Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Hematological adverse events in the management of glioblastoma.

BACKGROUND: Hematological adverse events (HAEs) are common during treatment for glioblastoma (GBM), usually associated with temozolomide (TMZ). Their clinical value is uncertain, as few investigations have focused on outcomes for HAEs during GBM treatment. METHODS: We combined data from two randomized clinical trials, RTOG 0525 and RTOG 0825, to analyze HAEs during treatment for GBM. We investigated differences between chemoradiation and adjuvant therapy, and by regimen received during adjuvant treatment. RESULTS: 1454 patients participated in these trials, of which 1154 (79.4%) developed HAEs. During chemoradiation, 44.4% of patients developed HAEs (54% involving more than one cell line), and were most commonly lymphopenia (50.6%), and thrombocytopenia (47.5%). During adjuvant treatment, 45% of patients presented HAEs (78.6% involving more than one cell line), and were more commonly leukopenia (62.7%), and thrombocytopenia (62.3%). Median overall survival (OS) and progression free survival (PFS) were longer in patients with HAEs (OS 19.4 months and PFS 9.9 months) compared to those with other or no adverse events (OS 14.1 months and PFS 5.9 months). There was no significant difference in survival between grade 1 and/or 2 versus grade 3 and/or 4 HAEs. History of HAEs during chemoradiation was a protective factor for presentation of HAEs during adjuvant therapy. CONCLUSION: HAEs are common during GBM treatment, and often involve more than one cell line (more likely during adjuvant therapy). HAEs may be associated with prolonged OS and PFS, particularly during adjuvant therapy. HAEs during chemoradiation was a protective factor for HAEs during adjuvant therapy.

Using the LACE index to predict hospital readmissions in congestive heart failure patients.

BACKGROUND: The LACE index has been used to predict the risk of unplanned readmission within 30 days after hospital discharge in both medical and surgical patients. The aim of this study is to validate the accuracy of using the LACE index in CHF patients. METHODS: This was a retrospective study. The LACE index score was calculated on each patient who was admitted to hospital due to an acute CHF exacerbation. Operational and clinical variables were collected from patients including basic clinical characteristics, length of hospitalization, comorbidities, number of previous ED visits in the past 6 months before the index admission, and the number of post discharge ED revisits at 30, 60, and 90 days. All variables were analyzed by multivariate logistic regression to determine the association between clinical variables and the hospital unplanned readmissions. C-statistic was used to discriminate those patients with high risk of readmissions. RESULTS: Of the 253 patients included in the study, 24.50% (62/253) experienced unplanned readmission to hospital within 30 days after discharge. The LACE index was slightly higher in patients readmitted versus patients not readmitted (12.17 ± 2.22 versus 11.80 ± 1.92, p = 0.199). Adjusted odds ratios based on logistic regression of all clinical variables showed only the number of previous ED visits (OR 1.79, 95% CI 1.30-2.47, p < 0.001), history of myocardial infarction (OR 2.51, 95% CI 1.02-6.21, p = 0.045), and history of peripheral vascular disease (OR 10.75, 95% CI 1.52-75.73, p = 0.017) increased the risk of unplanned readmission within 30 days of hospital discharge. However, patients with high LACE scores (≥10) had a significantly higher rate of ED revisits (15.04% vs 0%) within 30 days from the index discharge than those with low LACE scores (p = 0.030). CONCLUSION: The LACE index may not accurately predict unplanned readmissions within 30 days from hospital discharge in CHF patients. The LACE high risk index may have utility as a screening tool to predict high risk ED revisits after hospital discharge.

The inaccuracy of determining overcrowding status by using the national ED overcrowding study tool.

BACKGROUND: Emergency department (ED) crowding has become more common, and perceptions of crowding vary among different health care providers. The National Emergency Department Overcrowding Study (NEDOCS) tool is the most commonly used tool to estimate ED crowding but still uncertain of its reliability in different ED settings. OBJECTIVE: The objectives of this study are to determine the accuracy of using the NEDOCS tool to evaluate overcrowding in an extremely high-volume ED and assess the reliability and consistency of different providers' perceptions of ED crowding. MATERIAL AND METHODS: This was a 2-phase study. In phase 1, ED crowding was determined by the NEDOCS tool. The ED length of stay and number of patients who left without being seen were analyzed. In phase 2, a survey of simulated ED census scenarios was completed by different providers. The interrater and intrarater agreements of ED crowding were tested. RESULTS: In phase 1, the subject ED was determined to be overcrowded more than 75% of the time in which nearly 50% was rated as severely overcrowded by the NEDOCS tool. No statistically significant difference was found in terms of the average length of stay and the number of left without being seen patients under different crowding categories. In phase 2, 88 surveys were completed. A moderate level of agreement between health care providers was reached (κ = 0.5402, P < .0001). Test-retest reliability among providers was high (r = 0.8833, P = .0007). The strength of agreement between study groups and the NEDOCS was weak (κ = 0.3695, P < .001). CONCLUSION: Using the NEDOCS tool to determine ED crowding might be inaccurate in an extremely high-volume ED setting.

Association of CD47 Expression with Clinicopathologic Characteristics and Survival Outcomes in Muscle Invasive Bladder Cancer.

OBJECTIVE: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. MATERIALS AND METHODS: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively. RESULTS: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. CONCLUSION: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors.

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.

Hydrogen Peroxide Promotes the Production of Radiation-Derived EVs Containing Mitochondrial Proteins.

In spite of extensive successes, cancer recurrence after radiation treatment (RT) remains one of the significant challenges in the cure of localized prostate cancer (PCa). This study focuses on elucidating a novel adaptive response to RT that could contribute to cancer recurrence. Here, we used PC3 cell line, an adenocarcinoma from a bone metastasis and radio-resistant clone 695 cell line, which survived after total radiation dose of 66 Gy (2 Gy × 33) and subsequently regrew in nude mice after exposure to fractionated radiation at 10 Gy (2 Gy × 5). Clone 695 cells not only showed an increase in surviving fraction post-radiation but also an increase in hydrogen peroxide (H2O2) production when compared to PC3 cells. At the single cell level, confocal microscope images coupled with IMARIS rendering software demonstrate an increase in mitochondrial mass and membrane potential in clone 695 cells. Utilizing the Seahorse XF96 instrument to investigate mitochondrial respiration, clone 695 cells demonstrated a higher basal Oxygen Consumption Rate (OCR), ATP-linked OCR, and proton leak compared to PC3 cells. The elevation of mitochondrial function in clone 695 cells is accompanied by an increase in mitochondrial H2O2 production. These data suggest that H2O2 could reprogram PCa's mitochondrial homeostasis, which allows the cancer to survive and regrow after RT. Upon exposure to RT, in addition to ROS production, we found that RT induces the release of extracellular vesicles (EVs) from PC3 cells (p < 0.05). Importantly, adding H2O2 to PC3 cells promotes EVs production in a dose-dependent manner and pre-treatment with polyethylene glycol-Catalase mitigates H2O2-mediated EV production. Both RT-derived EVs and H2O2-derived EVs carried higher levels of mitochondrial antioxidant proteins including, Peroxiredoxin 3, Glutathione Peroxidase 4 as well as mitochondrial-associated oxidative phosphorylation proteins. Significantly, adding isolated functional mitochondria 24 h prior to RT shows a significant increase in surviving fractions of PC3 cells (p < 0.05). Together, our findings reveal that H2O2 promotes the production of EVs carrying mitochondrial proteins and that functional mitochondria enhance cancer survival after RT.

Molecular Tumor Board-Assisted Care in an Advanced Cancer Population: Results of a Phase II Clinical Trial.

PURPOSE: Multidisciplinary molecular tumor boards (MTBs) interpret next-generation sequencing reports and help oncologists determine best therapeutic options; however, there is a paucity of data regarding their clinical utility. The purpose of this study was to determine if MTB-directed therapy improves progression-free survival (PFS) over immediately prior therapy in patients with advanced cancer. METHODS: This single-arm, prospective phase II clinical trial enrolled patients with advanced cancer with an actionable mutation who received MTB-recommended targeted therapy between January 1, 2017, and October 31, 2020. MTB-recommended both on-label (level 1 evidence) and off-label (evidence levels 2 and 3) therapies. Of the 93 enrolled patients, 43 were treated frontline and 50 received second-line or greater-line therapy. The primary outcome was the probability of patients treated with second-line or greater-line MTB-directed therapy who achieved a PFS ratio ≥ 1.3 (PFS on MTB-directed therapy divided by PFS on the patient's immediately prior therapy). Secondary outcomes included PFS for patients treated frontline and overall survival and adverse effects for the entire study population. RESULTS: The most common disease sites were lung (35 of 93, 38%), gynecologic (17 of 93, 18%), GI (16 of 93, 17%), and head and neck (7 of 93, 8%). The Kaplan-Meier estimate of the probability of PFS ratio ≥ 1.3 was 0.59 (95% CI, 0.47 to 0.75) for patients treated with second-line or greater-line MTB-directed therapy. The median PFS was 449 (range 42-1,125) days for patients treated frontline. The median overall survival was 768 (range 22-1,240) days. There were four nontreatment-related deaths. CONCLUSION: When treated with MTB-directed therapy, most patients experienced improved PFS compared with immediately prior treatment. MTB-directed targeted therapy may be a strategy to improve outcomes for patients with advanced cancer.

The effect of dietary nitrate and vitamin C on endothelial function, oxidative stress and blood lipids in untreated hypercholesterolemic subjects: A randomized double-blind crossover study.

BACKGROUND: Vitamin C may enhance nitric oxide (NO) production through stepwise reduction of dietary nitrate (NO3) to nitrite (NO2) to NO. The combined effect of vitamin C and NO3 supplementation is relatively unexplored in untreated hypercholesterolemia. AIMS: We aimed to examine whether co-administration of vitamin C and nitrate for 4-weeks would improve endothelial function (primary outcome), plasma NO metabolites, oxidative stress, and blood lipids (secondary outcomes). METHODS: Subjects 50-70 years of age with low density lipoprotein (LDL) > 130 mg/dL and RHI ≤2 were enrolled in this randomized double-blind crossover study. Subjects were assigned to two 4-week supplementation treatments starting with 70 ml of concentrated beetroot juice (CBJ) with 1000 mg of vitamin C (NC) or CBJ with matched placebo (N), then switched to alternate treatment following 2-week washout. The change in reactive hyperemia index (RHI), sum of plasma NO metabolites (NO2 + NO3 (NOx)), oxidized LDL (oxLDL), and serum lipids were assessed at baseline and at 4-weeks of each treatment period. RESULTS: Eighteen subjects (11M:7F) completed all study visits. No significant treatment differences were observed in RHI change (N: 0.21 ± 0.12; NC: 0.20 ± 0.17; p = 0.99). Secondary analysis revealed that a subgroup of NC subjects who started with a baseline RHI of <1.67 (threshold value for ED) had greater improvements in RHI compared to subjects with RHI >1.67 (1.23 ± 0.15 to 1.96 ± 0.19; n = 8 vs. 1.75 ± 0.11 to 1.43 ± 0.10; n = 8; p = 0.02). Compared to N, NC experienced a significant increase in plasma NOx (N: 94.2 ± 15.5 µmol/L; NC: 128.7 ± 29.1 µmol/L; p = 0.01). Although there was no significant difference in oxLDL change between treatments (N: -1.08 ± 9.8 U/L; NC: -6.07 ± 9.14 U/L; p = 0.19), NC elicited significant reductions in LDL (N: 2.2 ± 2; NC: -10.7 ± 23; p = 0.049), triglycerides (N: 14.6 ± 43; NC: -43.7 ± 45; p = 0.03), and no change in serum high density lipoprotein. Within treatment group comparisons showed that only NC reduced oxLDL significantly from baseline to 4 weeks (p = 0.01). CONCLUSIONS: No between intervention differences were observed in RHI. RHI only improved in NC subjects with ED at intervention baseline. Four weeks of NC enriched the NO pool and promoted reduction of blood lipids and oxidative stress in subjects with hypercholesterolemia. These preliminary findings highlight a supplementation strategy that may reduce the progression of atherosclerotic disease and deserves further attention in studies using flow mediated dilation methods. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT04283630).

Multiple sclerosis outcomes after cancer immunotherapy.

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes. METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution. RESULTS: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors. CONCLUSIONS: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma Par-4 levels and apoptosis in diverse tumors.

Chloroquine and hydroxychloroquine (HCQ) are robust inducers of the tumor suppressor Par-4 secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells and inhibits metastasis in mice. We report the clinical results with pharmacodynamic analyses of our Phase I trial using neoadjuvant administration of HCQ in patients with surgically removable early stage solid tumors. This was a single-institution trial of oral HCQ (200 or 400 mg twice daily) given for 14 days prior to planned surgery. Dose escalation was based on isotonic regression to model safety and biological effect based on plasma Par-4 analysis. Eight of the nine patients treated with HCQ showed elevation in plasma Par-4 levels over basal levels. No toxicities were observed with these dose regimens. The resected tumors from the eight HCQ-treated patients with elevated plasma Par-4 levels, but not the resected tumor from the patient who failed to induce plasma Par-4 levels, exhibited TUNEL-positivity indicative of apoptosis. Resected tumors from all nine HCQ-treated patients showed p62/sequestosome-1 induction indicative of autophagy-inhibition by HCQ. Our findings indicate that both dose levels of HCQ were well-tolerated and that Par-4 secretion but not induction of the autophagy-inhibition marker p62 correlated with apoptosis induction in patients' tumors.

Profiles of Radioresistance Mechanisms in Prostate Cancer.

Radiation therapy (RT) is commonly used for the treatment of localized prostate cancer (PCa). However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently causing metastasis and cancer recurrence. Understanding the molecular events that cause radioresistance in PCa will enable us to develop adjuvant treatments for enhancing the efficacy of RT. Radioresistant PCa depends on the elevated DNA repair system and the intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and scavenge anti-cancer regimens, whereas the elevated heat shock protein 90 (HSP90) and the epithelial-mesenchymal transition (EMT) enable radioresistant PCa cells to metastasize after exposure to radiation. The up-regulation of the DNA repairing system, ROS, HSP90, and EMT effectors has been studied extensively, but not targeted by adjuvant therapy of radioresistant PCa. Here, we emphasize the effects of ionizing radiation and the mechanisms driving the emergence of radioresistant PCa. We also address the markers of radioresistance, the gene signatures for the predictive response to radiotherapy, and novel therapeutic platforms for targeting radioresistant PCa. This review provides significant insights into enhancing the current knowledge and the understanding toward optimization of these markers for the treatment of radioresistant PCa.

Extracellular redox state shift: A novel approach to target prostate cancer invasion.

AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2•- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.

Use of the SONET score to evaluate Urgent Care Center overcrowding: a prospective pilot study.

OBJECTIVES: To derive a tool to determine Urgent Care Center (UCC) crowding and investigate the association between different levels of UCC overcrowding and negative patient care outcomes. DESIGN: Prospective pilot study. SETTING: Single centre study in the USA. PARTICIPANTS: 3565 patients who registered at UCC during the 21-day study period were included. Patients who had no overcrowding statuses estimated due to incomplete collection of operational variables at the time of registration were excluded in this study. 3139 patients were enrolled in the final data analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: A crowding estimation tool (SONET: Severely overcrowded, Overcrowded and Not overcrowded Estimation Tool) was derived using the linear regression analysis. The average length of stay (LOS) in UCC patients and the number of left without being seen (LWBS) patients were calculated and compared under the three different levels of UCC crowding. RESULTS: Four independent operational variables could affect the UCC overcrowding score including the total number of patients, the number of results pending for patients, the number of patients in the waiting room and the longest time a patient was stationed in the waiting room. In addition, UCC overcrowding was associated with longer average LOS (not overcrowded: 133±76 min, overcrowded: 169±79 min, and severely overcrowded: 196±87 min, p<0.001) and an increased number of LWBS patients (not overcrowded: 0.28±0.69 patients, overcrowded: 0.64±0.98, and severely overcrowded: 1.00±0.97). CONCLUSIONS: The overcrowding estimation tool (SONET) derived in this study might be used to determine different levels of crowding in a high volume UCC setting. It also showed that UCC overcrowding might be associated with negative patient care outcomes.