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Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving

BackgroundHundreds of ongoing clinical trials combine radiation therapy, mostly delivered as stereotactic body radiotherapy (SBRT), with immune checkpoint blockade. However, our understanding of the effect of radiotherapy on the intratumoral immune balance is inadequate, hindering the optimal design of trials that combine radiation therapy with immunotherapy. Our objective was to characterize the intratumoral immune balance of the malignant prostate after SBRT in patients.MethodsSixteen patients with high-risk, non-metastatic prostate cancer at comparable Gleason Grade disease underwent radical prostatectomy with (n = 9) or without (n = 7) neoadjuvant SBRT delivered in three fractions of 8 Gy over 5 days completed 2 weeks before surgery. Freshly resected prostate specimens were processed to obtain single-cell suspensions, and immune-phenotyped for major lymphoid and myeloid cell subsets by staining with two separate 14-antibody panels and multicolor flow cytometry analysis.ResultsMalignant prostates 2 weeks after SBRT had an immune infiltrate dominated by myeloid cells, whereas malignant prostates without preoperative treatment were more lymphoid-biased (myeloid CD45+ cells 48.4 ± 19.7% vs. 25.4 ± 7.0%; adjusted p-value = 0.11; and CD45+ lymphocytes 51.6 ± 19.7% vs. 74.5 ± 7.0%; p = 0.11; CD3+ T cells 35.2 ± 23.8% vs. 60.9 ± 9.7%; p = 0.12; mean ± SD).ConclusionSBRT drives a significant lymphoid to myeloid shift in the prostate-tumor immune infiltrate. This may be of interest when combining SBRT with immunotherapies, particularly in prostate cancer.

Background Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. Methods This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. Results Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). Conclusions A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Purpose Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT. Methods and Materials PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure. Results A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure. Conclusions In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.

Background Postoperative mortality occurs in 1–2% of patients undergoing major inpatient surgery. The currently available prediction tools using summaries of intraoperative data are limited by their inability to reflect shifting risk associated with intraoperative physiological perturbations. We sought to compare similar benchmarks to a deep-learning algorithm predicting postoperative 30-day mortality. Methods We constructed a multipath convolutional neural network model using patient characteristics, co-morbid conditions, preoperative laboratory values, and intraoperative numerical data from patients undergoing surgery with tracheal intubation at a single medical centre. Data for 60 min prior to a randomly selected time point were utilised. Model performance was compared with a deep neural network, a random forest, a support vector machine, and a logistic regression using predetermined summary statistics of intraoperative data. Results Of 95 907 patients, 941 (1%) died within 30 days. The multipath convolutional neural network predicted postoperative 30-day mortality with an area under the receiver operating characteristic curve of 0.867 (95% confidence interval [CI]: 0.835–0.899). This was higher than that for the deep neural network (0.825; 95% CI: 0.790–0.860), random forest (0.848; 95% CI: 0.815–0.882), support vector machine (0.836; 95% CI: 0.802–870), and logistic regression (0.837; 95% CI: 0.803–0.871). Conclusions A deep-learning time-series model improves prediction compared with models with simple summaries of intraoperative data. We have created a model that can be used in real time to detect dynamic changes in a patient's risk for postoperative mortality.

Purpose Second malignancies (SMs) after radiation therapy are rare but serious sequelae of treatment. This study investigates whether radiation therapy use is associated with changes in baseline SM risk. Methods and Materials We extracted all patients with cancer, with or without SM, in the Surveillance, Epidemiology, and End Results database from 1973 to 2014. Cumulative incidence of SM for patients stratified by radiation therapy status was calculated using a competing risk model, both for the entire cohort and for subgroups based on the primary tumor's anatomic location. Results We identified 2,872,063 patients with cancer, including 761,289 patients who received radiation therapy and 2,110,774 who did not. The SM rate at 20 years for patients receiving radiation therapy versus no radiation therapy was 21.4% versus 18.8%. The relative risk for SM associated with radiation therapy for the overall group was 1.138 at 20 years. The relative risks for SM associated with radiation therapy to malignancies arising from central nervous system and orbits, head and neck, thorax, abdomen, and pelvis at 20 years were 0.704, 1.011, 0.559, 0.646, and 1.106 for men and 0.792, 1.298, 1.265, 0.780, and 0.988 for women, respectively. Conclusions The association between SM and radiation therapy varies with both sex and disease anatomic location, with the largest increase in SM seen in females irradiated to the head and neck region. Overall, the absolute change in SM rates associated with radiation therapy remains small, with differences in various clinical contexts.

Purpose: To establish the safety and efficacy of gantry-mounted linear accelerator-based stereotactic body radiation therapy (SBRT) for low- and intermediate-risk prostate cancer. Methods: We pooled 921 patients enrolled on 7 single-institution prospective phase II trials of gantry-based SBRT from 2006 to 2017. The cumulative incidences of biochemical recurrence (defined by the Phoenix definition) and physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities (defined per the original trials using Common Terminology Criteria for Adverse Events) were estimated using a competing risk framework. Multivariable logistic regression was used to evaluate the relationship between late toxicity and prespecified covariates: biologically effective dose, every other day versus weekly fractionation, intrafractional motion monitoring, and acute toxicity. Results: Median follow-up was 3.1 years (range, 0.5-10.8 years). In addition, 505 (54.8%) patients had low-risk disease, 236 (25.6%) had favorable intermediate-risk disease, and 180 (19.5%) had unfavorable intermediate-risk disease. Intrafractional motion monitoring was performed in 78.0% of patients. The 3-year cumulative incidence of biochemical recurrence was 0.8% (95% confidence interval [CI], 0-1.7%), 2.2% (95% CI, 0-4.3%), and 5.1% (95% CI, 1.0-9.2%) for low-, favorable intermediate-, and unfavorable intermediate-risk disease. Acute grade ≥2 GU and GI toxicity occurred in 14.5% and 4.6% of patients, respectively. Three-year cumulative incidence estimates of late grade 2 GU and GI toxicity were 4.1% (95% CI, 2.6-5.5%) and 1.3% (95% CI, 0.5-2.1%), respectively, with late grade ≥3 GU and GI toxicity estimates of 0.7% (95% CI, 0.1-1.3%) and 0.4% (95% CI, 0-0.8%), respectively. The only identified significant predictors of late grade ≥2 toxicity were acute grade ≥2 toxicity (P < .001) and weekly fractionation (P < .01), although only 12.4% of patients were treated weekly. Conclusions: Gantry-based SBRT for prostate cancer is associated with a favorable safety and efficacy profile, despite variable intrafractional motion management techniques. These findings suggest that multiple treatment platforms can be used to safely deliver prostate SBRT.

Importance Postoperative complications can significantly impact perioperative care management and planning. Objectives To assess machine learning (ML) models for predicting postoperative complications using independent and combined preoperative and intraoperative data and their clinically meaningful model-agnostic interpretations. Design, setting, and participants This retrospective cohort study assessed 111 888 operations performed on adults at a single academic medical center from June 1, 2012, to August 31, 2016, with a mean duration of follow-up based on the length of postoperative hospital stay less than 7 days. Data analysis was performed from February 1 to September 31, 2020. Main outcomes and measures Outcomes included 5 postoperative complications: acute kidney injury (AKI), delirium, deep vein thrombosis (DVT), pulmonary embolism (PE), and pneumonia. Patient and clinical characteristics available preoperatively, intraoperatively, and a combination of both were used as inputs for 5 candidate ML models: logistic regression, support vector machine, random forest, gradient boosting tree (GBT), and deep neural network (DNN). Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Model interpretations were generated using Shapley Additive Explanations by transforming model features into clinical variables and representing them as patient-specific visualizations. Results A total of 111 888 patients (mean [SD] age, 54.4 [16.8] years; 56 915 [50.9%] female; 82 533 [73.8%] White) were included in this study. The best-performing model for each complication combined the preoperative and intraoperative data with the following AUROCs: pneumonia (GBT), 0.905 (95% CI, 0.903-0.907); AKI (GBT), 0.848 (95% CI, 0.846-0.851); DVT (GBT), 0.881 (95% CI, 0.878-0.884); PE (DNN), 0.831 (95% CI, 0.824-0.839); and delirium (GBT), 0.762 (95% CI, 0.759-0.765). Performance of models that used only preoperative data or only intraoperative data was marginally lower than that of models that used combined data. When adding variables with missing data as input, AUROCs increased from 0.588 to 0.905 for pneumonia, 0.579 to 0.848 for AKI, 0.574 to 0.881 for DVT, 0.5 to 0.831 for PE, and 0.6 to 0.762 for delirium. The Shapley Additive Explanations analysis generated model-agnostic interpretation that illustrated significant clinical contributors associated with risks of postoperative complications. Conclusions and relevance The ML models for predicting postoperative complications with model-agnostic interpretation offer opportunities for integrating risk predictions for clinical decision support. Such real-time clinical decision support can mitigate patient risks and help in anticipatory management for perioperative contingency planning.

Background Handoffs or care transitions from the operating room (OR) to intensive care unit (ICU) are fragmented and vulnerable to communication errors. Although protocols and checklists for standardization help reduce errors, such interventions suffer from limited sustainability. An unexplored aspect is the potential role of developing personalized postoperative transition interventions using artificial intelligence (AI)-generated risks. Objectives This study was aimed to (1) identify factors affecting sustainability of handoff standardization, (2) utilize a human-centered approach to develop design ideas and prototyping requirements for a sustainable handoff intervention, and (3) explore the potential role for AI risk assessment during handoffs. Methods We conducted four design workshops with 24 participants representing OR and ICU teams at a large medical academic center. Data collection phases were (1) open-ended questions, (2) closed card sorting of handoff information elements, and (3) scenario-based design ideation and prototyping for a handoff intervention. Data were analyzed using thematic analysis. Card sorts were further tallied to characterize handoff information elements as core, flexible, or unnecessary. Results Limited protocol awareness among clinicians and lack of an interdisciplinary electronic health record (EHR)-integrated handoff intervention prevented long-term sustainability of handoff standardization. Clinicians argued for a handoff intervention comprised of core elements (included for all patients) and flexible elements (tailored by patient condition and risks). They also identified unnecessary elements that could be omitted during handoffs. Similarities and differences in handoff intervention requirements among physicians and nurses were noted; in particular, clinicians expressed divergent views on the role of AI-generated postoperative risks. Conclusion Current postoperative handoff interventions focus largely on standardization of information transfer and handoff processes. Our design approach allowed us to visualize accurate models of user expectations for effective interdisciplinary communication. Insights from this study point toward EHR-integrated, “flexibly standardized” care transition interventions that can automatically generate a patient-centered summary and risk-based report.

Purpose This study aimed to evaluate the feasibility and safety of prostate stereotactic body radiation therapy (SBRT) neoadjuvant to radical prostatectomy (RP) in a phase 1 trial. The primary endpoint was treatment completion rate without severe acute surgical complications. Secondary endpoints included patient-reported quality of life and physician-reported toxicities. Methods and Materials Patients with nonmetastatic high-risk or locally advanced prostate cancer received 24 Gy in 3 fractions to the prostate and seminal vesicles over 5 days, completed 2 weeks before RP. Patients with pN1 disease were treated after multidisciplinary discussion and shared decision making. Patient-reported quality of life (International Prostate Symptom Score and Expanded Prostate Cancer Index Composite 26-item version questionnaires) and physician-reported toxicity (Common Terminology Criteria for Adverse Events, version 4.03) were assessed before SBRT, immediately before surgery, and at 3-month intervals for 1 year. Results Twelve patients were enrolled, and 11 completed treatment (1 patient had advanced disease on prostate-specific membrane antigen positron emission tomography after enrollment but before treatment). There were no significant surgical complications. After RP, 2 patients underwent additional radiation therapy to nodes with androgen suppression for pN1 disease. Median follow-up after completion of treatment was 20.1 months, with 9 of 11 patients having a follow-up period of >12 months. Two patients had biochemical recurrence (prostate-specific antigen ≥0.05) within the first 12 months, with an additional 2 patients found to have biochemical recurrence after the 12-month period. The highest Common Terminology Criteria for Adverse Events genitourinary grades were 0, 1, 2, and 3 (n = 1, 4, 4, and 2, respectively), and the highest gastrointestinal grades were 0, 1, and 2 (n = 9, 1, and 1, respectively). At 12 months, incontinence was the only grade ≥2 toxicity. One and 2 of 9 patients had grade 2 and 3 incontinence, respectively. On the Expanded Prostate Cancer Index Composite (26-item version), the mean/median changes in scores from baseline to 12 months were –32.8/–31.1 for urinary incontinence, –1.6/–6.2 for urinary irritative/obstructive, –2.1/0 for bowel, –34.4/–37.5 for sexual function, and –10.6/–2.5 for hormonal. The mean/median change in International Prostate Symptom Score from baseline to 12 months was 0.5/0.5. Conclusions RP after neoadjuvant SBRT appears to be feasible and safe at the dose tested. The severity of urinary incontinence may be higher than RP alone.

Introduction: The post-anesthesia care unit (PACU) is a clinical area designated for patients recovering from invasive procedures. There are typically several geographically dispersed PACUs within hospitals. Patients in the PACU can be unstable and at risk for complications. However, clinician coverage and patient monitoring in PACUs is not well regulated and might be sub-optimal. We hypothesize that a telemedicine center for the PACU can improve key PACU functions. Objectives: The objective of this study is to demonstrate the potential utility and acceptability of a telemedicine center to complement the key functions of the PACU. These include participation in hand-off activities to and from the PACU, detection of physiological derangements, identification of symptoms requiring treatment, recognition of situations requiring emergency medical intervention, and determination of patient readiness for PACU discharge. Methods and analysis: This will be a single center prospective before-and-after proof-of-concept study. Adults (18 years and older) undergoing elective surgery and recovering in two selected PACU bays will be enrolled. During the initial three-month observation phase, clinicians in the telemedicine center will not communicate with clinicians in the PACU, unless there is a specific patient safety concern. During the subsequent three-month interaction phase, clinicians in the telemedicine center will provide structured decision support to PACU clinicians. The primary outcome will be time to PACU discharge readiness determination in the two study phases. The attitudes of key stakeholders towards the telemedicine center will be assessed. Other outcomes will include detection of physiological derangements, complications, adverse symptoms requiring treatments, and emergencies requiring medical intervention. Registration: This trial is registered on clinicaltrials.gov, NCT04020887 (16th July 2019).

Medical ontologies are widely used to represent and organize medical terminologies. Examples include ICD-9, ICD-10, UMLS etc. The ontologies are often constructed in hierarchical structures, encoding the multi-level subclass relationships among different medical concepts, allowing very fine distinctions between concepts. Medical ontologies provide a great source for incorporating domain knowledge into a healthcare prediction system, which might alleviate the data insufficiency problem and improve predictive performance with rare categories. To incorporate such domain knowledge, Gram, a recent graph attention model, represents a medical concept as a weighted sum of its ancestors' embeddings in the ontology using an attention mechanism. Although showing improved performance, Gram only considers the unordered ancestors of a concept, which does not fully leverage the hierarchy thus having limited expressibility. In this paper, we propose Hierarchical Attention Propagation (HAP), a novel medical ontology embedding model that hierarchically propagate attention across the entire ontology structure, where a medical concept adaptively learns its embedding from all other concepts in the hierarchy instead of only its ancestors. We prove that HAP learns more expressive medical concept embeddings -- from any medical concept embedding we are able to fully recover the entire ontology structure. Experimental results on two sequential procedure/diagnosis prediction tasks demonstrate HAP's better embedding quality than Gram and other baselines. Furthermore, we find that it is not always best to use the full ontology. Sometimes using only lower levels of the hierarchy outperforms using all levels.

Closure of the fascial layer can be challenging to learn for junior level residents. Wound dehiscence involving the fascial layer can lead to complicated clinical courses for patients, including readmission to the hospital, wound vacuum placement, antibiotic regimens, and re-operation. Typical suturing techniques taught in medical school focus more on basic techniques of suture placement such as interrupted or running techniques. The aim of this study is to introduce a method of practicing fascial closure using easily obtainable items. Though there is no substitute for placement of suture and closure of fascia in vivo, this method allows one to practice the motor repetition of fascial suture placement and provides one with the ability to check their work.

BACKGROUND: Preoperative cognitive dysfunction has been associated with adverse postoperative outcomes. There are limited data characterising the epidemiology of preoperative cognitive dysfunction in older surgical patients. METHODS: This retrospective cohort included all patients ≥65 yr old seen at the Washington University preoperative clinic between January 2013 and June 2018. Cognitive screening was performed using the Short-Blessed Test (SBT) and Eight-Item Interview to Differentiate Aging and Dementia (AD8) screen. The primary outcome of abnormal cognitive screening was defined as SBT score ≥5 or AD8 score ≥2. Multivariable logistic regression was used to identify associated factors. RESULTS: Overall, 21 666 patients ≥65 yr old completed screening during the study period; 23.5% (n=5099) of cognitive screens were abnormal. Abnormal cognitive screening was associated with increasing age, decreasing BMI, male sex, non-Caucasian race, decreased functional independence, and decreased metabolic functional capacity. Patients with a history of stroke or transient ischaemic attack, chronic obstructive pulmonary disease, diabetes mellitus, hepatic cirrhosis, and heavy alcohol use were also more likely to have an abnormal cognitive screen. Predictive modelling showed no combination of patient factors was able to reliably identify patients who had a

Logistic regression (LR) is widely used in clinical prediction because it is simple to deploy and easy to interpret. Nevertheless, being a linear model, LR has limited expressive capability and often has unsatisfactory performance. Generalized additive models (GAMs) extend the linear model with transformations of input features, though feature interaction is not allowed for all GAM variants. In this paper, we propose a factored generalized additive model (F-GAM) to preserve the model interpretability for targeted features while allowing a rich model for interaction with features fixed within the individual. We evaluate F-GAM on prediction of two targets, postoperative acute kidney injury and acute respiratory failure, from a single-center database. We find superior model performance of F-GAM in terms of AUPRC and AUROC compared to several other GAM implementations, random forests, support vector machine, and a deep neural network. We find that the model interpretability is good with results with high face validity.

INTRODUCTION AND OBJECTIVE:External beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), EBRT with a brachytherapy boost (EBRT+BT) with ADT, and radical prostatectomy (RP) with or with...

Key Points Question Is there an association between obstructive sleep apnea and delirium after major surgery? Findings In this cohort study of 7792 patients admitted to the intensive care unit after surgery, 26% had obstructive sleep apnea, and delirium occurred in 47%. After risk adjustment, there was no significant association between obstructive sleep apnea and postoperative delirium. Meaning This study found no association between obstructive sleep apnea and delirium in patients admitted postoperatively to the intensive care unit., Importance Obstructive sleep apnea has been associated with postoperative delirium, which predisposes patients to major adverse outcomes. Positive airway pressure may be an effective intervention to reduce delirium in this population. Objectives To determine if preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit and if preoperative positive airway pressure adherence modifies the association. Design, Setting, and Participants A retrospective single-center cohort study was conducted at a US tertiary hospital from November 1, 2012, to August 31, 2016, among 7792 patients admitted to an intensive care unit who underwent routine Confusion Assessment Method for the intensive care unit after major surgery. Patients were adults who had undergone a complete preoperative anesthesia assessment, received general anesthesia, underwent at least 1 delirium assessment, were not delirious preoperatively, and had a preoperative intensive care unit stay of less than 6 days. Statistical analysis was conducted from August 20, 2019, to January 11, 2020. Exposures Self-reported obstructive sleep apnea, billing diagnosis of obstructive sleep apnea, or STOP-BANG (Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender) questionnaire score greater than 4, as well as self-reported use of preoperative positive airway pressure. Main Outcomes and Measures Delirium within 7 days of surgery. Results A total of 7792 patients (4562 men; mean [SD] age, 59.2 [15.3] years) met inclusion criteria. Diagnosed or likely obstructive sleep apnea occurred in 2044 patients (26%), and delirium occurred in 3637 patients (47%). The proportion of patients with incident delirium was lower among those with obstructive sleep apnea than those without (897 of 2044 [44%] vs 2740 of 5748 [48%]; unadjusted risk difference, −0.04; 99% credible interval [CrI], −0.07 to −0.00). Positive airway pressure adherence had minimal association with delirium (risk difference, −0.00; 99% CrI, −0.09 to 0.09). Doubly robust confounder adjustment eliminated the association between obstructive sleep apnea and delirium (risk difference, −0.01; 99% CrI, −0.04 to 0.03) and did not change that of preoperative positive airway pressure adherence (risk difference, −0.00, 99% CrI, −0.07 to 0.07). The results were consistent across multiple sensitivity analyses. Conclusions and Relevance After risk adjustment, this study found no association between obstructive sleep apnea and postoperative delirium in the context of usual care in the intensive care unit, with 99% CrIs excluding clinically meaningful associations. With limited precision, no association was found between positive airway pressure adherence and delirium. Selection bias and measurement error limit the validity and generalizability of these observational associations; however, they suggest that interventions targeting sleep apnea and positive airway pressure are unlikely to have a meaningful association with postoperative intensive care unit delirium., This cohort study examines whether preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit (ICU) and if preoperative positive airway pressure adherence modifies the association.

Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls.To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures.This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized clinical trial, which was conducted at a single academic medical center between January 16, 2015, and May 7, 2018. Patients in the intervention group of the present study were enrolled in either arm of the ENGAGES clinical trial. Patients in the control group were selected from the Systematic Assessment and Targeted Improvement of Services Following Yearly Surgical Outcomes Surveys prospective observational cohort study, which created a registry of patient-reported postoperative outcomes at the same single center. The propensity score-matched cohort in the present study included 1396 patients (698 pairs) selected from a pool of 2013 eligible patients. All patients underwent elective surgical procedures with general anesthesia and had a hospital stay of 2 or more days. Data were analyzed from January 2, 2020, to January 11, 2022.The multicomponent safety intervention (offered to all patients in the ENGAGES clinical trial) included patient education on fall prevention techniques, home medication review by a geriatric psychiatrist (with communication of recommended changes to the surgeon), a self-administered home safety assessment, and targeted occupational therapy home visits with home hazard removal (offered to patients with a preoperative history of falls).The primary outcome was patient-reported falls within 1 year after an elective inpatient surgical procedure. The secondary outcome was quality of life 1 year after an elective surgical procedure, which was measured using the physical and mental composite summary scores on the Veterans RAND 12-item health survey (score range, 0-100 points, with 0 indicating lowest quality of life and 100 indicating highest quality of life).Among 1396 patients, the median age was 69 years (IQR, 64-75 years), and 739 patients (52.9%) were male. With regard to race, 5 patients (0.4%) were Asian, 97 (6.9%) were Black or African American, 2 (0.1%) were Native Hawaiian or Pacific Islander, 1237 (88.6%) were White, 3 (0.2%) were of other race, and 52 (3.7%) were of unknown race; with regard to ethnicity, 12 patients (0.9%) were Hispanic or Latino, 1335 (95.6%) were non-Hispanic or non-Latino, and 49 (3.5%) were of unknown ethnicity. Adherence to individual intervention components was modest (from 22.9% for completion of the self-administered home safety assessment to 28.2% for implementation of the geriatric psychiatrist's recommended medication changes). Falls within 1 year after surgical procedures were reported by 228 of 698 patients (32.7%) in the intervention group and 225 of 698 patients (32.2%) in the control group. No significant difference was found in falls between the 2 groups (standardized risk difference, 0.4%; 95% CI, -4.5% to 5.3%). After adjusting for preoperative quality of life, patients in the intervention group had higher physical composite summary scores (3.8 points; 95% CI, 2.4-5.1 points) and higher mental composite summary scores (5.7 points; 95% CI, 4.7-6.7 points) at 1 year compared with patients in the control group.In this cohort study, a multicomponent safety intervention was not associated with reductions in falls within the first year after an elective surgical procedure; however, an increase in quality of life at 1 year was observed. These results suggest a need for other interventions, such as those designed to increase adherence, to lower the incidence of falls after surgical procedures.

Purpose Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. Methods and Materials The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer–specific survival, and distant metastasis–free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. Results The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P Conclusions To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.

Objectives: To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy. Materials and methods: A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure. Results: The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS. Conclusions: With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.

Standard-of-care imaging for initial staging of prostate cancer (PCa) underestimates disease burden. Prostate-specific membrane antigen (PSMA) PET/CT detects PCa metastasis with superior accuracy, having a potential impact on the planning of definitive radiation therapy (RT) for nonmetastatic PCa. Our objectives were to determine how often definitive RT planning based on standard target volumes covers 68Ga-PSMA-11 PET/CT-defined disease and to assess the potential impact of 68Ga-PSMA-11 PET/CT on definitive RT planning. Methods: This was a post hoc analysis of an intention-totreat population of 73 patients with localized PCa without prior local therapy who underwent 68Ga-PSMA PET/CT for initial staging as part of an investigational new drug trial. Eleven of the 73 were intermediate- risk (15%), 33 were high-risk (45%), 22 were very-highrisk (30%), and 7 were N1 (9.5%). Clinical target volumes (CTVs), which included the prostate, seminal vesicles, and (in accord with the Radiation Therapy Oncology Group consensus guidelines) pelvic lymph nodes (LNs), were contoured on the CT portion of the PET/CT images by a radiation oncologist masked to the PET findings. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11-positive lesions not covered by planning volumes based on the CTVs were considered to have a major potential impact on treatment planning. Results: All patients had one or more 68Ga-PSMA-11-positive primary prostate lesions. Twenty-five (34%) and 7 (9.5%) of the 73 patients had 68Ga-PSMA- 11-positive pelvic LN and distant metastases, respectively. The sites of LN metastases in decreasing order of frequency were external iliac (20.5%), common iliac (13.5%), internal iliac (12.5%) obturator (12.5%), perirectal (4%), abdominal (4%), upper diaphragm (4%), and presacral (1.5%). The median size of the LN lesions was 6 mm (range, 4-24 mm). RT planning based on the CTVs covered 69 (94.5%) of the 73 primary lesions and 20 (80%) of the 25 pelvic LN lesions, on a per-patient analysis. Conclusion: 68Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 12 (16.5%) of the 73 patients whose RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 25 (37%) of the 66 patients whose RT fields covered the prostate and seminal vesicles but not the pelvic LNs.

To report our institutional experience using definitive chemoradiation via whole bladder (WB) and partial bladder (PB) treatment in muscle-invasive bladder cancer. Combining intensity-modulated radiation therapy with image-guidance can improve the therapeutic ratio. Retrospective analysis of 26 patients with clinical stage T2-4 N0-2 M0 urothelial cancer treated in 2009 to 2012; 16 received WB radiation and 10 received PB radiation. PB/tumor boost volume included visibly thickened bladder wall or tumor localized on cystoscopy. WB radiation delivered 45 to 50.4 Gy to bladder/lymph nodes, then sequential 19.8 to 21.6 Gy tumor boost (1.8 Gy/fx). PB radiation was 45 to 50 Gy to lymph nodes (1.8 to 2 Gy/fx) and simultaneous integrated boost to 55 to 62.5 Gy to tumor only (2.2 to 2.5 Gy/fx). The primary endpoint was local control, defined as no muscle-invasive recurrence. Secondary endpoints were overall survival, toxicity, and cost. Mean age was 77 and median follow-up was 20 months. Freedom from local recurrence was 86% at 2 years (PB 100%, WB 77%). Overall survival was 80% at 1 year (PB 88%, WB 75%), and 55% at 2 years (PB 70%, WB 48%, P=0.38). Failure was predominantly distant. Toxicities were minimal (3 late grade 3 ureteral, 1 acute grade 4 renal), and all resolved. No cystectomies were performed for toxicity. Hypofractionation reduces treatment time and costs by one third. Image-guided hypofractionated PB radiation provides local control with similar survival to WB therapy, with minimal toxicity. Hypofractionation also offers time and cost advantages. Our results need to be validated in a larger, multi-institutional cohort.

OBJECTIVES: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized. PATIENTS AND METHODS: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA ≥ 0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA ≥ 0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates. RESULTS: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P < 0.01). Preoperative PSA, T-stage, Gleason grade, and laterality were associated with biochemical progression on univariate and multivariate analyses. Right-sided margins were more likely to progress than left (hazard ratio, 1.67; P = 0.04). More right-sided margins were referred for SRT (55% right vs. 23% left vs. 22% bilateral), but were equally salvaged. Only T-stage and pre-SRT PSA independently influenced SRT success. CONCLUSIONS: Most PSM are iatrogenic, with right-sided more likely to progress (and sooner) than left sided. Margin laterality is a heretofore unrecognized independent predictor of biochemical relapse and hints at the need to modify the traditional unilateral surgical technique.

Purpose Salvage radiotherapy (SRT) is the standard of care offered when postprostatectomy prostate-specific antigen (PSA) levels are ≥ 0.2 ng/mL. However, emerging evidence suggests that early SRT (ie, SRT delivered at PSA values < 0.2 ng/mL, but generally ≥ 0.05 ng/mL) improves oncologic outcomes. We evaluated the feasibility of improving referral rates for discussion of early SRT by using a dynamic registry that identifies through the electronic medical record patients with rising postprostatectomy PSA levels. Methods We developed an iteratively updated registry that identifies patients who fall within two postoperative PSA strata: ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL. We compared referral rates to radiation oncology during a 3-year period before use of this registry with those during a 1-year period after promotion of the registry in multidisciplinary tumor board settings. Results Before promotion of the registry, referral rates for patients with PSA values ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL were 35% and 65%, respectively. After promotion of the registry, referral rates within each stratum increased significantly to 82% and 94%, respectively ( P < .05 for both by Fisher’s exact test). The overall rate of referral for patients with PSA values ≥ 0.05 to < 0.2 ng/mL rose from 48% to 90% ( P < .001). Conclusion The creation of a registry of patients with rising postprostatectomy PSA values can facilitate increased referral rates for early SRT without burdening providers with a clinical support tool embedded within the EMR itself. This is true even in the case of already high baseline rates of referral for early SRT. The changes reported herein most likely reflect a Hawthorne effect wherein the ability to track referrals rather than a direct function of the registry influenced practice patterns. Nonetheless, the registry provided an integral framework to allow for tracking.

Objective To evaluate whether preoperative urinary prostate cancer antigen 3 (PCA3) scores predict for adverse pathologic features (APFs) or progression-free survival (PFS) in men with intermediate- or high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP). Materials and Methods One hundred nine men with intermediate- (n = 52) or high-risk (n = 57) PCa who underwent RP were retrospectively identified. Logistic regression analysis was performed to evaluate the association of PCA3 score with various APFs (eg, extracapsular extension, seminal vesicle invasion, etc.). Among 78 men with ≥1 year of follow-up, the association between PCA3 score and PFS was assessed using Cox regression analysis. Results At RP, 52% of patients had at least 1 APF, and with median follow-up of 2.3 years, overall 3-year PFS was 70%. PCA3 was not a significant predictor of any APF on multivariate analysis (MVA), whereas canonical predictors (eg, biopsy Gleason score and initial prostate-specific antigen) remained predictive of various APFs. No significant predictors for PFS were found on MVA, although certain canonical predictors (eg, National Comprehensive Cancer Network risk group) were significant predictors of PFS on univariate analysis (UVA). PCA3 score was not a significant predictor of PFS on either UVA or MVA. Conclusion Unlike in lower risk cohorts, increasing PCA3 score was not associated with any APF in this higher risk cohort, despite enrichment for APFs, nor was it associated with PFS. Notably, multiple known preoperative predictors for APFs were significant on MVA, and multiple predictors were associated with PFS on UVA. Therefore, PCA3 may not be a useful adjunct predictive marker in men with intermediate- or high-risk PCa.

Purpose Patients with prostate cancer (PCa) containing Gleason pattern (GP) 5 disease experience a greater and earlier incidence of prostate cancer-specific mortality (PCSM) than general PCa patients. This affords the statistical power to compare PCSM outcomes among different treatment modalities even when restricting the analysis to patients treated in the modern era. The purpose of the present study was to compare the survival outcomes among patients with GP 5 PCa on needle core biopsy or transurethral resection of the prostate who underwent extremely dose-escalated radiation therapy (RT; exemplified by external beam RT with a brachytherapy boost [EBRT + BT]) versus radical prostatectomy (RP) in the modern era. Methods and Materials A total of 7669 men with a diagnosis of GP 5 PCa from 2004 to 2013 who had undergone EBRT + BT or RP were identified using the Surveillance, Epidemiology, and End Results database. After propensity score matching to balance the patient characteristics, PCSM was compared between modalities using a multivariate Fine and Gray competing risk model that accounted for other-cause mortality, with adjustment for age, race, GP, and clinical T stage. Results Patients treated with RP were younger and had a lower burden of GP 5, lower T stage, and lower other-cause mortality than patients who underwent EBRT + BT. After propensity score matching, no difference was found in PCSM between the RP and EBRT + BT groups (adjusted hazard ratio 1.018; P =.910). The cumulative 5-year PCSM incidence rates were 5.6% and 6.1% for patients undergoing RP and EBRT + BT, respectively. Patients with primary GP 5 experienced significantly greater PCSM than those with secondary GP 5, regardless of the treatment modality. Conclusions For patients with GP 5 PCa found on needle core biopsy or transurethral resection of the prostate, RP and EBRT + BT offer equivalent PCSM in a competing risk model after propensity score matching to balance the differences in patient characteristics.

With over a decade׳s worth of clinical experience to guide stereotactic body radiotherapy (SBRT) for the treatment of clinically localized prostate cancer (PCa), sufficient data exist for robust conclusions to be made regarding its efficacy and the toxicities associated with this treatment. We briefly review the fundamental radiobiological basis of SBRT for PCa and provide a comprehensive synthesis of the medical literature to date, focusing on clinical outcomes and toxicities. When possible, we draw comparisons to comparable data for conventionally fractionated radiotherapy. Finally, a brief overview of technical considerations is presented. Although randomized clinical trials comparing SBRT with conventionally fractionated radiotherapy are underway, the current body of evidence supports the efficacy and safety of SBRT for PCa.

BackgroundThe long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons.ObjectiveTo compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP.Design, setting, participantsRetrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy.Outcome measurements and statistical analysisKaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS).Results and limitationsThe median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p

Background and purpose Second malignancies (SM) after external beam radiotherapy (EBRT) or brachytherapy (BT) for prostate cancer (PCa) are rare but serious sequelae. Materials and methods The Surveillance, Epidemiology, and End Results (SEER) database was used to identify men diagnosed with cT1-2N0M0 PCa between 1999 and 2005, who underwent EBRT, BT or radical prostatectomy (RP). Patients with time interval to second malignancy or follow-up shorter than five and two years were excluded for solid and hematopoietic SM analyses respectively. Risks for solid and hematopoietic SM were evaluated via the multivariate Fine and Gray proportional hazards model. Results EBRT and BT resulted in similar increases in solid and hematopoietic SM compared to RP. In subgroup analysis stratified by treatment modality, only the EBRT cohort demonstrated significantly decreased solid and hematopoietic SM in years 2002–2005 compared to years 1999–2001, with adjusted-hazard ratios of 0.752 ( p =0.001) and 0.815 ( p =0.018) respectively. Conclusions EBRT and BT resulted in statistically equivalent increase in both solid and hematopoietic SM compared to RP. EBRT in more recent years resulted in significantly decreased solid and hematopoietic SM, coinciding with increased utilization of IMRT.

BACKGROUND Published guidelines regarding the optimal treatment strategies for brain metastases focus on patients with ≤3 lesions. As delivery techniques for stereotactic radiosurgery (SRS) improve, radiation oncologists are increasingly using it for patients with >3 metastases. In the current study, the authors sought to characterize practice patterns among practitioners to identify areas of controversy. METHODS A survey of practicing radiation oncologists was distributed via e-mail. Responses were collected from April 1 to May 5, 2016. Survey data were analyzed. RESULTS A total of 711 currently practicing radiation oncologists responded, for a response rate of 12.5%. Specialists in central nervous system tumors (CNS specialists) were more likely to treat higher numbers of patients with brain metastases with SRS. There was a significant difference in the optimal “cutoff number” used when deciding how many lesions to treat with SRS versus whole-brain radiotherapy. Cutoff numbers were significantly higher for high-volume CNS specialists (≥10 patients/month) than for either low-volume CNS specialists (5-9 patients/month) or high-volume, non-CNS specialists (8.1 vs 5.6 and 5.1, respectively; P3 brain metastases, and practice patterns are heterogeneous. Radiation oncologists, especially high-volume CNS specialists, are treating significantly more brain metastases with SRS than what currently is recommended by published consensus guidelines. Providers struggle with patients with a moderate intracranial disease burden. Further prospective studies are needed to support these practice patterns and guide decision making. Cancer 2017;123:2274–2282. © 2017 American Cancer Society.

DISC-0974 is a humanized monoclonal anti-HJV antibody with high binding affinity for human, rat and cynomolgus monkey HJV (100 pM, 240 pM and 110 pM Kd, respectively) [Kovac 2016]. DISC-0974 inhibits the interaction between HJV and the key hepcidin regulatory ligands, bone morphogenetic proteins (BMPs), leading to decreased SMAD phosphorylation (SMAD-P) and reduced hepcidin expression [Kovak 2016]. Elevated hepcidin is a hallmark of and plays a critical role in the pathogenesis of anemia of inflammation (and other forms of anemia) by reducing transferrin saturation and erythroid iron availability, leading to failure of erythropoiesis and decreased hemoglobin synthesis. DISC-0974 is being developed to reduce hepcidin synthesis and treat anemia in these patients. A critical early signal of therapeutic effect is the effect of DISC-0974 on transferrin saturation (TSAT). TSAT has therefore been used as the primary pharmacodynamic marker in a series of non-clinical studies to determine the relationship between drug exposure and pharmacological activity. In non-human primates (NHP) DISC-0974 elicits a dose-dependent reduction in hepcidin levels leading to increases in serum iron and consequently TSAT. PK/PD responses were examined over 60 days for a single 6 mg/kg intravenous dose of DISC-0974 in three male NHPs and in repeat dose studies occurring at 14 day intervals administered 3 times (vehicle, 0.6 and 3 mg/kg) or two times (60 mg/kg). In these studies, the serum iron response saturated in an exposure-dependent manner over the 0.6-60 mg/kg dose range. The onset of iron elevation lagged compared to the DISC-0974 maximal plasma concentrations by 1- 4 days post dose and persisted beyond what could be predicted by DISC-0974 plasma concentration alone. The observed PD responses were well-described by a delayed response PK/PD model of serum iron which was fit globally to all studies. We will present single and multiple dose simulations showing that low monthly doses of DISC-0974 are sufficient to elicit a biologically significant and controlled PD modulation (serum iron, TSAT, hepcidin) over a sustained period-of-time (Figure 1). DISC-0974 is under development for the treatment of anemia of inflammation associated with high hepcidin. Disclosures Blaustein: Disc Medicine:Current Employment, Current equity holder in private company.King:Disc Medicine:Current Employment, Current equity holder in private company.Nguyen:Disc Medicine:Current Employment, Current equity holder in private company.Savage:Disc Medicine:Current Employment, Current equity holder in private company.Beconi:Disc Medicine:Current Employment, Current equity holder in private company.

Postoperative mortality occurs in 1-2% of patients undergoing major inpatient surgery. The currently available prediction tools using summaries of intraoperative data are limited by their inability to reflect shifting risk associated with intraoperative physiological perturbations. We sought to compare similar benchmarks to a deep-learning algorithm predicting postoperative 30-day mortality.We constructed a multipath convolutional neural network model using patient characteristics, co-morbid conditions, preoperative laboratory values, and intraoperative numerical data from patients undergoing surgery with tracheal intubation at a single medical centre. Data for 60 min prior to a randomly selected time point were utilised. Model performance was compared with a deep neural network, a random forest, a support vector machine, and a logistic regression using predetermined summary statistics of intraoperative data.Of 95 907 patients, 941 (1%) died within 30 days. The multipath convolutional neural network predicted postoperative 30-day mortality with an area under the receiver operating characteristic curve of 0.867 (95% confidence interval [CI]: 0.835-0.899). This was higher than that for the deep neural network (0.825; 95% CI: 0.790-0.860), random forest (0.848; 95% CI: 0.815-0.882), support vector machine (0.836; 95% CI: 0.802-870), and logistic regression (0.837; 95% CI: 0.803-0.871).A deep-learning time-series model improves prediction compared with models with simple summaries of intraoperative data. We have created a model that can be used in real time to detect dynamic changes in a patient's risk for postoperative mortality.

To objectively compare the suitability of MRI pulse sequences and commercially available fiducial markers (FMs) for MRI-only prostate radiotherapy simulation. Most FMs appear as small signal voids in MRI images making them difficult to differentiate from tissue heterogeneities such as calcifications. In this study we use quantitative metrics to objectively evaluate the visibility of FMs in 27 patients and an anthropomorphic phantom with a variety of standard clinical MRI pulse sequences and commercially available FMs. FM visibility was quantified using the local contrast-to-noise-ratio (lCNR), the difference between the 80th and 20th percentile iso-intensity FM volumes (V fall) and the largest iso-intensity volume that can be distinguished from background: apparent-marker-volume (AMV). A larger lCNR and AMV, and smaller V fall represents a more easily identifiable FM. The number of non-marker objects visualized by each pulse sequence was calculated using FM-derived template-matching. The FM-based target-registration-error (TRE) between each MRI and the planning-CT image was calculated. Fiducial marker visibility was rated by two medical physicists with over three years of experience examining MRI-only prostate simulation images. The rater's classification accuracy was quantified using the F 1 score, which is the harmonic mean of the rater's precision and recall. These quantitative metrics and human observer ratings were used to evaluate FM identifiability in images from nine subtypes of T 1-weighted, T 2-weighted and gradient echo (GRE) pulse sequences in a 27-patient study. A phantom study was conducted to quantify the visibility of 8 commercially available FMs. In the patient study, the largest mean lCNR and AMV and, smallest normalized V fall were produced by the 3.0 T multiple-echo GRE pulse sequence (T 1-VIBE, 2° flip angle, 1.23 ms and 2.45 ms echo-times). This pulse sequence produced no false marker detections and TREs less than 2 mm in the left-right, anterior-posterior and cranial-caudal directions, respectively. Human observers rated the 1.23 ms echo-time GRE images with the best average marker visibility score of 100% and an F 1 score of 1. In the phantom study, the Gold-Anchor GA-200X-20-B (deployed in a folded configuration) produced the largest sequence averaged lCNR and AMV measurements at 16.1 and 16.7 mm3, respectively. Using quantitative visibility and distinguishability metrics and human observer ratings, the patient study demonstrated that multiple-echo GRE images produced the best gold FM visibility and distinguishability. The phantom study demonstrated that markers manufactured from platinum or iron-doped gold quantitatively produced superior visibility compared to their pure gold counterparts.

IntroductionObstructive sleep apnea (OSA) is common among older surgical patients, and delirium is a frequent and serious postoperative complication. Emerging evidence suggests that OSA increases the risk for postoperative delirium. We hypothesize that OSA is an independent risk factor for postoperative delirium, and that in patients with OSA, perioperative adherence to positive airway pressure (PAP) therapy decreases the incidence of postoperative delirium and its sequelae. The proposed retrospective cohort analysis study will use existing datasets to: (i) describe and compare the incidence of postoperative delirium in surgical patients based on OSA diagnosis and treatment with PAP; (ii) assess whether preoperatively untreated OSA is independently associated with postoperative delirium; and (iii) explore whether preoperatively untreated OSA is independently associated with worse postoperative quality of life. The findings of this study will inform on the potential utility and approach of an interventional trial aimed at preventing postoperative delirium in patients with diagnosed and undiagnosed OSA.Methods and AnalysisObservational data from existing electronic databases will be used, including over 100,000 surgical patients and ∼10,000 intensive care unit (ICU) admissions. We will obtain the incidence of postoperative delirium in adults admitted postoperatively to the ICU who underwent structured preoperative assessment, including OSA diagnosis and screening. We will use doubly robust propensity score methods to assess whether untreated OSA independently predicts postoperative delirium. Using similar methodology, we will assess if untreated OSA independently predicts worse postoperative quality of life.Ethics and disseminationThis study has been approved by the Human Research Protection Office at Washington University School of Medicine. We will publish the results in a peer-reviewed venue. Because the data is secondary and high risk for re-identification, we will not publicly share the data. Data will be destroyed after 1 year of completion of active IRB approved projects.Article summaryStrengths and limitations of this study, (containing 5 short bullet points, no longer than one sentence each, that relate specifically to the methods)Our granular database includes routine structured preoperative screening for OSA, processed laboratory results, and verified comorbid diagnoses.We have limited information on the severity of most comorbidities, creating the possibility for substantial residual confounding.Our database includes near-universal and standardized nurse-driven delirium evaluations at multiple time-points as well as clinician diagnoses.Compared to prior studies, the large sample size will allow for more aggressive confounder adjustment utilizing linked structured medical histories, intraoperative records, and administrative data.Selection bias and confounding by indication are important limitations, which we will address using advanced statistical methods.

Patients who present with stroke or transient ischemic attacks (TIA) in the setting of patent foramen ovale (PFO) mandate investigation of the lower extremities and pelvis in order to determine a possible source of thromboembolic disease. Imaging studies including Doppler ultrasound of the extremities may not be sufficient to diagnose the presence of anatomic variants that predispose patients to thrombus formation. May-Thurner syndrome (MTS) is characterized by extrinsic compression of the common iliac veins or inferior vena cava which leads to chronic physiologic changes within the vasculature. This condition increases risk of venous occlusion, diminution of venous flow, and most significantly, formation of thrombi. In this case report, we present a young Hispanic female diagnosed with ischemic cerebral vascular accident (CVA) secondary to thromboembolism in the setting of May-Thurner syndrome and a PFO, a rare etiology of cryptogenic CVA.

Background: The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown. Objective: To evaluate the clinical implications of LF after definitive RT. Design, setting, and participants: Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials. Outcome measurements and statistical analysis: Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints. Results and limitations: Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37–2.10]), PCSS (3.10 [95% CI 2.33–4.12]), and DMFS (HR 1.92 [95% CI 1.54–2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04–0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22–4.93], p = 0.01) than those who did not. Conclusions: LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined. Patient summary: Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer. Using individual patient-level data from six randomized trials, we have found that local failure events after definitive radiotherapy for high-grade prostate cancer are independent, significant predictors of distant metastasis–free survival, prostate cancer–specific survival, and overall survival. Using multistate modeling, we identify that most distant metastatic events occur from an apparent disease-free state, but an increasing proportion occurs over time subsequent to local failure events.