A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research

Robotic Wireless Sensor Networks

In this chapter, we present a literature survey of an emerging, cutting-edge, and multi-disciplinary field of research at the intersection of Robotics and Wireless Sensor Networks (WSN) which we refer to as Robotic Wireless Sensor Networks (RWSN). We define a RWSN as an autonomous networked multi-robot system that aims to achieve certain sensing goals while meeting and maintaining certain communication performance requirements, through cooperative control, learning and adaptation. While both of the component areas, i.e., Robotics and WSN, are very well-known and well-explored, there exist a whole set of new opportunities and research directions at the intersection of these two fields which are relatively or even completely unexplored. One such example would be the use of a set of robotic routers to set up a temporary communication path between a sender and a receiver that uses the controlled mobility to the advantage of packet routing. We find that there exist only a limited number of articles to be directly categorized as RWSN related works whereas there exist a range of articles in the robotics and the WSN literature that are also relevant to this new field of research. To connect the dots, we first identify the core problems and research trends related to RWSN such as connectivity, localization, routing, and robust flow of information. Next, we classify the existing research on RWSN as well as the relevant state-of-the-arts from robotics and WSN community according to the problems and trends identified in the first step. Lastly, we analyze what is missing in the existing literature, and identify topics that require more research attention in the future

Serotypes and Clonal Composition of Streptococcus pneumoniae Isolates Causing IPD in Children and Adults in Catalonia before 2013 to 2015 and after 2017 to 2019 Systematic Introduction of PCV13

The goal of this study was to investigate the distribution of serotypes and clonal composition of Streptococcus pneumoniae isolates causing invasive pneumococcal disease (IPD) in Catalonia, before and after systematic introduction of PCV13. Pneumococcal strains isolated from normally sterile sites obtained from patients of all ages with IPD received between 2013 and 2019 from 25 health centers of Catalonia were included. Two study periods were defined: presystematic vaccination period (2013 and 2015) and systematic vaccination period (SVP) (2017 to 2019). A total of 2,303 isolates were analyzed. In the SVP, there was a significant decrease in the incidence of IPD cases in children 5 to 17 years old (relative risk [RR] 0.61; 95% confidence interval [CI] 0.38 to 0.99), while there was a significant increase in the incidence of IPD cases in 18- to 64-year-old adults (RR 1.33; 95% CI 1.16 to 1.52) and adults over 65 years old (RR 1.23; 95% CI 1.09 to 1.38). Serotype 8 was the major emerging serotype in all age groups except in 5- to 17-year-old children. In children younger than 5 years old, the main serotypes in SVP were 24F, 15A, and 3, while in adults older than 65 years they were serotypes 3, 8, and 12F. A significant decrease in the proportions of clonal complexes CC156, CC191, and ST306 and an increase in those of CC180, CC53, and CC404 were observed. A steady decrease in the incidence of IPD caused by PCV13 serotypes indicates the importance and impact of systematic vaccination. The increase of non-PCV13 serotypes highlights the need to expand serotype coverage in future vaccines and rethink vaccination programs for older adults. IMPORTANCE We found that with the incorporation of the PCV13 vaccine, the numbers of IPD cases caused by serotypes included in this vaccine decreased in all of the age groups. Still, there was an unforeseen increase of the serotypes not included in this vaccine causing IPD, especially in the >65-year-old group. Moreover, a significant increase of serotype 3 included in the vaccine has been observed; this event has been reported by other researchers. These facts call for the incorporation of more serotypes in future vaccines and a more thorough surveillance of the dynamics of this microorganism

Amoeba Techniques for Shape and Texture Analysis

Morphological amoebas are image-adaptive structuring elements for morphological and other local image filters introduced by Lerallut et al. Their construction is based on combining spatial distance with contrast information into an image-dependent metric. Amoeba filters show interesting parallels to image filtering methods based on partial differential equations (PDEs), which can be confirmed by asymptotic equivalence results. In computing amoebas, graph structures are generated that hold information about local image texture. This paper reviews and summarises the work of the author and his coauthors on morphological amoebas, particularly their relations to PDE filters and texture analysis. It presents some extensions and points out directions for future investigation on the subject.Comment: 38 pages, 19 figures v2: minor corrections and rephrasing, Section 5 (pre-smoothing) extende

Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy: ER activity in pre-menopausal HR+ breast cancer during CT

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation. Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels. Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy. Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods. Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of “Departament de Salut”, exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s

The Bank of Standardized Stimuli (BOSS), a New Set of 480 Normative Photos of Objects to Be Used as Visual Stimuli in Cognitive Research

There are currently stimuli with published norms available to study several psychological aspects of language and visual cognitions. Norms represent valuable information that can be used as experimental variables or systematically controlled to limit their potential influence on another experimental manipulation. The present work proposes 480 photo stimuli that have been normalized for name, category, familiarity, visual complexity, object agreement, viewpoint agreement, and manipulability. Stimuli are also available in grayscale, blurred, scrambled, and line-drawn version. This set of objects, the Bank Of Standardized Stimuli (BOSS), was created specifically to meet the needs of scientists in cognition, vision and psycholinguistics who work with photo stimuli

An Ecological Alternative to Snodgrass & Vanderwart: 360 High Quality Colour Images with Norms for Seven Psycholinguistic Variables

This work presents a new set of 360 high quality colour images belonging to 23 semantic subcategories. Two hundred and thirty-six Spanish speakers named the items and also provided data from seven relevant psycholinguistic variables: age of acquisition, familiarity, manipulability, name agreement, typicality and visual complexity. Furthermore, we also present lexical frequency data derived from Internet search hits. Apart from the high number of variables evaluated, knowing that it affects the processing of stimuli, this new set presents important advantages over other similar image corpi: (a) this corpus presents a broad number of subcategories and images; for example, this will permit researchers to select stimuli of appropriate difficulty as required, (e.g., to deal with problems derived from ceiling effects); (b) the fact of using coloured stimuli provides a more realistic, ecologically-valid, representation of real life objects. In sum, this set of stimuli provides a useful tool for research on visual object-and word- processing, both in neurological patients and in healthy controls

Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

International audienc