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Background The novel da Vinci Single-Port (SP) robotic platform received the US FDA approval in 2018. The device, specifically conceived for single-site approach, is pushing through the limits of minimally invasive surgery. We sought to provide a comprehensive overview of the current status of the clinical experiences accomplished by the da Vinci SP in urology, and to discuss future perspectives. Methods A non-systematic literature review was performed focusing on single port articles in urological surgery using Medline/PubMed and Embase search electronic engines. The authors analyzed findings and a brief report of the clinical experience for surgical procedures completed by the SP platform was described. Results The current data available from single-port robotic established the safety and feasibility of urologic procedures using this novel platform. However, the results come from single-center case series, small cohorts and retrospective studies that need to be cautiously interpreted. Additional evidence is required to determine the asset of the SP platform in the urological community. Conclusions The SP robotic system opens new frontiers on the surgical scenery facilitating the completion of urological surgeries through a single incision. Further comparative studies will be required to assess perioperative and long-term oncological and functional outcomes among SP, multi-arm robotic and open approaches.

Resumen Antecedentes La novedosa plataforma robotica da Vinci Single-Port (single port [SP] = puerto unico [PU]) recibio la aprobacion de la FDA en 2018. El equipo, concebido especificamente para el acceso por un solo puerto, esta superando los limites de la cirugia minimamente invasiva. Buscamos proporcionar una vision global del estado actual de las experiencias clinicas logradas por el PU da Vinci en Urologia y discutir las perspectivas futuras. Metodos Se realizo una revision bibliografica no sistematica centrada en articulos de cirugia urologica de puerto unico utilizando los motores de busqueda Medline/PubMed y Embase. Los autores analizaron los hallazgos y se describio un breve informe de la experiencia clinica de los procedimientos quirurgicos llevados a cabo mediante la plataforma PU. Resultados Los datos actuales disponibles de la cirugia robotica de puerto unico han establecido la seguridad y la viabilidad de los procedimientos urologicos que utilizan esta novedosa plataforma. Sin embargo, los resultados provienen de series de casos de un solo centro, cohortes pequenas y estudios retrospectivos que deben ser interpretados con cautela. Se necesitan estudios adicionales para determinar el valor de la plataforma de PU en la comunidad urologica. Conclusiones El sistema robotico de PU abre nuevas fronteras en el escenario quirurgico facilitando la realizacion de cirugias urologicas a traves de una unica incision. Se necesitaran mas estudios comparativos para evaluar los resultados oncologicos y funcionales perioperatorios y a largo plazo entre los abordajes de PU, robotico multibrazo y abierto.

To characterize pulmonary toxicities associated with the use of novel immune checkpoint inhibitors Adverse event reports from immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 were captured from the W.H.O pharmacovigilance database (VigiBase) up until Dec. 31st 2019 and were analyzed to evaluate for measures of association between the use of immune checkpoint inhibitors and pulmonary toxicities. Disproportionality analysis using both frequentist and Bayesian approaches were used to detect signals between pulmonary immune-related adverse events and the use of these agents. A total of 9202 adverse pulmonary immune checkpoint inhibitor-related events were captured up until 2019. Adverse pulmonary events were compromised of 1305 airway, 18 alveolar, 5491 interstitial, 898 pleural, 560 vascular and 939 non-specific pulmonary events. We found a common association between all immune checkpoint inhibitors studied and pneumonitis, interstitial lung disease, pulmonary embolism and respiratory failure. We also noted other associations between immune checkpoint inhibitors, however not as uniformly across agents. Most of these immune-related adverse drug reactions were noted to be severe and accounted for a significant source of mortality in the reported cases. Immune checkpoint inhibitors are associated with a spectrum of inflammatory pulmonary toxicities. The breadth of pulmonary complications and prevalence may be underappreciated with the use of these agents.

Non-contacting laser ultrasound is used to measure Young’s modulus, shear modulus, and Poisson’s ratio as functions of temperature for Alloys 617 and 709. These alloys are of interest for structural applications in advanced nuclear reactors. Design rules for the construction of elevated-temperature nuclear components are presented in Section III, Division 5 of the American Society of Mechanical Engineers (ASME) Boiler and Pressure Vessel (B&PV) Code. The ASME B&PV Code for each material provides Young’s modulus values tabulated as a function of temperature and a single, temperature-independent Poisson’s ratio value. Elastic properties characterized by laser ultrasonics for Alloy 617 are in good agreement with data collected using an American Society for Testing and Materials (ASTM) standard resonant frequency technique and values reported from literature, demonstrating its accuracy. The shear modulus and Poisson’s ratio as functions of temperature for Alloy 709 have not been reported previously. Laser ultrasonics is well suited for determining temperature-dependent elastic properties, and the method offers the ability to perform measurements on small irregularly shaped specimens.

Conflicting evidence exists regarding whether hormone therapy for prostate cancer is associated with neurotoxicity. Thus, we aim to characterize the association between different types of hormone therapy and neurocognitive impairment in a real-world pharmacovigilance database.We queried VigiBase, the World Health Organization's international pharmacovigilance database, for reports of neurocognitive impairment among men who took hormone therapy from 1968 to 2021. We performed disproportionality analysis comparing rates of neurocognitive impairment with different types of hormone therapy versus other VigiBase drugs. Traditional hormonal therapy was defined as androgen deprivation therapy (ADT: gonadotropin-releasing-hormone agonists or antagonists) or first-generation androgen receptor (AR) antagonists. Novel AR signaling inhibitors (ARSIs) were defined as ARSIs with or without ADT. Differences were assessed using reporting odds ratio (ROR) with 95% confidence intervals (CI) and Empirical Bayes Estimator (EBE) values ≥1.0 signifying statistical significance.Odds of neurocognitive impairment were significantly elevated with traditional hormone therapy (ROR 1.47, 95% CI 1.34-1.62, EBE = 1.35) and novel ARSIs (ROR 2.40, 95% CI 2.28-2.54, EBE = 2.26). Odds of neurocognitive impairment were significantly elevated with enzalutamide (ROR 2.89, 95% CI 2.73-3.05, EBE = 2.70) and numerically increased with apalutamide (ROR 3.31, 95% CI 1.57-7.00, EBE = 0.98), but were decreased with abiraterone (ROR 0.68, 95% CI 0.55-0.84, EBE = 0.57).This study demonstrates elevated odds of neurocognitive impairment with hormone therapy in a real-world data set. Neurotoxicity risk was higher with novel ARSIs than traditional agents, and higher with enzalutamide than abiraterone. Due to limitations inherent to disproportionality analysis (measuring associations, not risk) and incomplete data prohibiting the ability to control for factors such as age or use of secondary drugs (e.g., concurrent use of novel ARSIs with ADT), results are exploratory in nature. The amalgamation of these and other conflicting data may contribute to clinical decision-making for men with prostate cancer eligible for treatment with these therapies, especially those with significant neurologic comorbidities.

BACKGROUND Venous thromboembolism (VTE) is a significant source of postoperative morbidity and mortality in patients undergoing common oncologic procedures. We sought to estimate the effect of surgical approach on the risk of developing a VTE. METHODS IBM Watson Health Marketscan Database was used to conduct this retrospective study. In total, 12 938 patients who underwent either a radical prostatectomy, partial colectomy, or hysterectomy via a minimally invasive or open approach. We used a propensity-weighted logistic regression analysis to assess the independent effect of surgical approach on VTE. The primary outcome of interest was the 90-day rate of VTE after surgery. RESULTS Patients undergoing minimally invasive surgery across all three surgical procedures were noted to have a lower odds of developing a VTE: (radical prostatectomy, odds ratio [OR]: 0.667, 95% confidence interval [CI]: 0.500-0.891; P = .006 |partial colectomy: OR, 0.620, 95% CI: 0.477-0.805; P

Introduction: Injuries to surrounding structures during radical prostatectomy (RP) are rare but serious complications. However, it remains unknown if injuries to intestines, rectum, or vascular structures occur at different rates depending on the surgical approach. Methods: We compared the frequency of these outcomes in open RP (ORP) and minimally invasive RP (MIS-RP) using the national American College of Surgeons National Surgical Quality Improvement Program database (2012–2017). Along with important metrics of clinical and surgical outcomes, patients were identified as undergoing surgical repair of small or large bowel, vascular structures, or hernias based on Current Procedural Terminology codes. Results: In our propensity matched analysis, a total of 13,044 patients were captured. Bowel injury occurred more frequently in ORP than in MIS-RP (0.89 vs. 0.26%, p < 0.01). By intestinal segment, rectal and large bowel injuries were more common in ORP than MIS-RP (0.41 vs. 0.11% and 0.31 vs. 0.05%, both p < 0.01). However, there was no statistically significant difference between the groups for small bowel injury (0.17 vs. 0.11%, p = 0.39). Vascular injury was more common in MIS-RP (0.18 vs. 0.08%, p = 0.08). Hernias requiring repair were only identified in the MIS-RP group (0.12%). Conclusion: When considering surgical approach, rectal and large bowel injuries were more common in ORP, while vascular injuries and hernia repair were more common in MIS-RP. Our findings can be used in counseling patients and identifying risk factors and strategies to reduce these complications.

Background Androgen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk. Methods We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. Findings We identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48—1•71), myocardial infarction (1•35, 1•16—1•58), arrythmia (2•04, 1•82—2•30), and heart failure (3•02, 2•60—3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12—1•30), myocardial infarction (1•80, 1•61—2•03) and heart failure (2•06, 1•76—2•41). Interpretation We found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone. Funding None

Testicular cancer is the most commonly diagnosed solid-organ neoplasm among young men, with variable incidence across racial groups. Testicular cancer incidence has increased since the 1970s, most notably among white men. Such trends in testicular cancer remain poorly understood. We investigated age-adjusted incidence rates of testicular cancer from 1975 to 2015 using Surveillance, Epidemiology and End Results data to further understand the nature of the temporal trends and potential drivers of disease. Across this time period, white men had the highest incidence and the largest increase in rate; however, we also note more recent increases in the incidence of testicular cancer across all racial groups being examined. PATIENT SUMMARY: We analyzed the rate of testicular cancer in the United States between 1975 and 2015. In that time, white patients had the highest rate and increase in rate of testicular cancer, but non-white patients also had increasing rates of disease.

INTRODUCTION AND OBJECTIVE:Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinom...

The EPA's Water Security Test Bed (WSTB) facility is a full-scale representation of a drinking water distribution system. In collaboration with the Idaho National Laboratory (INL), EPA designed the WSTB facility to support full-scale evaluations of water infrastructure decontamination, real-time sensors, mobile water treatment systems, and decontamination of premise plumbing and appliances. The EPA research focused on decontamination of 1) Bacillus globigii (BG) spores, a non-pathogenic surrogate for Bacillus anthracis and 2) Bakken crude oil. Flushing and chlorination effectively removed most BG spores from the bulk water but BG spores still remained on the pipe wall coupons. Soluble oil components of Bakken crude oil were removed by flushing although oil components persisted in the dishwasher and refrigerator water dispenser. Using this full-scale distribution system allows EPA to 1) test contaminants without any human health or ecological risk and 2) inform water systems on effective methodologies responding to possible contamination incidents.

Para-testicular rhabdomyosarcoma represents a significant portion of malignant pediatric scrotal tumors. Treatment of this tumor requires a multi-disciplinary approach, however surgery, including a retroperitoneal lymph node dissection, remains an important diagnostic and therapeutic tool in the treatment of this disease. Traditional approaches have been via open surgery, however with the advent of the robotic platform, minimally invasive retroperitoneal lymph node dissection with sound oncologic principles is now possible. Advantages of the robotic approach include decreased morbidity and enhanced recovery compared to the open approach. In this chapter, we describe the technique for a minimally invasive robotic retroperitoneal lymph node dissection.

Objective To examine the use of in-hospital pharmacologic thromboprophylaxis (PTP) in patients undergoing radical cystectomy between 2004 and 2014 and to assess the risk of venous thromboembolism (VTE) across the study period. Material and Methods We identified 8322 patients without contraindications to PTP undergoing radical cystectomy in the US using the Premier Healthcare Database. Nonparametric Wilcoxon type test for trend was employed to examine the trend of PTP utilization across the study period. Ensuing, we employed multivariable logistic regression and generalized linear regression models to examine the odds of receiving PTP and the risk of being diagnosed with VTE, respectively. Results Based on VTE risk-stratification, the majority of patients (87.8%) qualified as “high-risk.” Across the study period the use of PTP increased (Odds ratio 1.02, 95% confidence interval (CI) 1.00-1.03, P = .044), but remained underutilized as the maximum percentage of patients receiving in-hospital PTP did not exceed 58.6%. The risk of VTE did not vary across the study period (risk ratio 0.97, 95%CI 0.92-1.02, P = .178). Conclusion Utilization of PTP increased throughout the study period, while the risk of VTE did not change. Future studies are necessary to improve implementation of guideline-driven care, as PTP remained underutilized throughout the study period.

Reoperation after radical cystectomy (RC) is common but the types of reoperation after RC and associated risk factors have not been fully characterized. Here, we provide a detailed, contemporary account of the factors that drive surgical reoperation within the first 30-days after surgery, identify at risk patient populations, and describe common reoperations.The American College of Surgeons National Surgical Quality Improvement Program database (2012-2017) was analyzed to identify 30-day reoperation rates after RC. Captured variables included demographic, preoperative, operative, and postoperative characteristics. Postoperative characteristics included complications, including types of reoperation, length of stay, unplanned readmissions, and discharge destination. Pearson chi-squared and multivariable logistic regression models were used for analysis.A total of 10,848 patients underwent RC and there were 633 (5.84%) unplanned reoperations. On multivariable logistic regression, patient factors associated with increased risk of reoperation included longer operative times at index procedure (90th percentile operative time) (OR1.41 [1.08-1.83], P = 0.02), smoking (OR1.34 [1.11-1.63], P0.01), obesity (BMI≥30) (OR 1.29 [1.04-1.60], P = 0.02) and chronic obstructive pulmonary disease (OR1.74 [1.36-2.3], P0.01). Other significant factors included clinically significant hypertension, perioperative blood transfusion, and male sex. The most common reoperation procedures were those performed on the gastrointestinal tract, accounting for 60.59% (349) of all reoperations, followed by skin/subcutaneous procedures 14.76% (85), followed by Genitourinary procedures at 8.16% (47). Patients who underwent reoperation were at higher risk for readmission, discharge to a facility, and death (P0.01).Reoperation after RC is associated with approximately 5% rate of reoperation within 30 days of surgery. The most common reason for reoperation was related to the gastrointestinal tract, accounting for more than 60% of all reoperations. Risk factors for reoperation included longer surgical times, smoking, obesity, chronic obstructive pulmonary disease, perioperative blood transfusion, and clinically significant hypertension. Knowledge of these factors can aid in operative planning and counseling and lead to possible strategies to reduce reoperations in the early perioperative setting.

Laser-generated ultrasound was used to monitor microstructure evolution during thermal processing of as-cast, polycrystalline binary uranium-zirconium metallic fuel alloys with compositions of U-20wt.%Zr (U-20Zr), U-50wt.%Zr (U-50Zr) and U-80wt.%Zr (U-80Zr). Ultrasonic waveforms were recorded during heating and cooling the samples from room temperature to >973 K and back. A phase transition temperature for all three compositions was estimated from the temperature at which an abrupt and rapid reduction in ultrasonic velocities was observed. Microstructural features on the length scale of tens of micrometers were inferred from the observation of scattering of ultrasonic waves by elastic heterogeneities above ~823 K in U-20Zr, while a hysteresis in the ultrasonic velocities of U-80Zr upon cooling was attributed to a partial retention of the high temperature phase following thermal annealing. The U-50Zr alloy exhibited a reversible viscoelastic response above 933 K, as evidenced by the observation of high frequency attenuation of the shear component of the waveforms at high temperature. Ultrasonic measurements were supplemented by in situ transmission electron microscopy (TEM). The TEM images revealed that the δ-U-Zr matrix in the three compositions underwent a spinodal decomposition above ~823 K into nanoscale regions. The ultrasonic measurements revealed larger, micron-scale structure evolution in the U-20Zr alloy at the same temperature. This large-scale structure is associated with heterogeneous regions having different Zr content. Our findings show the potential heating rate dependence of microstructural evolution in U-Zr alloys and highlight differences in the thermomechanical response and associated length scales during thermal annealing between single- and dual-phase compositions. These results demonstrate the utility of laser ultrasonics to rapidly and efficiently scan phase boundaries and monitor micrometer-scale structure evolution in metallic fuel alloys.

Purpose Many head and neck surgical procedures are considered clean-contaminated wounds and antibiotic prophylaxis is recommended. Despite prophylaxis, the incidence of surgical site infections remains significant – especially in the setting of free tissue transfer. The antibiotic course is often of a longer duration after free tissue transfer than the recommended 24 hour post-operatively. Currently, there is no consensus on appropriate antibiotic regimen or duration at this time. This study investigates the outcomes of a 7-day perioperative antibiotic regimen after microvascular reconstruction of the head and neck at our institution. Materials and methods A retrospective review was performed of 72 patients undergoing microvascular free tissue at our institution between 09/2011 and 03/2014. The antibiotic regimen, post-operative surgical (including surgical site infections) and medical complications were noted. Our rates of complications and adverse events were compared to all surgical patients, as well as all inpatients hospital-wide with use of the University Health System Consortium database. Results Seventy-two subjects met inclusion criteria for this study. The majority of subjects received cefazolin/metronidazole (69.4%). Subjects with beta-lactam allergy received clindamycin (12.5%). The remainder received an alternative regimen (18.1%). All received at least 7 days of antibiotics. The rate of hospital acquired C. difficile diarrhea was 0.57% hospital-wide, 1.13% in Otolaryngology patients, and 1.4% in this study. There were no instances of a multi-drug resistant infection or any adverse reactions to the administration of antibiotics. When compared with other antibiotic regimens, clindamycin was associated with a significantly increased rate of either medical or surgical infections (OR 14.38, p = 0.02) and longer hospital stay (average = 18 days, p Conclusion The use of a 7-day prophylactic antibiotic regimen is not associated with an increased risk of antibiotic-associated infections, multi-drug resistant infections, or antibiotic-associated complications. The use of clindamycin is associated with increased risk of medical and surgical infections post-operatively and should be avoided in the prophylactic perioperative phase after free tissue transfer of the head and neck.

Purpose Does surgical approach (minimally invasive vs. open) and type (radical vs. partial nephrectomy) affects opioid use and workplace absenteeism. Materials and Methods Retrospective multivariable regression analysis of 2,646 opioid-naïve patients between 18 and 64 undergoing radical or partial nephrectomy via either a minimally invasive vs. open approach for kidney cancer in the United States between 2012 and 2017 drawn from the IBM Watson Health Database was performed. Outcomes included: (1) opioid use in opioid-naïve patients as measured by opioid prescriptions in the post-operative setting at early, intermediate and prolonged time periods and (2) workplace absenteeism after surgery. Results Patients undergoing minimally invasive surgery had a lower odds of opioid use in the early and intermediate post-operative periods (early: odds ratio [OR], 0.77; 95% confidence interval [CI], 0.62–0.97; p=0.02, intermediate: OR, 0.60; 95% CI, 0.48–0.75; p, Graphical Abstract

Industrial Control Systems (ICS) are used to control physical processes in critical infrastructure. These systems are used in a wide variety of operations such as water treatment, power generation and distribution, and manufacturing. While the safety and security of these systems are of serious concern, recent reports have shown an increase in targeted attacks aimed at manipulating physical processes to cause catastrophic consequences. This trend emphasizes the need for algorithms and tools that provide resilient and smart attack detection mechanisms to protect ICS. In this paper, we propose an anomaly detection framework for ICS based on a deep neural network. The proposed methodology uses dilated convolution and long short-term memory (LSTM) layers to learn temporal as well as long term dependencies within sensor and actuator data in an ICS. The sensor/actuator data are passed through a unique feature engineering pipeline where wavelet transformation is applied to the sensor signals to extract features that are fed into the model. Additionally, this paper explores four variations of supervised deep learning models, as well as an unsupervised support vector machine (SVM) model for this problem. The proposed framework is validated on Secure Water Treatment testbed results. This framework detects more attacks in a shorter period of time than previously published methods.

To determine the utility of allergy evaluation in patients with chronic refractory laryngeal symptoms.Case series with chart review.Tertiary academic medical center.All patients who underwent in vitro allergy testing at a single institution from 2006 to 2010, for a total of 998 patients.Charts of patients who underwent in vitro allergy testing were identified. The charts were reviewed for the primary indication for allergy testing, as categorized into rhinitis complaints, chronic sinusitis, otitis media, and refractory laryngeal symptoms (globus, cough, throat clearing, increased secretions, and hoarseness). Results of allergy tests and comorbid conditions were analyzed and compared among groups.The positive yield of allergy testing in patients with primary laryngeal indications was 51.8%, 63.3% for rhinitis, 60.9% for sinusitis, and 33.3% for otitis media. The odds ratio of having a positive test was not statistically different for patients with laryngeal symptoms, rhinitis, or sinusitis. Patients with chronic laryngeal symptoms and positive allergy testing were most often sensitized to dust mites (63%) and least often sensitized to molds (1.3%).Allergy testing in patients with chronic laryngeal symptoms yields positive results in equivalent proportion to patients with other common presenting symptoms. Dust mites sensitization is the most common sensitization in patients with allergic laryngitis.

671 Background: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting. Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p = 0.003) respectively. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.

34 Background: Gonadotropic releasing hormone (GnRH) agonists and antagonists are first-line for advanced prostate cancer, but may be associated with cardiac toxicity. Observational studies show a relatively lower risk for GnRH antagonists, but a randomized trial found no difference. We compared the reporting of cardiac events for GnRH agonists and antagonists. Methods: We used VigiBase, the World Health Organization global database of case safety reports, which collects data from more than 130 countries to extract drug-adverse event (AE) pairs. Using Medical Dictionary for Regulatory Activities terminology, we identified AEs related to GnRH antagonist (degarelix) or agonist (leuprolide, goserelin, triptorelin, histrelin) therapy for prostate cancer, including myocardial infarction, heart failure, cardiomyopathies, new-onset valvular dysfunction, and other major cardiac events. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected. Results: We found 10,504 AEs for GnRH agonists, and 1,606 for GnRH antagonists; 805 (7.7%) were cardiac for agonists, and 102 for antagonists (6.4%). We found no signal for overall cardiac events or any subgrouping for GnRH antagonists, but identified a signal both for overall cardiac events (ROR 1.20, 95% CI 1.12-1.29) and myocardial infarction (1.76, 1.57-1.97) for GnRH agonists. Conclusions: Using validated pharmacovigilance methodology, we found a signal for myocardial infarction for GnRH agonists, but did not detect one for GnRH antagonists. As cardiovascular disease is the most common cause of non-cancer death in prostate cancer patients, this finding is of specific relevance in the current era of novel second-line anti-androgen therapies which may compound toxicity when added to first-line therapy. The relative cardiac toxicity of GnRH agonist therapy compared to GnRH antagonists merits renewed attention.

672 Background: Better outcomes have been generally associated with higher volume providers/hospitals. Recent work found an association between higher volume facilities and survival for advanced cancer patients. Volume and treatment complications for medical cancer therapy is unexplored. We studied a retrospective cohort of patients with metastatic renal cell carcinoma receiving immunotherapy at high and low volume hospitals. Methods: We used Premier Healthcare Data, which includes administrative data from all payors at over 700 community and academic hospitals, and captures 20% of all hospital discharges in the US, including infusions performed in hospital clinics. Using ICD9 codes we identified patients with metastatic renal cell carcinoma treated with nivolumab from 2015-17. Clinicodemographic data were obtained for patients and hospitals. The primary exposure was dichotomized hospital treatment volume (top quartile = high volume). Outcomes were immunotherapy-related complications for which the patient re-presented to the Emergency Department or was readmitted, and readmission for other cause. We performed mixed effects logistic regression adjusting for complex survey design to achieve national representation. Results: We included 15,724 weighted hospital encounters (5,835 at low-volume hospitals and 9,889 at high-volume hospitals). Urban, teaching hospitals were more likely to be high volume, but all patient factors were balanced. We observed 1,457 complications at high volume hospitals and 1,734 at low volume hospitals. There were no significant differences by volume of hospital in overall rates of complications (OR 0.92, 95% CI 0.82-1.09) or in rates of individual complications, with the exception of ocular complications (n=11, all low volume hospitals). We observed that high volume hospitals significantly reduced odds for readmission (OR 0.09, 0.03-0.24) unrelated to immunotherapy complications. Conclusions: We found no difference in immunotherapy-related complication rates by facility volume. This is reassuring for community administration of immunotherapy. Further study is needed to elucidate why we saw significantly more therapy-unrelated readmissions at lower volume hospitals.

70 Background: The standard of care for advanced prostate cancer is androgen deprivation therapy (ADT). The novel second generation agents abiraterone and enzalutamide were initially approved in castration resistant disease, but are now being used in the hormone sensitive setting. The FDA issued a 2010 warning about cardiovascular risks associated with ADT, but the risk of novel agents is less well understood, especially in comparison to each other. We sought to define the comparative cardiac risk profile of enzalutamide and abiraterone. Methods: We used VigiBase, the World Health Organization database of individual case safety reports, which collects data from more than 130 countries to identify drug associated adverse events (AE). Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac AEs related to abiraterone or enzalutamide therapy for prostate cancer. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: Vigibase contained 8203 AEs for abiraterone and 26024 for enzalutamide; 808 (9.9%) were cardiac-related for abiraterone, and 1000 for enzalutamide (3.8%). We found no disproportionality signal for cardiac events or any subtype for enzalutamide, but identified significantly higher odds of overall cardiac events (ROR 1.64, 95% CI 1.53—1.76), myocardial infarction (1.34, 1.17—1.58), arrythmia (2.09, 1.87—2.34), and heart failure (3.35, 2.92—3.85) for patients taking abiraterone. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of cardiac events for abiraterone but not for enzalutamide. Clinicians may need to consider these findings in the context of their patients’ comorbidities when prescribing ADT.

A 40-year-old woman was referred by her primary care physician for evaluation after a routine physical exam revealed bilateral brownish pigmentation of the tympanic membrane. Head and neck examination in the otolaryngology clinic revealed bluish hue of both sclera, teeth, and portions of her pinnae. A hearing test revealed bilateral mild sensorineural hearing loss. The patient had a history of taking minocycline for 14 years, and the hyperpigmentation that she had is known to be a rare complication of prolonged minocycline use. However, to our knowledge, this is the first case showing photographic evidence of minocycline-induced tympanic membrane hyperpigmentation. Minocycline-induced hyperpigmentation should be considered when a patient presents with brown or blue discoloration of the tympanic membrane.

DNA damage responses are relevant to prostate cancer initiation, progression and treatment. Few models of the normal and malignant human prostate that maintain stromal-epithelial interactions in vivo exist in which to study DNA damage responses. We evaluated the feasibility of maintaining tissue slice grafts at subcutaneous vs subrenal capsular sites in RAG2(-/-)γC(-/-) mice to study the DNA damage responses of normal and malignant glands.We compared the take rate and histology of tissue slice grafts from fresh, precision cut surgical specimens that were maintained for 1 to 4 weeks in subcutaneous vs subrenal capsular sites. Induction of γH2AX, p53, ATM and apoptosis was evaluated as a measure of the DNA damage response after irradiation.The take rate of subcutaneous tissue slice grafts was higher than typically reported but lower than at the subrenal capsular site. Subcutaneous tissue slice grafts frequently showed basal cell hyperplasia, squamous metaplasia and cystic atrophy, and cancer did not survive. In contrast, normal and malignant histology was well maintained in subrenal capsular tissue slice grafts. Regardless of implantation site the induction of γH2AX and ATM occurred in tissue slice graft epithelium 1 hour after irradiation and decreased to basal level by 24 hours, indicating DNA damage recognition and repair. As observed previously in prostatic ex vivo models, p53 was not activated. Notably, tumor but not normal cells responded to irradiation by undergoing apoptosis.To our knowledge this is the first study of DNA damage responses in a patient derived prostate tissue graft model. The subrenal capsular site of RAG2(-/-)γC(-/-) mice optimally maintains normal and malignant histology and function, permitting novel studies of DNA damage responses in a physiological context.

Resonant ultrasound spectroscopy (RUS) is a useful technique for measuring the elastic properties of materials. In this study, two experimental approaches for performing RUS are experimentally analyzed and compared: 1) contact transduction using piezoelectric transducers (PZT) and 2) laser transduction using pulse laser excitation and laser interferometric detection. A single Zircaloy sample cut from a nuclear pressure tube was used for this study. By virtue of the non-contact nature, the quality factor, Q, for laser RUS is shown to be higher than the contact RUS. In addition, the probe beam for laser-RUS can be scanned to form a 2D image of each vibrational mode, which in turn enables unique mode identification. These defining characteristics of laser-RUS enable straightforward discrimination of closely spaced resonant modes and provide key advantages for improving the resolution of resonant ultrasound spectroscopy.

Noncontacting, laser-based resonant ultrasound spectroscopy (RUS) was applied to characterize the microstructure of a polycrystalline sample of high purity copper. The frequencies and shapes of 40 of the first 50 resonant vibrational modes were determined. The sample's elastic constants, used for theoretical prediction, were estimated using electron backscatter diffraction data to form a polycrystalline average. The difference in mode frequency between theory and experiment averages 0.7% per mode. The close agreement demonstrates that, using standard metallurgical imaging as a guide, laser-based RUS is a promising approach to characterizing material microstructure. In addition to peak location, the Q of the resonant peaks was also examined. The average Q of the laser- generated and laser-detected resonant ultrasound spectrum was 30% higher than a spectrum produced employing a piezoelectric transducer pair for excitation and detection.