7 receptor ligand CCL21 (secondary lymphoid chemokine, SLC). Based on the results demonstrating that CCL21 is an effective anti cancer agent in the pre-clinical lung tumor model systems, a phase I clinical trial was initiated using intratumoral injection of CCL21 gene modified autologous DC in lung cancer. Results from the trial thus far indicate tolerability, immune enhancement and tumor shrinkage via this approach.

Comparison of laparoendoscopic single-site donor nephrectomy and conventional laparoscopic donor nephrectomy: donor and recipient outcomes.

OBJECTIVE: To present a comparison of perioperative donor outcomes and recipient graft function in a series of patients undergoing laparoendoscopic single-site donor nephrectomy (LESS-DN) versus conventional laparoscopic donor nephrectomy (LDN). METHODS: Data were collected for 50 consecutive LESS-DN patients and a matched cohort of 50 LDN patients. The donor outcomes analyzed included operative time, estimated blood loss, complications, visual analog pain scores, and recovery time. The recipient outcomes analyzed included serum creatinine at discharge and follow-up and the incidence of delayed graft function. RESULTS: The mean total operative time was shorter in the LDN group than in the LESS-DN group (P < .0001). Linear regression analysis of the LESS-DN operative times relative to case number showed a significant decrease in the operative time with increasing case number (r(2) = 0.19, P = .002). No statistically significant differences were found in estimated blood loss, warm ischemia time, length of stay, or visual analog pain scores between the 2 groups. However, the surgical incision was significantly smaller in the LESS-DN group (P < .0001). After discharge, the patient-reported time to complete recovery was faster in the LESS-DN group (P = .01). The incidence of complications was similar in both groups; however, major complications only occurred in the LDN group. No differences were found in the recipient serum creatinine values or the incidence of delayed graft function. CONCLUSION: Our initial experience with LESS-DN is encouraging. This retrospective matched-pair comparison between LESS-DN and LDN suggests that the single-port approach might be associated with quicker convalescence. Longer operative times in the LESS-DN group could simply represent the learning curve of a novel procedure.

Laparoendoscopic single site live donor nephrectomy: single institution report of initial 100 cases.

PURPOSE: Laparoendoscopic single site surgery is a recent advance in minimally invasive urology. We report outcomes from our initial 100 consecutive laparoendoscopic single site live donor nephrectomies done by a single surgeon and provide a matched comparison of conventional laparoscopic live donor nephrectomies done by the same surgeon. MATERIALS AND METHODS: From 2009 to 2010 at a tertiary referral center 100 consecutive laparoendoscopic single site live donor nephrectomies were performed by a single surgeon through a periumbilical incision using the GelPoint® system. No extraumbilical incisions or punctures were made. A retrospective review was performed using a prospectively managed database of standard perioperative and convalescent parameters. Comparison was made using a matched cohort of conventional live donor nephrectomies done by the same surgeon. RESULTS: Mean operative time was longer in the laparoendoscopic single site group (156 vs 130 minutes) but there was no difference in estimated blood loss or warm ischemia time. There was no difference in the complication rate between the 2 groups. Mean hospital stay and visual analog pain scores were similar in the groups but the laparoendoscopic group showed improved convalescence with faster return to work, normal activity and 100% recovery. Recipient graft function was equivalent in the 2 groups. CONCLUSIONS: In this retrospective, matched comparison laparoendoscopic single site live donor nephrectomy was associated with longer operative time but equivalent recipient graft function and improved convalescence. The benefits of laparoendoscopic single site surgery over conventional laparoscopy may be limited. However, with respect to live donor nephrectomy the benefits of laparoendoscopic single site surgery may nevertheless prove beneficial to decrease barriers to live organ donation.

Hsp90 inhibition increases p53 expression and destabilizes MYCN and MYC in neuroblastoma.

Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. MYCN and MYC are oncoproteins that play crucial roles in determining the malignancy of unfavorable neuroblastoma. The Hsp90 superchaperone complex assists in the folding and function of a variety of oncogenic client proteins. Inhibition of Hsp90 by small molecule inhibitors leads to the destabilization of these oncogenic proteins and consequently suppresses tumor malignancy. Nonetheless, little is known about the effect of Hsp90 inhibition on the stability of MYCN and MYC proteins. In this study, we investigated the effect of Hsp90 inhibition on the phenotype of unfavorable neuroblastoma cells including its effect on MYCN and MYC expression. Two MYCN-amplified neuroblastoma cell lines (IMR5 and CHP134) and two non-MYCN-amplified cell lines (SY5Y and SKNAS) were used to address the effect of Hsp90 inhibition on the malignant phenotype of neuroblastoma. It was found that Hsp90 inhibition in neuroblastoma cell lines resulted in significant growth suppression, a decrease in MYCN and MYC expression, and an increase in the expression of p53. In the TP53-mutated SKNAS cell line, Hsp90 inhibition enhanced the expression of the favorable neuroblastoma genes EFNB2, MIZ-1 and NTRK1 (TrkA). In addition, Hsp90 inhibition reduced HDAC6 expression and enhanced tubulin acetylation. Together our data suggest that Hsp90 inhibition suppresses the growth of neuroblastoma through multiple cellular pathways and that MYC/MYCN destabilization is among the important consequences of Hsp90 inhibition.