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TPS543 Background: Cholangiocarcinoma (CCA) is treated with CIS and GEM (CISGEM), but prognosis is poor. Hyaluronan (HA) accumulation in solid tumors may impede drug and immune cell access. PEGPH20 targets tumors that accumulate HA (HA-high). This study (NCT03267940) plans to enroll 70 subjects to evaluate the safety and activity of PEGPH20 + programmed cell death-ligand 1 (PD-L1) agent atezolizumab, (PEGCISGEMATEZO), & PEGPH20 + CISGEM (PEGCISGEM) in HA-high subjects with CCA and gallbladder cancer. Study will comprise initial run-in and expansion portions. Primary endpoints include incidence of AEs and other laboratory/safety parameters and ORR (RECIST v1.1). Secondary endpoints include PK parameters; DOR, DCR, PFS, and ORR (RECIST v1.1 and immune-modified RECIST); and OS and OS by PD-L1 expression. Methods: ~6 HA-high subjects will be enrolled in PEGCISGEM arm run-in portion and undergo at ≥1 cycle; subsequently, 6 HA-high subjects will enter the PEGCISGEMATEZO arm. Treatment period will be 21-day cycles. In the expansion portion, ~50 HA-high subjects will be enrolled and randomized in a 2:2:1 ratio into PEGCISGEMATEZO, PEGCISGEM, and CISGEM arms. PEGPH20 is planned to be administered at 3.0 μg/kg on Days 1, 8 and 15 of all cycles in both portions. ATEZO will be administered at 1200 mg 1–3 hours after PEGPH20 on Day 1 of each 21-day cycle in the PEGCISGEMATEZO arm in both portions. In the PEGCISGEM & PEGCISGEMATEZO arms, dosing schedule for CISGEM is the same during both portions, with administration of 25 mg/m2 CIS and 1000 mg/m2 GEM on Days 2 and 9 of each cycle. In CISGEM control arm (expansion only), dosing schedule will be on Days 1 and 8 of each cycle. Treatment will continue until death, withdrawal of consent, disease progression, or unacceptable toxicity. Tumor response will be evaluated using RECIST v1.1. AEs will be graded per NCI CTCAE v4.03. Tumor samples will be tested retrospectively for PD-L1 expression. Safety data will be periodically monitored by an independent data monitoring committee. Clinical trial information: NCT03267940.

276 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

AbstractBackgroundCare for patients with thyroid nodules is complex and multidisciplinary, and research demonstrates variation in care. The objective was to develop clinical guidelines and quality metrics to reduce unwarranted variation and improve quality.MethodsMultidisciplinary expert consensus and modified Delphi approach. Source documents were workflow algorithms from Kaiser Permanente Northern California and Cancer Care of Ontario based on the 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer.ResultsA consensus‐based, unified preoperative, perioperative, and postoperative workflow was developed for North American use. Twenty‐one panelists achieved consensus on 16 statements about workflow‐embedded process and outcomes metrics addressing safety, access, appropriateness, efficiency, effectiveness, and patient centeredness of care.ConclusionA panel of Canadian and United States experts achieved consensus on workflows and quality metric statements to help reduce unwarranted variation in care, improving overall quality of care for patients diagnosed with thyroid nodules.

ABSTRACTObjectiveCervical cerclage, when performed in twin gestation, has been reported to be associated with poor outcome. However, the role of first‐trimester history‐indicated cerclage among women with a twin pregnancy and a history of preterm birth has not been evaluated. The aim of this study was to assess pregnancy outcomes among women with a twin pregnancy who underwent first‐trimester history‐indicated cervical cerclage compared with outcomes in those managed expectantly.MethodsThis was a retrospective matched case–control study. The study group comprised all women with a twin pregnancy who had undergone first‐trimester history‐indicated cerclage during the period 2006 to 2017 at Hadassah‐Hebrew University Medical Center. A control group of women with a twin pregnancy who were managed expectantly was established by matching age, history of spontaneous preterm birth (20–36 weeks' gestation) and year of delivery. Pregnancy and delivery characteristics and neonatal outcomes were compared between the two groups.ResultsData from 82 women with a twin gestation were analyzed, of whom 41 underwent first‐trimester history‐indicated cerclage and 41 were matched controls who were managed expectantly. Gestational age at delivery was higher in the cerclage group than in those managed expectantly (median 35 vs 30 weeks; P < 0.0001). Rates of spontaneous preterm birth before 24 weeks (2.4% vs 19.5%; odds ratio (OR), 0.10 (95% CI, 0.01–0.87); P = 0.03), before 28 weeks (12.2% vs 34.1%; OR, 0.27 (95% CI, 0.09–0.84); P = 0.03), before 32 weeks (22.0% vs 56.1%; OR, 0.22 (95% CI, 0.08–0.58); P = 0.003) and before 34 weeks (34.1% vs 82.9%; OR, 0.11 (95% CI, 0.04–0.30); P < 0.0001) were significantly lower in the cerclage group than in the control group. Median birth weight was higher in the cerclage group (2072 g vs 1750 g; P = 0.003), with lower rates of low birth weight (< 2500 g) (65.0% vs 89.4%; P = 0.001) and very low birth weight (< 1500 g) (21.3% vs 37.9%; P = 0.03) than in the group managed expectantly. Rates were also lower in the cerclage group for stillbirth, admission to the neonatal intensive care unit, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, neonatal mortality and composite adverse neonatal outcome.ConclusionsHistory‐indicated cerclage performed in the first trimester, as compared with expectant management, in women with a twin pregnancy had an overall positive effect on pregnancy and neonatal outcomes. These findings suggest the need for adequate randomized trials on cerclage placement in this subset of women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.

Objectives: Patients and caregivers can experience a range of physical, psychologic, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. Design: We sought to identify technical, safety, and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. Subjects and Setting: Seventeen Thrive sites from the United States, United Kingdom, and Australia were represented by a range of healthcare professionals. Measurements and Main Results: Via an iterative process of in-person and email/conference calls, members of the Collaborative defined the key areas on which peer support models could be defined and compared, collected detailed self-reports from all sites, reviewed the information, and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Within the Thrive Collaborative, six general models of peer support were identified: community based, psychologist-led outpatient, models-based within ICU follow-up clinics, online, groups based within ICU, and peer mentor models. The most common barriers to implementation were recruitment to groups, personnel input and training, sustainability and funding, risk management, and measuring success. Conclusions: A number of different models of peer support are currently being developed to help patients and families recover and grow in the postcritical care setting.