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The unfolded protein response (UPR) is a complex adaptive signaling pathway activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress (ERS) triggers a cascade of responses that converge upon C/EBP homologous protein (CHOP) to drive inflammation and apoptosis. Herein, we sought to determine whether liver injury and fibrosis after small bowel resection (SBR) were mediated by a maladaptive hepatic ERS/UPR. C57BL/6 mice underwent 50% proximal SBR or sham operation. Markers of liver injury and UPR/ERS pathways were analyzed. These were compared with experimental groups including dietary fat manipulation, tauroursodeoxycholic acid (TUDCA) treatment, distal SBR, and global CHOP knockout (KO). At 10 wk, proximal SBR had elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) (

BACKGROUND The childhood obesity epidemic has grown exponentially and is known to disproportionately affect minority groups. Successful treatment of this complex health issue requires a multidisciplinary approach including metabolic and bariatric surgery (MBS) for qualifying pediatric patients. This study examines current national trends in pediatric bariatric surgery from 2010 to 2017 using the National Inpatient Sample. METHODS This study analyzed MBS among pediatric patients RESULTS From 2010 to 2017, annual bariatric procedure rates increased from 2.29 to 4.62 per 100 000 (P < .001). Laparoscopic sleeve gastrectomy outpaced Roux-en-Y gastric bypass and laparoscopic adjustable gastric band over time (0.31–3.99 per 100 000, P < .0001). The mean age was stable over time 18.10–17.96 (P = .78). The cohort was primarily female (76.5% to 75.4%), white (54.0% to 45.0%), and privately-insured (59.9% to 53.4%). Preoperative BMI increased from 2010 to 2017 (P < .001), whereas number of obesity-related comorbidities was stable (P > .05). Length of stay was CONCLUSIONS Pediatric MBS is underutilized nationally with disproportionately lower rates among minority groups. Despite incremental progress, further investigation into the racial and social determinants that limit access to pediatric weight loss surgery is critical.

Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome. NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.

BACKGROUND: Short bowel syndrome resulting from small bowel resection (SBR) is associated with significant morbidity and mortality. Many adverse sequelae including steatohepatitis and bacterial overgrowth are thought to be related to increased bacterial translocation, suggesting alterations in gut permeability. We hypothesized that after intestinal resection, the intestinal barrier is altered via toll-like receptor 4 (TLR4) signaling at the intestinal level. METHODS: B6 and intestinal-specific TLR4 knockout (iTLR4 KO) mice underwent 50% SBR or sham operation. Transcellular permeability was evaluated by measuring goblet cell associated antigen passages via two-photon microscopy. Fluorimetry and electron microscopy evaluation of tight junctions (TJ) were used to assess paracellular permeability. In parallel experiments, single-cell RNA sequencing measured expression of intestinal integral TJ proteins. Western blot and immunohistochemistry confirmed the results of the single-cell RNA sequencing. RESULTS: There were similar number of goblet cell associated antigen passages after both SBR and sham operation (4.5 versus 5.0, P > 0.05). Fluorescein isothiocyanate–dextran uptake into the serum after massive SBR was significantly increased compared with sham mice (2.13 ± 0.39 ng/μL versus 1.62 ± 0.23 ng/μL, P < 0.001). SBR mice demonstrated obscured TJ complexes on electron microscopy. Single-cell RNA sequencing revealed a decrease in TJ protein occludin (21%) after SBR (P < 0.05), confirmed with immunostaining and western blot analysis. The KO of iTLR4 mitigated the alterations in permeability after SBR. CONCLUSIONS: Permeability after SBR is increased via changes at the paracellular level. However, these alterations were prevented in iTLR4 mice. These findings suggest potential Intestinal barrier protein targets for restoring the intestinal barrier and obviating the adverse sequelae of short bowel syndrome.

Murine ileocecal resection (ICR) has been used to investigate intestinal adaptation. The established model often includes the sacrifice of significant length of the proximal colon. Here, we optimized a highly selective vascular approach to the ICR, with primary jejunal-colic anastomosis yielding maximal colonic preservation.Forty C57BL/6 mice underwent a highly vascularly selective ICR. The terminal branches of the ileocecal artery are isolated apart from the mesenteric branches supplying the small bowel to be resected. The distal 50% of small bowel and cecum are resected; a primary jejuno-colonic anastomosis is performed. Animals were sacrificed at postoperative weeks 2 (n = 10) and 10 (n = 29). Proximal 50% small bowel resection (SBR) with jejuno-ileal anastomosis was also performed for comparison.The entire colon (with exception of the cecum) was preserved in 100% of animals. Ninety-seven percent of animals survived to postoperative week 10, and all exhibited structural adaptation in the remnant small intestine epithelium. Crypts deepened by 175%, and villi lengthened by 106%, versus 39% and 29% in the proximal SBR cohort, respectively. Colonic proliferation, structural adaptation, and functional adaptation (measured by p-histone 3, luminal-facing apical crypt border size, and sucrase isomaltase, respectively) were increased in ICR compared with proximal SBR.Highly selective isolation of the cecal vasculature allows for greater colon preservation and yields enhanced remnant intestine epithelial adaptation. ICR is also associated with greater colonic adaptation and unique plasticity toward an intestinal phenotype. These findings underscore major differences between resection sites and offer insights into the critical adaptive mechanisms in response to massive intestinal loss.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic β-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. At 10 wk, pancreatic insulin content and secretion was measured by ELISA. Immunohistochemistry was performed to determine structural alterations in pancreatic α-and β-cells. Western blot analysis was used to measure GLP-1R expression, and immunoassay was used to measure plasma insulin and GLP-1. Experiments were repeated by administering a GLP-1 agonist (exendin-4) to a cohort of mice following SBR. After SBR, there was pancreatic islet hypertrophy and impaired glucose tolerance. The proportion of α and β cells was not grossly altered. Whole pancreas and pancreatic islet insulin content was not significantly different; however, SBR mice demonstrated decreased insulin secretion in both static incubation and islet perfusion experiments. The expression of pancreatic GLP-1R was decreased approximately twofold after SBR, compared with sham and serum GLP-1, was decreased. These metabolic derangements were mitigated after administration of the GLP-1 agonist. Following massive SBR, there is significant hypertrophy of pancreatic islet cells with morphologically intact α- and β-cells. Significantly reduced pancreatic insulin release in both static and dynamic conditions demonstrate a perturbed second phase of insulin secretion. GLP-1 is a key mediator of this amplification pathway. Decreased expression of serum GLP-1 and pancreatic GLP-1R in face of no change in insulin content presents a novel pathway for enteropancreatic glucose regulation following SBR. NEW & NOTEWORTHY Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

This review aims to discuss the role of nutrition and feeding practices in necrotizing enterocolitis (NEC), NEC prevention, and its complications, including surgical treatment. A thorough PubMed search was performed with a focus on meta-analyses and randomized controlled trials when available. There are several variables in nutrition and the feeding of preterm infants with the intention of preventing necrotizing enterocolitis (NEC). Starting feeds later rather than earlier, advancing feeds slowly and continuous feeds have not been shown to prevent NEC and breast milk remains the only effective prevention strategy. The lack of medical treatment options for NEC often leads to disease progression requiring surgical resection. Following resection, intestinal adaptation occurs, during which villi lengthen and crypts deepen to increase the functional capacity of remaining bowel. The effect of macronutrients on intestinal adaptation has been extensively studied in animal models. Clinically, the length and portion of intestine that is resected may lead to patients requiring parenteral nutrition, which is also reviewed here. There remain significant gaps in knowledge surrounding many of the nutritional aspects of NEC and more research is needed to determine optimal feeding approaches to prevent NEC, particularly in infants younger than 28 weeks and

Purpose: Most prostate cancer mortality can be attributed to metastatic castration resistant prostate cancer, an advanced stage that remains incurable despite recent advances. The AR (androgen receptor) signaling axis remains active in castration resistant prostate cancer. Recent studies suggest that expression of the AR-V (AR splice variant) AR-V7 may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. Our objective was to develop a fast and sensitive assay for AR-Vs in patients.Materials and Methods: Two approaches were assessed in this study. The first approach was based on depletion of leukocytes and the second one used RNA purified directly from whole blood preserved in PAXgene® tubes. Transcript expression was analyzed by quantitative reverse transcription-polymerase chain reaction.Results: Through a side-by-side comparison we found that the whole blood approach was suitable to detect AR-Vs. The specificity of the assay was corroborated in a cance...

Careful descriptions of men with prostate cancer (PCa)-specific mortality are scant in nontrial settings. The present retrospective review describes the clinical characteristics, timelines, and treatment histories from initial presentation to death in a cohort of men with metastatic, castrate-resistant PCa (mCRPC). Unique to the present study is the unequivocal attribution of PCa death by a single experienced clinician.A total of 119 patients who had been treated at Tulane Cancer Center and had died of mCRPC from 2008 to 2015 were studied through a retrospective review of the medical records.The median age at diagnosis was 65 years (range, 40-85 years), and 34.4% of the patients presented with metastatic disease (stage M1). Of these patients, 56% had received definitive primary therapy, all had received androgen-deprivation therapy, and 52% had received docetaxel. The patients had received a median of 7 (1-14) systemic therapies before death. Most were secondary hormonal manipulations after the diagnosis of mCRPC (median, 4; range, 0-9). The median survival was 69 months (range, 5-270 months) after diagnosis, and the median age at death was 73 years (range, 47-95 years). The presence of metastases at diagnosis was a significant predictor of early death (hazard ratio, 4.33; P.001), and definitive primary therapy was a significant predictor of longer survival (P.001). The median survival for patients presenting with metastases was 39 months (range, 5-235 months) compared with 100 months (range, 6-270 months) for those with localized disease (P.001). The median age at diagnosis between the docetaxel- and non-docetaxel-treated patients was significantly different at 62 and 71 years, respectively (P = .002).The present retrospective analysis provides initial views clarifying the clinical characteristics of men dying of mCRPC and the therapies they received before death. Additional data are needed in multi-institutional settings to confirm these findings.

Prostate cancer patients with liver metastases have a poor prognosis. To date, no study exists investigating the relationship between liver tumor burden and clinical laboratory markers.Metastatic castrate-resistant prostate cancer (mCRPC) patients with radiographic evidence of liver metastases were selected for this study. Volumetric measurements of liver metastases were ascertained for all available patients. Prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin and hemoglobin (HGB) levels were then assessed to coincide with the scan dates. Univariate and multivariate mixed-model regression analysis were performed to evaluate the relationship between laboratory markers and liver lesion volume. Data sets with non-normal distribution were logarithmically transformed. Akaike information criteria (AIC) was used to identify the most reliable multivariate model.In our heavily pretreated liver-metastatic patient population, univariate analysis demonstrated a statistically significant positive correlation between PSA (p = 0.0002), ALP (p = 0.0305), AST (p 0.0001), ALT (p = 0.0049), and LDH (p = 0.0019) and liver lesion volume. Additionally, ALB (p = 0.0006) and HGB (p = 0.0103) had statistically significant negative correlation. Multivariate analysis identified AST and hemoglobin assessments as the best predictors of increasing liver lesion burden. Preliminary data on circulating tumor DNA (ctDNA) mutational and amplification findings are also reported.Analysis identified AST and hemoglobin as optimal predictors of liver lesion volume. These patients have a heavy burden of ctDNA abnormalities. Further studies with a larger patient population are needed to verify these results. Micro Abstract: This study investigates the association between liver lesion burden and clinical laboratory markers in castrate-resistant prostate cancer patients with hepatic metastases. Our univariate analysis identified multiple laboratory markers as significant indicators of worsening hepatic disease. Multivariate analysis demonstrated that AST and hemoglobin were the most effective predictors of change in liver lesion volume.

Background Radium-223 has shown clinical efficacy in metastatic castration-resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 radium-223 doses. Patients and Methods We conducted retrospective analyses of patients who received radium-223 (n = 135). Patients were classified into 3 cohorts: 1 to 2, 3 to 4, or 5 to 6 radium-223 doses. We evaluated the association of clinical and laboratory variables with the number of cycles administered (5-6 vs. 1-4 doses). Results Twenty-five patients (18.5%) received 1 to 2 radium-223 doses, 27 (20.0%) received 3 to 4, and 83 (61.5%) received 5 to 6. The most common reasons for treatment discontinuation included disease progression (61.5%, n = 40), patient preference (15.4%, n = 10), and toxicity (10.8%, n = 7). Factors associated with therapy completion in univariate analysis included previous sipuleucel-T treatment ( P = .068), no previous abiraterone or enzalutamide treatment ( P = .007), hemoglobin ≥ lower limit of normal (LLN; P = .006), white blood cell count ≥ LLN ( P = .045), absolute neutrophil count (ANC) ≥ LLN ( P = .049), lower alkaline phosphatase ( P = .029), and lower lactate dehydrogenase levels ( P = .014). Factors associated with therapy completion in multivariable analysis included previous sipuleucel-T treatment ( P = .009), hemoglobin ≥ LLN ( P = .037), and ANC ≥ LLN ( P = .029). Conclusion Several clinical parameters are associated with radium-223 therapy completion. In general, these parameters reflect earlier disease stage. These data are hypothesis-generating and prospective testing of the optimal number of radium-223 doses is warranted.

250 Background: Liver metastases (mets) are a particularly poor prognostic group among mCRPC patients. The objective of this study is to characterize mCRPC patients who have had treatment with Abi or Enza to identify risk factors that may be associated with subsequent development of liver mets. Methods: A sample of 67 patients (n = 17 liver mets and 50 non-liver met patients matched by treatment history) seen at Tulane Cancer Center were selected for analysis. All patients had prior Abi and or Abi/Enza. Race, age at PCa diagnosis and Gleason Score at PCa diagnosis were assessed. For patients with liver mets, total liver metastatic volume was measured using CT scans and correlated against PSA, LDH and AST values at the time of the scan. Wilcoxon rank sum tests were run analyzing PSA, LDH and AST at the start of Abi treatment, end of Abi treatment as well the duration of Abi treatment, and the nadir PSA for these patients. Results: Patients were predominantly Caucasian, had a median Gleason Score of 8 at diagnosis and were at a median age of 57 for those with liver mets and 62 for non-liver met at PCa diagnosis. Pearson correlation analysis of the total liver lesion volume and lab values revealed a significant correlation for LDH (R = 0.491, < 0.01) and AST (R = 0.368, p < 0.05), but not for PSA. Further evaluation of PSA and AST values at the start and end of Abi treatment as well as at nadir PSA revealed no statistically significant differences between liver met patients and non-liver met patients. However, there was a significant difference (p = 0.015) between LDH levels at the end of Abi treatment with a median of 347 U/L for liver met and 238 U/L for non-liver met patients. Conclusions: LDH and AST levels correlate with extent of liver metastases. Additionally, elevated LDH at the end of Abi treatment is indicative of an increased risk for developing liver metastases. Larger sample sizes and molecular characterization of these tumors are required to gain more insights into this important patient population.

339 Background: The current treatment paradigm for metastatic, castrate-resistant prostate cancer (mCRPC) has rapidly changed and six therapies [abiraterone (Abi), enzalutamide (Enza), docetaxel (Doc), cabazitaxel (Cab), radium-223 (Ra-223), and sipuleucel-T (Sip-T)] have now been proven to prolong overall survival. Though sequential therapy is the norm, few studies have reported on the variety and prevalence of these agents over the course of patient's lifetime. Herein, we sought to describe the temporal frequencies of mCRPC therapies in patients who completed all of their therapies. Methods: Retrospective chart reviews were conducted on 119 patients who died from mCRPC at Tulane Cancer Center from 2008-2015 (thus completing all possible therapies). Many patients were not treated with multiple life-prolonging therapies given the timing of their death. Post-mCRPC therapies were longitudinally sequenced and a frequency table was generated for first, second, third, etc. line of therapies. Results: Median duration from initial androgen deprivation therapy to mCRPC was 29 months (range: 0-252) and 34.4% of the cohort presented with distant metastatic disease (M1) at diagnosis. The most common front line mCRPC therapies were nilutamide, Doc, Abi, and ketoconazole (Keto) in that order. Keto, Doc, dexamethasone, and Abi were the most common second line therapies. Abi, Doc, DES, and Cab were the most prevalent third line therapies. Doc, Abi, Cab, and Ra-223 were most common fourth line therapies. The median overall survival for our cohort was 69 months (range: 5-270 months) from initial diagnosis. Conclusions: This retrospective analysis provides a temporal snapshot of the timing and frequency of treatments for men dying from mCRPC from 2008-2015. More recent patients are likely to have greater access to contemporary therapies.

249 Background: Abi and Enza are used in treating metastatic CRPC. Primary resistance is well described but little data exists for early treatment responders. Further characterization of patients with early PSA declines was the goal of this study. Methods: Single institution, retrospective reviews were performed on 84 CRPC patients (pts) treated with Abi or Enza. PSAs were recorded for the duration of treatment. The primary end point was to describe receiver operating characteristics (ROC) of early PSA changes, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥ 50% decrease in PSA from baseline). 12 additional clinical covariates were also evaluated as treatment response predictors. Results: 30/63 pts in the Abi treatment group and 12/44 pts in the Enza treated group had a PSA treatment response at some point. Among the “eventual” Abi responders, some achieved a response early; 16/30 at 4 weeks and 22/30 at 8 weeks. Of Enza “eventual” responders, 7/12 achieved response at 4 weeks. For early responders (either 4 or 8 weeks), Abi pts median treatment time was 336 days. Enza early responders median treatment was time 303 days. For ROC analysis of PSA changes at 4 & 8 weeks, in terms of predicting ‘eventual’ responders, the Abi group had an area under the curve (AUC) of 0.86 ± 0.07 and 0.93 ± 0.08, respectively. Enza ROC analysis of PSA change at 4 weeks had an AUC of 0.97 ± 0.03. Sensitivities and specificities were also described for various PSA change thresholds in each group. Ideal cut-off points for Abi at 4 weeks was a 37% decrease in PSA (sensitivity: 0.74, specificity: 0.97) and at 8 weeks was a 33% decrease (0.82, 0.97). For Enza ideal cut-off at 4 weeks was a 31% PSA decrease (0.82, 0.93). Covariate analysis of the Abi pts indicated that metastasis at diagnosis (P = 0.048) and prior taxanes predicted resistance to treatment (P = 0.019), as measured by < 50% decline in PSA. All covariates in the Enza pts failed to reach significance. Conclusions: Results suggest that early PSA changes for both Enza and Abi may be a reliable way for clinicians to predict long-term PSA response. This may allow for earlier modifications to be made in patient management for those not achieving an early PSA response.

270 Background: Body mass index (BMI) at diagnosis is associated with increased risk of fatal prostate cancer, but the link between BMI at mCRPC and cancer progression is less clear. Cachexia, often defined as involuntary weight loss > 5% over 6 months, is common in advanced cancers. The goal of this study was to examine the link between BMI at mCRPC and weight change as it relates to cancer progression, the outcomes of survival, and treatment use in a single-institution setting. Methods: 58 mCRPC patients treated at Tulane Hospital were identified, 41 of whom had an overweight BMI at mCRPC (BMI > 25) and 17 with normal BMI at mCRPC (BMI < 25). All patients had a confirmed prostate cancer death. Survival, treatment history, and percent weight change were compared according to BMI status. Rate of percent weight change was defined as the change in weight per day, from date of mCRPC diagnosis to the last treatment stop date or death date (“mCRPC days”). Linear regression, overall survival (OS), and nonparametric analyses were performed. Results: There was no significant difference between the normal and overweight BMI groups in overall survival, from date of diagnosis to death (median = 1835 days vs. 2710 days respectively). Additionally, the difference in survival from mCRPC to death was not statistically significant (median = 630 days vs. 799 days, p = 0.115). Use of Taxotere was not significantly different (47% vs. 68% respectively); however, overweight patients (n = 28) more likely received Abiraterone than normal BMI patients (n = 2) (p-value = 0.0001). The rate of percent weight change was significantly different for normal and overweight patients (mean = –0.050%/day vs. –0.019%/day, p = 0.003). Linear regression analysis showed that mCRPC days had a significant effect on percent weight change (p = 0.0109), and this effect was not significantly different between BMI groups (p = 0.6991). Conclusions: Survival after mCRPC was not significantly different between BMI groups. We observed a significant effect of mCRPC days on percent weight change, with a similar effect for both BMI groups. This outcome is expected, as more time would allow for greater weight changes to occur. Larger studies are needed to fully evaluate these observations.

e16076 Background: R223, an alpha-emitting radioisotope, has emerged as a viable treatment option for patients with CRPC with bone metastases. Despite the benefits on quality of life and improvemen...

239 Background: Careful study of treatments in men with prostate cancer (PCa)-specific mortality is scant in non-trial settings. We sought to examine the characteristics and use of selected therapies in men dying from PCa, beginning from the time of diagnosis. Unique herein is the unequivocal attribution of PCa death by a single experienced clinician. Methods: Patients dying from PCa at Tulane Cancer Center from 2008 to 2014 (n=96) were studied through retrospective chart reviews. All patients died of metastatic, castrate-resistant disease (mCRPC). Results: The median age at diagnosis for the deceased cohort was 66 years (95% CI: 64-68 years); 29% of patients initially presented with metastatic PCa. 59% of patients had definitive primary therapy (radical prostatectomy or radiation). Though most men died prior to availability of the newer FDA-approved agents, patients received a median of 7 (range: 1-14) therapies. Median survival was 60 months (95% CI: 45.8-74.2 mo) after diagnosis with a median PSA pre-death of 171 (range: 0-3530) and median age at death of 73 years (95% CI: 71-75 years). At death, 4% of men had a PSA < 4 and 20% of men had a normal LDH (< 241 U/L). Distant metastatic disease at diagnosis was a significant predictor of death (HR=4.33, p

214 Background: FDA approval of three life-prolonging agents for metastatic castrate resistant prostate cancer (mCRPC) has occurred since April 2011. Two agents, abiraterone (abi) and enzalutamide (enza), disrupt androgen signaling. The third, radium-223 dichloride (Ra-223), targets bone metastases via alpha radiation. We sought to explore associations between prior abi/enza progression, number of Ra-223 cycles, prognostic factors, and overall survival (OS). Methods: Forty-two mCRPC patients (pts) treated with Ra-223 were identified. The sample was stratified based on progression (or not) on abi or enza prior to starting Ra-223. Number of Ra-223 doses administered, prognostic variables before Ra-223 treatment, and Kaplan-Meier estimates of overall survival (OS) were compared. Results: A strong association (p = 0.016) was demonstrated between prior abi/enza failure and number of Ra-223 doses administered. Patients without prior abi/enza failure were more likely to receive ≥ 4 doses of Ra-223 (94.12% vs 60.0%; odds ratio [OR] = 10.667; 95% CI, 1.214 – 93.699; p = 0.033). In comparison, those not receiving at least 4 doses of Ra-223 had a negative predictor in OS (p = .001) with a median survival of 89 days (n = 10; 95% CI, 44.064 – 133.936) compared to 303 days (n=15; 95% CI, 170.452 – 435.548). Patients initiating Ra-223 treatment after abi/enza progression had a higher median PSA (207.5 vs 49.2 ng/mL, p = 0.001), LDH (315 vs 253.5 U/L, p = 0.007) and alkaline phosphatase (ALP) (191 vs 106 U/L, p = 0.004). Conclusions: Our retrospective single institution analysis indicates that mCPRC patients who previously failed abi/enza are significantly less likely to complete 4 or more Ra-223 doses. These patients had significantly worse prostate cancer by a variety of standard prognostic variables. More information is needed from larger data sets to better understand this patient population and to best determine the optimal timing of Ra-223 administration.

210 Background: Ra-223 is an α-emitter that binds to the newly formed bone matrix and targets osteoblastic metastatic lesions. Treatment with Ra-223 delays symptomatic skeletal-related events (SREs) and improves overall survival (OS) in men with mCRPC. Concerns about the efficacy and safety of Ra-223 in the pre-chemotherapy space, given alone or in combination with Abiraterone Acetate (AA) or enzalutamide (ENZ), have been raised. Methods: To determine the feasibility, efficacy and safety profile of Ra-223 given alone or in combination with AA or ENZ to men with docetaxel-naïve mCRPC a retrospective study was conducted. PSA decline, rPFS and safety data for patients (pts) treated at Cleveland Clinic (CC) and Tulane University (TU) were analyzed. Results: Fifty-one (27 CC and 24 TU) chemo-naïve mCRPC pts with bone metastases were identified. The median age was 63 (46-87). Testosterone suppression was maintained during treatment. Pre-treatment alkaline phosphatase (ALP) was elevated in 16 pts (33%). In addition to bone, 24 pts (47%) had soft-tissue metastases. While 23 pts received Ra-223 alone, 22 pts (43%) received concomitant AA or ENZ therapy. To date, the median number of Ra-223 cycles received is 5 (1-6) with 39% of pts (20/51) receiving all 6 cycles. PSA declines >30% were observed in 31% of pts. All but one pt had at least some decline in ALP. ALP decline >30% was observed in 68% of pts. Reasons for treatment discontinuation included; completion of 6 cycles 39% (20/51); PD 35% (18/51); AEs 8% (4/51) and pt choice 4% (2/51). Grade (G) 3/4 AEs were observed in 4 pts; G3 anemia (n=3) and G4 thrombocytopenia (n=1). The vast majority of pts had PSA progression (81%) and 42% of pts have died. Estimated median time to PSA progression and OS are 3.9 (95% C.I. 1.84-4.82) and 11.0 months (95% C.I. 7.5-16.4), respectively. Pts with normal baseline hemoglobin levels and those who received concomitant AA tended to have better PSA progression-free and OS (p