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Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment–naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC cohort (n = 226) was immunostained for PD-L1 and used as a validation cohort. PD-L1 expression on tumor cells (TC) and/or immune cells (IC) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: “adaptive-1” (TC: 0, IC > 1%), “adaptive-2” (TC > 1% to < 25%, IC > 1%), “constitutive” (TC ≥ 25%, IC: 0), and “combined” (TC ≥ 25%, IC > 1%). “Constitutive” tumors were characterized by reduced numbers of all ICs and poor outcome. In contrast, “adaptive-1” tumors exhibited abundant T cells, including high counts of cytotoxic CD3+CD8+ and PD-1+CD3+CD8+ cells, but low counts of PD-L1+CD3+CD8+ cells and associated with the best outcome. “Adaptive-2” tumors displayed higher proportions of PD-L1+CD3+CD8+ T cells and tumor-associated macrophages (CD68+ and CD68+CD206+) compared with “adaptive-1” tumors. In the “combined” pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved overall survival. ICs were closer to PD-L1− than to PD-L1+ PDAC cells. TP53 and PIK3CA alterations tended to be more frequent in PD-L1+ tumors. The 5 MSI cases were PD-L1−. The distinct PD-1/PD-L1–associated immunoarchitectural patterns underpin the heterogeneity of the immunologic responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

In 2013, El Rey launched as an ad-supported cable channel. Cofounded and majority owned by Robert Rodriguez, El Rey tapped into the filmmaker-entrepreneur's appeal by targeting both a young Latino audience and a wider audience of genre fans. Unfortunately, shifting industrial, economic, cultural, and technological conditions ultimately led the channel to cease operations in 2020. This article traces El Rey's evolution from its initial inception up through its programming strategies in the COVID-19 era. El Rey is presented as a smallf, upstart channel that differentiated itself in an increasingly challenging television landscape. Although larger structural conditions in the end made its survival untenable, the story of El Rey can be seen as representing a new direction for linear cable television in the 2010s.

Changes in cerebral blood flow are associated with stroke, aneurysms, vascular cognitive impairment, neurodegenerative diseases and other pathologies. Brain angiograms, typically performed via computed tomography or magnetic resonance imaging, are limited to millimetre-scale resolution and are insensitive to blood-flow dynamics. Here we show that ultrafast ultrasound localization microscopy of intravenously injected microbubbles enables transcranial imaging of deep vasculature in the adult human brain at microscopic resolution and the quantification of haemodynamic parameters. Adaptive speckle tracking to correct for micrometric brain-motion artefacts and ultrasonic-wave aberrations induced during transcranial propagation allowed us to map the vascular network of tangled arteries to functionally characterize blood-flow dynamics at a resolution of up to 25 μm and to detect blood vortices in a small deep-seated aneurysm in a patient. Ultrafast ultrasound localization microscopy may facilitate the understanding of brain haemodynamics and of how vascular abnormalities in the brain are related to neurological pathologies. Ultrafast ultrasound localization microscopy of intravenously injected microbubbles enables transcranial imaging of deep vasculature in the adult human brain at microscopic resolution and the quantification of haemodynamic parameters.

Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p &lt, 0.001), presence of distant metastases (p &lt, 0.001), and shorter disease-free survival (p &lt, 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.

The development of disease-modifying therapies for Parkinson’s disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson’s disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein–induced neurotoxicity and neuroinflammation in preclinical Parkinson’s disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector–mediated α-synuclein–based Parkinson’s disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein–induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein–induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4(+) and CD8(+) T cell infiltration. This observed lack of protection against α-synuclein–induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson’s disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01007-8.

Background: In the PAKT study, addition of the oral AKT inhibitor capivasertib to 1st-line paclitaxel therapy for metastatic TNBC resulted in significantly longer progression-free survival (PFS; primary endpoint; Schmid, J Clin Oncol 2020). The stratified PFS hazard ratio was 0.74 (95% CI, 0.50-1.08; one-sided P=0.06; predefined significance level of 0.10, one-sided; median PFS 5.9 vs 4.2 months with capivasertib vs placebo). Overall survival (OS) results were immature at the primary analysis with 53% of events but suggested long OS with capivasertib (HR, 0.61; 95% CI, 0.37-0.99; two-sided P=0.04). Here we report final results. Methods: This double-blind, placebo-controlled, randomised phase II trial, recruited women with untreated, metastatic TNBC. Total of 140 patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, 15) with either capivasertib (400mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS in the ITT population and in patients with and without PIK3CA/AKT1/PTEN-alterations. Results: With a median F/U of 40.0 months, median OS was longer in the capivasertib arm (19.1 vs 13.5 months, stratified HR 0.70, 95% CI 0.47-1.05, p=0.085). In contrast to the earlier analysis, no meaningful differences were seen in terms of benefit with capivasertib between patients with or without alterations of PIK3CA/AKT1/PTEN. Median OS numerically favoured capivasertib vs placebo both in the PIK3CA/AKT1/PTEN-altered (stratified HR 0.58, 95% CI 0.21-1.58, p=0.290) and PIK3CA/AKT1/PTEN non-altered subgroup (stratified HR 0.74, 95% CI 0.47-1.18, p=0.207). The safety profile of capivasertib plus paclitaxel was unchanged. Conclusions: Final OS results show a numerical trend favouring capivasertib; effects were observed regardless of PIK3CA/AKT1/PTEN alterations. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line Capivasertib plus paclitaxel for metastatic TNBC in the ongoing Capitello290 randomised phase III trial in patients with and without PIK3CA/AKT1/PTEN alterations. Citation Format: Peter Schmid, Jacinta Abraham, Stephen Chan, Adrian Murray Brunt, Gia Nemsadze, Richard D Baird, Yeon Hee Park, Peter Hall, Timothy Perren, Robert C Stein, László Mangel, Jean-Marc Ferrero, Melissa Phillips, John Conibear, Javier Cortes, Andrew Foxley, Elza de Bruin, Robert McEwen, Myria Nikolaou, Daniel Stetson, Brian Dougherty, Aaron Prendergast, Max McLaughlin-Callan, Matthew Burgess, Cheryl Lawrence, Hayley Cartwright, Kelly Mousa, Nicholas Turner, Duncan Wheatley. Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-11.

Summary Background The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. Methods In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC–IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov , NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. Findings Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI −0·4 to 4·9, p=0·095; group 3 vs group 1, −0·8, −3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference −1·8, 95% CI −3·6 to −0·1, p=0·043; group 3 vs group 1, −2·9, −4·7 to −1·1, p=0·0018). Interpretation We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. Funding Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Transcranial Doppler ultrasonography, performed by experienced sonographers, is a noninvasive, flexible, accessible, and accurate tool for the bedside monitoring of cerebral flow and treatment response. Identification of the intracranial vessels is based on: velocity and direction, depth of signal, spatial relationship with other vessels, and response to ipsilateral and contralateral carotid compression. One of the main fields of clinical application of transcranial sonography is assessment and monitoring of cerebral vasospasm, which is a common complication of subarachnoid hemorrhage (SAH). Mean flow velocities of these vessels are directly proportional to flow and inversely proportional to the section of the vessel. Any situation that leads to a variation of one of these factors can thus affect mean velocities. Following peak systolic and mean blood flow velocities of the vessel in its whole length is mandatory. Additional information about systemic or circulatory conditions that may affect blood flow velocities should be gained, and vasospasm ratios (Lindegaard, Soustiel, and Sloan) should be used within the framework of a strict ultrasound monitoring protocol.

Die Diagnostik neuroendokriner Neoplasien des Pankreas (PanNEN) hat in den letzten Jahren v. a. im Bereich der WHO-Klassifikation, der TNM-Einteilung sowie der Gradierung Veränderungen erfahren. Zudem wurden einzelne neue diagnostische sowie prädiktive immunhistochemische Marker eingeführt. Die meisten Fortschritte wurden auf der Ebene der molekularen Pathogenese von PanNEN erzielt. Mittels „next generation sequencing“ wurden der „mammalian target of rapamycin (mTOR) pathway“, Hypoxie, aber auch epigenetische Veränderungen als wichtige tumorigene Mechanismen identifiziert. Im vorliegenden Artikel werden die wichtigsten Entwicklungen in der morphologischen und immunhistochemischen Diagnostik von PanNEN und deren molekularer Hintergrund beleuchtet., The diagnostics of pancreatic neuroendocrine tumors (PanNEN) have changed in recent years especially concerning the World Health Organization (WHO) classification, TNM staging and grading. Furthermore, some new prognostic and predictive immunohistochemical markers have been introduced. Most progress, however, has been made in the molecular pathogenesis of these neoplasms. Using next generation sequencing techniques, the mammalian target of rapamycin (mTOR) pathway, hypoxia and epigenetic changes were identified as key players in tumorigenesis. In this article the most important developments of morphological as well as immunohistochemical diagnostics together with the molecular background of PanNEN are summarized.

Aim: The aim of this study was to compare the long-term outcome of women with primary or locally advanced breast cancer randomised to receive either doxorubicin and cyclophosphamide (AC) or doxorubicin and docetaxel (AD) as primary chemotherapy. Patients and methods: Eligible patients with histology-proven breast cancer with primary tumours ≥ 3 cm, inflammatory or locally advanced disease, and no evidence of distant metastases, were randomised to receive a maximum of 6 cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) i/v or doxorubicin (50 mg/m(2)) plus docetaxel (75 mg/m(2)) i/v every 3 weeks, followed by surgery on completion of chemotherapy. Results: Clinical and pathologic responses have previously been reported 1. Time to relapse, site of relapse, and all-cause mortality were recorded. This updated analysis compares long-term disease-free (DFS) and overall survival (OS) using stratified log rank methods. A total of 363 patients were randomised to AC (n = 181) or AD (n = 182). At a median follow-up of 119 months, there is no significant difference between the two groups for DFS (P = 0.274) and OS (P = 0.327). The 10-year DFS for AC is 54% (95% CI 47-62%) and for AD 60% (95% CI 52-67). The 10-year OS is 49% (95% CI 42-57%) for AC and 51% (95% CI 43-58%) for AD. Metastatic breast cancer accounted for 89% of deaths in those treated with AC and 86% in those treated with AD. Estrogen receptor (ER) and nodal status were independent prognostic factors for DFS and OS (p Conclusions: This was one of the first studies to evaluate taxanes versus anthracyclines in the neoadjuvant setting. Our mature data do not support an added clinical benefit for the simultaneous administration of AD compared to AC. This supports current practice with respect to sequential treatment with taxanes followed by anthracyclines leading to an increase in pathological complete response rate and better survival outcomes. 1. Evans TR, Yellowlees A, Foster E et al. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an Anglo-Celtic cooperative Oncology group study. J Clin Oncol 2005, 23: 2988–2995. Citation Format: Chara Stavraka, T. R. Jeffry Evans, Joanna Dunlop, Helena Earl, David A. Cameron, Robert E Coleman, Timothy Perren, Robert CF Leonard, Janine L Mansi. 10-year outcome for women randomized in a phase III trial comparing doxorubicin and cyclophosphamide with doxorubicin and docetaxel as primary medical therapy in early breast cancer: An anglo-celtic cooperative oncology group study [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 P2-16-15.

Background:\ud Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.\ud Methods:\ud In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).\ud Findings:\ud Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0–26·0] in group 1, 24·9 months [24·0–25·9] in group 2, 25·3 months [23·9–26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6–not reached] in group 1, 20·8 months [11·9–59·0] in group 2, 21·0 months [12·0–54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.\ud Interpretation:\ud Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.\ud Funding:\ud Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

ObjectiveTwo randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing therapy on safety and oncologic outcomes in patients with advanced ovarian cancer in the UK.MethodsBetween May 2013 and April 2015, patients with high-risk stage IIIB–IV advanced ovarian cancer received bevacizumab (7.5 or 15 mg/kg every 3 weeks, typically for ≤12 months, per UK clinical practice) combined with front-line chemotherapy, with bevacizumab continued as maintenance therapy. Co-primary endpoints were progression-free survival and safety (NCI-CTCAE v4.0). Patients were evaluated per standard practice/physician’s discretion.ResultsA total of 299 patients received bevacizumab-containing therapy. The median age was 64 years (range 31–83); 80 patients (27%) were aged ≥70 years. Surgical interventions were primary debulking in 21%, interval debulking in 36%, and none in 43%. Most patients (93%) received bevacizumab 7.5 mg/kg with carboplatin/paclitaxel. Median duration of bevacizumab was 10.5 months(range ConclusionsMedian progression-free survival in this study was similar to that in the high-risk subgroup of the ICON7 phase III trial. Median progression-free survival was shortest in patients who did not undergo surgery.

Purpose Previous research studies assume that influential consumers (“influentials”), who play a powerful role in the marketplace, are persuasive (or not) based on innate, static personality traits. By contrast, this paper proposes an emergence-based view of influentials. Grounded in dynamic self-concept theory, this research establishes that individuals possess an “influential” self-concept that can be activated by firm-originated communications. Specifically, the authors examine the impact of firm feedback on the three dimensions of influentials (and the corresponding traits and behaviors): who they are (propensity to connect with others), who they know (WOM) and what they know (expert power). Design/methodology/approach The study tests whether an influential self can be evoked by marketers using a longitudinal experimental test with data collected in three periods. The data are analyzed using a multi-mediation model and partial least squares structural equation modeling. Findings The results reveal that even after controlling for the extroversion trait, firm-originated positive feedback increases perceived expert power of participants, which increases word-of-mouth behavior in a subsequent period, both directly and indirectly via an enhanced propensity to connect with others. Research limitations/implications Cultivating the influential self-concept requires time to ensure that the self-concept is sufficiently realized to become an enduring self-concept. Practical implications By cultivating influentials, practitioners are able to leverage diffusion mechanics and reduce costs and inefficiencies associated with traditional customer relationship management marketing strategies focused on finding them. Social implications These findings have implications across all domains that rely on the diffusion and adoption of ideas or products via influentials, including but not limited to public policy, politics, public health and sustainability, in that influentials can be evoked and leveraged to diffuse ideas in these important social domains. Originality/value This paper provides empirical evidence that firms can evoke influential consumer behavior challenging existing views of influence as a static personality trait. It casts a line to connect influential consumers to the nascent study of social emergence.

Background and Purpose Current guidelines do not provide firm directions on atrial fibrillation (AF) screening after ischemic stroke (IS). We sought to investigate the association of implantable cardiac monitoring (ICM) duration with the yield of AF detection in IS patients. Methods We included studies reporting AF detection rates by ICM in IS patients with negative initial AF screening. We excluded studies reporting prolonged cardiac monitoring with devices other than ICM, not providing AF detection rates or monitoring duration, and reporting overlapping data for the same population. The random-effects model was used for all pooled estimates and meta-regression analyses. Results We included 28 studies (4,531 patients, mean age 65 years). In meta-regression analyses, the proportion of AF detection by ICM was independently associated with monitoring duration (coefficient=0.015; 95% confidence interval [CI], 0.005 to 0.024) and mean patient age (coefficient=0.009; 95% CI, 0.003 to 0.015). No associations were detected with other patient characteristics, including IS subtype (cryptogenic vs. embolic stroke of undetermined source) or time from IS onset to CM implantation. In subgroup analyses, significant differences (P12 and ≤24 months: 26% [95% CI, 22% to 31%]; >24 months: 34% [95% CI, 29% to 39%]). Conclusions Extended duration of ICM monitoring and increased patient age are factors that substantially increase AF detection in IS patients with initial negative AF screening.

We investigated the glucose metabolism in an adeno-associated viral vector based alpha-synuclein rat model for Parkinson's disease (PD) using longitudinal 18F-FDG PET imaging, which resulted in an improved characterization of this animal model. We generated a PD specific pattern (PDSP) based on a multivariate classification approach to differentiate between a PD and control group at a late disease stage, where the neurodegeneration is considered nearly complete. In particular, we applied a principal component analysis prior to classification by a support vector machine (SVM). Moreover, by using a SVM for regression to predict corresponding motor scores, a PD motor pattern (PDMP) was derived as well. The PDSP mainly corresponds to the PDMP and overlaps to a large extent with the human pattern. We were able to quantify disease expression at previous time points by projecting onto the PDSP and PDMP. While a univariate analysis indicated metabolic changes which did not persist through time, both PDSP and PDMP were able to differentiate significantly (p-value

Context Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery. Objective To evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI. Design Post hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH. Patients Six of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included. Interventions All patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results. Main Outcome Measures Lesion-based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs ≥20 mm or insulinoma. Results In six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients. Conclusion 68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and may guide the surgical strategy.

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers, with a median survival of only three to six months. Standard treatment options and even targeted therapies have so far failed to improve long-term overall survival. Thus, novel treatment modalities for ATC, such as immunotherapy, are urgently needed. CD47 is a "don't eat me" signal, which prevents cancer cells from phagocytosis by binding to signal regulatory protein alpha on macrophages. So far, the role of macrophages and the CD47-signal regulatory protein alpha signaling axis in ATC is not well understood. Methods: This study analyzed 19 primary human ATCs for macrophage markers, CD47 expression, and immune checkpoints by immunohistochemistry. ATC cell lines and a fresh ATC sample were assessed by flow cytometry for CD47 expression and macrophage infiltration, respectively. CD47 was blocked in phagocytosis assays of co-cultured macrophages and ATC cell lines. Anti-CD47 antibody treatment was administered to ATC cell line xenotransplanted immunocompromised mice, as well as to tamoxifen-induced ATC double-transgenic mice. Results: Human ATC samples were heavily infiltrated by CD68- and CD163-expressing tumor-associated macrophages (TAMs), and expressed CD47 and calreticulin, the dominant pro-phagocytic molecule. In addition, ATC tissues expressed the immune checkpoint molecules programmed cell death 1 and programmed death ligand 1. Blocking CD47 promoted the phagocytosis of ATC cell lines by macrophages in vitro. Anti-CD47 antibody treatment of ATC xenotransplanted mice increased the frequency of TAMs, enhanced the expression of macrophage activation markers, augmented tumor cell phagocytosis, and suppressed tumor growth. In double-transgenic ATC mice, CD47 was expressed on tumor cells, and blocking CD47 increased TAM frequencies. Conclusions: Targeting CD47 or CD47 in combination with programmed cell death 1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care.

Purpose Recovery after liver transplant (LT) requires extensive resources, including prolonged intensive care unit stays. The objective of this study was to use an assessment tool to determine if LT recipients remain in ICU beyond designated indications. Methods Records from 100 consecutive LTs performed in a single institution were retrospectively reviewed. An admission, discharge, and triage screening (ADT) tool was utilized to assess the indications for each ICU day. Data collected included demographics; pre-, intra-, and post-operative course; and complications. Days not meeting ADT criteria were considered additional ICU days. Results 100 patients: mean age 55 years (range 24–78 years) and mean MELD score 30 (range 6–47). Three recipients who died within one week were excluded. Forty-eight (49.5%) patients had a total of 75 additional days on initial ICU stay. Univariate analysis revealed no significant differences between patients with and without additional days. 12/97 (12.4%) patients returned to ICU including 5/48 and 7/49 with and without additional days. Conclusion Nearly half of the LT recipients remained in ICU an average of 1.6 additional days. Monitoring of organ function appeared to be the most common reason. Opportunities to improve resource utilization could include transfer to an intermediate/progressive care (“step-down”) unit.

Andrea Saporito,1 José Aguirre,2 Alain Borgeat,2 Andreas Perren,3 Luciano Anselmi,1 Roberto Poggi,4 Bruno Minotti,5 Stefano Cafarotti,6 Davide La Regina,7 Samuele Ceruti81Service of Anesthesiology, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 2Department of Anesthesiology, Balgrist University Hospital, Zürich, Switzerland; 3Department of Intensive Care, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 4Service of Anesthesiology, Ospedale Regionale di Lugano, Lugano, Switzerland; 5Department of Emergency Medicine, St Gallen General Hospital, St Gallen, Switzerland; 6Service of Thoracic Surgery, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 7Service of Visceral Surgery, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 8Department of Intensive Care, Geneva University Hospital (HUG), Geneva, SwitzerlandIntroduction: Breast surgery is associated with persistent postsurgical pain; usually related to poorly treated acute pain. Paravertebral block has been successfully employed in analgesic protocols for breast surgery; its impact on postdischarge pain (PDP) has not been investigated. The aim of this study was to assess characteristics of PDP after breast surgery, the development of chronic postoperative pain (CPP) and its impact on health care costs.Methods: We conducted a retrospective, observational study on a continuous cohort of adult female patients undergoing local breast cancer surgery under combined anesthesia. All patients were interviewed 6 months after hospital discharge. The survey was specifically conceived to assess incidence, features and duration of PDP. The overall cost of additional healthcare resources consumed with a specific relationship to persistent PDP was estimated.Results: A database of 244 patients was preliminarily analyzed. Of these, 188 were included in the following statistical analysis; 123 patients (65.2%) reported significant PDP, with a median intensity on NRS of 6 (IQR=2), more frequently described as burning and associated with paresthesia and/or hyperalgesia (87 patients, 46%). One hundred and six patients (56.5%) reported this pain as interfering with their normal daily activities, work and sleep. In 26.8% of cases (50 patients) symptoms lasted more than 1 month and in 28 patients (15.0%) pain became chronic. The majority of patients self-treated their pain with non-steroideal anti-inflammatory drugs, but in 50 patients (26.8%) this therapy was reported as ineffective. This additional consumption of healthcare resources led to a significant economical impact.Conclusion: PDP and CPP seem to be common complications after breast cancer surgery, even if a combined anesthesia technique with a thoracic paravertebral block is performed, leading to severe consequences on patients’ quality of life and increasing consumption of healthcare resources after discharge.Trial number: NCT03618459 (www.clinicaltrials.gov).Keywords: breast surgery, paravertebral block, regional anesthesia, postoperative pain

Tibial plateau fractures occur frequently during downhill skiing. There is a lack of information about the outcome and development of posttraumatic osteoarthritis after internal fixation of such fractures at long-term follow-up in skiers. A population of 83 skiers was followed up in a case series after internal fixation of intra-articular tibial plateau fractures AO-OTA 41 B1-B3 and C1-C3. Functional outcomes Visual Analog Scale, Tegner Activity Scale, Modified Lysholm Score, Hospital for Special Surgery (HSS) Knee Score and X-ray images of the affected knees (preoperative, postoperative and at time of follow-up) were obtained. Radiological evaluation focused on severity of osteoarthritis according to the Kellgren and Lawrence score of the lateral, medial and retropatellar knee compartments separately. Subgroup analyses for fracture type and age were performed separately. Patients age was 49.8 ± 12.9 years (range 19–74 years) at the time of surgery, with a mean follow-up period of 10.3 ± 1.9 years (range 6–14 years). All tibial plateau fractures affected the lateral compartment, while the medial compartment was affected in addition as part of bicondylar fractures in two cases. Both the Tegener Activity Scale and Lysholm Score decreased significantly during the follow-up period and their median values dropped from 6 (range 3–7) to 5 (range 2–7) and from 100 (range 90–100) to 95 (range 58–100), respectively (both p

Objectives\ud This is a protocol for a Cochrane Review (intervention). The objectives are as follows:\ud \ud To analyse the effects of a supervised exercise programme following successful lower limb revascularisation compared with standard care following lower limb revascularisation in patients with symptomatic peripheral artery disease (PAD).

Introduction Acute limb ischaemia (ALI) forms a significant part of the vascular surgery workload and carries with it high rates of morbidity and mortality. Anaemia is also common amongst vascular surgical patients and has been linked with poor outcomes in some subgroups. We aimed to assess the frequency of anaemia in patients with ALI and its impact on survival and complications following revascularisation to help direct future efforts to optimise outcomes in this patient group. Methods A retrospective analysis of prospectively collected departmental data on patients undergoing surgical intervention for ALI between 2014 and 2018 was performed. Anaemia was defined as a pre-operative haemoglobin (Hb) of Results There were 158 patients who underwent treatment for ALI: 89 (56.3%) of these were non-anaemic with a mean Hb of 146 (SD = 18.4), and 69 (43.7%) were anaemic with a mean Hb of 106 (SD = 13.4). Anaemic patients had a significantly higher risk of death than their non-anaemic counterparts on univariate analysis (HR = 2.11, 95% CIs, 1.28–3.5, p = 0.0036). There was ongoing divergence in survival up to around 6 months between anaemic and non-anaemic groups. Under the Cox model, anaemia was similarly significant as a predictor of death (HR = 2.15, 95% CIs, 1.17–3.95, p = 0.013), accounting for recorded comorbidities, medication use and blood transfusion. Conclusions Anaemia is a significant and independent risk factor for death following revascularisation for ALI and can be potentially be modified. Vascular surgical centres should ensure they have robust pathways in place to identify and consider treating anaemia. There is scope for further work to assess how to best optimise a patient’s levels of circulating haemoglobin.

Objectives: Better markers of early response to neoadjuvant chemotherapy (NACT) in patients with breast cancer are required to enable the timely identification of non-responders and reduce unnecessary treatment side-effects. Early functional imaging may better predict response to treatment than conventional measures of tumour size. The purpose of this study was to test the hypothesis that the change in tumour blood flow after one cycle of NACT would predict pathological response. Methods: In this prospective cohort study, dynamic contrast-enhanced MRI was performed in 35 females with breast cancer before and after one cycle of epirubicin and cyclophosphamide-based NACT (EC90). Estimates of tumour blood flow and tumour volume were compared with pathological response obtained at surgery following completion of NACT. Results: Tumour blood flow at baseline (mean ± SD; 0.32 ± 0.17 ml/min/ml) reduced slightly after one cycle of NACT (0.28 ± 0.18 ml/min/ml). Following treatment 15 patients were identified as pathological responders and 20 as non-responders. There were no relationships found between tumour blood flow and pathological response. Conversely, tumour volume was found to be a good predictor of pathological response (smaller tumours did better) at both baseline (area under the receiver operating characteristic curve 0.80) and after one cycle of NACT (area under the receiver operating characteristic curve 0.81). Conclusion & advances in knowledge: The change in breast tumour blood flow following one cycle of EC90 did not predict pathological response. Tumour volume may be a better early marker of response with such agents.

Purpose of Review Classification and nomenclature of neuroendocrine neoplasms (NEN) have frequently changed over the last years. These changes reflect both increasing knowledge and international standardisation. Recent Findings The most recent changes in the Gastro-Entero-Pancreatic system induced the concept of well-differentiated NET with high proliferation rate (NET G3), explaining partially the heterogeneity of G3 NEN. Even if the nomenclature in pulmonary NEN is still different, the terms ‘carcinoid’ and ‘atypical carcinoid’ are widely overlapping with NET G1 and NET G2. Molecular data shows an additional heterogeneity both in well-differentiated NET and poorly differentiated NEC. However, no studies are available demonstrating clinical usefulness yet. Summary The heterogeneity of NEN regarding the organ of origin, differentiation and molecular subtypes make development of personalised therapy a challenge needing more international and interdisciplinary collaborations and clinical trials allowing stratification according to biological subgroups.

Self-efficacy is an important predictor of people’s behaviour and wellbeing. In this longitudinal study we investigated patterns of stability and change in early childhood educator self-efficacy (ESE) in child-centred educational practice and its predictors. Early childhood educators completed a questionnaire twice. Latent profile analysis yielded four profiles: decrease profile (21.2%), increase profile (25.0%), low profile (9.6%), and high profile (44.2%). Profiles were used as the outcome of a multinomial logistic regression analysis. The analyses showed that educators’ experience, number of hours worked per week, and institution are significant predictors for profile membership: educators with less professional experience and fewer working hours per week have a higher probability of being in the low profile. Family-based educators have a higher probability of being in the decrease profile than centre-based educators. The lack of opportunities to increase self-efficacy available to less experienced, part-time educators and family-based working educators are discussed in frame of Bandura’s (1997) sources of self-efficacy. Practical interventions such as coaching and tandem building are proposed to strengthen ESE., Frontiers in Education, vol. 6

Background Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of ‘platinum-sensitive’ ovarian cancer and has been shown to improve progression-free survival (PFS). Patients and methods ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. Results After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch–Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: −0.09 to 9.74 months). Conclusions Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken., Highlights • Cediranib is an oral VEGF receptor kinase inhibitor and ICON6 explored its activity in recurrent ovarian cancer. • In a randomised trial cediranib with chemotherapy and as maintenance significantly prolonged PFS. • Cessation of cediranib supply led to a reduction in sample size and OS was underpowered. • A mature survival analysis showed a non-significant increase in the median and Restricted Mean Survival Time (RMST) with cediranib. • There was a clinical benefit of cediranib but further research is needed to determine its role in recurrent ovarian cancer.

Background: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. Patients and Methods: Multicenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Results: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23months (5–187months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. Conclusions: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Objective: We sought to explore the technical and legal readiness of healthcare institutions for novel data-sharing methods that allow clinical information to be extracted from electronic health records (EHRs) and submitted securely to the Food and Drug Administration's (FDA's) blockchain through a secure data broker (SDB). Materials and Methods: This assessment was divided into four sections: an institutional EHR readiness assessment, legal consultation, institutional review board application submission, and a test of healthcare data transmission over a blockchain infrastructure. Results: All participating institutions reported the ability to electronically extract data from EHRs for research. Formal legal agreements were deemed unnecessary to the project but would be needed in future tests of real patient data exchange. Data transmission to the FDA blockchain met the success criteria of data connection from within the four institutions' firewalls, externally to the FDA blockchain via a SDB. Discussion: The readiness survey indicated advanced analytic capability in hospital institutions and highlighted inconsistency in Fast Healthcare Interoperability Resources format utilitzation across institutions, despite requirements of the 21st Century Cures Act. Further testing across more institutions and annual exercises leveraging the application of data exchange over a blockchain infrastructure are recommended actions for determining the feasibility of this approach during a public health emergency and broaden the understanding of technical requirements for multisite data extraction. Conclusion: The FDA's RAPID (Real-Time Application for Portable Interactive Devices) program, in collaboration with Discovery, the Critical Care Research Network's PREP (Program for Resilience and Emergency Preparedness), identified the technical and legal challenges and requirements for rapid data exchange to a government entity using the FDA blockchain infrastructure.

Background and Purpose: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level. Methods: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded. Results: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0–2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3–5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year. Conclusions: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03245866.

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Clinically, complication rates of brachial arterial catheterization appear to far exceed those of the radial or common femoral arteries. The study objective was to define the complication rate after brachial arterial line insertion. All patients undergoing arterial line placement to the brachial artery in the surgical intensive care units (SICUs) at our institution were retrospectively identified and included in the study (January 2016-December 2018). Demographics, complications (distal ischemia, thrombosis/dissection, brachial sheath hematoma, catheter-related sepsis, and inadvertent dislodgement), and outcomes were collected and analyzed. Over the study period, 53 patients underwent brachial arterial catheterization. Common admitting services were cardiothoracic surgery (n = 31, 58%), transplant surgery (n = 7, 13%), and neurosurgery (n = 4, 7%). The mean age was 55 ± 17 58 (24-84) years, and 58% (n = 31) were male. The hospital length of stay (LOS) was 37 ± 35 23 (1-132) days, and ICU LOS was 30 ± 27 20 (1-127) days. Mortality was 57% (n = 30). Complications of brachial arterial line placement occurred in 21 patients (40%). In summary, brachial arterial catheters were associated with high mortality and prolonged ICU length of stay. This likely reflects the critically ill nature of patients in whom conventional-site arterial line placement is not possible. Complications following brachial arterial catheterization were unacceptably high. On this basis, we recommend that the brachial artery be avoided whenever possible for arterial line placement in the SICU.

Objectives The influence of different forms of treatment limitation on mortality rate in the ICU is not known despite the common use of the latter as a quality indicator. The aim of the present study was to assess the prevalence of treatment limitation and its influence on ICU mortality rate. Primary outcomes were prevalence of treatment limitation and its influence on severity-adjusted ICU mortality rate. Secondary outcomes included the association of limitation with age, sex, type of admission, diagnostic group, treatment intensity, and length of ICU stay. Design Retrospective, observational study. Setting All Swiss adult ICUs. Interventions None. Patients A total of 166,764 patients were admitted to an ICU in 2016 and 2017. Of these, 9139 were excluded because of readmission or invalid coding. Measurements and main results Of 157,625 ICU patients, 20,916 (13.3%) had a fully defined treatment limitation. Among this group, treatment limitation was defined upon ICU admission in 12,854 (61%), the decision to limit treatment was based on the patient's advance directives in 9,951 (48%), and in 15,341 (73%), there was a decision to deliberately withhold certain treatment modalities. The mortality odds ratio for the group with a treatment limitation, considering relevant cofactors, was 18.1 (95% CI 16.8-19.4). Conclusions Every seventh patient in a Swiss ICU has some kind of treatment limitation, and this most probably affects the severity-adjusted mortality rate. Thus, mortality data as a quality indicator or benchmark in intensive care can only meaningfully be interpreted if existence, grade, cause, and time of treatment limitation are taken into account.

Standardized pathologic reporting for cancers improves patient care and prognostic determination. However, access in many countries is limited. To address this issue, the International Collaboration on Cancer Reporting (ICCR), a not-for-profit organization, has the mission to develop and disseminate standardized data sets for global use. Within endocrine organs, the parathyroid gland has rarely been included in formal pathologic data sets. Utilizing an expert international panel of eleven members, an evidence-based data set was developed for parathyroid carcinoma and atypical parathyroid neoplasms. This data set consists of sixteen core (required) elements viewed as essential for documentation of these conditions. Characterizing parathyroid carcinomas and atypical neoplasms begins with correlative clinical information, the operative procedure, specimens submitted, and site of the disease. The pathologic features essential to document include parathyroid weight, size, classification, and, when a carcinoma, the tumor grade. Histologic grade of parathyroid carcinoma incorporates other core elements including necrosis, mitotic count, perineural invasion, and lymphovascular invasion. Documenting the extent of disease locally into adjacent organs, regionally, and distally is critical for staging. Pathologic staging is now included as part of the American Joint Committee on Cancer 8th edition and is included in this data set. Ancillary studies should be recorded when performed as noncore elements. Standardized pathologic data sets for endocrine organs including the parathyroid gland are now available through the ICCR website. These essential resources enhance international standardization for documenting these rare tumors for both patient care and future guidelines.

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-na&iuml, ve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months, p = 0.005). In treatment-na&iuml, ve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months, p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA-125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n = 214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n = 244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P = .10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P = .09).

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10%of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas. The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.

OBJECTIVES: Outcomes for patients with MBC vary according to disease phenotype and treatment history. We present UK real-world patient characteristics, treatment patterns and outcomes for patients with HR+/HER2- BC treated at a single cancer center. METHODS: A retrospective review of health records including coded data, unstructured text and clinical review of patients treated from January 2012 to March 2018 identified females ≥ 18 years with metastatic or locally advanced HR+/HER2- BC. Those enrolled in clinical trials, with operable local recurrence as only disease site, incomplete treatment records or significant secondary malignancy were excluded. Patient characteristics, systemic, local (radiotherapy/surgery) and supportive treatments, health care resource use (HRU) and overall survival (OS) are presented. OS was estimated using the Kaplan-Meier method, censoring patients alive at study end. RESULTS: 253 patients meeting study inclusion criteria were identified (median age 67, IQR 56,76; 84% post-menopausal), of whom 47 (19%) had locally advanced disease (T4 and/or N3), 75 (30%) had MBC at initial presentation and 131 (52%) had metastatic disease at first recurrence. Among patients with MBC at initial presentation, all received systemic treatment following diagnosis, including chemotherapy (35%), endocrine (93%) and targeted therapy (i.e. everolimus 7%). Among those recurring with MBC, 97% subsequently received systemic treatment, including chemotherapy (50%), endocrine (93%) and targeted therapy (27%). For patients recurring with MBC, the most common first line therapies (LoT) were letrozole (20%), exemestane (single agent, 15%), anastrozole (14%), everolimus (with exemestane, 11%) and paclitaxel (9%). For patients diagnosed with MBC, the most common first LoT were letrozole (47%), anastrozole (23%) and EC (11%). At second LoT, the most commonly used regimen for patients recurring with MBC was fulvestrant (13%) and for patients with MBC at initial diagnosis, it was exemestane (19%). Median OS for patients recurring with MBC was estimated to be 2.11 years (IQR 1.80,3.05), compared with 2.65 years (IQR 2.24,2.95) for those with metastatic disease at initial diagnosis. Median available follow-up time for the whole cohort was 2.85 years (IQR 1.42,4.82). CONCLUSIONS: Patients with overt metastatic disease at presentation comprise a substantial proportion of those treated for MBC. With the follow-up time available, estimated median OS for patients with metastatic disease at initial presentation appears somewhat better than for those recurring with metastatic disease. Real world analysis demonstrates diverse treatment pathways for patients with HR+, HER2- MBC, reflecting the individualized care they receive. Citation Format: Twelves C, Cheeseman S, Thompson M, Riaz M, Perren T, Ahat-Donker N, Sopwith W, Myland M, Lee A, Turner S, Hall G. “Real world” characteristics, treatment patterns and outcomes of patients with hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-14.

General surgeons have become increasingly subspecialised in their elective practice. Emergency laparotomies, however, are performed by a range of subspecialists who may or may not have an interest in the affected area of gastrointestinal tract. This retrospective cohort study evaluates the impact of surgical subspecialisation on patient outcomes following emergency laparotomy.Data was collected for patients who underwent an emergency abdominal procedure on the gastrointestinal tract in the North of England from 2001 to 2016. This included demographics, co-morbidities, diagnoses and procedures undertaken. Patients were grouped according to consultants' subspecialist interest. The primary outcome of interest was 30-day postoperative mortality.24,291 emergency laparotomies were performed with an associated 30-day postoperative mortality of 11.7%. Laparotomies undertaken by upper gastrointestinal (UGI) or colorectal surgeons have significantly lower mortality (10.1%) when compared with other subspecialities (13.5%). More specifically, mortality was decreased for UGI (7.9% vs. 12.9%) and colorectal procedures (10.9% vs. 14.2%) when performed by surgeons with a specialist interest in the relevant area of the gastrointestinal tract (both p 0.001). The utilisation of laparoscopic surgery is higher, in both UGI (21.8% vs. 9.0%) and colorectal procedures (7.2% vs. 3.5%), when the causative pathology is relevant to the surgeon's subspeciality (both p 0.001).Mortality following emergency laparotomy is improved when performed under the care of gastrointestinal surgeons. Both UGI and colorectal emergency procedures have improved outcomes, with lower mortality and higher rates of laparoscopy, when under the care of a surgeon with a subspecialist interest in the affected area of the gastrointestinal tract.

Objective The aim of this case series was to describe the experience of Swiss physical therapists in the treatment of patients with COVID-19 during their acute care hospital stay and to discuss challenges and potential strategies in the clinical management of these patients. Methods We report 11 cases of patients with COVID-19 from 5 Swiss hospitals that illustrate the various indications for physical therapy, clinical challenges, potential treatment methods, and short-term response to treatment. Results Physical therapists actively treated patients with COVID-19 on wards and in the intensive care unit. Interventions ranged from patient education, to prone positioning, to early mobilization and respiratory therapy. Patients were often unstable with quick exacerbation of symptoms and a slow and fluctuant recovery. Additionally, many patients who were critically ill developed severe weakness, postextubation dysphagia, weaning failure, or presented with anxiety or delirium. In this setting, physical therapy was challenging and required specialized and individualized therapeutic strategies. Most patients adopted the proposed treatment strategies, and lung function and physical strength improved over time. Conclusion Physical therapists clearly have a role in the COVID-19 pandemic. Based on our experience in Switzerland, we recommend that physical therapists routinely screen and assess patients for respiratory symptoms and exercise tolerance on acute wards. Treatment of patients who are critically ill should start as soon as possible to limit further sequelae. More research is needed for awake prone positioning and early breathing exercises as well as post-COVID rehabilitation. Impact To date, there are few data on the physical therapist management of patients with COVID-19. This article is among the first to describe the role of physical therapists in the complex pandemic environment and to describe the potential treatment strategies for countering the various challenges in the treatment of these patients.

Background Capturing accurate clinical data in real time is a challenge during public health emergencies. The United States Critical Illness and Injury Trials Group-Program for Emergency Preparedness is committed to improving these preparedness efforts. Objectives We aimed to create an electronic Acute Physiology and Chronic Health Evaluation (APACHE) II data collection instrument that (1) leverages Research Electronic Data Capture (REDCap) automated calculations and logic, (2) may be shared across sites, (3) overcomes limitations in existing APACHE II instruments in the REDCap library, and (4) suggests changes to be made to data collection instruments during emergencies. Methods The APACHE II instrument was implemented using REDCap. Data fields were divided into four sections: age, Acute Physiology, Glasgow Coma Scale, and chronic health status. Usability testing was followed by two preliminary evaluations: a comparison to existing APACHE II instruments and a simulated emergency exercise. Results The final instrument consisted of 34 data fields. It produced an accurate APACHE II score and was faster to complete than two previous implementations (average of 97.5 seconds vs. 323.5 and 183.5 seconds). During the simulated emergency exercise, the instrument was used at 10 sites to create 34 patient records; median time to complete the instrument was 150.5 seconds. Conclusion This project demonstrated feasibility of improving the accuracy and efficiency of a data collection instrument. Future efforts should focus on expanding these methods to develop other scoring tools for use during emergencies and additional testing to ensure it is ready for use during a real emergency.

Unlike general anaesthesia, neuraxial anaesthesia (NA) reduces the burden and risk of respiratory adverse events in the post-operative period. However, both patients affected by chronic obstructive pulmonary disease (COPD) and chest wall disorders and/or neuromuscular diseases may experience the development or the worsening of respiratory failure, even during surgery performed under NA; this latter negatively affects the function of accessory respiratory muscles, resulting in a blunted central response to hypercapnia and possibly in an exacerbation of cardiac dysfunction (NA-induced relative hypovolemia). According to European Respiratory Society (ERS) and American Thoracic Society (ATS) guidelines, non-invasive ventilation (NIV) is effective in the post-operative period for the treatment of both impaired pulmonary gas exchange and ventilation, while the intra-operative use of NIV in association with NA is just anecdotally reported in the literature. Whilst NIV does not assure a protected patent airway and requires the patient’s cooperation, it is a handy tool during surgery under NA: NIV is reported to be successful for treatment of acute respiratory failure; it may be delivered through the patient’s home ventilator, may reverse hypoventilation induced by sedatives or inadvertent spread of anaesthetic up to cervical dermatomes, and allow the avoidance of intubation in patients affected by chronic respiratory failure, prolonging the time of non-invasiveness of respiratory support (i.e., neuromuscular patients needing surgery). All these advantages could make NIV preferable to oxygen in carefully selected patients.