bluuebunny/crossref_metadata_2025 huggingface dataset:
Do team and task performance improve after training situation awareness? A randomized controlled study of interprofessional intensive care teams
Authors: Jonsson Karin , Brulin Christine , Härgestam Maria , Lindkvist Marie , Hultin Magnus
Published: June 2021

Background

When working in complex environments with critically ill patients, team performance is influenced by situation awareness in teams. Moreover, improved situation awareness in the teams will probably improve team and task performance. The aim of this study is to evaluate an educational programme on situation awareness for interprofessional teams at the intensive care units using team and task performance as outcomes.

Method

Twenty interprofessional teams from the northern part of Sweden participated in this randomized controlled intervention study conducted in situ in two intensive care units. The study was based on three cases (cases 0, 1 and 2) with patients in a critical situation. The intervention group (n = 11) participated in a two-hour educational programme in situation awareness, including theory, practice, and reflection, while the control group (n = 9) performed the training without education in situation awareness. The outcomes were team performance (TEAM instrument), task performance (ABCDE checklist) and situation awareness (Situation Awareness Global Assessment Technique (SAGAT)). Generalized estimating equation were used to analyse the changes from case 0 to case 2, and from case 1 to case 2.

Results

Education in situation awareness in the intervention group improved TEAM leadership (p = 0.003), TEAM task management (p = 0.018) and TEAM total (p = 0.030) when comparing cases 1 and 2; these significant improvements were not found in the control group. No significant differences were observed in the SAGAT or the ABCDE checklist.

Conclusions

This intervention study shows that a 2-h education in situation awareness improved parts of team performance in an acute care situation. Team leadership and task management improved in the intervention group, which may indicate that the one or several of the components in situation awareness (perception, comprehension and projection) were improved. However, in the present study this potential increase in situation awareness was not detected with SAGAT. Further research is needed to evaluate how educational programs can be used to increase situation awareness in interprofessional ICU teams and to establish which components that are essential in these programs.

Trial registration

This randomized controlled trial was not registered as it does not report the results of health outcomes after a health care intervention on human participants.
Diagnostic accuracy of prehospital serum S100B and GFAP in patients with mild traumatic brain injury: a prospective observational multicenter cohort study – “the PreTBI I study”
Authors: Seidenfaden Sophie-Charlott , Kjerulff Julie Linding , Juul Niels , Kirkegaard Hans , Møller Mette Fogh , Münster Anna-Marie Bloch , Bøtker Morten Thingemann
Published: June 2021

Background

The biomarker serum S100 calcium-binding protein B (S100B) is used in in-hospital triage of adults with mild traumatic brain injury to rule out intracranial lesions. The biomarker glial fibrillary acidic protein (GFAP) is suggested as a potential diagnostic biomarker for traumatic brain injury. The aim of this study was to investigate the diagnostic accuracy of early prehospital S100B and GFAP measurements to rule out intracranial lesions in adult patients with mild traumatic brain injury.

Methods

Prehospital and in-hospital blood samples were drawn from 566 adult patients with mild traumatic brain injury (Glasgow Coma Scale Score 14–15). The index test was S100B and GFAP concentrations. The reference standard was endpoint adjudication of the traumatic intracranial lesion based on medical records. The primary outcome was prehospital sensitivity of S100B in relation to the traumatic intracranial lesion.

Results

Traumatic intracranial lesions were found in 32/566 (5.6%) patients. The sensitivity of S100B > 0.10 μg/L was 100% (95%CI: 89.1;100.0) in prehospital samples and 100% (95% CI 89.1;100.0) in in-hospital samples. The specificity was 15.4% (95%CI: 12.4;18.7) in prehospital samples and 31.5% (27.5;35.6) in in-hospital samples. GFAP was only detected in less than 2% of cases with the assay used.

Conclusion

Early prehospital and in-hospital S100B levels < 0.10 μg/L safely rules out traumatic intracranial lesions in adult patients with mild traumatic brain injury, but specificity is lower with early prehospital sampling than with in-hospital sampling. The very limited cases with values detectable with our assay do not allow conclusions to be draw regarding the diagnostic accuracy of GFAP.

Trial registration

ClinicalTrials.gov identifier: NCT02867137.
Post-discharge telephonic follow-up of pediatric patients affected by SARS-CoV2 infection in a single Italianpediatric COVID center: a safe and feasible way to monitor children after hospitalization
Authors: Clemente Vitangelo , Tripiciano Costanza , Moras Patrizio , Deriu Daniele , Di Giuseppe Martina , Piscitelli Anna Lucia , Cammerata Michela , De Ioris Maria Antonietta , Calò Carducci Francesca Ippolita , Bernardi Stefania , Campana Andrea , D’Argenio Patrizia , Rossi Paolo
Published: June 2021

Background

SARS-CoV-2 infection in children is often non severe and in the majority of cases does not require long term hospitalization, nevertheless it is burdened with social issues and managing difficulties.

To our knowledge there is no literature on telephonic follow up in pediatric patients with positive PCR for SARS-CoV-2 on rhino-pharyngeal swab after discharge. The aim of the study is to describe our experience in a telephonic follow up which can allow early and safe discharge from hospital while keeping the patients under close clinical monitoring.

Materials and methods

Sixty-five children were admitted for SARS-CoV-2 infection at Bambino Gesù Pediatric Hospital COVID Center from 16th March to 3rd July. We monitored through a telephonic follow-up, using a specific survey, the patients discharged still presenting a positive PCR for SARS-CoV-2. We checked if any symptoms occurred at home until recovery, defined as two consecutive negative PCR for SARS-CoV-2 on rhino-pharyngeal swabs.

Results

During the follow up 7 patients had mild and self-limited symptoms related to SARS-CoV-2 infection, while 2 patients were re-hospitalized. One patient had Multisystem Inflammatory Syndrome in Children (MIS-C), the other patient had an increase in troponin and D-dimers.

We also monitored the average time of viral shedding, resulting in a median duration of 28 days.

Conclusion

Our experience describes the daily telephonic follow up as safe in pediatric patients discharged with positive PCR. As a matter of fact it could avoid long term hospitalization and allow to promptly re-hospitalize children with major complications such as MIS-C.
Acute toxic exposures in children: analysis of a three year registry managed by a Pediatric poison control Center in Italy
Authors: Marano M. , Rossi F. , Ravà L. , Khalil Ramla M. , Pisani M. , Bottari G. , Genuini L. , Zampini G. , Nunziata J. , Reale A. , Barbieri M. A. , Celeani F. , Di Nardo M. , Cecchetti C. , Stoppa F. , Villani A. , Raponi M. , Livadiotti S. , Pontrelli G.
Published: June 2021

Introduction

Acute pediatric poisoning is an emerging health and social problem. The aim of this study is to describe the characteristics of a large pediatric cohort exposed to xenobiotics, through the analysis of a Pediatric Poison Control Center (PPCc) registry.

Methods

This study, conducted in the Pediatric Hospital Bambino Gesù of Rome, a reference National Pediatric Hospital, collected data of children whose parents or caregivers contacted the PPCc by phone (group “P”), or who presented to the Emergency Department (group “ED”), during the three-year period 2014–2016. Data were prospectively and systematically collected in a pre-set electronic registry. Comparisons among age groups were performed and multivariable logistic regression models used to investigate associations with outcomes (hospital referral for “P”, and hospital admission for “ED”group).

Results

We collected data of 1611 children on group P and 1075 on group ED. Both groups were exposed to both pharmaceutical and non-pharmaceutical agents. Pharmaceutical agent exposure increased with age and the most common route of exposure was oral. Only 10% among P group were symptomatic children, with gastrointestinal symptoms. Among the ED patients, 30% were symptomatic children mostly with gastrointestinal (55.4%) and neurologic symptoms (23.8%). Intentional exposure (abuse substance and suicide attempt), which involved 7.7% of patients, was associated with older age and Hospital admission.

Conclusions

Our study describes the characteristics of xenobiotics exposures in different paediatric age groups, highlighting the impact of both pharmacological and intentional exposure. Furthermore, our study shows the utility of a specific PPCc, either through Phone support or by direct access to ED. PPCc phone counselling could avoid unnecessary access to the ED, a relevant achievement, particularly in the time of a pandemic.
Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial
Authors: Marx Gernot , Zacharowski Kai , Ichai Carole , Asehnoune Karim , Černý Vladimír , Dembinski Rolf , Ferrer Roca Ricard , Fries Dietmar , Molnar Zsolt , Rosenberger Peter , Sanchez-Sanchez Manuel , Schürholz Tobias , Dehnhardt Tamara , Schmier Sonja , von Kleist Elke , Brauer Ute , Simon Tim-Philipp
Published: June 2021

Background

Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime.

Methods

This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90.

Discussion

This study aims to generate evidence regarding which regimen—a gelatine-crystalloid regimen or a pure crystalloid regimen—is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload.

Trial registration

The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466. Registered on 17 March 2016.
The immune modulatory effects of umbilical cord-derived mesenchymal stromal cells in severe COVID-19 pneumonia
Authors: Ciccocioppo Rachele , Gibellini Davide , Astori Giuseppe , Bernardi Martina , Bozza Angela , Chieregato Katia , Elice Francesca , Ugel Stefano , Caligola Simone , De Sanctis Francesco , Canè Stefania , Fiore Alessandra , Trovato Rosalinda , Vella Antonio , Petrova Varvara , Amodeo Giuseppe , Santimaria Monica , Mazzariol Annarita , Frulloni Luca , Ruggeri Marco , Polati Enrico , Bronte Vincenzo
Published: June 2021

Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.
Systematic review: Advances of fat tissue engineering as bioactive scaffold, bioactive material, and source for adipose-derived mesenchymal stem cells in wound and scar treatment
Authors: Gentile Pietro , Sterodimas Aris , Calabrese Claudio , Garcovich Simone
Published: June 2021

Fat tissue (FT) has been used for many years in regenerative surgery as a bioactive material through the lipofilling/fat graft (F-GRF)–nano-fat technique, as a bioactive scaffold when it was enriched with adipose-derived mesenchymal stem cells (AD-MSCs) contained in the stromal vascular fraction (SVF), and as a direct source of AD-MSCs used in wound healing (WH) and scar treatment (ST). This systematic review aims to describe the advances in FT engineering applied to regenerative surgery (from bench to clinic), through the use of AD-MSCs, SVF contained in F-GRF in WH and ST. The work has been performed by assessing in the selected studies autologous graft of AD-MSCs, SVF, and F-GRF compared to any control for ST and WH. The protocol was developed following the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) guidelines. A multistep search of the PubMed, MEDLINE, Embase, PreMEDLINE, Ebase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus database, and Cochrane databases has been performed to identify papers on AD-MSCs, SVF, and F-GRF use in WH and ST in which FT was used as bioactive material–scaffold and source of AD-MSCs. Of the 714 articles initially identified, 453 articles focusing on regenerative strategies in WH and ST were selected and, consequently, only 84 articles that apparently related to AD-MSC, SVF, and F-GRF were analyzed. Of these, 61 articles identified as pre-clinical, experimental, and in vitro, and 5 articles identified as a comment and systematic review were excluded. Only 18 original articles which strictly and exclusively focused on autologous AD-MSCs, SVF, and F-GRF in ST and WH were analyzed. The included studies had to match predetermined criteria according to the PICOS (patients, intervention, comparator, outcomes, and study design) approach. The identified studies described microscopic and clinical outcomes in patients treated with AD-MSCs, SVF, and F-GRF. Collected data confirmed the safety and efficacy of FT both as bioactive material–scaffold and source of AD-MSCs in WH and ST without major side effects.

Graphical abstract
Correction to: Risk factors for developing severe COVID-19 in China: an analysis of disease surveillance data
Authors: Geng Meng-Jie , Wang Li-Ping , Ren Xiang , Yu Jian-Xing , Chang Zhao-Rui , Zheng Can-Jun , An Zhi-Jie , Li Yu , Yang Xiao-Kun , Zhao Hong-Ting , Li Zhong-Jie , He Guang-Xue , Feng Zi-Jian
Published: June 2021

An amendment to this paper has been published and can be accessed via the original article.
2D transition metal carbides (MXenes) in metal and ceramic matrix composites
Authors: Wyatt Brian C. , Nemani Srinivasa Kartik , Anasori Babak
Published: June 2021

Two-dimensional transition metal carbides, nitrides, and carbonitrides (known as MXenes) have evolved as competitive materials and fillers for developing composites and hybrids for applications ranging from catalysis, energy storage, selective ion filtration, electromagnetic wave attenuation, and electronic/piezoelectric behavior. MXenes’ incorporation into metal matrix and ceramic matrix composites is a growing field with significant potential due to their impressive mechanical, electrical, and chemical behavior. With about 50 synthesized MXene compositions, the degree of control over their composition and structure paired with their high-temperature stability is unique in the field of 2D materials. As a result, MXenes offer a new avenue for application driven design of functional and structural composites with tailorable mechanical, electrical, and thermochemical properties. In this article, we review recent developments for use of MXenes in metal and ceramic composites and provide an outlook for future research in this field.
A new route for caesium lead halide perovskite deposition
Authors: Falsini Naomi , Ristori Andrea , Biccari Francesco , Calisi Nicola , Roini Giammarco , Scardi Paolo , Caporali Stefano , Vinattieri Anna
Published: June 2021

Inorganic metal halide perovskites are relevant semiconductors for optoelectronic devices. The successful deposition of thin films of CsPbBr3 and CsPbCl3 has recently been obtained by Radio-Frequency magnetron sputtering. In this work we compare the morphological, structural and optical characteristics of the two materials obtained with this deposition technique. A detailed photoluminescence (PL) spectroscopy study of the as-grown samples was conducted at the macro and micro scale in a wide temperature range (10-300 K) to fully characterize the PL on sample areas of square centimeters, to assess the origin of the inhomogeneous broadening and to quantify the PL quantum yield quenching. Our results prove that this technique allows for the realization of high quality nanometric films with controlled thickness of relevance for optoelectronic applications.
Risk homozygous haplotype regions for autism identifies population-specific ten genes for numerous pathways
Authors: Agarwala Swati , Ramachandra Nallur B.
Published: June 2021

Background

Recessive homozygous haplotype (rHH) mapping is a reliable tool for identifying recessive genes by detecting homozygous segments of identical haplotype structures. These are shared at a higher frequency amongst probands compared to parental controls. Finding out such rHH blocks in autism subjects can help in deciphering the disorder etiology.

Objectives

The study aims to detect rHH segments of identical haplotype structure shared at a higher frequency in autism subjects than controls to identify recessive genes responsible for autism manifestation.

Methods

In the present study, 426 unrelated autism genotyped probands with 232 parents (116 trios) were obtained from Gene Expression Omnibus (GEO) Database. Homozygosity mapping analyses have been performed on the samples using standardized algorithms using the Affymetrix GeneChip® 500K SNP Nsp and Sty mapping arrays datasets.

Results

A total of 38 homozygous haplotype blocks were revealed across sample datasets. Upon downstream analysis, 10 autism genes were identified based on selected autism candidate genes criteria. Further, expressive Quantitative Trait Loci (QTL) analysis of SNPs revealed various binding sites for regulatory proteins BX3, FOS, BACH1, MYC, JUND, MAFK, POU2F2, RBBP5, RUNX3, and SMARCA4 impairing essential autism genes CEP290, KITLG, CHD8, and INS2. Pathways and processes such as adherens junction, dipeptidase activity, and platelet-derived growth factor—vital to autism manifestation were identified with varied protein-protein clustered interactions.

Conclusion

These findings bring various population clusters with significant rHH genes. It is suggestive of the existence of common but population-specific risk alleles in related autism subjects.
Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3.
Authors: Cristofanilli Massimo , Rugo Hope S. , Im Seock-Ah , Slamon Dennis J. , Harbeck Nadia , Bondarenko Igor , Masuda Norikazu , Colleoni Marco , DeMichele Angela , Loi Sherene , Iwata Hiroji , O'Leary Ben , Bananis Eustratios , Liu Yuan , Huang Xin , Kim Sindy , Lechuga Mariajose , Turner Nicholas C.
Published: June 2021

1000

Background: In PALOMA-3, a randomized, double-blind, placebo-controlled, phase 3 study, PAL+FUL significantly prolonged progression-free survival (PFS) compared with placebo (PBO) + FUL (1-sided P<0.0001). The final protocol-specified OS analysis, which was conducted with a median follow-up of 44.8 months (mo), showed improved OS with PAL+FUL vs PBO+FUL (median OS, 34.9 vs 28.0 mo; hazard ratio, 0.814 [95% CI, 0.644–1.029]; 1-sided P=0.0429). Here, we report the results from an OS analysis with a longer median follow-up of 73.3 mo. Methods: A total of 521 patients (pts) with HR+/HER2– ABC who had progressed on prior endocrine therapy were randomized 2:1 to PAL (125 mg/d orally, 3/1 week schedule) + FUL (500 mg intramuscular injection) or PBO+FUL. Investigator-assessed PFS was the primary endpoint; OS was a key secondary endpoint. An ad hoc OS analysis was performed when 393 events (75% of the total population) were observed. Circulating tumor DNA (ctDNA) analysis was conducted among pts who consented for this study. Results: Improvement in OS continues to be observed with longer follow-up, with a hazard ratio of 0.806 (95% CI, 0.654–0.994; 1-sided nominal P=0.0221). The 5-year OS rate was 23.3% (95% CI, 18.7–28.2) with PAL+FUL and 16.8% (95% CI, 11.2–23.3) with PBO+FUL. Favorable OS with PAL+FUL vs PBO+FUL was observed in most subgroups except among pts who were endocrine resistant or had prior chemotherapy for ABC. No new safety signals were identified. Eighteen pts remain on study treatment, including 15 (4.3%) on PAL+FUL and 3 (1.7%) on PBO+FUL. A post-study cyclin-dependent kinase 4/6 inhibitor was received by 20 pts (7.5%) in the PAL+FUL arm and 32 pts (22.2%) in the PBO+FUL arm. ctDNA analyses of tumor mutation profiles (ie, ESR1, PIK3CA, RB1) at the end of treatment and their effect on OS will also be presented. Conclusions: The clinically meaningful improvement in OS with PAL+FUL was maintained with >6 years of median follow-up in pts with HR+/HER2– ABC who had progressed on prior endocrine treatment. Pfizer (NCT01942135) Clinical trial information: NCT01942135 .[Table: see text]
Clinical impact of molecular tumor profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study.
Authors: Church Alanna J. , Corson Laura , Kao Pei-Chi , Imamovic-Tuco Alma , Kang Wenjun , Pinto Navin R. , Maese Luke , Laetsch Theodore Willis , Kim AeRang , Colace Susan , Macy Margaret E , Applebaum Mark A. , Bagatell Rochelle , Sabnis Amit J. , Weiser Daniel , Glade Bender Julia Lynne , Volchenboum Samuel Louis , DuBois Steven G. , London Wendy B. , Janeway Katherine A.
Published: June 2021

10005

Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was > 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.
Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC).
Authors: Jhaveri Komal L. , Boni Valentina , Sohn Joohyuk , Villanueva-Vásquez Rafael , Bardia Aditya , Schmid Peter , Lim Elgene , Patel Jaymin M. , Perez-Fidalgo Jose Alejandro , Loi Sherene , Im Seock-Ah , Kshirsagar Smita , Gates Mary R. , Bond John , Eng-Wong Jennifer , Chang Ching-Wei , Turner Nicholas C. , Lopez Miranda Elena , García-Estévez Laura , Bellet Meritxell
Published: June 2021

1017

Background: Targeting ER activity and/or E synthesis is a mainstay of ER+ BC treatment, but many pts relapse during/after adjuvant endocrine therapy (ET) or develop resistance via ESR1 mutations that drive E-independent transcription and proliferation. Most tumors remain ER signaling-dependent and pts may respond to second-/third-line ET after disease progression (PD) on prior therapies (Di Leo 2010; Baselga 2012). Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated ± palbociclib with encouraging antitumor activity in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797; Jhaveri 2019; Lim 2020). We present updated interim data from the dose-escalation and -expansion single-agent giredestrant cohorts. Methods: Pts had ≤2 prior therapies in the LA/mBC setting with disease recurrence/PD while being treated with adjuvant ET for ≥24 mo and/or ET in the LA/mBC setting, and derived a clinical benefit (CB) from therapy (tumor response/stable disease [SD] ≥6 mo). Pts received 10, 30, 90/100, or 250 mg PO giredestrant QD on D1–28 of each 28-day cycle. Pts were postmenopausal (medical menopause on LHRH agonists was allowed with ≥100 mg giredestrant). Results: Clinical cutoff: Jul 31, 2020; median prior therapy lines in the LA/mBC setting: 1; mean dose intensity: 98%. Safety/activity: see the table below. No adverse events (AEs) led to study drug withdrawal. No dose-limiting toxicities (DLTs) occurred; maximum tolerated dose was not reached. Most common AEs in 107 pts: fatigue (22; 21%), arthralgia (18; 17%), and nausea (17; 16%); largely grade 1/2. Related grade 3 AEs were infrequent (5; 5%); none were grade 4/5 per investigator assessment (grade 5 duodenal perforation occurred with 90/100 mg after stopping giredestrant due to PD). 8 (7%) had bradycardia (none with 10 mg or the 30 mg phase 3 dose; all grade 1 except one grade 2 at 250 mg; no treatment interruptions/dose reductions were required). Objective responses and CB were observed at all doses. Conclusions: Single-agent giredestrant was well tolerated at all doses, with no DLTs. AEs were generally low grade and in keeping with expected AEs for ETs. Clinical activity was observed at all doses. Updated data, including biomarker and correlative data, will be presented. Clinical trial information: NCT03332797 .[Table: see text]
Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
Authors: Hamilton Erika P. , Wang Judy S. , Pluard Timothy J. , Johnston Stephen R. D. , Morikawa Aki , Dees Elizabeth Claire , Jones Robert Hugh , Haley Barbara B. , Armstrong Anne Caroline , Cohen Adam Louis , Munster Pamela N. , Wright Gail Lynn Shaw , Kayali Fadi , Korpal Manav , Xiao Jianjun Alan , Long Jenny , Destenaves Benoit , Gao Lei , Gualberto Antonio , Juric Dejan
Published: June 2021

1018

Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]
Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study.
Authors: Palmieri Carlo , Linden Hannah M. , Birrell Stephen , Lim Elgene , Schwartzberg Lee S. , Rugo Hope S. , Cobb Patrick Wayne , Jain Kirti , Vogel Charles L. , O'Shaughnessy Joyce , Johnston Stephen R. D. , Getzenberg Robert H. , Barnette K. Gary , Steiner Mitchell S. , Brufsky Adam , Overmoyer Beth
Published: June 2021

1020

Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and <40% is 18% (p<0.0001). Best objective tumor response (BOR) in patients with ≥40% AR is 48% and <40% is 0% (p<0.0001). At ≥40% AR, median radiographic progression free survival (rPFS) is 5.47 and mean is 7.15 months vs <40% AR where the median rPFS is 2.72 and mean is 2.7 months. Similar %AR staining correlation was observed in the 18mg cohort. Enobosarm treatment was well tolerated with significant positive effects on quality of life measurements. Conclusions: Enobosarm is a novel oral selective AR activating agent in which a higher % AR staining correlates with a greater antitumor activity. By targeting and activating AR, enobosarm may represent a new hormone treatment approach for AR+/ER+ MBC. The phase 3, ARTEST trial will commence in early 2021 and randomize patients with AR+/ER+/HER2- heavily treated MBC that have progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor to receive enobosarm or standard endocrine therapy. Clinical trial information: NCT02463032 .[Table: see text]
Prevalence of HER2 low in breast cancer subtypes using the VENTANA anti-HER2/neu (4B5) assay.
Authors: Scott Marietta , Vandenberghe Michel Erminio , Scorer Paul , Boothman Anne-Marie , Barker Craig
Published: June 2021

1021

Background: Breast cancer patients with HER2 low expression by immunohistochemistry (IHC), defined as IHC1+ or IHC2+ without gene amplification (ISH-) do not respond to conventional anti-HER2 therapies such as trastuzumab or pertuzumab. The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) showed efficacy in late line HER2-overexpressing patients, with some responses in patients with low HER2 expression. Two of the market leading IHC IVDs are Dako Herceptest and Ventana 4B5. T-DXd is being investigated in HER2 low patients as determined by the VENTANA anti-HER2/neu (4B5) assay in the phase III DESTINY-Breast04 study. There is a paucity of information on prevalence of IHC1+/2+ in different breast cancer subtypes, which this study aims to address. Methods: HER2 status was calculated from 3750 consecutive primary or metastatic breast cancer patient samples successfully stained using the 4B5 assay and scored locally according to ASCO/CAP 2018 guidelines. Samples were obtained from 3 anatomic pathology labs that support networks of US community hospitals. 500 additional breast cancer samples, pre-selected to include a range of IHC staining (concordance cohort), were stained with both 4B5 and HercepTest (Dako/Agilent) and scored (IHC0, IHC1+, IHC2+, IHC3+) at a central laboratory. Results: Prevalence of HER2 categories in 3750 consecutive breast cancer samples is presented in the table below. >50% of estrogen-receptor positive (ER+ve) and progesterone receptor positive (PR+ve) subtypes are HER2 low. In the 500 sample concordance cohort, 28.0% were IHC1+/2+ using the 4B5 assay compared with 11.6% using HercepTest. HercepTest identified IHC1+/2+ staining in 21.6% [95%CI:15.1,29.4] of the patients classified as IHC1+/2+ by 4B5. 98.3% [95%CI: 96.2, 99.5] of samples IHC0 by 4B5 were also IHC0 by Herceptest. Conclusions: HER2 IHC1+/2+ (ISH-) by Ventana 4B5 represent a significant proportion of breast cancer patients and more than 50% of ER+ve and PR+ve subtypes. The 4B5 assay classed several patients as IHC1+/2+ that are IHC0 by Herceptest, but almost all patients IHC0 by 4B5 were also IHC0 by Herceptest.[Table: see text]
A retrospective study of characteristics and survival in patients with breast cancer brain metastases classified by subtype using NCI SEER registry.
Authors: Devanaboyina Monika , Bailey Morgan Marie , Hamouda Danae M.
Published: June 2021

1031

Background: Breast cancer brain metastasis (BCBM) de novo is associated with the worst prognosis among all types of metastases in breast cancer (BC). Analysis of factors associated with BCBM stratified by subtype of BC could lead to earlier identification of metastasis. Methods: 1,268 patients with BCBM at the time of BC diagnosis and known clinical subtype (580 HR+/HER2-, 225 HR+/HER2+, 176 HR-/HER2+, and 287 HR-/HER2-) who were ≥ 20 years of age from 2010 to 2017 were identified using the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program 18 registry. Baseline characteristics and survival were analyzed using Chi-Square and Kaplan-Meier methods. Results: Patients with HR-/HER2+ BC were the most likely to present with BCBM, compared to all BC patients (prevalence of 13.9% vs. 4.7%; p<0.001). Further analysis demonstrated that HER2+ patients had an odds ratio of presenting with BCBM of 2.52 (95% CI: 2.24-2.84) compared to HER2- patients. Interestingly, in patients ages 20-39 with HR-/HER2+ BC, higher rates of brain metastases are noted within the BCBM group compared to all HR-/HER2+ breast cancer cases (28% vs. 7.6%; p<0.001). The same trend is seen within the HR-/HER2+ African American population, with those in the BCBM group experiencing higher rates of brain metastases compared to all BC cases with the same subtype (14.3% vs. 5.9%; p<0.001). Upon exploring insurance demographics, uninsured patients with HR-/HER2+ BCBM had much higher rates of brain metastases compared to all HR-/HER2+ BC cases (14.8% vs 6.4%; p=0.001). When examining TNM status, significant associations were noted between brain metastases and increased tumor and nodal status. Patients with T4 or N3 status with HR-/HER2+ BCBM exhibited much higher rates of metastasis compared to all BC cases with the same subtype (p<0.001). Analysis of survival outcomes showed a median overall survival of 12 months for patients with HR-/HER2+ BCBM. The results displayed in the table below show that HR-/HER2- BCBM patients had the lowest 5-year percent survival, while HR+/HER2+ BCBM patients had the highest 5-year survival. Conclusions: This SEER database study provides insight into the demographics, clinical variables, and outcomes for BC clinical subtypes, specifically HR-/HER2+, from 2010 to 2017 in the United States. HR-/HER2+ breast cancer patients within the noted high-risk populations should be made aware of the increased rates of brain metastases compared to the general BC population, as earlier identification of brain metastases within the HR-/HER2+ cohort could improve patient survival.[Table: see text]
Concordance of HER2+ status by IHC/ISH and ERBB2 status by NGS in a real-world clinicogenomic database and analysis of outcomes in patients (pts) with metastatic breast cancer (mBC).
Authors: Cho-Phan Cheryl D. , Snider Jeremy , Zhang Liangliang , McGregor Kimberly , Schrock Alexa Betzig , Castellanos Emily
Published: June 2021

1036

Background: HER2 overexpression/amplification measured by IHC or ISH is a predictive biomarker for HER2-targeted therapies. Next-generation sequencing (NGS) can identify ERBB2 amplification (amp) and mutations. We examined clinical characteristics, NGS testing patterns, and outcomes of pts treated with 1L HER2 therapy with HER2+ mBC based on ERBB2 amp status using a real-world (RW) clinico-genomic database (CGDB). Methods: Pts with mBC (HER2+ by IHC and/or ISH) treated with 1L HER2 therapy who had undergone NGS and were treated within the Flatiron Health (FH) network were eligible. Clinical characteristics and HER2 testing results were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports and linked to genomic data from Foundation Medicine (FMI) in the nationwide (US-based), de-identified FH-FMI CGDB. Demographic, clinical and genomic characteristics were summarized and stratified by concordance between HER2+ (IHC 3+ or ISH amp+) and ERBB2amp+ status [copy number (CN) ≥ 5]. NGS testing patterns and 1L HER2 therapy were characterized and stratified by concordance status. Concordance was assessed based on contemporaneous timing of paired test specimen collection dates (FMI NGS ≤ 30 days of HER2+ status). RW overall survival (rwOS) stratified by HER2+/ ERBB2 amp concordance was estimated with Kaplan-Meier analysis and adjusted Cox proportional hazards models. Results: Among 268 eligible pts, HER2+/ ERBB2amp+ concordance was 66% (176/268); concordance among contemporaneous paired specimens was 73% (106/145). Demographic and clinical features were overall well-balanced with most pts treated at community sites [94%, (252/268)]; the discordant (HER2+/ ERBB2amp-) group (95/268) had more pts with hormone receptor positive disease (73% vs 62%). Concordance by assay type varied; IHC+ only, IHC+/ISH+, and ISH+ only agreement was 72% (95/132), 76% (26/34) and 52% (50/96), respectively. A higher proportion of discordance (35% vs 19%) was seen in pts treated at community vs. academic sites. Median rwOS was 32.9 months (IQR 25.9-38.9) among concordant (HER2+/ ERBB2amp+) and 15.5 months (IQR 8.9-30.1) among discordant (HER2+/ ERBB2amp-) pts, aHR = 0.71 [95% CI: 0.48-1.03; p = 0.073]. Conclusions: Among RW pts with HER2+ mBC receiving 1L HER2 therapy, discordance between ERBB2amp and IHC/ISH HER2 testing methods was observed. Pts with tumors HER2+ by IHC and/or ISH but negative for ERBB2amp had a trend towards worse rwOS following receipt of HER2 therapy compared to concordant cases. Contemporaneous timing of specimen collection was associated with greater concordance. Future analyses on the additive value of ERBB2 CN as a predictive marker, and assessing factors that may affect discordance such as intratumor HER2 heterogeneity, tumor content, and biopsy site are warranted.
Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB).
Authors: Curigliano Giuseppe , Mueller Volkmar , Borges Virginia F. , Hamilton Erika P. , Hurvitz Sara A. , Loi Sherene , Murthy Rashmi Krishna , Okines Alicia Frances Clare , Paplomata Elisavet , Cameron David A. , Carey Lisa A. , Gelmon Karen A. , Hortobagyi Gabriel N. , Krop Ian E. , Loibl Sibylle , Pegram Mark D. , Slamon Dennis J. , Ramos Jorge , Zhang Chiyu , Winer Eric P.
Published: June 2021

1043

Background: Tucatinib (TUC) is an oral tyrosine kinase inhibitor (TKI) highly specific for HER2. TUC is approved for use in combination with trastuzumab (T) and capecitabine (C) in patients (pts) with and without brain metastases (BM) who have received 1 or more prior anti-HER2–based regimens in the metastatic setting. In the primary analysis from the pivotal HER2CLIMB trial, the addition of TUC to T and C in pts with HER2+ metastatic breast cancer showed a statistically significant and clinically meaningful prolongation of progression-free (PFS) (HR = 0.54 [95% CI: 0.42, 0.71]; P < 0.001) and overall survival (OS) (HR = 0.66 [95% CI: 0.50, 0.88]; P = 0.005) (Murthy, et al. NEJM 2020). TUC in combination with T and C was well tolerated with few discontinuations other than for disease progression. Based on these data, the protocol was amended for unblinding of sites to treatment assignment to allow for crossover from the placebo arm to receive TUC in combination with T and C. Methods: HER2CLIMB (NCT02614794) is a global, randomized, double-blind, placebo-controlled trial in pts with unresectable locally advanced or metastatic HER2+ breast cancer previously treated with T, pertuzumab, and T-emtansine (T-DM1), including pts with untreated, treated stable, or treated and progressing BM. Overall 612 pts were randomized 2:1 to receive TUC 300 mg BID or placebo, each in combination with T and C. Randomization was stratified by BM, ECOG performance status, and geographic region. Protocol prespecified analysis of OS, PFS (by investigator assessment) and safety in the total study population will be performed at approximately 2 years from the last patient randomized. Results: Updated Kaplan-Meier time-to-event analysis of OS and PFS with hazard ratios and 95% confidence intervals for TUC arm vs placebo arm will be presented overall, as well as for OS in the prespecified subgroups reported previously (Murthy, et al. NEJM 2020). Safety and tolerability assessments will include frequency of adverse events by severity, dose modifications and discontinuation of study medications. Conclusions: Conclusions will be presented in the presentation. Clinical trial information: NCT02614794 .