Independent Predictors of Postoperative Stroke With Cardiopulmonary Bypass.

OBJECTIVE: To assess predictive factors of postoperative stroke in cardiac surgery using cardiopulmonary bypass (CPB). DESIGN: This study was a retrospective observational study. SETTING: This study was conducted at a single institution (Liverpool Hospital, NSW, Australia). PARTICIPANTS: All patients with CPB treated surgically at Liverpool Hospital, NSW, between January 2016 and December 2018 INTERVENTIONS: Patients underwent cardiac surgery with CPB. MEASUREMENTS AND MAIN RESULTS: The primary outcome was cerebrovascular accident, or stroke. Univariate and multivariate analyses via Firth's logistic regression with regard to stroke were performed. The study comprised 1,092 patients over a three-year period. In this cohort, the stroke rate was 3.1%. Via univariate analysis of factors in relation to stroke post-CPB, recent or past stroke (odds ratio [OR] 5.43 v 2.32), diabetes mellitus (OR 1.92), dialysis dependence (OR 5.67), elective procedures (OR 0.34), aortic procedures (OR 4.02), bypass and cross-clamp times (OR 1.02 and 1.04), postoperative atrial fibrillation (OR 2.28), and hypoperfusion times all reached the significance level of p ≤ 0.1 to be included in the multivariate analysis. Multivariate analysis to find independent factors in relation to stroke yielded diabetes mellitus (OR 2.49; p = 0.025), dialysis dependence (OR 3.82; p = 0.03), aortic procedures (OR 3.93; p = 0.014), and elective procedures (OR 0.24; p = 0.026) as independently predictive or protective with regard to postoperative stroke. CONCLUSIONS: Independent predictors of stroke in this single center cohort included dialysis dependence, diabetes, and aortic procedures. Elective procedures were shown to be an independent protective factor.

Evidence-Based Determination of Cut-Off Points for Increased Cardiac-Surgery Mortality Risk With EuroSCORE II and STS: The Best-Performing Risk Scoring Models in a Single-Centre Australian Population.

OBJECTIVES: Risk scoring models (RSMs) are commonly used for estimation of postoperative-mortality risk in patients undergoing cardiac surgery, but their prediction accuracy may vary in different populations and clinical situations. The prognostic accuracies of some RSMs have not yet been fully evaluated in the Australian population. In this retrospective observational study, our aims were to assess the performance of four contemporary RSMs, to identify the best RSMs for prediction of postoperative-mortality in the single-centre cohort, and to determine a statistical threshold for classification of patients with increased or "higher" mortality risk. METHODS: The study population included patients who underwent cardiac surgery at Liverpool Hospital between January 2013 and December 2014. Demographic information was collected, and mortality risks were estimated with the ES2 (EuroSCORE II), STS (Society of Thoracic Surgeons Score), AS (AusSCORE total) and ASMR (AusSCORE multi-risk) RSMs. (Additive EuroSCORE) (AES) and LES (logistic EuroSCORE) were included for historical interest. Discrimination, the ability to stratify patients between mortality and no mortality outcomes, and calibration, the comparison of risk score estimated and observed outcome in the population, were evaluated for each RSM, to determine their predictive accuracy in the study population. Discrimination was assessed by the AUC (area under the receiver operating characteristic curve), and acceptable calibration by the p-value greater than 0.05 for the Hosmer-Lemeshow (H-L) test. The best AUCs in contempory models were compared using the DeLong test. For ES2 and STS risk scores, cut-off points, or thresholds, for patients at increased risk of mortality were derived using Youden's J-statistics, calculated from sensitivity and specificity of models in predicting mortality. RESULTS: From a total study population of 898 patients, 738 had scores for all six RSMs. The three EuroSCORE risk models and Youden's J-statistics analysis included the total population. Of the models in contemporary use, ES2 had higher discrimination (AUC=0.850) in this population than ASMR (AUC=0.767, p=0.024) and AS (AUC=0.739) and non-significantly higher discrimination than STS (AUC=0.806, p=0.19). All contemporary models had acceptable calibration but the older LES (H-L p=0.024) did not. Estimated mortality was closest to observed mortality with the ES2 model. Both AES and LES over predicted mortality. The RSM with the highest discrimination in isolated coronary artery bypass graft surgery (CAGs) (AUC=0.847), isolated valves (AUC=0.830), and females (AUC=0.784) was the ES2 model. STS discrimination was highest in CAGs plus valve procedures (AUC 0.891), and males (STS AUC=0.891). Cut-off points for risk scores to define increased risk populations were 3.0% for ES2 and 1.7% for STS. Similar proportions of patients in each RSM (ES2-26% to STS-32%) were defined as higher risk by the model threshold score depending on type of procedure. CONCLUSION: Among RSMs in contemporary use, ES2 and STS showed the best discrimination and acceptable calibration. Caution is recommended in specific subgroups. Increased mortality risk score cut-off points could be identified for these two RSMs in this single-centre cohort.

Syngeneic murine model for prostate cancer using RM1 cells transfected with gp100.

BACKGROUND: Prostate cancer (PC) is the most commonly diagnosed solid tumor in men. A major challenge in PC immunotherapy is the lack of an animal model that resembles human adenocarcinoma and allows for manipulation or monitoring of the immune response. Mouse models are needed for preclinical testing of new immunotherapies, whether used alone or in combination with established drugs, and to develop companion biomarkers that can be validated in clinical trials. METHODS: To develop a syngeneic prostate adenocarcinoma model with a well-defined tumor antigen, murine RM1 PC cells were transfected with the endogenous mouse melanoma protein, gp100 (RM1-gp100). Gp100 was attractive because it is a self-protein and it instantly allowed us to use the large trove of immune research tools developed for melanoma research. A dendritic cell (DC) vaccine was used as model immunotherapy to demonstrate that adoptive immunotherapy against gp100 decreases the growth of RM1-gp100 but not RM1. RESULTS: Expressing gp100 did not change the growth of RM1 cell in vitro or in vivo. The DCs pulsed with RM1-gp100 could be used to stimulate Pmel-1 lymphocyte proliferation and activation. Pmel-1 lymphocytes could be adoptively transferred into C57Bl/6 mice that were treated with DCs pulsed with RM1-gp100. The resulting Pmel-1 lymphocytes were monitored to assess the primary cellular immune response and memory response. CONCLUSION: We describe a murine model for prostate adenocarcinoma with a well-characterized antigen that can be used in an immunologically intact mice to monitor the temporal CD8+ lymphocyte-mediated antitumor immunity.

Risk Factors for Surgical Shunting in a Large Cohort With Ischemic Priapism.

BACKGROUND: Ischemic priapism is treated with a stepwise algorithm, but some patients may benefit from immediate shunt placement. AIM: To identify risk factors for surgical shunt placement in a large series of patients with ischemic priapism. METHODS: We identified all patients presenting to our institution with ischemic priapism from January 2010 to December 2018. Multivariable was performed to assess risk factors for surgical shunting. Receiver operating characteristic curve analysis (Youden Index) was used to assess which cutoff time for the duration of priapism was most predictive requiring shunting. OUTCOMES: We assess risk factors for surgical shunting and what duration of priapism was most predictive of requiring a shunt. RESULTS: We identified a total of 169 ischemic priapism encounters from 143 unique patients, of which 26 (15%) encounters resulted in a surgical shunt. Patients treated with a shunt had longer priapism durations than those without (median 36 vs 10 hours, P < .001). Independent predictors of a surgical shunt on multivariate logistic regression were the duration of priapism in hours (odds ratio: 1.05, 95% confidence interval: 1.02-1.10; P < .001) and history of prior priapism (odds ratio: 3.15, 95% confidence interval: 1.03-9.60; P = .045). Receiver operating characteristic curve analysis using priapism duration to predict the need for shunt generated an area under curve of 0.83. A duration of 24 hours correlated to a sensitivity of 0.77 and specificity of 0.90. CLINICAL IMPLICATIONS: These results can be used to counsel future patients and assist in the decision-making process for providers. STRENGTHS & LIMITATIONS: This is one of the largest series of priapism in the literature. Most (74%) of the priapism were due to intracavernosal injections so the results may not be generalizable to populations with different priapism etiologies. CONCLUSION: In this study of 169 priapism encounters, we found that the priapism duration and history of prior priapism were independent predictors of surgical shunt placement. These results can aid urologists in the counseling and decision-making process of these challenging cases. Zhao H, Dallas K, Masterson J, et al. Risk Factors for Surgical Shunting in a Large Cohort With Ischemic Priapism. J Sex Med 2020;17:2472-2477.

Underrepresentation of functional conditions of the lower urinary tract in adults in US federal research funding.

AIMS: Evaluation and treatment of functional conditions of the lower urinary tract (fcLUT), a subset of benign urinary tract conditions, is highly subjective due to overlapping symptomatology. Despite high prevalence and socioeconomic cost, there has been little improvement in their treatment and lack of progress in understanding their pathophysiology. This study investigates trends in quantity, monetary amounts, and awardees' characteristics of federally funded research awards for fcLUT compared to nonurologic benign conditions (NUBCs) and urologic malignancies. METHODS: Data were extracted from the National Institutes of Health (NIH) and federal RePORTER databases in December 2019. We identified currently active awards in fcLUT, NUBC, and malignant urologic conditions and the associated demographic features of awardees. The authors also examined temporal funding trends for such awards. RESULTS: These database searches revealed that there are consistently fewer awards and funding dollars for the study of fcLUT compared to other benign conditions with similar prevalences. While most research topics have received increased funding in awards and overall funding dollars over time, fcLUT funding has remained relatively flat. Urologists are also underrepresented; only 11 of the 86 recipients of NIH R01 awards to study fcLUT have clinical training in urology. CONCLUSIONS: Even when compared to NUBC, funding for the study of fcLUT remains low and has stagnated over time. Further, investigators who are clinicians in the field of urology are in the minority of those doing this study. Given the need for clinical perspectives in fcLUT research, the lack of urologist representation will inhibit discovery and translational advances.

Balanced Chest Drainage Prevents Post-Pneumonectomy Pulmonary Oedema.

BACKGROUND: Pneumonectomy in the adult patient is associated with a mortality of 1-9%. Death is often due to post pneumonectomy pulmonary oedema (PPPO). The use of balanced chest drainage system (BCD) in the setting of post pneumonectomy has been reported to be of benefit in the prevention of PPPO. This study seeks to compare the incidence of PPPO in patients who underwent pneumonectomy and whose empty pleural space was managed either with CRD or BCD. METHODS: This retrospective observational cohort study involved 98 patients who were operated on by one surgeon at Liverpool Hospital, Sydney, Australia from 1997 to 2019. The patients were divided into two groups according to the era in which they had their pneumonectomy. Group 1 consisted of 18 patients managed with clamp-release drainage between 1997 and 2002. Group 2 consisted of 80 patients managed with balanced chest drainage between 2003 and 2019. The primary outcomes of interest were the development of PPPO and death. Demographic and clinico-pathological variables between the groups were compared including whether the phrenic nerve was sacrificed, volume of infused intraoperative fluid, duration of single lung ventilation, intraoperative tidal volumes, agents of anaesthetic induction and maintenance, mean urine output in the first 4 postoperative hours, institution of a postoperative 1.5 L fluid restriction, total chest drainage, day of chest drain removal, presence of radiological postoperative mediastinal shift, post-pneumonectomy pulmonary oedema and death. Group characteristics were compared using t-test and chi-squared for continuous and categorical variables respectively. Univariate and multivariate analysis was also undertaken using the Firth method of logistic regression for rare occurrences in a stepwise fashion. RESULTS: Through univariate analysis, balanced chest drainage, postoperative fluid restriction and intraoperative fluid infusion showed significant effect on PPPO. Through multivariate analysis, balanced chest drainage was found to have independent protective value for PPPO and mortality. CONCLUSION: Compared with clamp-release drainage, balanced chest drainage results in a lower incidence of post-pneumonectomy pulmonary oedema and death.

Human Chorionic Gonadotropin monotherapy for the treatment of hypogonadal symptoms in men with total testosterone > 300 ng/dL.

PURPOSE: The 2018 American Urological Association guidelines on the Evaluation and Management of Testosterone Deficiency recommended that 300 ng/dL be used as the threshold for prescribing testosterone replacement therapy (TRT). However, it is not uncommon for men to present with signs and symptoms of testosterone deficiency, despite having testosterone levels greater than 300 ng/dL. There exists scant literature regarding the use of hCG monotherapy for the treatment of hypogonadism in men not interested in fertility. We sought to evaluate serum testosterone response and duration of therapy of hCG monotherapy for men with symptoms of hypogonadism, but total testosterone levels > 300 ng/dL. MATERIALS AND METHODS: We performed a multi-institutional retrospective case series of men receiving hCG monotherapy for symptomatic hypogonadism. We evaluated patient age, treatment indication, hCG dosage, past medical history, physical exam findings and serum testosterone and gonadotropins before and after therapy. Descriptive analysis was performed and Mann Whitney U Test was utilized for statistical analysis. RESULTS: Of the 20 men included in the study, treatment indications included low libido (45%), lack of energy (50%), and erectile dysfunction (45%). Mean testosterone improved by 49.9% from a baseline of 362 ng/dL (SD 158) to 519.8 ng/dL (SD 265.6), (p=0.006). Median duration of therapy was 8 months (SD 5 months). Fifty percent of patients reported symptom improvement. CONCLUSIONS: Treatment of hypogonadal symptoms with hCG for men who have a baseline testosterone level > 300 ng/dL appears to be safe and effi cacious with no adverse events.

START: a system for flexible analysis of hundreds of genomic signal tracks in few lines of SQL-like queries.

BACKGROUND: A genomic signal track is a set of genomic intervals associated with values of various types, such as measurements from high-throughput experiments. Analysis of signal tracks requires complex computational methods, which often make the analysts focus too much on the detailed computational steps rather than on their biological questions. RESULTS: Here we propose Signal Track Query Language (STQL) for simple analysis of signal tracks. It is a Structured Query Language (SQL)-like declarative language, which means one only specifies what computations need to be done but not how these computations are to be carried out. STQL provides a rich set of constructs for manipulating genomic intervals and their values. To run STQL queries, we have developed the Signal Track Analytical Research Tool (START, http://yiplab.cse.cuhk.edu.hk/start/ ), a system that includes a Web-based user interface and a back-end execution system. The user interface helps users select data from our database of around 10,000 commonly-used public signal tracks, manage their own tracks, and construct, store and share STQL queries. The back-end system automatically translates STQL queries into optimized low-level programs and runs them on a computer cluster in parallel. We use STQL to perform 14 representative analytical tasks. By repeating these analyses using bedtools, Galaxy and custom Python scripts, we show that the STQL solution is usually the simplest, and the parallel execution achieves significant speed-up with large data files. Finally, we describe how a biologist with minimal formal training in computer programming self-learned STQL to analyze DNA methylation data we produced from 60 pairs of hepatocellular carcinoma (HCC) samples. CONCLUSIONS: Overall, STQL and START provide a generic way for analyzing a large number of genomic signal tracks in parallel easily.

High-resolution Diffusion-weighted Imaging to Detect Changes in Tumor Size and ADC, and Predict Adverse Biopsy Histology during Prostate Cancer Active Surveillance.

PURPOSE: Majority of men with low-risk prostate cancer can be managed with active surveillance (AS). This study evaluates a high-resolution diffusion-weighted imaging (HR-DWI) technique to predict adverse biopsy histology (AH), defined as Gleason score ≥7 on any biopsy or ≥3 increase in number of positive biopsy cores on systematic biopsies. We test the hypothesis that high-grade disease and progressing disease undergo subtle changes during even short intervals that can be detected by HR-DWI. EXPERIMENTAL DESIGN: In a prospective clinical trial, serial multiparametric MRIs, incorporating HR-DWI and standard DWI (S-DWI) were performed approximately 12 months apart prior to prostate biopsy (n = 59). HR-DWI, which uses reduced field-of-view and motion compensation techniques, was compared with S-DWI. RESULTS: HR-DWI had a 3-fold improvement in spacial resolution compared with S-DWI as confirmed using imaging phantoms. For detecting AH, multiparametric MRI using HR-DWI had a sensitivity of 75% and specificity of 83.9%, and MRI using S-DWI had a sensitivity of 71.4% and specificity of 54.8%. The AUC for HR-DWI was significantly higher (0.794 vs. 0.631, P = 0.014). Secondary analyses of univariable predictors of AH showed tumor size increase [OR 16.8; 95% confidence interval (CI): 4.06-69.48; P < 0.001] and apparent diffusion coefficient (ADC) decrease (OR 5.06; 95% CI: 1.39-18.38; P = 0.014) on HR-DWI were significant predictors of AH. CONCLUSION: HR-DWI outperforms S-DWI in predicting AH. Patient with AH have tumors that change in size and ADC that could be detected using HR-DWI. Future studies with longer follow-up should assess HR-DWI for predicting disease progression during AS. SIGNIFICANCE: We report on a prospective clinical trial using a MRI that has three times the resolution of standard MRI. During AS for prostate cancer, two high-resolution MRIs performed approximately a year apart can detect tumor changes that predict the presence of aggressive cancers that should be considered for curative therapy such as prostatectomy or radiation.

Implementation and Validation of a High-fidelity Simulation Model for Surgical Resident Training: Management of Acute Intraoperative Hemorrhage during Robot-assisted Surgery.

OBJECTIVE: To improve our previous simulation-based training module by using sustainable material to mold an anatomically accurate terrain and reproducing major vascular injuries encountered during robot-assisted nephrectomy. METHODS: The simulator was built with a pump, gauge, and valve linked via silicone tubing. Artificial blood was made from cornstarch, water, and red dye, and pumped through 3D-Med artificial vessels with the dimensions of an average renal artery. Silicone was used to emulate the pliability of organic tissue and mold an anatomically accurate terrain. Eight urologic residents participated in the pilot simulation. We employed validated assessment tools including Non-Technical Skills for Surgeons and Objective Structured Assessment of Technical Skills forms to guide debrief sessions moderated by an expert physician after individual performance evaluations. RESULTS: The apparatus demonstrated high reproducibility across all simulation scenarios, enhancing resident problem-solving skills. Residents' pre-simulation surveys revealed significant concern regarding their acute hemorrhage management. Residents' post-simulation survey demonstrated average realism scores increased from 4.375 to 4.75. Residents also felt the simulator enhanced learning, offering valuable practice and knowledge applicable to their surgical specialty. CONCLUSION: The management of acute hemorrhage during robot-assisted surgery remains a space for additional surgical education and training. Our simulation successfully provided a reliable, reproducible training for residents to practice their technical and non-technical skills in managing acute hemorrhage.

An Analysis of Stated Insurance Coverage and Estimated Patient-Incurred Costs of Treatments for Lower Urinary Tract Symptoms.

IMPORTANCE: Lower urinary tract symptoms (LUTSs) affect more than half of all adults, yet clinical care remains poor. Anecdotally, patients and health care providers express frustration over obstacles from insurance providers to obtaining LUTS treatment; however, little information concerning actual patient-incurred costs for these medications is available. OBJECTIVES: This study aimed to analyze coverage by 5 major insurance companies and patient costs for LUTS pharmacotherapy. STUDY DESIGN: For each of 5 major nationwide insurance providers (Aetna, Blue Cross/Blue Shield, Cigna, Humana, United HealthCare), formulary coverage of medications for overactive bladder, interstitial cystitis/bladder pain syndrome, and genitourinary syndrome of menopause were reviewed for low- and high-cost plans. When not covered, the best preinsurance cash price of medications was determined from GoodRx. RESULTS: This qualitative analysis demonstrates that no guideline-directed therapy was universally covered by all insurance providers at low cost, regardless of the availability of generic alternatives. Medication prices ranged from $3 to $900 per month across plans. Inconsistencies in coverage and medication prices were common across insurance providers, between similar medications used for treatment of a given condition, and between a provider's low- and high-cost plans. CONCLUSIONS: Even medications that are U.S. Food and Drug Administration-approved and indicated by guidelines can have patient costs that are prohibitive. Because lack of care for LUTSs profoundly affects quality of life, the ability to live independently, and overall morbidity, improved price transparency is required to understand the health implications of limited coverage on LUTS care.

Case report: Management of infiltrative basosquamous carcinoma of the sternum.

INTRODUCTION AND IMPORTANCE: Basosquamous carcinoma (BSC) is a rare cutaneous cancer defined as a basal-cell carcinoma that has differentiated into a squamous-cell carcinoma. It is aggressive and infiltrative, and known for its multiple recurrences and risk for metastasis. CASE PRESENTATION: This article describes the case of a 78-year-old man who presented with a several-year history of an infiltrative BSC of his chest-wall invading into his sternum. CLINICAL DISCUSSION: He was subsequently treated surgically with a chest-wall wide-local excision and sub-total sternectomy, reconstructed with titanium plates and a musculocutaneous anterolateral thigh free-flap. CONCLUSION: This case highlights a surgical approach to advanced chest-wall BSC.

Human mutation D157G in ferroportin leads to hepcidin-independent binding of Jak2 and ferroportin down-regulation.

Mutations in the iron exporter ferroportin (Fpn) result in iron overload in macrophages or hepatocytes depending upon the mutation. Patients with Fpn mutation D157G show high serum ferritin and normal to slightly elevated transferrin saturation. Here, we show that Fpn(D157G)-green fluorescent protein (GFP) is down-regulated independent of hepcidin, and that this down-regulation is due to the constitutive binding of Jak2 and Fpn phosphorylation. Expression of Fpn(D157G)-GFP in Danio rerio results in a severe growth defect, which can be rescued by iron supplementation. These results identify a hepcidin-independent regulation of Fpn that can result in alterations in iron homeostasis.

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux.

Ferroportin (Fpn) is the only known iron exporter in vertebrate cells and plays a critical role in iron homeostasis regulating cytosolic iron levels and exporting iron to plasma. Ferroportin1 (FPN1) expression can be transcriptionally regulated by iron as well as other transition metals. Fpn can also be posttranslationally regulated by hepcidin-mediated internalization and degradation. We demonstrate that zinc and cadmium induce FPN1 transcription through the action of Metal Transcription Factor-1 (MTF-1). These transition metals induce MTF-1 translocation into the nucleus. Zinc leads to MTF-1 binding to the FPN1 promoter, while iron does not. Silencing of MTF-1 reduces FPN1 transcription in response to zinc but not in response to iron. The mouse FPN1 promoter contains 2 MTF-1 binding sites and mutation of those sites affects the zinc and cadmium-dependent expression of a FPN1 promoter reporter construct. We demonstrate that Fpn can transport zinc and can protect zinc sensitive cells from high zinc toxicity.

Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2.

Hepcidin is a hormone secreted in response to iron loading and inflammation. Hepcidin binds to the iron exporter ferroportin, inducing its degradation and thus preventing iron entry into plasma. We determined that hepcidin binding to ferroportin leads to the binding and activation of the protein Janus Kinase2 (Jak2), which is required for phosphorylation of ferroportin. Ferroportin is a dimer and both monomers must be capable of binding hepcidin for Jak2 to bind to ferroportin. Once Jak2 is bound to the ferroportin dimer, both ferroportin monomers must be functionally competent to activate Jak2 and for ferroportin to be phosphorylated. These results show that cooperativity between the ferroportin monomers is required for hepcidin-mediated Jak2 activation and ferroportin down-regulation. These results provide a molecular explanation for the dominant inheritance of hepcidin resistant iron overload disease.

Bronchial artery pseudoaneurysm presenting with hoarseness: Diagnosis and endovascular management.

Bronchial artery pseudoaneurysm is a rare entity which is diagnosed radiologically; with or without symptoms. Symptoms of phonation changes with bronchial artery pseudoaneurysm are yet to be reported. This article describes the case of a 56-year-old man who presented with a history of a hoarse voice. This was investigated with computed tomography of his chest which diagnosed a bronchial artery pseudoaneurysm under the arch of the aorta. He was subsequently treated with coil embolization. The original symptoms improved with this intervention. This case highlights the rare presentation of hoarseness of voice in this rare condition.

Is treatment of hypogonadism safe for men after a solid organ transplant? Results from a retrospective controlled cohort study.

Male solid organ transplant patients are at increased risk of hypogonadism and the safety of treating these patients for hypogonadism is unknown. We sought to evaluate the safety of treating hypogonadism in the solid organ transplant recipient. To accomplish this, we performed a retrospective review between 2009 and 2017 of patients treated at a single academic urology clinic. Men who underwent a solid organ transplant with a diagnosis of hypogonadism (Testosterone <350 ng/dl) were included. In total, 87 hypogonadal transplant recipients were included (29 no treatment; 58 treated). Treatment modalities included non-testosterone therapies (human chorionic gonadotropin, clomiphene), topical, injectable, and subcutaneous T preparations. There was no difference between groups for baseline characteristics including age, length of follow-up since transplant, baseline testosterone, and transplant type. There was no difference in prostate cancer diagnoses, erythrocytosis, rejection, infections, number of unplanned admissions per patient. While there was no difference in the proportion of deaths in untreated (21%; n = 6) and treated transplant recipients (7%; n = 4; p = 0.08), the median survival was longer in men treated with T (p = 0.03). Treatment of hypogonadism in solid organ recipients did not increase the risk for adverse effects related to treatment of hypogonadism or solid organ transplant.

Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity.

PURPOSE: There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering. EXPERIMENTAL DESIGN: Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy. RESULTS: Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. CONCLUSIONS: Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.

Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma.

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to The Cancer Genome Atlas cohort revealed that deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by cyclin dependent kinase 4/6 (CDK4/6) inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a-/- AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth compared with anti-PD-1 or CDK4/6 inhibitor alone. CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.