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The evolution of behavioral and ecological specialization can have marked effects on the tempo and mode of phenotypic evolution. Head-first burrowing has been shown to exert powerful selective pressures on the head and body shapes of many vertebrate and invertebrate taxa. In wrasses, burrowing behaviors have evolved multiple times independently, and are commonly used in foraging and predator avoidance behaviors. While recent studies have examined the kinematics and body shape morphology associated with this behavior, no study to-date has examined the macroevolutionary implications of burrowing on patterns of phenotypic diversification in this clade. Here, we use three-dimensional geometric morphometrics and phylogenetic comparative methods to study the evolution of skull shape in fossorial wrasses and their relatives. We test for skull shape differences between burrowing and non burrowing wrasses and evaluate hypotheses of shape convergence among the burrowing wrasses. We also quantify rates of skull shape evolution between burrowing and non burrowing wrasses to test for whether burrowing constrains or accelerates rates of skull shape evolution in this clade. We find that while burrowing and non burrowing wrasses exhibit similar degrees of morphological disparity, for burrowing wrasses, it took nearly twice as long to amass this disparity. Furthermore, while the disparities between groups are evenly matched, we find that most burrowing species are confined to a particular region of shape space with most species exhibiting narrower heads than many non-burrowing species. These results suggest head-first burrowing constrains patterns of skull shape diversification in wrasses by potentially restricting the range of phenotypes that can perform this behavior.

Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.Results: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for ≥12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells.Conclusions: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade. Clin Cancer Res; 16(13); 3485–94. ©2010 AACR.

Supplementary Data from Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells

Abstract.—Modularity is a ubiquitous feature of organismal design that plays an important role in structuring patterns of morphological diversification. Modularity can facilitate evolutionary changes by allowing subsets of traits to coevolve as integrated units and follow quasi-independent evolutionary trajectories, a pattern that may be particularly consequential in the case of highly complex morphological structures. Here we examine modularity in a complex and highly kinetic structure, the teleost skull, and ask if a modular organization of the skull has influenced the diversification dynamics of the shapes of its osteological components across the labrid phylogeny. We compiled one of the largest 3D morphological data sets of fishes to date and used geometric morphometrics to quantify patterns of cranial shape evolution across 184 species of wrasses (Labridae). We then tested several hypotheses of modularity inspired by functional and developmental relationships between cranial bones and compared phenotypic rates among modules. We also compared the fit of models of trait evolution for the entire skull and the various articulated bones that it comprises. Our analyses indicated strong support for a 2-module hypothesis, one that encompasses the oral and pharyngeal jaws and another module comprised of the neurocranium, hyoid apparatus, and operculum. This functional hypothesis yielded one of the highest significant rate differentials across modules, yet we also found that the best-fitting models of trait evolution differed among skull bones. These results suggest that modularity can influence morphological diversification in complex biological structures via differences in both the tempo and mode of evolutionary change. [3D geometric morphometrics, cranial morphology, evolutionary modularity, Labridae, phenotypic rates, structural complexity.]

To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage.Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation.A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20 mg/kg Q2W and 30 mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30 mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability.The identified significant covariates were not considered clinically meaningful. Both weight-based (30 mg/kg Q3W) and two-tiered flat dosing (1800/2400 mg Q3W, 70 kg threshold) strategies are expected to provide similar exposures of zanidatamab.

PURPOSE To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. METHODS EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4–expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti–PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. RESULTS Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti–PD-(L)1 treatment, liver metastases, or upper-tract disease. CONCLUSION Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

PURPOSE Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti–programmed death 1 or anti–programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody–drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma. METHODS EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti–PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability. RESULTS Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti–PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients. CONCLUSION Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti–PD-1/L1 therapies.

SummaryLocally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody–drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration–time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports.

As experienced for most power electronic applications in the past, efficiency is also becoming one of the key characteristic for automotive applications, affecting the design of future high-voltage components for electric vehicles. In case of traction inverters, mainly semiconductor losses deteriorate system efficiency and thus, upgrading the switches in hard-switched PWM-controlled 2-level inverters is a direct measure to significantly reduce system losses. For this task, SiC MOSFETs are a promising class of power semiconductors with superior device characteristics. With SiC high power modules becoming available on a broader basis, proper design-in approaches are necessary in order to obtain robust and cost-effective system solutions. Addressing this topic, a new full-SiC power module suited for direct replacement of existing Si-based solutions is described in this paper. A simulation and measurement-based analysis of the efficiency benefits of such a retrofit solution for a 400 V based drivetrain with up to 300 kW of output power is presented. Simulation results predict a loss reduction on inverter level of around 50 % compared to the Si IGBT based solution with respect to steady-state part load operation. The simulation results are verified by drivetrain test bench measurements showing a very high accuracy of the simulation model. Drive cycle simulations indicate an advantage in terms of energy consumption of up to 6.6 % for the drivetrain equipped with SiC MOSFETs over its counterpart equipped with Si IGBTs.

Summary Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure. Electronic supplementary material The online version of this article (10.1007/s10637-018-0655-0) contains supplementary material, which is available to authorized users.

Diet has a strong influence on the morphology and physiology of vertebrates. Members of numerous fish clades have provided excellent comparative models for examining the effects of diet, primarily carnivory vs. herbivory, on organ systems. In this study, we comparatively examined the effects of carnivory, specifically independent evolutions of piscivory and durophagy, on body dimensions, organ topology, and organ proportions between nine moray species (Muraenidae). We found that organ placement via the anteroposterior organ positions differed between members in the two diet categories, although general organ topology is conserved. The stomach (31 - 55%) and intestine (68 - 76%) consistently occupied the majority of the body cavity irrespective of diet. Diet was shown to influence overall body dimensions and relative organ proportions across all moray species. Durophagous morays have shorter head lengths and body depths, and shorter heart, liver, gall bladder, and spleen lengths compared to piscivorous species. There was also greater variation in organ lengths among durophagous species than within piscivorous species. We attribute this greater variation in organ lengths to the multiple independent origins of durophagy within Muraenidae. Our single intraspecific comparison of the California moray, Gymnothorax mordax, a piscivorous species, revealed that all organs scale isometrically with body cavity length over ontogeny. The stomach grows proportionally with body cavity length and is the second longest organ in G. mordax at all ontogenetic stages, with the longest being the intestine. This suggests that morays can consume large quantities of prey or relatively large individual prey throughout their life history. In addition to scaling patterns of G. mordax, our study is the first to investigate the effects of diet and the intraspecific scaling patterns on the viscera of members of the Muraenidae, a clade of obligate carnivores that inhabit most marine ecosystems.

The hydration of reactive periclase (MgO) in the presence of hydromagnesite (Mg5(CO3)4(OH)2·4H2O) was investigated by a variety of physical and chemical techniques. This system is of potential interest as low CO2 binder, if the magnesium carbonate is produced by carbonation from naturally occurring magnesium silicates such as olivine or serpentine. In contrary to thermodynamic prediction not artinite (Mg2(CO3)(OH)2·3H2O), but a very poorly-crystalline form of brucite (Mg(OH)2), and an unknown amorphous hydrate which partially loses its crystal water at about 100°C were the main hydration products. Mortars based on such a binder show a reasonable compressive strength of 21 MPa after 28 days of hydration, which could be further optimized.

The hydration of reactive periclase (MgO) in the presence of hydromagnesite (Mg5(CO3)4(OH)2·4H2O) was investigated by a variety of physical and chemical techniques. This system is of potential interest as low CO2 binder, if the magnesium carbonate is produced by carbonation from naturally occurring magnesium silicates such as olivine or serpentine. In contrary to thermodynamic prediction not artinite (Mg2(CO3)(OH)2·3H2O), but a very poorly-crystalline form of brucite (Mg(OH)2), and an unknown amorphous hydrate which partially loses its crystal water at about 100°C were the main hydration products.

We report a study of p-Si(100) surface layers modified by plasma immersion ion implantation (PIII) and dry oxidation. This is expected to allow one to engineer near-surface layers with different thicknesses and levels of amorphization. Hydrogen ions were introduced into a shallow near-surface Si region through PIII with energy of 2 keV and doses ranging from 1013 ion/cm2 to 1015 ion/cm2. The implanted Si surface was subjected to oxidation in dry oxygen atmosphere at temperatures ranging from 700 °C to 800 °C. The optical and structural properties of the modified Si layers were studied in detail by spectroscopic ellipsometry (SE) in the IR spectral range of 300 – 4000 cm−1. The surface morphology was examined by atomic force microscopy (AFM) imaging at different scales and by fractal analysis. Through decomposition of the main Si-O bands into Gaussian peaks, different Si oxidation states were identified, suggesting non-stoichiometric oxide layer composition.

Background: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. Methods: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. Results: The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. Conclusions: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.

Background Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive cancer with low survival rates. Anti-PD-(L)1 antibodies are current treatment options for patients who progressed during or after platinum-based chemotherapy. While some of these patients achieve durable responses with anti-PD-(L)1 therapy, response rates are ≤21%; as such, novel therapies are needed for patients after treatment with platinum and anti-PD-(L)1 therapies. Enfortumab vedotin (EV) is an investigational humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is highly expressed in la/mUC. In a multicohort phase 2 study of EV (EV-201; NCT03219333), which included sites in Japan and Korea, single-agent EV 1.25 mg/kg was generally well tolerated. In Cohort 1 of EV-201 (closed to enrollment), EV demonstrated a confirmed ORR of 44% and a median DoR of 7.6 months as assessed by independent central review in patients with la/mUC with prior platinum chemotherapy and antiPD(L)1. Trial design EV-301 (NCT03474107) is a global, multicenter, open-label, phase 3 trial being conducted in the USA, Europe, and Asia, including sites in Japan, Korea, and Taiwan. Adult patients with la/mUC and an ECOG score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with anti-PD-(L)1 are eligible; these patients are consistent with the population in Cohort 1 of EV-201. Approximately 550 patients will be randomized (1:1) to receive EV (1.25 mg/kg) by IV on Days 1, 8, and 15 of each 28-day cycle (Arm A), or investigator’s choice of IV docetaxel, paclitaxel, or vinflunine (where approved) on Day 1 of each 21day cycle (Arm B). Treatment with EV will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include PFS, DoR, ORR, and assessment of safety/tolerability and quality-of-life parameters. Clinical trial identification NCT03474107. Legal entity responsible for the study Astellas Pharma US, Inc. Funding Astellas Pharma US, Inc. Disclosure D.P. Petrylak: Research grant / Funding (institution): Astellas ; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Bellicum; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche Laboratories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Clovis; Shareholder / Stockholder / Stock options: Tyme; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin. J.E. Rosenberg: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: EMD Serono. J. Lee: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Korea; Advisory / Consultancy, Research grant / Funding (institution): Ipsen Korea; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Novartis Korea; Advisory / Consultancy: Astellas Korea; Advisory / Consultancy: BMS Korea. I. Duran: Advisory / Consultancy: Seattle Genetics. Y. Loriot: Advisory / Consultancy: Astellas; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. G. Sonpavde: Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Onyx-Amgen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Agensys; Advisory / Consultancy: Astellas; Speaker Bureau / Expert testimony: Clinical Care Options; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Uptodate; Advisory / Consultancy: Biotheranostics; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Janssen; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: NCCN. C. Wu: Full / Part-time employment: Astellas. E.M. Gartner: Full / Part-time employment: Seattle Genetics, Inc. A. Melhem-Bertrandt: Full / Part-time employment: Astellas. T. Powles: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Merck; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.

The surface topography and fractal properties of GexSb(As)40−xS50Te10 (x = 10, 20, 27 at.%) films, evaporated onto glass substrates, have been studied by atomic force microscopic imaging at different scales. The surface of the chalcogenide films is smooth (

4505 Background: Locally advanced or metastatic urothelial cancer (la/mUC) remains a lethal disease with limited treatment options for patients (pts) who progress on or after platinum and/or checkpoint inhibitor (CPI). Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in UC. EV-201 is a pivotal, single-arm, two-cohort study of EV in la/mUC patients with prior CPI and platinum-containing chemotherapy (Cohort 1) or a CPI and no prior chemotherapy (Cohort 2). Here, we present preliminary data from Cohort 1. Methods: Pts in this open-label, multicenter study received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. The primary endpoint was confirmed ORR per RECIST 1.1 by blinded independent central review. Secondary endpoints are duration of response, PFS, OS, safety/tolerability. Results: Between Oct 2017 and Jul 2018, EV-201 enrolled 128 pts in Cohort 1 (la/mUC pts previously treated with platinum and a CPI), 125 of whom were treated with EV (70% male; median age 69 y [range 40–84 y]; 34% upper tract; a median of 2 prior systemic therapies). As of 03 Jan 2019, the confirmed ORR was 42% (95% CI: 33.6%–51.6%), with 9% CR. The ORR in CPI non-responders was 38% (95% CI: 27.3%–49.2%), and 36% (95% CI: 22.9%–50.8%) in pts with liver metastases (LM). Most common treatment-related AEs, as determined by investigators, included fatigue (50%), alopecia (48%), and decreased appetite (41%). Treatment-related AEs of interest include any rash (48% all grade, 11% ≥ G3) and any peripheral neuropathy (50% all grade, 3% ≥ G3). One death was reported as treatment related by the investigator (interstitial lung disease), but was confounded by a suspected pulmonary infection. Conclusions: Preliminary results from this EV pivotal study demonstrated a clinically meaningful ORR, consistent with the phase 1 trial, in la/mUC pts with prior platinum and CPI, including LM pts, where there is a high unmet need. EV was well tolerated with a manageable safety profile in these pts. Updated data, including duration of response, PFS, and OS will be presented. Clinical trial information: NCT03219333.

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.

377 Background: Enfortumab vedotin (EV) is an antibody–drug conjugate that delivers MMAE, a microtubule disrupting agent, to tumors expressing Nectin-4, a protein found on most urothelial cancers. Preliminary results of the EV-101 study (NCT02091999) suggest EV is active and tolerable. Methods: Patients with mUC treated with ≥1 prior chemotherapy, or those ineligible for cisplatin, received EV 1.25 mg/kg on Day 1, 8, and 15 every 28 day cycle. The primary objective was tolerability; antitumor activity (ORR per RECIST v1.1), assessed every 8 wk, was a secondary objective. Results: As of14 Sept 2018,112 pts with mUC received EV with a median follow up of 13.4 mo. Bladder was the primary tumor site in 86 pts (77%) and 33 (29.5%) had liver metastases (LM). Nearly all pts received prior platinum chemotherapy; 89 (79.5%) received prior anti-PD(L)1. EV was well tolerated; fatigue (53%), alopecia (46%), and decreased appetite (42%) were the most commonly reported treatment-related AEs (TRAEs). Anemia (8%), hyponatremia (7%), UTI (7%), and hyperglycemia (6%) were the grade ≥3 AEs reported in ≥5% of pts regardless of attribution; 4 fatal TRAEs were reported (respiratory failure, urinary tract obstruction, diabetic ketoacidosis, multi-organ failure). Confirmed ORR was 42% (CR, n = 5; PR, n = 42). Among responders, median duration of response was 7.7 mo (95% CI 5.6, 9.6) and 23.4% of responses were ongoing with a median follow up of 11.3 mo. Estimated median PFS and OS were 5.4 mo (95% CI 5.1, 6.3) and 12.5 mo (95% CI 9.3, 16.1), respectively; OS at 1 yr was 51.8%. Similar results were seen in pts with prior anti-PD(L)1 and with LM (Table). Conclusions: Single-agent EV was generally well tolerated and provided encouraging response and survival data in a population with an unmet medical need including pts with LM, which is associated with poor prognosis. Phase 2 and 3 monotherapy studies as well as evaluation of combination therapies are ongoing. Clinical trial information: NCT02091999. [Table: see text]

Treatment completion (commonly referred to as termination) is a routine and essential component of the treatment process. Although the relevant literature has discussed how to complete treatment, much less discussion and guidance exists regarding when, and under what conditions, treatment should be considered complete. The current article reviews various approaches to defining treatment completion, identifying three general patterns within the psychotherapy literature: clinician judgment, patient outcomes, and number of sessions attended. We propose defining treatment completion in terms of patient skill mastery and competency, and provide an overview of how patient competency is used to define treatment progress and completion within Brief Cognitive Behavioral Therapy for suicidal patients.

4504Background: Patients (pts) with mUC are in need of novel therapies. Enfortumab vedotin (EV) is an antibody–drug conjugate that delivers a microtubule-disrupting agent to tumors expressing Necti...

TPS542 Background: The majority of patients with locally advanced or metastatic urothelial cancer (la/mUC) will not respond to immune checkpoint inhibitors (CPIs) given in the post-platinum or cisplatin ineligible setting, and there are currently no approved standard therapies after disease progression. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. Nausea (36%), pruritus (31%), and fatigue (30%) were the most commonly reported treatment-related AEs. The most common grade ≥3 AEs (regardless of attribution) were urinary tract infection (11%) and hypophosphatemia (9%). EV showed an objective response rate (ORR) of 41% (29 out of 71 pts) across all dose levels and 53% (16 out of 30 pts) ORR at the recommended phase 2 dose of 1.25 mg/kg. The ORR was not diminished in pts with prior CPI use (44%), prior taxane use (41%) or in pts with liver metastases (47%). These encouraging results along with a favorable safety and tolerability profile warrant further investigation of EV as a monotherapy. Methods: This single-arm, open label, multicenter phase 2 study (NCT03219333) evaluates the antitumor activity and safety of EV monotherapy in ~120 pts with la/mUC. Pts must have previously received a CPI and either have received prior platinum or be ineligible for cisplatin. Pts must have histologically or cytologically documented transitional cell carcinoma of the urothelium that progressed during or following receipt of most recent therapy. The primary objective is to determine antitumor activity of EV as measured by ORR. Secondary objectives include assessment of duration of response, disease control rate, PFS, OS, and safety/tolerability of EV. Pts must have tumor tissue available for exploratory analyses. Response is assessed per RECIST v1.1. Study enrollment began in Sept 2017. Clinical trial information: NCT03219333.

Poly(ADP-ribose) polymerase inhibitors are an exciting new class of antineoplastic agents that impair the ability of cells to recover from DNA damage. They are most effective in the setting of inherent DNA repair defects, such as in cancers resulting from BRCA gene mutations, or in the setting of DNA-damaging chemotherapeutic agents. This article reviews the background and development of these agents in the laboratory, as well as the rationale for the biologic correlative studies used in clinical trials. The most recent data from the clinical trials of olaparib (AZD2281, KU-0059436), BSI-201, AG014699, ABT-888, and INO-1001 and descriptions of ongoing studies are also presented.

High spectral (1.5 cm − 1 ) and spatial (~ 1000 nm lateral and vertical) resolution Raman spectra taken at room temperature in the depth of a thin (350 nm) YBCO film with good superconducting properties are presented and discussed. The differences between Raman spectra corresponding to different depths in the film are interpreted as depth-dependant changes in the film's structure, degree of oxygenation, and superconducting properties. These changes are in agreement to what we expect from a film obtained by pulsed laser deposition technique. The resonance of the most significant Raman shift (500 cm − 1 ), monitoring the oxygen content of YBCO films, for 488 nm excitation light, was used to overcome the relatively small penetration depth of visible light in YBCO (~ 200 nm). We found the range of parameters for the depth profiling Raman system such as to obtain the maximum signal intensity and a reasonable number of distinctive Raman spectra corresponding to different depths of the YBCO film.

Hydroxyapatite (HA) biocoatings were obtained using two different deposition methods: sol–gel and sputtering. A direct comparison of films obtained using different techniques is necessary because of possible formation of multi-phases and components in HA films. HA films were investigated using spectroscopic ellipsometry (SE) as a powerful method to evaluate composition and structural properties of the films. For both types of films, sputtering and sol–gel, a weak dispersion of the refractive index within the wavelength range 0.4–0.7 µm was found. This corresponds to a high energy bandgap and a high optical transparency in the UV–VIS range. The internal porosity varying in a wide range in the sol–gel films was evaluated using a modeling of SE data. Additionally to SE studies, structural, chemical and optical characterizations of the films were performed using Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). Two absorption bands observed in the wavelength ranges 550–600 cm− 1 and 1000–1200 cm− 1 can be attributed to the major absorption modes associated with HA in agreement with published data. From XPS analysis, the atom ratio Ca/P was found for sol–gel films close to the stoichiometric value 1.67. For sputtering films, a higher Ca/P ratio of about 2.1 was estimated. However, similar FTIR spectra have been recorded for both sputtering and sol–gel films. XRD studies show also similar crystallization conditions by annealing at temperatures higher than 500 °C.

We report spectroscopic characterization of epitaxial YBCO thin films grown on LaAlO3 by pulsed laser deposition. Raman spectroscopy and spectroscopic ellipsometry were used for film characterization and the results were correlated with X-ray diffraction measurements. The mentioned techniques allowed us to analyze crystallographic, micro-structural, and morphological properties of YBCO thin films. We also demonstrated that relatively low resolution Raman spectroscopy and spectroscopic ellipsometry are reliable techniques for a rapid and non-destructive characterization of epitaxial YBCO thin films.

BaTiO 3 thin films were deposited on Pt/Ti/SiO 2 /Si by rf planar-magnetron sputtering. The films thickness increases with the decrease of both deposition pressure and sample-discharge centre distance. The films annealed at 900 °C, for 8 h, present direct band gap energy ranged between 3.57 and 3.59 eV. The dependence of the structure and microstructure (texture, degree of crystallinity), as well as of the optical characteristics on the deposition parameters, was analysed. Using spectroscopic ellipsometry (SE) measurements coupled with the Bruggeman Effective Medium Approximation (B-EMA), the layer structure and the surface roughness, were determined. The root mean square roughness values of the surface layer, estimated by atomic force microscopy (AFM) analyses, are ranged between 10 and 20 nm and were in good agreement with SE data. The obtained films have tetragonal unit cell and show densely packed, non-columnar morphology and hexagon-like crystallite shape.

OBJECTIVES. The Hawaii Child Asthma Research to Elevate Standards (CARES) Program implemented an emergency department (ED)-based education and management program to facilitate National Asthma Education and Prevention Program (NAEPP) guideline understanding among asthmatic children and their families, ED staff, and health care providers. METHODS. The multipronged approach used: (1) 2-phased prospective tracking system of ED asthma patients; (2) ED-based educational intervention for patients/families; and (3) asthma education for ED staff and community-based health care providers. Data were collected across 4 EDs during phase I (October 8, 2002, to October 1, 2003) and phase II (October 1, 2003, to July 8, 2004). Follow-up data were collected by telephone 3 weeks (phase I), and 3 weeks and 3 months (phase II) after the ED encounter. The patient/family intervention was delivered throughout phase II. During phase I, ED and community-based health care professionals developed strategies for building an integrated asthma care system. ED staff training was delivered before phase II. Continuing medical education for health care providers was delivered before and during the first month of phase II. RESULTS. Tracking data on 706 phase I and 353 phase II patient encounters revealed that the majority of patients with persistent asthma did not use long-term controller medications and did not possess a written asthma action plan. From preintervention to postintervention, the number of patients possessing a written asthma action plan increased from 48 to 322. Of 186 persistent asthmatics, 34 were using controller medications daily, 34 as needed, and 118 not at all. Daily use increased to 80 3 weeks postintervention and to 68 3 months postintervention. CONCLUSION. An ED-based childhood asthma tracking system can serve as a basis for designing and implementing an ED-based educational intervention. ED staff, primary care providers, and others can work together to promote asthma care.

Owing to their peculiar characteristics, bismuth oxides are used in various domains, such as microelectronics, sensor technology, optical coatings, transparent ceramic glass manufacturing, etc. Bismuth oxide system exhibit high oxide ionic conductivity and have been proposed as good electrolyte materials for application, such as solid oxide fuel cell (SOFC) and oxygen sensor. Antimony doped and undoped Bi 2 O 3 films were deposited onto glass substrate from bismuth nitrate and antimony precursor solutions. As chelating agent polyethyleneglycol (PEG) was used and the above-mentioned precursor solutions were sufficiently viscous. In the present paper, the formation of different phases belonging to Bi–O system during thermal treatments of the Bi-based films is investigated by means of spectroscopic ellipsometry (SE), polarising microscope observation, X-ray diffractometry (XRD), and infrared spectrometry (IR). The thickness and the porosity of the films were evaluated. These preparation techniques, differing mainly in precursor materials and method of deposition, lead to different quality of the resulting films.

Tin-doped indium oxide (ITO) thin films have been deposited by sol–gel process using ‘sols’ of indium and tin isopropoxides. The thickness of one deposited ITO layer is approximately 50 nm. The desired thickness was obtained by 1–5 successive depositions. The XTEM cross-sectional view of an ITO sample with five depositions showed a clear delimitation of the layers with an alternating structure dense/porous ITO layers. The void fraction in porous regions varies between 20 and 25%. Cubic bixbyite In 2 O 3 nanocrystals with size of 10–20 nm and no phases separation of tin oxide were observed. The optical properties of the films have been investigated by optical transmission and spectroscopic ellipsometry. Reliable optical constants and porosity are obtained only with the model of internal structure based on XTEM results.

This study was conducted to investigate maturation of the medial olivocochlear efferent system (MOCS) in pre- and full-term neonates using Quickscreen (Otodynamics Ltd) and to confirm previous findings on transient otoacoustic emission (TEOAE) suppression in neonates. MOCS maturation was investigated in 46 neonates born at the Chaim Sheba Medical Center, Tel Hashomer, Israel, using Quickscreen. All neonates were normal with no family history of general or auditory disease and no risk factors for hearing impairment. MOCS function appears gradually in human pre-term neonates and is considered to reach maturity shortly after term birth. The clinical value of MOCS testing in specific populations of newborns at risk for hearing and/or brainstem function can be legitimately raised as activation of the MOCS clearly alters cochlear output. The present results can be interpreted to support the testing of infants at risk of developing abnormal MOCS function using a commercially available rapid TEOAE measurement system.

431 Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was < 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999.

Studies of environmental chemicals in human milk have been carried out in many countries, but few have been conducted in the United States. These studies are useful for monitoring population trends in exposure to chemicals, for research into the determinants of environmental chemicals in milk and relationships between the levels found and the health status of the women and their infants, and for risk assessment. This article provides practical advice on data and information reporting for such studies. Participation in these studies comes at a difficult time for the breast-feeding mothers, so it is important that the mothers support the study and its goals. A key goal of any study of environmental chemicals in human milk must be to ensure that the breast-feeding process is not disrupted by unwarranted concerns about harm to the infant from chemicals in human milk. Therefore, it is essential that reporting of information be a two-way process. Information needs to be supplied to participating mothers before, during, and after their participation in the study. Information supplied before participation is necessary to satisfy the ethical requirement for informed consent; information supplied during participation includes advice on expressing, collecting, and storing milk samples, and how to avoid sample contamination; and information supplied to each participant at the end of the study includes a report of their individual results and a summary of study results and outcomes generally. The key instrument for obtaining data from the participants is the study questionnaire. This needs to be prepared in accordance with principles of good questionnaire development, and preferably should be interviewer administered. The questionnaire content will vary according to the objectives of the study. Although studies of environmental chemicals in human milk are logistically complex and demanding, they are practicable and, with careful planning and execution, yield important data.

Background Although bilirubin, which crosses the blood–brain barrier, can cause irreversible brain damage, it also possesses antioxidant properties that may be protective against oxidative stress. Intestinal ischemia–reperfusion (IR) injury results in cell destruction, mediated via the generation of reactive oxygen species. Although increased serum bilirubin is correlated with increased antioxidant potential in the face of hyperoxia, evidence of bilirubin-associated protective effect against IR injury remains nonspecific. We therefore sought to investigate whether hyperbilirubinemia would be protective against IR injury to the intestine. Methods Young adult rats were randomly assigned to one of three groups: 1) IR/control (n = 12); 2) IR/hyperbilirubinemia (n = 10), in which IR was generated while the rats were treated with a continuous infusion of bilirubin; and 3) hyperbilirubinemia controls (n = 10). Blood and intestinal tissue samples were obtained to determine serial thiobarbituric acid reducing substances (index of lipid peroxidation) and for xanthine oxidase/xanthine dehydrogenase and glutathione/glutathione disulfide ratios. Intestinal histopathology was graded from 1 (normal) to 4 (severe necrotic lesions). Results Histopathologic scoring and circulating and tissue thiobarbituric acid reducing substances were highest in the IR/control animals compared with either the IR/hyperbilirubinemics or the controls. All of these are consistent with the most severe injury in this group. Xanthine oxidase/xanthine dehydrogenase ratios were not significantly different among the groups. Conclusion Hyperbilirubinemia ameliorates the extent of intestinal IR injury in our model and appears to act as an antioxidant. This study supports the concept that bilirubin possesses some beneficial properties in vivo, although no direct clinical conclusions can be drawn from these data.