Patient Withdrew Research Articles

SAT0109 DISTINCT EFFECTS OF METHOTREXATE IN COMBINATION WITH ADALIMUMAB OR ETANERCEPT ACCORDING TO CCP ANTIBODY STATUS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Considerable evidence suggesting enhanced efficacy of anti-TNF therapy for rheumatoid arthritis (RA) when co-administered with methotrexate (MTX) led us to explore the applicability of the published data to our patient cohort.Objectives:This retrospective study aimed to investigate the efficacy of MTX in combination with adalimumab (ADA) and etanercept (ETN) for RA, examining changes in disease activity score (DAS28-CRP) on first starting treatment, and rates of withdrawal due to inefficacy over up to 10 years of treatment in routine clinical practice.Methods:309 patients with RA who had started ADA or ETN as a first-line biologic at UCLH from 2003 onwards were identified. Demographic and treatment details, DAS28-CRP (DAS) at the biologic-naïve baseline and at a first appointment for review on anti-TNF were extracted from clinical records. ANOVA was used to investigate the level of association between change in DAS and anti-TNF type, concomitant therapy, anti-CCP (CCP), rheumatoid factor (RF), age, disease duration and number of DMARD trials by anti-TNF initiation, year of initiation and gender. Kaplan-Meier with log rank tests were used to explore associations between anti-TNF type, MTX, CCP and RF and rates of withdrawal due to inefficacy, and Cox Proportional Hazards to check whether these remained significant after controlling for any other significant factors.Results:179 patients were on ADA and 130 ETN; 44% were on concomitant MTX (Table 1).Table 1.Numbers of patients co-prescribed MTX with ADA or ETN according to CCP statusCCP positive nTotal nETN without MTX3754with MTX5776ADA without MTX5482with MTX6597Median follow up since anti-TNF initiation was 7 years. Median age at initiation was 51 years, and disease duration 4 years. 82% were female. 241 were seropositive, including 24 positive for CCP only and 28 RF only.Mean biologic-naïve (baseline) DAS was 5.75, and 3.52 on first review (mean 20 weeks of treatment, n= 274) with mean change -2.23. MTX, even accounting for dose, failed to explain a significant amount of the variance in DAS response at first review either as a main effect or in interaction with anti-TNF type, CCP or RF. The only significant factor was 4+ DMARD trials prior to initiation (lower mean DAS response, p=0.010).Next, we analysed withdrawal of anti-TNF for inefficacy over up to 10 years. Kaplan-Meier analyses revealed that CCP positive patients had higher inefficacy withdrawal rates (p =0.004). Of note, CCP positive patients treated with MTX had lower withdrawal rates for inefficacy (Figure 1, p=0.006). Intriguingly, there was a trend towards higher rates in patients treated with MTX if CCP negative (p=0.14). Co-administration of MTX appeared to reduce rates of inefficacy withdrawal for patients on ETN (p=0.006) but not ADA (p =0.784). For CCP positive patients on ETN, MTX was strongly associated with lower rates of inefficacy withdrawal (Figure 1, p=.002).CCP status and the CCP*MTX interaction remained significant in the multivariate Cox model (Table 2). The MTX*ETN interaction was also included by the backward stepwise variable selection procedure although with p 0.069.Table 2.Variables in the Cox ModelHazard Ratio for discontinuation related to inefficacy95% CI for HRMTX2.180.93, 5.13CCP3.711.74, 7.92CCP*MTX0.350.14, 0.91ETN*MTX0.610.36, 1.04Disease duration > 5 years0.610.41, 0.90Gender (male)0.620.36, 1.054+ DMARD trials1.651.02, 2.67Biologic-naive Global VAS/cm1.261.11, 1.42Overall model p < .0005RF with a univariate Cox significance of 0.172 was less closely associated with rate of withdrawal for inefficacy compared to anti-CCP positivity (p 0.005).Conclusion:There was no apparent benefit of MTX with anti-TNF with respect to initial DAS response, but MTX was associated with a reduction in withdrawals for inefficacy though only in CCP positive patients treated with ETN.Disclosure of Interests:None declared

PANasta Trial: Cattell Warren versus Blumgart techniques of pancreatico-jejunostomy following pancreato-duodenectomy—A double-blinded multi-centered trial, trial results.

4619 Background: Pancreatic anastomosis failure following pancreatic head excision, for suspected pancreatic cancer, leads to longer recovery and failure to start or complete adjuvant chemotherapy. The aim of this study is to evaluate whether a Blumgart anastomosis (BA) reduces the post operative pancreatic fistula (POPF) rate compared to a more traditional Cattell-Warren anastomosis (CWA). Methods: Patients with suspected pancreatic cancer, undergoing elective pancreato-duodenectomy were randomized intra-operatively to either a BA or a CWA. Anastomoses were constructed according to prior agreed techniques and an operative manual describing key surgical steps. Quality control of these key steps and adherence to the arm of randomization was ensured by operative photographs. Surgical drain amylase was measured post-operatively to establish the primary end point of POPF. These were graded A (biochemical) or B and C (clinically relevant, CR-POPF). Secondary endpoints included: Entry in adjuvant therapy, hospital stay, mortality and survival. Overall survival was estimated using the method of Kaplan Meier and defined as the time from randomisation until death by any cause with alive patients censored at the end of study date. Results: Between May 5 2015 and August 7 2017, 238 patients were randomized, 2 patients withdrew, leaving 236 patients for analysis (112 BA, 124 CWA). Median age was 70 years, 63% were men. Median time from diagnosis to randomization (surgery) was 33 days for both arms. In the BA arm there were 28 POPF’s (15-A, 10-B and 3-C) and 32 in the CWA arm (18-A, 12-B and 2-C), p = 0.887. In total 27 patients (11.4%) developed a CR-POPF, BA 13 (5.5%), CWA 14 (5.9%), p = 0.857. 75% of eligible patients entered chemotherapy, with a median (IQR) time to the start treatment of 2.55 (2.27, 3.15) months for the BA group and 2.87 (2.56, 3.75) for the CWA group. Median hospital stay (IQR) in days was 13 (10-24) for BA and 14.5 (10-22) for CWA, p = 0.232. The overall surgical related mortally at 90 days was 1.7%. 44 study deaths were observed, 35 were due to disease progression (BA 19, CWA 16). A hazard ratio (95% CI) of 0.72 (0.4, 1.311) shows better, but not statistically significant survival for the CWA group. Conclusions: This is the largest surgical trial ever conducted comparing these techniques and there was no significant difference in the POPF rate between the BA and CWA anastomoses. In a UK population the clinically relevant POPF rate is 11% and 75% of eligible patients enter chemotherapy. Clinical trial information: ISRCTN52263879 .

Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV no squamous non-small cell lung cancer (NSCLC) (STELLA study): Results for the primary endpoint in a confirmatory, double-blind, randomized, controlled study.

e21542 Background: MB02 is a proposed biosimilar of the reference bevacizumab. A multinational, double-blind, randomized, parallel group clinical study (STELLA) is undergoing to confirm clinical similarity between MB02 and bevacizumab in patients with stage IIIB/IV no squamous NSCLC. Methods: Subjects were randomized 1:1 to MB02 or bevacizumab (15 mg/kg) plus chemotherapy (paclitaxel [P] 200 mg/m2 and carboplatin [C] AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (Week 52). As primary study endpoint, the efficacy by means of the objective response rate (ORR) evaluated by an independent radiological committee (IRC) was compared between arms at Week 18. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS), safety and immunogenicity (assessed at 18 and 52 weeks). Results: 627 patients were randomized: MB02 (n = 315) and bevacizumab (n = 312). Demographic and baseline characteristics were well balanced between arms. The ORR results were comparable for subjects receiving MB02 or bevacizumab plus P/C. A Risk Ratio (RR) of 1.013 (90% CI: -0.037% to 0.059) and a Risk Difference (RD) of 0.011 (90% CI: -0.037% to 0.059), were within the similarity margin predefined by FDA (0.73, 1.36) and EMA (-12%, +12%) respectively. This ORR assessed by IRC was consistent with the investigator assessment criteria. There was no significant difference between arms for secondary efficacy endpoints (PFS/OS) at week 18. Up to primary endpoint cut-off point, the safety assessment showed no significant differences between MB02 and bevacizumab arms (including the immunogenicity assessment) in terms of nature, frequency and severity of the adverse events (AE), being anaemia and hypertension the most common IMP-related AEs, with a RD between treatment groups < 5%. New signals or observable trends were no reported for MB02-treated subjects. Additional information on the secondary endpoints will be available at week 52 (end of monotherapy period). Conclusions: The statistical analysis executed for ORRs confirm the equivalence of MB02 and bevacizumab, supporting the clinical activity of MB02 treatment. MB02 was well tolerated with manageable AEs in patients with Stage IIIB/IV NSCLC. Clinical trial information: NCT03296163.

Open label, phase II study of axitinib, a selective inhibitor of vascular endothelial growth factor receptors, in patients with stage III malignant melanoma.

e22062 Background: This open-label, phase II study investigated the clinical activity and safety profile of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) in patients with stage III melanoma. Methods: Eligible patients had histology proven stage III melanoma, at least 1 target lesion as defined by RECIST, and no prior systemic therapy. Primary end point was objective response rate (ORR) according to RECIST v1.1; response was also considered if there was a ≥ 25% reduction in the involved nodal basin specific uptake value (SUV) on PET/CT. Secondary endpoints included duration of response (DOR), progression free survival (PFS), and overall survival (OS). Axitinib 5mg was given orally twice each day; treatment continued until tumor progression, unmanageable toxicity, or if the patient withdrew consent. After two months of therapy, patients then underwent definitive surgical resection of their involved nodal basins; one month after surgery patients would restart axitinib. In the 1st stage, 18 patients were to be enrolled; if there was ≥ 1 response, then the study would proceed to the 2nd stage with enrollment of additional 14 patients. At the end of the study, if there were at least 4 confirmed responses, then axitinib would be recommended for further studies in this patient population. Results: Fifteen patients were screened, and eleven patients were initiated on protocol therapy. Median age was 63 years (range 37-88). Three patients (27%) had BRAF mutations. Objective response rate was 45.5% [95% confidence interval (CI), 16.7-76.6], comprised of one complete and four partial responses, with two patients ongoing. Median duration of response was 8 months (95% CI, 3.5-13.3). Stable disease was observed in one patient, with an overall disease control rate of 54.5% (95% CI, 23.3-83.2]. Median progression free survival was 4 months [95% CI, 2.8-8.5]. Median overall survival was 59 months [95% CI, 29.6-67.5]. The most frequently reported ( > 15%) nonhematologic, treatment-related adverse effects were hypertension, fatigue, and diarrhea. Conclusions: Axitinib showed single-agent activity among patients with stage III melanoma and had favorable effect as a neoadjuvant therapy. Axitinib was well tolerated and safety profiles were consistent with previous reports from previous studies in patients with melanoma. Axitinib alone or combined with other therapies merits further research. Clinical trial information: NCT01321437.

Recruitment and retention in a self-directed “walking” intervention: Feasibility study in women with metastatic breast cancer during active treatment.

e13084 Background: Health related quality of life (HRQOL) and physical function are greatly impacted by the diagnosis and treatment of metastatic breast cancer (MBC). This study investigates the ability of women with MBC to engage in moderate walking during active treatment, with exercise monitored through a FitbitTM activity tracker. Methods: This is a single-site feasibility study of a home-based, self-directed physical activity intervention for women with MBC who could have had up to three lines of treatment. Questionnaires were completed at baseline, 12 weeks, and 24 weeks. Results: Sixty patients were consented, with mean age 55 (SD 11.1), 21% non-white, and 56% ECOG = 0. 36% were in their 3rd or 4th line of chemotherapy treatment. 65% had metastases to the bone, 46% to the lung, and 33% to the liver; mean number of metastasis sites was 2 (range 1 to 4). N = 52 completed all baseline measurements; N = 40 remained in the study at 3 months, and N = 29 at 6 months. Of the N = 31 (52%) lost to attrition, N = 6 were due to death, N = 5 due to deterioration, and N = 20 due to patient withdrawal from the study. Mean walking steps per day of at least 4000 was achieved in months 1, 2 and 3 by 41%, 50%, and 41% of participants. In months 4, 5 and 6, these percentages were 45%, 51% and 39%. On a scale from 1 = very confident to 10 = not at all confident about “continuing to walk or be physically active after completing the study”, confidence scores were 2.8 (SD 2.8) at 3 months and 2.9 (2.9) at 6 months. Conclusions: Forty-nine percent of women with MBC who signed up for a home-based walking program during active treatment were able to complete the 24-week intervention, with high proportions of these women walking more than 4000 steps per day. Moderate walking is feasible for women with MBC on active treatment.

Pembrolizumab as First-line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer (KEYNOTE-052): Outcomes in Older Patients by Age and Performance Status

BackgroundPatients with treatment-naive advanced urothelial cancer (UC) ineligible for cisplatin-based chemotherapy are typically older and have comorbidities, representing a difficult-to-treat population. ObjectiveTo evaluate the safety and antitumor activity of first-line pembrolizumab in subgroups of cisplatin-ineligible older patients (aged ≥65 and ≥75 yr) with advanced UC in KEYNOTE-052 (NCT02335424), including those with poor performance status (Eastern Cooperative Oncology Group performance status score 2 [ECOG PS2]). Design, setting, and participantsPatients were cisplatin ineligible, had treatment-naive, histologically/cytologically confirmed, locally advanced/metastatic UC with measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had ECOG PS0–2. Patient subgroups analyzed were aged ≥65yr (n = 302), ≥75 yr (n = 179), ≥65yr with ECOG PS2 (≥65yr+ECOG PS2; n = 119), and ≥75 yr+ECOG PS2 (n = 78). InterventionAll patients received pembrolizumab 200mg intravenously every 3 wk until confirmed progression, intolerable toxicity, patient withdrawal, or 24 mo of therapy. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR) as per RECIST v1.1. The key secondary endpoints were overall survival (OS), duration of response (DOR), and safety. Results and limitationsORRs for the ≥65yr, ≥75 yr, ≥65yr+ECOG PS2, and ≥75 yr+ECOG PS2 subgroups were 29%, 27%, 29%, and 31%, respectively; rates of complete and partial responses were similar across subgroups (9%, 5%, 6%, and 6%, and 20%, 22%, 23%, and 24%, respectively). Median DOR and OS were also consistent across the ≥65yr and ≥65yr+ECOG PS2 subgroups and the ≥75 yr and ≥75 yr+ECOG PS2 subgroups. Study limitations included open-label design, lack of a comparator group, and nature of post hoc exploratory analysis. ConclusionsThe clinical benefit of pembrolizumab in advanced UC appeared to be consistent regardless of age and/or poor performance status. Patient summaryThis study looked at whether older age and poorer performance status affect how well patients with previously untreated advanced urothelial cancer ineligible for standard-of-care treatment respond to pembrolizumab. Outcomes with pembrolizumab were not affected by older age or poorer performance status, making it an effective option.

PD17-11 PHASE II CLINICAL TRIAL: SHORT-TERM ONCOLOGIC OUTCOMES OF NANOPARTICLE-DIRECTED FOCAL PHOTOTHERMAL LASER ABLATION

You have accessJournal of UrologyProstate Cancer: Localized: Ablative Therapy I (PD17)1 Apr 2020PD17-11 PHASE II CLINICAL TRIAL: SHORT-TERM ONCOLOGIC OUTCOMES OF NANOPARTICLE-DIRECTED FOCAL PHOTOTHERMAL LASER ABLATION Mahir Maruf*, Arvin George, Steven Canfield, Vahara Tamisetti, Ethan Wajswol, Alex Zhu, Matthew S. Davenport, Sara C. Lewis, and Ardeshir R. Rastinehad Mahir Maruf*Mahir Maruf* More articles by this author , Arvin GeorgeArvin George More articles by this author , Steven CanfieldSteven Canfield More articles by this author , Vahara TamisettiVahara Tamisetti More articles by this author , Ethan WajswolEthan Wajswol More articles by this author , Alex ZhuAlex Zhu More articles by this author , Matthew S. DavenportMatthew S. Davenport More articles by this author , Sara C. LewisSara C. Lewis More articles by this author , and Ardeshir R. RastinehadArdeshir R. Rastinehad More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000860.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Whole gland treatment of low and intermediate risk prostate cancer (PCa) results in substantial morbidity with variable survival benefit. Focal therapy of PCa may be an alternative that provides cancer control while preserving quality of life. Nanoparticle directed focal photothermal laser ablation (FLA) is a novel ablative modality causing thermal ablation via laser excitation of gold nanoparticles. We aim to report short term oncologic efficacy of nanoparticle FLA. METHODS: In a single-arm multi-center Phase 1/2 clinical trial (NCT02680535), men with organ-confined Gleason Grade group (GGG) ≤ 3 PCa with an MRI visible lesion were prospectively enrolled. Prior to therapy, patients received an intravenous infusion of AuroShellsTM followed by laser excitation under MRI/US fusion guidance. A repeat MRI and fusion biopsy was performed 3 and 12 months post-ablation. The primary outcome of this study was presence of any PCa in the ablation zone at biopsy. Secondary outcome was success defined by the Delphi consensus criteria of any Gleason pattern 4 or GG1 >3mm cancer core length. RESULTS: In total, 45 patients were enrolled. After one patient withdrew, 44 patients (median age 69 years, PSA 8.7ng/ml, gland volume 48.5ml3, and PSA density 0.135 ng/ml2) with 45 lesions underwent nanoparticle directed FLA. At 3 months, 45 biopsies were performed, of which 30 (66.7%) were negative for any PCa. At 3 months, 25/41 patients (61%) had a PSA response >50%. A higher proportion of those with a negative biopsy at 3 months had a PSA response >50% when compared to those with a positive biopsy (64.3% vs 53.8%, p=0.524). Neither age, GGG, pre-treatment PSA, gland volume, or PSA density were associated with biopsy results at 3 months. At 12 months, 25 biopsies were performed of which 18 (72%) were negative for PCa. At 3 months, 35 of 45 (77.8%) lesions met Delphi consensus criteria for success following focal ablation. CONCLUSIONS: Nanoparticle-directed FLA is a feasible and promising ablative modality with acceptable short-term oncologic outcomes. Source of Funding: Philips Healthcare and Nanospectra Biosciences © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e373-e374 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mahir Maruf* More articles by this author Arvin George More articles by this author Steven Canfield More articles by this author Vahara Tamisetti More articles by this author Ethan Wajswol More articles by this author Alex Zhu More articles by this author Matthew S. Davenport More articles by this author Sara C. Lewis More articles by this author Ardeshir R. Rastinehad More articles by this author Expand All Advertisement PDF downloadLoading ...

Safety and Efficacy of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Myocardial Infarction in the Presence of Intracoronary Thrombus: An Analysis From the Grand Drug-eluting Stent Registry

PurposeTo evaluate the safety and efficacy of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with acute myocardial infarction (AMI) in the presence of intracoronary thrombus undergoing percutaneous coronary interventions. MethodsThis study, performed from January 1, 2004, to November 31, 2014, at 55 centers in Korea, was based on the Grand Drug-Eluting Stent registry, which is a Korean, nationwide, multicenter, pooled registry of drug-eluting stents. The registry enrolled all-comers without any exclusion criteria except patient withdrawal of consent. A total of 1329 patients with AMI who had an overt intracoronary thrombus at the initial coronary angiography were analyzed. The efficacy end point was a 1-year major adverse cardiovascular event, defined as a composite of all death, myocardial infarction, target lesion revascularization, and stent thrombosis. The primary safety end point was any 30-day bleeding event. FindingsGPIs were associated with a significantly higher rate of any bleeding events at 30 days (0.9% vs 2.9% in the non-GPI and GPI groups, respectively; P = 0.015), whereas GPI use was the only significant independent predictor of 30-day bleeding events by multivariable Cox proportional hazards regression analysis (hazard ratio = 4.76; 95% CI, 1.66–13.64; P = 0.004). Regarding the efficacy end points, no significant differences were noted according to GPI use (7.0% vs 9.0%, P = 0.287), and GPI use has no significant effect on 1-year major adverse cardiovascular events (hazard ratio = 1.33; 95% CI, 0.82–2.15; P = 0.253). ImplicationsEarly upstream use of GPIs should not be considered even in the presence of an intracoronary thrombotic occlusion. ClinicalTrials.gov identifier: NCT03507205.

Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced Non–Small Cell Lung Cancer After Second-Line Treatment Failure

There is currently no standard treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) without driver gene variation after failure of 2 or more lines of chemotherapy. To assess the efficacy and safety of apatinib combined with oral vinorelbine. This phase 2 prospective nonrandomized clinical trial evaluating the efficacy and safety of apatinib plus vinorelbine recruited patients from Hunan Cancer Center, Hunan, China, from January 1, 2017, to November 30, 2018. Eligible patients were those with wild-type advanced NSCLC whose disease did not respond to at least 2 lines of chemotherapy. Patients were evaluated until December 31, 2019. Data were analyzed from July 2019 to December 2019. Apatinib at an initial dose of 500 mg once daily and oral vinorelbine 60 mg/m2 once weekly were administered until disease progression, patient withdrawal, or occurrence of unacceptable toxic effects. The primary end point was overall response rate. Secondary end points were overall survival, progression-free survival, and safety. The potential efficacy of apatinib plus vinorelbine was identified using drug susceptibility assay based on 3-dimensional coculture of tumor cells derived from 3 patients with lung adenocarcinoma. Among 30 patients enrolled, the median (range) age was 63 (34-78) years and 18 (60%) were men. Most patients (27 patients [90%]) had stage IV disease, and the median (range) number of prior unsuccessful treatments was 2 (2-5) lines of chemotherapy. Twenty-five patients (83%) completed the treatment, while 5 patients (17%) discontinued treatment owing to intolerable adverse events. The overall response rate was 36.7% (11 patients) and the disease control rate was 76.7% (23 patients). The median progression-free survival was 4.5 (95% CI, 2.4-6.6) months, and the median overall survival was 10.0 (95% CI, 4.8-17.1) months. Hand-foot syndrome was the most common adverse event observed, including grade 3 hand-foot syndrome observed in 5 patients (17%) and grade 4 hand-foot observed in 1 patient (3%). Grade 3 weakness was observed in 1 patient (3%). These findings suggest that apatinib combined with oral vinorelbine is a potentially effective regimen with an acceptable safety profile. This regimen may have potential as a treatment option for patients with wild-type advanced NSCLC whose disease failed at least 2 prior lines of chemotherapy. ClinicalTrials.gov Identifier: NCT03652857.

A phase IIa randomized placebo-controlled trial of pomegranate fruit extract/POMx in subjects with clinically localized prostate cancer undergoing active surveillance.

285 Background: Due to its high prevalence and often indolent natural history, prostate cancer(PC) active surveillance(AS) is an ideal setting for chemoprevention. Studies assessing pomegranate and its extracts have shown promising anti-proliferative and pro-apoptotic effects in cell lines and animal models and a single-arm clinical trial of pomegranate fruit extract(PFE) reported an increase in PSA doubling time(PSADT) during AS. The primary objective of this trial was to assess the effect of PFE supplementation on plasma levels of Insulin-like Growth Factor-1(IGF-1). Secondary objectives addressed PSA doubling time(PSADT), tumor volume on end-of-study(EOS) biopsy and plasma and prostate tissue biomarkers. Methods: Men with organ-confined favorable-risk PC on AS were randomly assigned to receive PFE 1,000 mg(n=15) or placebo(n=15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the one-year intervention. Tissue biomarkers were assessed by immunohistochemistry(IHC) with automated quantitation. Results: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the one-year intervention. No differences in plasma IGF-1 levels(p=0.5), PSADT, or tissue biomarkers of apoptosis or proliferation were observed. A significant increase in urolithin A(a urinary metabolite of pomegranate) was observed in the PFE arm. IHC analyses of both tumor (Table) and normal-appearing tissue adjacent to tumor showed reductions from baseline in IGF-1, 8-OHdG(DNA damage marker), and androgen receptor expression associated with PFE treatment. A trend towards a reduction in the maximum percent of biopsy core tumor involvement was observed(p=0.06) in PFE. Conclusions: PFE administration for 12-months was not associated with a decrease in plasma IGF-1 levels nor an increase in PSADT. However, exploratory analyses suggest that PFE may contain bioactive compounds capable of altering biomarkers in PC and normal-appearing adjacent tissue providing a rationale for further investigation of PFE in the active surveillance population.

A phase II study of sEphB4-HSA in metastatic castration-resistant prostate cancer (mCRPC).

TPS274 Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the transmembrane ligand EphrinB2 leads to T-cell suppression and immune evasion. A soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) binds to EphrinB2 and blocks interaction with the cell surface EphB4 receptor to promote immune infiltration and induce tumor cell death. Here we report an ongoing phase II study exploring the preliminary efficacy and safety of sEphB4-HSA in patients with progressive disease after frontline therapy for mCRPC. Methods: Eligibility criteria include mCRPC with disease progression after second generation AR targeted therapy (i.e., abiraterone or enzalutamide), ECOG PS ≤ 2, and adequate renal, hepatic and hematological functions. Pts having received 4 or more prior treatment therapies for mCRPC are excluded. The primary objective is efficacy as reflected by PSA response using PCWG3 criteria. Secondary objectives include safety and tolerability by CTCAE v 5.0, time to PSA progression, overall response by RECIST 1.1 and PCWG3 (bone) criteria, and rPFS. Translational endpoints include expression of EphB4 and EphrinB2 in metastatic tumor samples by immunohistochemistry and correlation with alterations in MYC, PTEN/PI3K, AR, and p53 pathways. sEphB4-HSA is administered as IV infusion over 60 min every 14 days with spacing to every 21 days after 6 cycles. Therapy will continue till disease progression, unacceptable toxicity, treatment delay ≥4 weeks, or patient withdrawal. Preliminary efficacy will be assessed using PSA response rate (PR and CR) with a Simon two stage minimax trial design assuming the undesirable overall response rate (null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting success to be approximately 30% or more. Toxicity will be evaluated by the DSMC after the first stage including 15 patients. If 2 or more respond, then an additional 10 patients will be added. Clinical trial information: NCT04033432.

Abstract PD10-03: Quality of life in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with palbociclib in real-world practice settings

Abstract Background: Palbociclib in combination with endocrine therapy (ie, an aromatase inhibitor [AI] or fulvestrant) is a current standard of care for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/mBC). Findings from the PALOMA clinical trials have shown that patients receiving palbociclib with AI or fulvestrant maintained stable quality of life (QoL). However, no data are currently available from real-world settings regarding patients’ QoL experiences while receiving palbociclib. Methods: This noninterventional, prospective, multicenter study evaluated female and male patients diagnosed with HR+/HER2- ABC/mBC and treated with palbociclib as indicated by the attending physician in the routine course of care. QoL was assessed using the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 was collected at enrollment prior to receiving palbociclib (baseline), monthly for the first 3 months of treatment with palbociclib, and then every 3 months until the end of treatment or patient withdrawal or death. The EORTC QLQ-C30 could be completed using an interactive Web response system or a paper questionnaire. Here we report demographic characteristics and interim analysis of QoL assessments as measured by EORTC QLQ-C30 at baseline and at 3 and 6 months postbaseline. Descriptive analyses are presented for subscales of the EORTC QLQ-C30. Results: 522 patients who completed ≥6 months of palbociclib treatment as of May 20, 2019, were included in this interim analysis; 394 were prescribed palbociclib as first-line treatment. The remaining 128 patients initiated palbociclib in second and later lines. Median age at enrollment was 64 years, 98% of patients were female, and 83% were white. More than half of all patients (n=285) received palbociclib in combination with letrozole or anastrozole; of the remaining patients, 218 received palbociclib plus fulvestrant and 19 received palbociclib plus exemestane. Mean (SD) EORTC QLQ-C30 scores remained similar over the first 6 months of treatment: 66.2 (22.6) at baseline, 68.3 (19.7) at 3 months, and 70.2 (21.3) at 6 months. In addition, the mean scores for each functional scale and symptom scale on the EORTC QLQ-C30 also remained stable over the first 6 months (Table). With the exception of pain scores (which declined by 7 points), the change from baseline at 6 months generally was less than 5 points across the different subscales of EORTC QLQ-C30. Conclusions: The 522 patients examined in this interim analysis experienced stable to modestly improved QoL from baseline to 6 months after starting palbociclib. Changes from baseline in EORTC QLQ-C30 scores generally were below the 10-point threshold regarded as clinically meaningful. These early findings indicate that patients enrolled in the study have maintained their baseline QoL while being treated with palbociclib. Funding: Pfizer (NCT03280303) EORTC QLQ-C30Baseline3 Months6 MonthsGlobal Health/Quality of Life*n (missing)474 (48)292 (230)409 (113)Mean (SD) score66.2 (22.6)68.3 (19.7)70.2 (21.3)Functional scales score, mean (SD)*Physical functioning75.6 (23.3)75.8 (21.9)77.2 (21.4)Role functioning72.5 (31.9)76.7 (26.1)77.1 (26.8)Emotional functioning74.8 (22.8)77.7 (22.3)79.7 (20.5)Cognitive functioning78.8 (24.6)82.7 (20.6)80.1 (22.0)Social functioning76.4 (28.3)79.5 (25.5)81.5 (24.7)Symptom scales score, mean (SD)†Fatigue34.3 (25.7)35.0 (23.6)33.7 (22.2)Nausea and vomiting11.3 (20.2)10.4 (16.4)10.6 (19.3)Pain33.5 (30.0)27.3 (27.2)26.5 (26.9)Dyspnea22.2 (28.3)18.7 (22.5)18.8 (24.1)Insomnia29.3 (30.1)27.5 (31.7)27.4 (27.9)Appetite loss21.1 (27.9)19.4 (26.4)17.9 (26.5)Constipation18.4 (26.6)15.2 (23.8)16.0 (23.8)Diarrhea12.3 (22.1)12.0 (20.8)12.6 (22.0)Financial difficulties25.0 (32.4)23.9 (30.4)22.1 (29.5)*Higher scores indicate a better level of functioning. †Higher scores indicate more severe symptoms. Citation Format: Gabrielle Rocque, Joanne L Blum, Aldemar Montero, Ibrahim Nakhoul, Sobha Kurian, Richard C Frank, Bijoy Telivala, Mayank Ajmera, David Coblentz, Joseph C Cappelleri, Yao Wang, Debu Tripathy. Quality of life in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with palbociclib in real-world practice settings [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-03.

Abstract P6-10-06: Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy

Abstract Importance: It is essential to refine the populations most likely to benefit from targeted chemotherapy combinations. Background: MINDACT showed that molecularly low risk patients, as assessed by the Amsterdam 70-gene profile MammaPrint® (Agendia) (MP), did not benefit from chemotherapy. In the I-SPY2 trial, MP low risk Hormone Receptor (HR) positive/HER2 negative patients are not eligible; however, HR negative or HER2 positive patients were considered high risk and included for treatment with chemotherapy plus novel agents. The neoadjuvant setting provides an opportunity to evaluate whether molecularly low risk HER2 positive patients are good candidates for neoadjuvant chemo/anti-HER2 therapy, where pathologic complete response (pCR) and 3-year outcomes are measured. Objective: To evaluate and further characterize the fraction of and outcomes for patients molecular low-risk disease in the I-SPY2 trial. Methods: The I-SPY2 platform trial is an ongoing multicenter phase 2 multi-arm study utilizing adaptive design and evaluating efficacy and tolerability of investigational agents in combination with standard-of-care chemotherapy for patients with high-risk anatomic stage II/III breast cancer. Patients with HR+HER2- MP low-risk tumors are not eligible. All enrolled patients undergo pretreatment biopsy for genomic evaluation of early recurrence risk with MP for risk stratification and with the 80-gene BluePrint® (Agendia) test for intrinsic subtype classification. Primary endpoint of the study is pCR in breast and lymph nodes (ypT0/is, ypN0). Secondary outcomes included event-free survival (EFS) and distant-recurrence free survival (DRFS). Following standard neoadjuvant treatment with or without a concomitant investigational agent, patients are followed for long-term outcomes. EFS and DRFS at 3 and 5 years in the pCR vs non-pCR groups within histologic and molecular subtypes are determined using the Kaplan Meier method. Results: Of the 1038 enrolled patients by November 2016, 24 patients (3.2%) had molecular low-risk disease as determined by MP. Of these, 21 (87.5%) had HR+HER2+, 1 (4.2%) had HR-HER2+, and 2 (8.4%) had HR-HER2-. BluePrint expression subtyping classified 17 as luminal-type, 6 HER2 enriched-type and 1 basal type. One patient withdrew consent for follow-up. Of the 23 remaining, none achieved pCR and only one (HR+/HER2+) had an EFS event (with median follow-up of 4.3 years). Overall, EFS and DRFS data were available for 950 of the 1038 patients (as of February 2019), with median follow-up of 3.8 years. Of the 173 HR+HER2+ in this cohort, 20 (11.6%) had molecular low-risk tumors. The EFS and DRFS for the 173 HER2+HR+ pCR group is 97% and 98% (non-pCR group 89% and 94%), respectively at 3 years. Removing the molecular low-risk HER2+ patients from the denominator reveals the worse outcome for patients with non pCR: EFS 86% and DRFS 92% at 3 years. The difference is more apparent at 5 years, changing from 74% to 66% for EFS and from 81% to 75% for DRFS. Intrinsic subtypes vary and do not predict early risk. Conclusions: I-SPY2 focuses on women with high clinical risk with only 3.2% of enrolled patients having low molecular risk tumors. However, 12% of HER+ breast cancer enrolled patients had molecular low risk tumors of which 95% were also HR+. In this group, early recurrence is very low despite absence of pCR and irrespective of intrinsic subtype. Refining the population using molecular high-risk classification of patients reveals a greater difference between the pCR and non-pCR groups within the HR+HER2+ subtype in the EFS and DRFS analysis. Clinical trial designs could address the opportunity to find more targeted and less toxic treatments for the HER2+ low molecular risk patient population. Citation Format: Paula R Pohlmann, Christina Yau, Angela DeMichele, Claudine Isaacs, Judy C Boughey, Nola Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, W. Fraser Symmans, I-SPY 2 TRIAL Consortium, Donald A Berry, Laura Esserman. Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-06.

Phase I results of the phase I/II study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer.

78 Background: Previous study demonstrated that activation of RAS/MAPK pathway is associated with reduced tumor infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple negative breast cancer (TNBC). Further study showed that inhibition of MAPK pathway with a MEK inhibitor is synergistic with anti-PD1/PD-L1 therapies. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy without prior anti-PD-1/PD-L1/PD-L2 therapies were enrolled. Treatment was started with a 2-week run in period with single agent binimetinib. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks at both dose levels. Phase I study was based on the standard 3+3 design. Results: A total of 12 patients were enrolled and treated in the phase 1. Five patients were enrolled at dose level 0, 1 patient withdrew prior to treatment and 1 patient was not evaluable for dose limiting toxicity (DLT). Among 3 evaluable patients, 2 patients experienced DLT with grade 3 flank pain and ALT abnormality. Additional 8 patients were enrolled at dose level -1. Out of 6 evaluable patients for DLT, there was 1 DLT observed with grade 3 AST and ALT abnormality. However, this particular patient had liver metastasis with grade 1 AST and ALT abnormality at baseline and her liver function test (LFT) normalized in 3 weeks after treatment discontinuation and oral prednisone. Other grade 1-2 common AEs included rash, LFT increase, abdominal pain, mucositis, nausea, cardiac troponin T increase without EKG change. The efficacy data will be presented at the meeting after the phase II interim analysis. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe based on the initial cohort. Phase II part is currently ongoing with binimetinib 30 mg twice daily and pembrolizumab 200 mg every 3 weeks with a total of 23 patients planned where the safety and efficacy of this combination will be further evaluated. Clinical trial information: NCT03106415.

A Prospective Trial to Compare Deep Inspiratory Breath Hold With Prone Breast Irradiation

PurposeTo compare heart and lung doses for adjuvant whole breast irradiation (WBI) between radiation plans generated supine with deep inspiratory breath hold (S-DIBH) and prone with free-breathing (P-FB) and examine the effect of breast volume (BV) on dosimetric parameters. Methods and MaterialsPatients with left breast ductal carcinoma in situ or invasive cancer receiving adjuvant WBI were enrolled on a single-institutional prospective protocol. Patients were simulated S-DIBH and P-FB; plans were generated using both scans. Wilcoxon signed-rank and rank-sum tests were used to compare intrapatient differences between plans for the entire cohort and within BV groups defined by tertiles. ResultsForty patients were enrolled. Thirty-four patients are included in the analysis owing to patient withdrawal or inability to hold breath. With WBI dose of 4005 to 4256 cGy, mean heart dose (MHD) was 80 cGy in S-DIBH and 77 cGy in P-FB (P = .08). Mean ipsilateral lung dose (MLD) was 453 cGy in S-DIBH and 45 cGy in P-FB (P < .0001). Mean and max left anterior descending artery doses were 251 cGy and 551 cGy in S-DIBH, respectively (P = .1), and 324 cGy and 993 cGy in P-FB, respectively (P = .3). Hot spot and separation were 109% and 22 cm in S-DIBH, respectively, and 107% and 16 cm in P-FB, respectively (P < .0001). For patients with smallest BV, S-DIBH improved MHD and left anterior descending artery doses; for those with largest BV, P-FB improved cardiac dosimetry. With increasing BV, there was an increasing advantage of P-FB for MHD (P = .05), and max (P = .03) and mean (P = .02) left anterior descending artery doses, and the reduction in MLD, hot spot, and separation with P-FB increased (P < .05). ConclusionsMHD did not differ between P-FB and S-DIBH, whereas MLD was significantly lower with P-FB. Analysis according to breast volume revealed improved cardiac dosimetry with S-DIBH for women with smallest BV and improved cardiac dosimetry with P-FB for women with larger BV, thereby providing a dosimetric rationale for using breast size to help determine the optimal positioning for WBI.

P436 Evaluation of targeted vitamin D supplementation regimen in postoperative patients with Crohn’s disease

Abstract Background Vitamin D with a serum 25(OH)D concentration above 100 nmol/l was associated with disease remission in patients with IBD and suggested that targeted administration may be an anti-inflammatory drug. This study was designed to assess the effectiveness, safety, and predictive measures of a vitamin D regimen in postoperative patients with Crohn’s disease to achieve the above goals. Methods In a prospective study, patients with Crohn’s disease and serum 25(OH)D concentrations &amp;lt;75 nmol / L were prescribed an oral vitamin D supplement at a dose of one year, and adjusted 4-weekly to aim for a serum 25(OH)D level of 100–125 nmol/l. Results Thirty-two postoperative patients with Crohn’s colitis had an average 25(OH)D concentration of 51.5 (range 25–74 nmol / L). 25 patients reached the target level and six patients reached 90–94 nmol / L. Because of the reoperation, one patient withdrew in 6 months. Patients with BMI &amp;lt;30 kg / m2 could reach the target dose (p = 0.006), and the total dose was negatively correlated with the initial serum 25(OH)D (Spearman r = 0.86, p = 0.002). One patient developed a high level (146 nmol/L) at 2 months and the other had new hypercalciuria. There are no serious adverse events attributable to treatment. Clinical disease activity continued to decline (p = 0.015), but faecal calprotectin (p = 0.264), inflammatory cycle markers (p = 0.513) and Rutgeerts score (p = 0.428) did not decrease. Conclusion Specific oral vitamin D regimens can successfully and safely reach or approach target levels, improve symptom-based activity scores, but do not alter objective indicators of intestinal or systemic inflammation. A modified version of this dose-escalation protocol is suitable for randomised placebo-controlled trials, and the further randomised controlled trial was needed.

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD. To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations. An escalating dose of oral ambroxol to 1.26 g per day. This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018. Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity. Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations. The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD. ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.

Clinical Efficacy and Safety of Atorvastatin for Chronic Subdural Hematoma: A Randomized Controlled Trial

The aim of the present investigation was to observe the efficacy and safety of atorvastatin on chronic subdural hematoma patients. A total of 58 chronic subdural hematoma patients were recruited in this study, randomly divided into the control group and the atorvastatin treatment group (2 patients withdrew; n=28 each group). Before and after 24 w of treatment, the clinical outcome in patients was evaluated. The activities of daily living and neurological deficit scoring standard scores were assessed at 4, 8, 12 and 24 w after treatment. Levels of clinical biochemical indicators, serum high-sensitivity C-reactive protein, interleukin 6, matrix metalloproteinase 9 and tumour necrosis factor α were presented. Furthermore, hematoma volume was detected, which was used to assess the speed and degree of hematoma absorption. The adverse reactions and recurrence rates were recorded. The total effective rate of the atorvastatin treatment group was significantly higher than that of the control group (p=0.024). Following treatment, the activities of daily living score (98.3±9.64) of the treatment group was significantly higher than that of the control group (83.8±6.85; p=0.013). Moreover, the neurological deficit scoring standard score (13.8±3.89) of the atorvastatin-treated group was distinctly lower than that of the control group (20.1±4.67; p=0.021). On w 24 of treatment, compared to the control group, the serum high-sensitivity C-reactive protein, interleukin 6, matrix metalloproteinase 9 and tumour necrosis factor α levels in the treatment group were significantly reduced. Hematoma volume of the treatment group was significantly absorbed compared to the control group (p=0.008). There was no statistical significance in the incidence of various adverse reactions between the two groups. The recurrence rate of the control group (3.60 %) was significantly higher than that of the atorvastatin treatment group (25.00 %; p<0.05). These findings demonstrated that atorvastatin could reduce inflammatory response, promote hematoma absorption, protect neurological status and reduce the recrudescence rate for patients with chronic subdural hematoma.

Nurses' Experiences and Factors Related to Their Attitudes Regarding Discussions with Patients and Family Members about Do-Not-Resuscitate Decisions and Life-Sustaining Treatment Withdrawal: A Hospital-Based Cross-Sectional Study.

This study aimed to evaluate nurses’ experiences and factors related to their attitudes regarding discussions of do-not-resuscitate (DNR) and withdrawal of life-sustaining treatment (LST) with patients and their families. A cross-sectional survey was conducted in a tertiary hospital in Taiwan. Nurses aged ≥ 20 years who were in charge of acute inpatient care were randomly recruited. A semi-structured questionnaire was used to evaluate participants’ experiences and attitudes regarding discussions of DNR and LST withdrawal for terminal patients. Logistic regression with adjustment for covariates was used to analyze factors related to participants’ attitudes toward discussions about DNR and LST withdrawal with patients and families in the future care of terminal patients. The participants were 132 nurses. They had significantly more discussions about DNR and LST withdrawal with patients’ families than with patients. Regression analysis showed that participants who had past experiences in actively initiating DNR discussions with patients or patients’ families were significantly more likely to discuss DNR with patients in the future care of terminal patients, but participants aged 40.0 to 60.0 years were significantly less likely to have DNR discussions than those aged 20.0 to 29.9 years. Experiences of actively initiated DNR or LST discussions with patients’ families were significantly more likely to discuss DNR with patients’ families, but those aged 40.0 to 60.0 years were also significantly less likely to have DNR discussions than those aged 20.0 to 29.9 years. Experience in actively initiating discussions about LST withdrawal with patients’ families, being male, and possessing an education level higher than university were significantly related to LST withdrawal discussions with terminal patients or their families in the future. In conclusion, there need to be more discussions about DNR and LST withdrawal with patients. To protect patients’ autonomy and their rights to make decisions about their DNR and LST, measures are needed to facilitate DNR and LST discussions with patients to ensure better end-of-life care.

Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury

Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery. To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes. This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures. A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care. Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale-Extended score. A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg; P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively; P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively; P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65; P = .02) for worse outcomes. In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.