Thrombosis Rates and Genetic Thrombophilia Risk Among Patients With Advanced Germ Cell Tumors Treated With Chemotherapy.

INTRODUCTION: Men with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation. PATIENTS AND METHODS: Men with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel. RESULTS: This 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72). CONCLUSIONS: A previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies.

It's complicated: The relationship of non-narcotic medications and postoperative opioid use in radical cystectomy patients.

INTRODUCTION: The effect of individual non-narcotic analgesics in cystectomy enhanced recovery after surgery (ERAS) is unknown. Additionally, many non-narcotic medications are associated with side effects pertinent to the cystectomy population. To better understand the actual use and utility of these medications, we sought to characterize the association between non-narcotic medications and milligram morphine equivalent (MME) narcotic score during the postoperative inpatient stay. METHODS: We reviewed 260 consecutive ERAS cystectomy patients. The MME impact of non-narcotic compliance and cumulative dose of medication received was evaluated separately with general linear models. We also assessed relationship of non-narcotic compliance to patient reported pain score, length of stay (LOS), and time to return of bowel function (ROBF) and performed manual review of postoperative documentation to identify reasons for medication noncompliance. RESULTS: Compliance with postoperative acetaminophen, gabapentin, and ketorolac was low. There was an inverse relationship between ketorolac dose and MME on postoperative day 1 (-0.026 MME/mg; P = 0.004) and postoperative day 2 (-0.33 MME/mg; P < 0.001). Compliance with ketorolac was associated with lower MME on postoperative day 1 (26.1 MME v. 33.6 MME; P = 0.023). There were no such associations identified with gabapentin or acetaminophen. Gabapentin compliance was associated with earlier ROBF (3.7 days v. 4.3 days; P = 0.006). Ketorolac compliance was associated with lower pain score on POD1 (3.25 VAS v. 4.07 VAS; P = 0.019) and POD2 (3.05 VAS v. 3.85 VAS; P = 0.040) There was no association between medication compliance and LOS. The most common reasons identified for non-compliance with gabapentin and ketorolac were renal function concerns (38% and 40% respectively), bleeding concerns with ketorolac (20%) and concerns for neurologic adverse effect with gabapentin (16%). CONCLUSION: Compliance with non-narcotic medications in our ERAS cystectomy protocol was poor. There was a modest association with ketorolac and postoperative MME but no association with gabapentin or acetaminophen. Further study will clarify the role of these medications for cystectomy patients. Component specific analysis of protocolized care is valuable and may alter care pathways.

Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme.

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Estrogen-mediated individual differences in female rat voluntary running behavior.

Regular exercise has numerous health benefits, but the human population displays significant variability in exercise participation. Rodent models, such as voluntary wheel running (VWR) in rats, can provide insight into the underlying mechanisms of exercise behavior and its regulation. In this study, we focused on the role of estrogen on VWR in female rats. Female rats run more than males, and we aimed to determine to what extent running levels in females were regulated by estrogen signaling. The running behavior of rats (duration, speed, and total distance run) was measured under normal physiological conditions, ovariectomy (OVX), and estrogen replacement in an OVX background. Results show cyclic variations in running linked to the estrous cycle. Ovariectomy markedly reduced running and eliminated the cyclic pattern. Estrogen replacement through estradiol benzoate (EB) injections and osmotic minipumps reinstated running activity to pre-OVX levels and restored the cyclic pattern. Importantly, individual differences and ranking are preserved such that high versus low runners before OVX remain high and low runners after treatment. Further analysis revealed that individual variation in running distance was primarily caused by rats running different speeds, but rats also varied in running duration. However, it is noteworthy that this model also displays features distinct from estrogen-driven running behavior under physiological conditions, notably a delayed onset and a broader duration of running activity. Collectively, this estrogen causality VWR model presents a unique opportunity to investigate sex-specific mechanisms that control voluntary physical activity.NEW & NOTEWORTHY This study investigates estrogen's role in voluntary wheel running (VWR) behavior in female rats. Female rats exhibit greater running than males, with estrogen signaling regulating this activity. The estrous cycle influences running, whereas ovariectomy reduces it, and estrogen replacement restores it, maintaining individual differences under all conditions. Both running speed and duration contribute to VWR variations. These findings emphasize individual estrogen regulation in female exercise and provide an estrogen replacement animal model for investigating neurobiological underpinnings that drive voluntary exercise behavior.

EGGNet, a Generalizable Geometric Deep Learning Framework for Protein Complex Pose Scoring.

Computational prediction of molecule-protein interactions has been key for developing new molecules to interact with a target protein for therapeutics development. Previous work includes two independent streams of approaches: (1) predicting protein-protein interactions (PPIs) between naturally occurring proteins and (2) predicting binding affinities between proteins and small-molecule ligands [also known as drug-target interaction (DTI)]. Studying the two problems in isolation has limited the ability of these computational models to generalize across the PPI and DTI tasks, both of which ultimately involve noncovalent interactions with a protein target. In this work, we developed Equivariant Graph of Graphs neural Network (EGGNet), a geometric deep learning (GDL) framework, for molecule-protein binding predictions that can handle three types of molecules for interacting with a target protein: (1) small molecules, (2) synthetic peptides, and (3) natural proteins. EGGNet leverages a graph of graphs (GoG) representation constructed from the molecular structures at atomic resolution and utilizes a multiresolution equivariant graph neural network to learn from such representations. In addition, EGGNet leverages the underlying biophysics and makes use of both atom- and residue-level interactions, which improve EGGNet's ability to rank candidate poses from blind docking. EGGNet achieves competitive performance on both a public protein-small-molecule binding affinity prediction task (80.2% top 1 success rate on CASF-2016) and a synthetic protein interface prediction task (88.4% area under the precision-recall curve). We envision that the proposed GDL framework can generalize to many other protein interaction prediction problems, such as binding site prediction and molecular docking, helping accelerate protein engineering and structure-based drug development.

Evaluation of a novel augmented reality educational tool and its effects on patient experience: A randomized controlled trial.

Introduction: Patient education is an essential element of the treatment pathway. Augmented reality (AR), with disease simulations and three-dimensional visuals, offers a developing approach to patient education. We aim to determine whether this tool can increase patient understanding of their disease and post-visit satisfaction in comparison to current standard of care (SOC) educational practices in a randomized control study. Methods: Our single-site study consisted of 100 patients with initial diagnoses of kidney masses or stones randomly enrolled in the AR or SOC arm. In the AR arm, a physician used AR software on a tablet to educate the patient. SOC patients were educated through traditional discussion, imaging, and hand-drawn illustrations. Participants completed pre- and post-physician encounter surveys adapted from the Press Ganey® patient questionnaire to assess understanding and satisfaction. Their responses were evaluated in the Readability Studio® and analyzed to quantify rates of improvement in self-reported understanding and satisfaction scores. Results: There was no significant difference in participant education level (P = 0.828) or visit length (27.6 vs. 25.0 min, P = 0.065) between cohorts. Our data indicate that the rate of change in pre- to post-visit self-reported understanding was similar in each arm (P ≥ 0.106 for all responses). The AR arm, however, had significantly higher patient satisfaction scores concerning the educational effectiveness and understanding of images used during the consultation (P < 0.05). Conclusions: While AR did not significantly increase self-reported patient understanding of their disease compared to SOC, this study suggests AR as a potential avenue to increase patient satisfaction with educational tools used during consultations.

Global and regional temperature change over the past 4.5 million years.

Much of our understanding of Cenozoic climate is based on the record of δ18O measured in benthic foraminifera. However, this measurement reflects a combined signal of global temperature and sea level, thus preventing a clear understanding of the interactions and feedbacks of the climate system in causing global temperature change. Our new reconstruction of temperature change over the past 4.5 million years includes two phases of long-term cooling, with the second phase of accelerated cooling during the Middle Pleistocene Transition (1.5 to 0.9 million years ago) being accompanied by a transition from dominant 41,000-year low-amplitude periodicity to dominant 100,000-year high-amplitude periodicity. Changes in the rates of long-term cooling and variability are consistent with changes in the carbon cycle driven initially by geologic processes, followed by additional changes in the Southern Ocean carbon cycle.

Human Ageing Genomic Resources: updates on key databases in ageing research.

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here, we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).

Delphi Plus: A novel methodology for identifying evidence-based data standards for health service decision-making.

The underlying tenet of evidence-based decision-making in health services is assessing all the relevant evidence. Using the traditional qualitative and quantitative approaches to identifying evidence may not capture the full spectrum of factors that need to be addressed. A selective mixed-method approach may provide a comprehensive assessment of the relevant knowledge. This paper adds to the methodological literature by outlining a novel sequential, mixed-method, exploratory process for identifying evidence-based data standards that may be used for health service decision-making. The three-phase process, entitled Delphi Plus, engages peer-nominated topic-specific experts to assess all publicly available and practice-based items and, through a series of reviews, reach an evidence-based consensus on standards for decision-making. Each process phase is outlined in-depth and supplemented by practical learnings gained through its implementation. The Delphi Plus methodology provides the first comprehensive process for combining the published and practised data to develop evidence-based data standards. The routine use of Delphi Plus would provide a framework for benchmarking in health services, enabling greater monitoring and evaluation of client outcomes and improving quality care. This manuscript describes the process of implementing Delphi Plus and provides an example of data standards generated from its use, which directly inform the Australian Government's Primary Health Care 10 Year Plan.

Higher social tolerance is associated with more complex facial behavior in macaques.

The social complexity hypothesis for communicative complexity posits that animal societies with more complex social systems require more complex communication systems. We tested the social complexity hypothesis on three macaque species that vary in their degree of social tolerance and complexity. We coded facial behavior in >3000 social interactions across three social contexts (aggressive, submissive, affiliative) in 389 animals, using the Facial Action Coding System for macaques (MaqFACS). We quantified communicative complexity using three measures of uncertainty: entropy, specificity, and prediction error. We found that the relative entropy of facial behavior was higher for the more tolerant crested macaques as compared to the less tolerant Barbary and rhesus macaques across all social contexts, indicating that crested macaques more frequently use a higher diversity of facial behavior. The context specificity of facial behavior was higher in rhesus as compared to Barbary and crested macaques, demonstrating that Barbary and crested macaques used facial behavior more flexibly across different social contexts. Finally, a random forest classifier predicted social context from facial behavior with highest accuracy for rhesus and lowest for crested, indicating there is higher uncertainty and complexity in the facial behavior of crested macaques. Overall, our results support the social complexity hypothesis.

Implementing evidence-based clinical and business data standards in Australian private practice clinics is feasible.

AIMS: To assess the feasibility of implementing data standards in Australian primary care dietetics practices. METHODS: A mixed-methods pragmatic study of dietitians working in primary care. Using a four-point Likert scale, participants were surveyed on their baseline use of the 45 business and 33 clinical evidenced-based data standards. The content validity index and kappa statistic for each standard were calculated with a kappa statistic of 0.60-0.74 considered 'Good' and > 0.74 'Excellent'. After 4 weeks of assessment, dietitians were surveyed on the feasibility of implementing each standard and standards in total. Qualitative feedback on enablers and barriers to implementing standards was gathered and triangulated with interviews with select participants. RESULTS: Forty-five dietitians from every Australian state and territory completed both surveys (response rate: 100%). At baseline, 24% of business and 79% of clinical standards were rated 'Good' or 'Excellent' for current usage. The feasibility of implementing standards was rated 'Good' or 'Excellent for 86% of the business and 97% of the clinical standards. Software, training and time limitations are enablers and barriers to implementing standards. CONCLUSION: Embedding data standards within dietetics practices are feasible and have broad applicability for assessing outcomes of care.

Persistent opioid and benzodiazepine use after radical cystectomy in enhanced recovery after surgery (ERAS) patients.

OBJECTIVES: Opioid use, misuse, and diversion is of paramount concern in the United States. Radical cystectomy is typically managed with some component of opioid pain control. We evaluated persistent opioid and benzodiazepine use after radical cystectomy and assessed the impact of their preoperative use on this outcome. We also explored associations between preoperative use and perioperative outcomes. METHODS AND MATERIALS: We used prospectively maintained data from our enhanced recovery after surgery (ERAS) cystectomy database and the Prescription Reporting with Immediate Medication Utilization Mapping (PRIMUM) database to identify controlled substance prescriptions for radical cystectomy patients. We separated patients by frequency of preoperative opioid and/or benzodiazepine prescriptions (0, 1, 2+) and used these cohorts to explore persistent use (prescription 3-12 months after surgery) alongside perioperative outcomes. RESULTS: Our cohort included 257 patients undergoing cystectomy at a single institution from 2017 to 2021. Preoperative opioid and benzodiazepine prescriptions were documented for 120 (46.7%) and 26 (10.1%) patients, respectively. Persistent opioid use was observed in 20 (14.6%) of opioid-naive patients (no prescriptions in 9 months prior to surgery) while 13 (19.7%) patients with 1 preoperative prescription and 28 (51.9%) patients with 2 or more preoperative prescriptions demonstrated persistent use. New persistent benzodiazepine use occurred in 6 (2.6%) patients. Overall persistent benzodiazepine use was present in 11 (4.3%) patients. In a multivariable model, preoperative opioid and benzodiazepine prescriptions were associated with persistent opioid use (P < 0.001; P = 0.027 respectively). No association was identified between preoperative opioid or benzodiazepine usage and perioperative outcomes including length of stay, return of bowel function, inpatient opioid usage, inpatient or discharge complications, readmissions, or emergency department visits. Inpatient pain scores were noted to be higher in patients with ≥ 2 preoperative opioid prescriptions (P = 0.037). CONCLUSIONS: Persistent opioid use was present in 23.7% of patients, with a new persistent use rate of 14.6%. Benzodiazepine use was less frequent than opioids, with a small number demonstrating new persistent use. Preoperative opioid and benzodiazepine use is associated with persistent opioid use postoperatively. Preoperative opioid and benzodiazepine use did not affect perioperative outcomes in our cohort.

Low co-expression of PD-L1 and oncogenic receptor tyrosine kinases HER2 and cMET in urothelial carcinoma is associated with discordant expression between primary and metastatic sites.

OBJECTIVES: Novel regimens targeting immune checkpoints and the cMET or HER2 pathways are under investigation in metastatic urothelial carcinoma (mUC) though co-expression of these molecular targets has not been defined. We sought to characterize the protein co-expression rates of PD-L1, cMET and HER2 in primary and metastatic mUC lesions and agreement rates in paired biopsies. MATERIALS AND METHODS: We assessed PD-L1, cMET and HER2 protein expression by immunohistochemistry (IHC) in archival mUC samples identified from an institutional database (n = 143). Correlation of expression between primary and metastatic biopsies was performed in patients with available paired biopsies (n = 79). Protein expression levels by predefined thresholds were measured, and Cohen's kappa statistics (κ) were utilized to assess the agreement in expression between paired primary and metastatic samples. RESULTS: In primary tumors (n = 85), high expression of PD-L1, cMET, and HER2 was observed in 14.1%, 34.1%, and 12.9%, respectively. In metastatic samples (n = 143), high expression of PD-L1, cMET and HER2 was detected in 9.8%, 41.3%, and 9.8%, respectively. Expression agreement rates between paired specimens (n = 79) were PD-L1: 79.7% (κ = 0.09), cMET: 69.6% (κ = 0.35), HER2: 84.8% (κ = 0.17). High PD-L1/cMET co-expression was observed in only 5.1% (n = 4) of primary and 4.9% (n = 7) of metastatic specimens. High co-expression of PD-L1/HER2 occurred in 3.8% (n = 3) of primary samples and no metastatic samples. The overall co-expression agreement between paired samples was 55.7% (κ = 0.22) for PD-L1/cMET and 67.1% (κ = 0.06) for PD-L1/HER2, but agreement for high co-expression between paired samples was very low (2.5% for PD-L1/cMET and 0% for PD-L1/HER2). CONCLUSIONS: Tumor co-expression of high cMET or HER2 and PD-L1 is low in this cohort. Agreement of high co-expression between primary and metastatic sites is rare. Biomarker-based strategies used in selection of patients for contemporary trials testing combinations of immune checkpoint inhibitors with either cMET or HER2-targeted agents should account for discordant biomarker expression between primary and metastatic sites.

The persistence of stress-induced physical inactivity in rats: an investigation of central monoamine neurotransmitters and skeletal muscle oxidative stress.

Introduction: Sedentary lifestyles have reached epidemic proportions world-wide. A growing body of literature suggests that exposures to adverse experiences (e.g., psychological traumas) are a significant risk factor for the development of physically inactive lifestyles. However, the biological mechanisms linking prior stress exposure and persistent deficits in physical activity engagement remains poorly understood. Methods: The purpose of this study was twofold. First, to identify acute stress intensity thresholds that elicit long-term wheel running deficits in rats. To that end, young adult male rats were exposed to a single episode of 0, 50, or 100 uncontrollable tail shocks and then given free access to running wheels for 9 weeks. Second, to identify stress-induced changes to central monoamine neurotransmitters and peripheral muscle physiology that may be maladaptive to exercise output. For this study, rats were either exposed to a single episode of uncontrollable tail shocks (stress) or left undisturbed in home cages (unstressed). Eight days later, monoamine-related neurochemicals were quantified by ultra-high performance liquid chromatography (UHPLC) across brain reward, motor, and emotion structures immediately following a bout of graded treadmill exercise controlled for duration and intensity. Additionally, protein markers of oxidative stress, inflammation, and metabolic activity were assessed in the gastrocnemius muscle by Western blot. Results: For experiment 1, stress exposure caused a shock number-dependent two to fourfold decrease in wheel running distance across the entire duration of the study. For experiment 2, stress exposure curbed an exercise-induced increase of dopamine (DA) turnover measures in the prefrontal cortex and hippocampus, and augmented serotonin (5HT) turnover in the hypothalamus and remaining cortical area. However, stress exposure also caused several monoaminergic changes independent of exercise that could underlie impaired motivation for physical activity, including a mild dopamine deficiency in the striatal area. Finally, stress potently increased HSP70 and lowered SOD2 protein concentrations in the gastrocnemius muscle, which may indicate prolonged oxidative stress. Discussion: These data support some of the possible central and peripheral mechanisms by which exposure to adverse experiences may chronically impair physical activity engagement.

Impact of diabetes and chronic kidney disease on active surveillance outcomes for small renal masses: A cohort study.

Introduction: The American Cancer Society estimates 79,000 individuals will be diagnosed with kidney cancer in 2022, most of which are initially found as small renal masses (SRMs). Proper management of SRM patients includes careful evaluation of risk factors such as medical comorbidities and renal function. To investigate the importance of these risk factors, we examined their effect on crossover to delayed intervention (DI) and overall survival (OS) in patients undergoing active surveillance (AS) for SRMs. Methods: This is an Institutional Review Board-approved retrospective analysis of AS patients presented at kidney tumor conferences with SRMs between 2007 and 2017. Univariable and multivariable logistic regression analyses were performed to determine how factors including estimated glomerular filtration rate (eGFR), diabetes, and chronic kidney disease are associated with DI and OS. Results: A total of 111 cases were reviewed. In general, AS patients were elderly and had significant comorbidities. On univariate analysis, intervention was more likely to occur in patients with a younger age (P = 0.01), better kidney function (P = 0.01), and higher tumor growth rates (GRs) (P = 0.02). Higher eGFR was associated with better survival (P = 0.03), while higher tumor GRs (P = 0.014), greater Charlson Comorbidity Index (P = 0.01), and larger tumors (P = 0.01) were associated with worse OS. Of the comorbidities, diabetes was found to be an independent predictor of worse OS (P = 0.01). Conclusions: Patient-level factors - such as diabetes and eGFR - are associated with the rate of DI and OS among SRM patients. Consideration of these factors may facilitate better AS protocols and improve patient outcomes for those with SRMs.

Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline.

PURPOSE: The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management of non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS/METHODS: The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January 2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (Table 1).[Table: see text]Results:This Guideline provides updated, evidence-based recommendations regarding diagnosis and management of non-metastatic UTUC including risk stratification, surveillance and survivorship. Treatments discussed include kidney sparing management, surgical management, lymph node dissection (LND), neoadjuvant/adjuvant chemotherapy and immunotherapy. CONCLUSION: This standardized guideline seeks to improve clinicians' ability to evaluate and treat patients with UTUC based on available evidence. Future studies will be essential to further support these statements for improving patient care. Updates will occur as the knowledge regarding disease biology, clinical behavior and new therapeutic options develop.

Prognostic value of galectin-1 and galectin-3 expression in localized urothelial bladder cancer.

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens. Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis. Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy. Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity.

Renal Mass Biopsy Mandate Is Associated With Change in Treatment Decisions.

PURPOSE: To prevent avoidable treatment and make more informed care decisions about small renal masses, the use of renal mass biopsies has increased since the early 2000s. In April 2017, Atrium Health Carolinas Medical Center began requiring biopsies before all percutaneous thermal ablation procedures for renal masses. We aim to determine the effect of this preablation biopsy mandate on small renal mass treatment decisions. MATERIALS AND METHODS: Our study is a retrospective analysis of a prospectively managed database designed to track patients with small renal masses presented at the Kidney Tumor Program from 2000-2020. We separated patients into 2 cohorts (pre- and postmandate) based on the initial encounter date, excluding those from April 2017-April 2018 to allow for implementation of the mandate. We also excluded patients with masses >4 cm. RESULTS: Overall, we found no significant difference between the pre- and postmandate cohorts, with race as an exception. Implementation of the mandate coincided with an increase in biopsies for both ablation and nonablation treatment pathways (P < .001, P = .01). Renal mass biopsy rates increased in all socioeconomic groups except the lowest quartile. Additionally, Black/Hispanic patients had the highest biopsy rate. We found significant changes in treatment decisions between our cohorts: surgery decreased 24% (P < .001), active surveillance increased 28% (P < .001), and patients with no follow-up decreased 8% (P = .03). CONCLUSIONS: Our data indicate that a preablation renal mass biopsy mandate is associated with the wider use of biopsies for all small renal mass patients, fewer surgical interventions, and an increase in active surveillance.

Systems Biology of Ageing.

The ageing process is highly complex involving multiple processes operating at different biological levels. Systems Biology presents an approach using integrative computational and laboratory study that allows us to address such complexity. The approach relies on the computational analysis of knowledge and data to generate predictive models that may be validated with further laboratory experimentation. Our understanding of ageing is such that translational opportunities are within reach and systems biology offers a means to ensure that optimal decisions are made. We present an overview of the methods employed from bioinformatics and computational modelling and describe some of the insights into ageing that have been gained.