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.

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.

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.

Towards realizing nano-enabled precision delivery in plants.

Nanocarriers (NCs) that can precisely deliver active agents, nutrients and genetic materials into plants will make crop agriculture more resilient to climate change and sustainable. As a research field, nano-agriculture is still developing, with significant scientific and societal barriers to overcome. In this Review, we argue that lessons can be learned from mammalian nanomedicine. In particular, it may be possible to enhance efficiency and efficacy by improving our understanding of how NC properties affect their interactions with plant surfaces and biomolecules, and their ability to carry and deliver cargo to specific locations. New tools are required to rapidly assess NC-plant interactions and to explore and verify the range of viable targeting approaches in plants. Elucidating these interactions can lead to the creation of computer-generated in silico models (digital twins) to predict the impact of different NC and plant properties, biological responses, and environmental conditions on the efficiency and efficacy of nanotechnology approaches. Finally, we highlight the need for nano-agriculture researchers and social scientists to converge in order to develop sustainable, safe and socially acceptable NCs.

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.

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.

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.

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.

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.

Early oncological outcomes for bladder urothelial carcinoma patients treated with robotic-assisted radical cystectomy.

OBJECTIVE: • To determine oncological outcomes including early survival rates among unselected bladder urothelial carcinoma (BUC) patients treated with robotic-assisted radical cystectomy (RRC). PATIENTS AND METHODS: • Clinicopathologic and survival data were prospectively gathered for 85 consecutive BUC patients treated with RRC. • The decision to undergo a robotic rather than open approach was made without regard to tumor volume or surgical candidacy. • Kaplan-Meier survival rates were determined and stratified by tumor stage and LN positivity, and multivariate analysis was performed to identify independent predictors of survival. RESULTS: • Patients were relatively old (25% >80 years; median 73.5 years), with frequent comorbidities (46% with ASA class ≥ 3). Of these patients 28% had undergone previous pelvic radiation or pelvic surgery, and 20% had received neoadjuvant chemotherapy. • Extended pelvic lymphadenectomy was performed in 98% of patients, with on average 19.1 LN retrieved. • On final pathology, extravesical disease was common (36.5%). • Positive surgicalmargins were detected in five (6%) patients, all of whom had extravesical tumors with perineural and/or lymphovascular invasion, and most of whom were >80 years old. • At a mean postoperative interval of 18 months, 20 (24%) patients had developed recurrent disease, but only three (4%) patients had recurrence locally. Disease-free, cancer-specific and overall survival rates at 2 years were 74%, 85% and 79%, respectively. Patients with low-stage/LN(-) cancers had significantly better survival than extravesical/LN(-) or any-stage/LN(+) patients, with stage being the most important predictor on multivariate analysis. CONCLUSION: • RRC can achieve adequately high LN yields with a low positive margin rate among unselected BUC patients. • Early survival outcomes are similar to those reported in contemporary open series, with an encouragingly low incidence of local recurrence, however long-term follow-up and head-to-head comparison with the open approach are still needed.

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.

Critical analysis of complications after robotic-assisted radical cystectomy with identification of preoperative and operative risk factors.

OBJECTIVE: To better characterize short- and long-term complications in patients after robotic-assisted radical cystectomy (RRC) using standardized complications-reporting systems, and to identify preoperative and operative risk factors predicting their occurrence. PATIENTS AND METHODS: Data were collected for 79 consecutive patients with bladder cancer undergoing RRC with extracorporeal urinary diversion by one surgeon at our institution. Complications occurring < or =90 days after RRC were graded according to two standardized reporting methods (Memorial Sloan Kettering Cancer Center and Modified Clavien), and additionally stratified by organ system. Nineteen preoperative and operative variables were tested by univariate analysis for association with the occurrence of one or more postoperative complications. Variables with a significant (P < 0.05) or near-significant (P < 0.20) association on univariate analysis were included in multivariate analysis to identify independent risk factors. RESULTS: Patients were of relatively poor health, with 58% having an American Society of Anesthesiology class or Charlson Index score of > or =3. Advanced bladder disease was frequent (41% had pT3/pT4). After RRC, one or more complications occurred within 90 days of surgery for 39/79 (49%) patients. The vast majority of complications were low grade (79%), and mostly infectious (41%) or gastrointestinal (27%). Sixteen high-grade complications occurred in 13/79 (16%) patients. Urinary obstruction, abscess, enteric fistula, gastrointestinal bleeding and thromboembolism constituted most of the high-grade complications, nearly half (seven of 16) of which occurred 31-90 days after RRC. On multivariate analysis, only preoperative renal insufficiency and intraoperative intravenous (i.v.) fluids of >5000 mL were significantly associated with postoperative complications of any grade, with respective odds ratios (ORs) of 4.2 and 4.1. For high-grade complications, significant independent risk factors included an age of > or = 65 years, operative blood loss of > or =500 mL and intraoperative i.v. fluids of >5000 mL, with respective ORs of 12.7, 9.7 and 42.1. CONCLUSION: Even among relatively sick patients with frequent advanced disease, the vast majority of complications after RRC are low grade. High-grade complications are infrequent and similar in nature to high-grade events after open RC, and a notable proportion may occur at >30 days after RRC underscoring the importance of longer reporting intervals. The surgeon's ability to limit blood loss and i.v. fluids during RRC may provide effective risk reduction, particularly for high-grade events.

Antagonism of BMP4 signaling disrupts smooth muscle investment of the ureter and ureteropelvic junction.

PURPOSE: Congenital ureteropelvic junction obstruction has been associated with aberrant ureteral smooth muscle organization. Recent evidence has shown that BMP4 may be involved in ureteral morphogenesis. We determined whether the disruption of BMP4 signaling results in abnormal smooth muscle investment of the ureter and ureteropelvic junction. MATERIALS AND METHODS: We used a Cre mediated Bmp4 knockout system to conditionally excise the Bmp4 gene in developing mouse embryos. Kidney rudiments were isolated from embryos at varying gestational ages from WT and conditional knockout mice. Metanephric kidney explants were cultured in the presence or absence of the BMP antagonist Noggin. Agarose beads pre-incubated with Gremlin, another BMP antagonist, were used for localized disruption of BMP signaling. Frozen sections and whole metanephric explants were then analyzed by immunofluorescence. RESULTS: Bmp4 gene excision resulted in a dose dependent loss of ureteral smooth muscle. Antagonism of BMP signaling inhibited ureteral smooth muscle investment in a dose dependent manner and was paralleled by a dose dependent decrease in the immediate downstream targets of BMP signaling, phosphorylated Smad1, 5 and 8. Localized antagonism of BMP resulted in the focal disruption of ureteral smooth muscle investment. CONCLUSIONS: We report that decreased BMP signaling, whether by the loss of BMP4 in vivo or direct antagonism in vitro, results in a gradual reduction of the normal, well organized coat of smooth muscle surrounding the ureter. Our results also suggest that this occurs via a direct Smad dependent pathway. This raises the possibility that abnormalities in BMP4 signaling may have a role in the development of congenital ureteropelvic junction obstruction.

Transperineal vs Transrectal Prostate Biopsy-The PREVENT Randomized Clinical Trial.

This randomized clinical trial compares the effect of transperineal vs transrectal prostate biopsy on infection rates after biopsy.

Robotic vs open radical cystectomy: prospective comparison of perioperative outcomes and pathological measures of early oncological efficacy.

OBJECTIVE: To prospectively compare perioperative and pathological outcomes in a consecutive series of patients undergoing radical cystectomy (RC) and urinary diversion by the open or the robotic approach. PATIENTS AND METHODS: From February 2006 to April 2007, 54 consecutive patients underwent RC by one surgeon at our institution. Twenty-one were open, while 33 utilized the da Vinci robotic system (Intuitive Surgical, Sunnyvale, CA, USA). Data was collected prospectively, including patient demographics, operative and postoperative variables, and pathological outcomes. RESULTS: The robotic cohort had decreased blood loss (400 vs 750 mL, P = 0.002) and transfusion requirement (2.0 vs 0.5 units, P = 0.007), but increased operative duration (390 vs 300 min, P = 0.03). The time to resumption of a regular diet (4 vs 5 days, P = 0.002) and the hospital stay (5 vs 8 days, P = 0.007) were decreased in the robotic group. Overall the complication rates were similar (24% open, 21% robotic, P = 0.3). The open cohort had more patients with extravesical disease (57 vs 28%, P = 0.03) and nodal metastasis (34 vs 19%, P = 0.04). There were three patients in the open group and two in the robotic with positive margins (P = 0.2). The median number of lymph nodes removed was similar in the open and robotic cohorts (20 vs 17, P = 0.6). CONCLUSION: Robotic-assisted RC appears to offer some operative and perioperative benefits compared with the open approach without compromising pathological measures of early oncological efficacy, such as lymph node yield and margin status. Larger, randomized studies with long-term follow-up are required to confirm these findings and establish oncological equivalence.

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.

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.

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.