Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

Comparative biological activity of palbociclib and ribociclib in hormone receptor-positive breast cancer.

This study examines the biological effects of palbociclib and ribociclib in hormone receptor-positive breast cancer, pivotal to the HARMONIA prospective phase III clinical trial. We explore the downstream impacts of these CDK4/6 inhibitors, focusing on cell lines and patient-derived tumor samples. We treated HR+ breast cancer cell lines (T47D, MCF7, and BT474) with palbociclib or ribociclib (100 nM or 500 nM), alone or combined with fulvestrant (1 nM), over periods of 24, 72, or 144 h. Our assessments included PAM50 gene expression, RB1 phosphorylation, Lamin-B1 protein levels, and senescence-associated ß-galactosidase activity. We further analyzed PAM50 gene signatures from the CORALLEEN and NeoPalAna phase II trials. Both CDK4/6 inhibitors similarly inhibited proliferation across the cell lines. At 100 nM, both drugs partially reduced p-RB1, with further decreases at 500 nM over 144 h. Treatment led to reduced Lamin-B1 expression and increased senescence-associated ß-galactosidase activity. Both drugs enhanced Luminal A and reduced Luminal B and proliferation signatures at both doses. However, the HER2-enriched signature significantly diminished only at the higher dose of 500 nM. Corresponding changes were observed in tumor samples from the CORALLEEN and NeoPalAna studies. At 2 weeks of treatment, both drugs significantly reduced the HER2-enriched signature, but at surgery, this reduction was consistent only with ribociclib. Our findings suggest that while both CDK4/6 inhibitors effectively modulate key biological pathways in HR+/HER2- breast cancer, nuances in their impact, particularly on the HER2-enriched signature, are dose-dependent, influenced by the addition of fulvestrant and warrant further investigation.

Prognosis and treatment outcomes for patients with stage IA triple-negative breast cancer.

To evaluate the role of chemotherapy in stage IA triple-negative breast cancer, we conducted a retrospective population-based study including 8601 patients. The use of chemotherapy significantly increased from 2010 to 2019 in patients with T1b and T1c tumors (p = 0.001 and p < 0.001, respectively). Receipt of chemotherapy was associated with improved breast cancer-specific survival (BCSS, adjusted hazard ratio = 0.70; p = 0.006), particularly in patients with T1c tumors (5-year BCSS 94.5% vs. 91.2%).

Management of early-stage HER2-positive breast cancer and attitudes towards HER2DX test in Spain: insights from a nationwide survey.

PURPOSE: This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. METHODS: An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. RESULTS: The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. CONCLUSION: In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

A 14-gene B-cell immune signature in early-stage triple-negative breast cancer (TNBC): a pooled analysis of seven studies.

BACKGROUND: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC. METHODS: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper. FINDINGS: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I2 = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I2 = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I2 = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I2 = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis. INTERPRETATION: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments. FUNDING: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Sklodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM.

Establecimiento del esquema de purificación de los antígenos de SOBERANA®02, SOBERANA®Plus y SOBERANA 01 / Establishment of the purification scheme for SOBERANA®02, SOBERANA®Plus and SOBERANA 01 antigens

La urgente necesidad de desarrollar y producir vacunas seguras y efectivas para garantizar la reducción de la propagación del coronavirus de tipo 2 causante del síndrome respiratorio agudo severo, hizo que el Centro de Inmunología Molecular y el Instituto Finlay de Vacunas, desarrollaran dos vacunas y un candidato vacunal contra la COVID-19, que tienen como componente la molécula del dominio de unión al receptor (aa 319-541) del virus. Para establecer el proceso productivo, se realizaron experimentos en los posibles pasos del proceso de purificación de la molécula del dominio de unión al receptor (aa 319-541), con vistas a su posterior transferencia tecnológica a escala industrial. Dicha molécula está fusionada con una etiqueta de hexahistidina en su extremo C-terminal y presenta nueve residuos de cisteína en su secuencia que forman cuatro enlaces disulfuros intramoleculares, quedando una cisteína libre que permite obtener dos moléculas: dimérica y monomérica, antígenos que forman parte de las vacunas SOBERANA®02 y SOBERANA®Plus y el candidato vacunal SOBERANA 01. Se determinaron las mejores condiciones de adsorción de las matrices cromatográficas de afinidad por quelatos metálicos, intercambio catiónico y exclusión molecular. Se evaluó el desempeño del proceso a escala piloto y se caracterizó la molécula de acuerdo a sus propiedades físico-químicas y biológicas. Los resultados obtenidos mostraron un 60,02 ± 5,15por ciento de recuperación total de la proteína de interés, con más del 98% de pureza en ambas moléculas, una eficiente remoción de contaminantes y una antigenicidad mayor del 90por ciento referido al monómero control del dominio de unión al receptor con 99 por ciento de pureza, lo que demuestra que el proceso establecido es eficiente en la obtención de un producto con la calidad requerida(AU)

The urgent need to develop and produce safe and effective vaccines to guarantee the reduction of the spread of the type 2 coronavirus that causes severe acute respiratory syndrome, led the Center for Molecular Immunology and the Finlay Vaccine Institute to develop two vaccines and one candidate vaccine to combat the 2019 coronavirus pandemic. As part of the establishment of the production process, experiments were carried out on the possible steps of the purification process of the receptor binding domain molecule (aa 319-541) with a view to its subsequent technological transfer on an industrial scale. This molecule is fused with a hexahistidine tag at its C-terminal end and has nine cysteine residues in its sequence that form four intramolecular disulfide bonds; leaving a free cysteine that allows two molecules to be obtained: dimeric and monomeric, which constitute the antigens of the SOBERANA®02 and SOBERANA®Plus vaccines and the SOBERANA 01 vaccine candidate. The best adsorption conditions of the chromatographic matrices of affinity for metal chelates, cationic exchange and molecular exclusion were determined. The performance of the process was evaluated on a pilot scale and the molecule was characterized according to its physical-chemical and biological properties. The results obtained showed a 60.02 ± 5.15percent total recovery of the protein of interest with more than 98% purity in both molecules, an efficient removal of contaminants and an antigenicity greater than 90percent referred to the control monomer of the domain receptor binding with 99% purity; which demonstrates that the established process is efficient in obtaining a product with the required quality(AU)

PEGylation Strategy for Improving the Pharmacokinetic and Antitumoral Activity of the IL-2 No-alpha Mutein.

BACKGROUND: In a previous work, an IL-2Rßγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems. OBJECTIVE: In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein. METHODS: Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies. RESULTS: IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently. CONCLUSION: PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses.

Evaluation of OMOP CDM, i2b2 and ICGC ARGO for supporting data harmonization in a breast cancer use case of a multicentric European AI project.

OBJECTIVE: Observational research in cancer poses great challenges regarding adequate data sharing and consolidation based on a homogeneous data semantic base. Common Data Models (CDMs) can help consolidate health data repositories from different institutions minimizing loss of meaning by organizing data into a standard structure. This study aims to evaluate the performance of the Observational Medical Outcomes Partnership (OMOP) CDM, Informatics for Integrating Biology & the Bedside (i2b2) and International Cancer Genome Consortium, Accelerating Research in Genomic Oncology (ICGC ARGO) for representing non-imaging data in a breast cancer use case of EuCanImage. METHODS: We used ontologies to represent metamodels of OMOP, i2b2, and ICGC ARGO and variables used in a cancer use case of a European AI project. We selected four evaluation criteria for the CDMs adapted from previous research: content coverage, simplicity, integration, implementability. RESULTS: i2b2 and OMOP exhibited higher element completeness (100% each) than ICGC ARGO (58.1%), while the three achieved 100% domain completeness. ICGC ARGO normalizes only one of our variables with a standard terminology, while i2b2 and OMOP use standardized vocabularies for all of them. In terms of simplicity, ICGC ARGO and i2b2 proved to be simpler both in terms of ontological model (276 and 175 elements, respectively) and in the queries (7 and 20 lines of code, respectively), while OMOP required a much more complex ontological model (615 elements) and queries similar to those of i2b2 (20 lines). Regarding implementability, OMOP had the highest number of mentions in articles in PubMed (130) and Google Scholar (1,810), ICGC ARGO had the highest number of updates to the CDM since 2020 (4), and i2b2 is the model with more tools specifically developed for the CDM (26). CONCLUSION: ICGC ARGO proved to be rigid and very limited in the representation of oncologic concepts, while i2b2 and OMOP showed a very good performance. i2b2's lack of a common dictionary hinders its scalability, requiring sites that will share data to explicitly define a conceptual framework, and suggesting that OMOP and its Oncology extension could be the more suitable choice. Future research employing these CDMs with actual datasets is needed.

Assessment of the HER2DX Assay in Patients With ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab.

Importance: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+ BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy. Objective: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+ BC who are receiving deescalated neoadjuvant therapy. Design, Setting, and Participants: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+ BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles. Interventions and Exposures: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+ BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial. Main Outcomes and Measures: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0). Results: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P < .001). The pCR rates in the HER2DX high, medium, and low pCR score groups were 92.6%, 63.6%, and 29.0%, respectively (high vs low odds ratio, 30.6; P < .001). The HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, ERBB2 immunohistochemistry score, HER2DX ERBB2 expression score, and prediction analysis of microarray 50 ERBB2-enriched subtype. The correlation between the HER2DX pCR score and prognostic risk score was weak (Pearson coefficient, -0.12). Performance of the risk score could not be assessed due to lack of recurrence events. Conclusions and Relevance: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+ BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches.

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer.

Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.

Individualizing Curative-Intent Therapy in HER2-Positive Early-Stage Breast Cancer.

OPINION STATEMENT: Human epidermal growth factor receptor 2-positive (HER2+) breast cancers have been historically considered an aggressive entity with high rates of recurrence and poor survival. However, during the last 20 years, there has been a dramatic change in prognosis due to the incorporation of different anti-HER2 therapies into the neo/adjuvant chemotherapy backbone. Neoadjuvant dual blockade with trastuzumab and pertuzumab has become the standard of care for women with stage II and III HER2+ breast cancer. Trastuzumab emtansine (T-DM1) has been shown to improve outcomes if pathological complete response (pCR) is not achieved, and adjuvant extended therapy with neratinib has increased disease-free survival (DFS) and may have an impact in central nervous system (CNS) recurrences. However, these agents are both toxic for individual patients and costly for the overall healthcare system, and there are still patients that experience recurrence despite therapy improvements. At the same time, it has been shown that some patients with early-stage HER2+ breast cancer can be effectively treated with less intensive systemic therapy, using only taxane and trastuzumab, or that the chemotherapy backbone can be omitted completely. The current challenge is to properly identify which patients can receive a de-intensified regimen and which need new intensification strategies. Tumor size, nodal status, and pCR achievement after neoadjuvant treatment are well-known risk factors that can aid in making clinical decisions, but they do not accurately predict all patient outcomes. Various biomarkers have been proposed to better characterize the clinical and biological heterogeneity of HER2+ breast cancer. Immune infiltration, intrinsic subtype, intratumoral heterogeneity, and dynamic changes during treatment have been described as important prognostic and/or predictive features. The integration of all these factors will be key in the proper identification of the true risk, and individualized treatment strategy, for each patient.

Nodal positivity and systemic therapy among patients with clinical T1-T2N0 human epidermal growth factor receptor-positive breast cancer: Results from two international cohorts.

BACKGROUND: The optimal treatment strategy for patients with small human epidermal growth factor receptor 2 (HER2)-positive tumors is based on nodal status. The authors' objective was to evaluate pathologic nodal disease (pathologic lymph node-positive [pN-positive] and pathologic lymph node-positive after preoperative systemic therapy [ypN-positive]) rates in patients who had clinical T1-T2 (cT1-cT2)N0M0, HER2-positive breast cancer treated with upfront surgery or neoadjuvant chemotherapy (NAC). METHODS: Two databases were queried for patients who had cT1-cT2N0M0, HER2-positive breast cancer: (1) the Dana-Farber Brigham Cancer Center (DF/BCC) from February 2015 to October 2020 and (2) the Hospital Clinic of Barcelona and the Hospital Clinico of Valencia (HCB/HCV) from January 2012 to September 2021. The pN-positive/ypN-positive and axillary lymph node dissection (ALND) rates were compared between patients who underwent upfront surgery versus those who received NAC. RESULTS: Among 579 patients from the DF/BCC database, 368 underwent upfront surgery, and 211 received NAC; the rates of nodal positivity were 19.8% and 12.8%, respectively (p = .021). The pN-positive rates increased by tumor size (p < .001), reaching 25% for those with cT1c tumors. The ypN-positive rates did not correlate with tumor size. NAC was associated with decreased nodal positivity (odds ratio, 0.411; 95% confidence interval, 0.202-0.838), but the ALND rates were similar (22 of 368 patients [6.0%] who underwent upfront surgery vs. 18 of 211 patients [8.5%] who received NAC; p = .173). Among 292 patients from the HCB/HCV database, 119 underwent upfront surgery, and 173 received NAC; the rates of nodal positivity were 21% and 10.4%, respectively (p = .012). The pN-positive rates increased with tumor size (p = .011). The ALND rates were equivalent by treatment strategy (23 of 119 patients [19.3%] who underwent upfront surgery vs. 24 of 173 patients [13.9%] who received NAC; p = .213). CONCLUSIONS: Among patients who had cT1-cT2N0M0, HER2-positive breast cancer, approximately 20% who underwent upfront surgery were pN-positive, and the rate reached 25% for those with cT1c tumors. Given the opportunity for tailored therapy among lymph node-positive, HER2-positive patients, these data provide rationale for future analyses investigating the utility of routine axillary imaging in patients with HER2-positive breast cancer.

Recomendaciones de «no hacer» en cuidados intensivos pediátricos en España: selección por método Delphi / Paediatric intensive care ‘do not do’ recommendations in Spain: Selection by Delphi method

Introducción: La asistencia sanitaria no está exenta de prácticas diagnósticas y terapéuticas poco efectivas, inseguras o ineficientes. Como reacción han sido propuestas recomendaciones de «no hacer» por diferentes sociedades científicas y autoridades sanitarias. Nuestro objetivo fue seleccionar y consensuar un grupo de recomendaciones de «no hacer» (RNH) en cuidados intensivos pediátricos en España. Material y método: Esta investigación se desarrolló en dos fases: primera, recopilación de posibles RNH; segunda, selección por método Delphi de las más importantes según prevalencia de la práctica a modificar, gravedad de sus potenciales riesgos, y facilidad con la que podría ser modificada. Tanto las propuestas como las evaluaciones fueron realizadas por miembros de grupos de trabajo de la Sociedad Española de Cuidados Intensivos Pediátricos (SECIP) coordinados por correo electrónico. El listado inicial de RNH fue reduciéndose en base al coeficiente de variación (<80%) de sus evaluaciones. Resultados: Fueron propuestas 182 RNH por 30 intensivistas. Los 14 evaluadores del Delphi lograron reducir el set inicial a 85 RNH y tras una segunda ronda se llegó a la selección final de 26 RNH. Las dimensiones de calidad más representadas en nuestro set final son la efectividad clínica y la seguridad de pacientes. Conclusiones: Nuestro trabajo ha permitido seleccionar y consensuar una serie de recomendaciones para evitar prácticas inseguras, ineficientes o inefectivas en intensivos pediátricos en España, lo que podría ser útil para mejorar la calidad de nuestra actividad clínica. (AU)

Introduction: Health care is not free of ineffective, unsafe or inefficient diagnostic and therapeutic practices. To address this, different scientific societies and health authorities have proposed ‘do not do’ recommendations (DNDRs). Our goal was the selection by consensus of a set of DNDRs for paediatric intensive care in Spain. Material and method: The research was carried out in two phases: first, gathering potential DNDRs; second, selecting the most important ones, using the Delphi method, based on the prevalence of the practice to be modified, the severity of its potential risks and the ease with which it could be modified. Proposals and evaluations were both made by members of working groups of the Sociedad Española de Cuidados Intensivos Pediátricos (SECIP, Spanish Society of Paediatric Intensive Care), coordinated by email. The initial set of DNDRs was reduced based on the coefficient of variation (<80%) of the corresponding evaluations. Results: A total of 182 DNDRs were proposed by 30 intensivists. The 14 Delphi evaluators managed to pare down the initial set to 85 DNDRs and, after a second round, to the final set of 26 DNDRs. The care quality dimensions most represented in the final set are clinical effectiveness and patient safety. Conclusions: This study allowed the selection by consensus of a series of recommendations to avoid unsafe, inefficient or ineffective practices in paediatric intensive care in Spain, which could be useful for improving the quality of clinical care in our field. (AU)

Paediatric intensive care 'do not do' recommendations in Spain: Selection by Delphi method.

INTRODUCTION: Health care is not free of ineffective, unsafe or inefficient diagnostic and therapeutic practices. To address this, different scientific societies and health authorities have proposed 'do not do' recommendations (DNDRs). Our goal was the selection by consensus of a set of DNDRs for paediatric intensive care in Spain. MATERIAL AND METHOD: The research was carried out in 2 phases: first, gathering potential DNDRs; second, selecting the most important ones, using the Delphi method, based on the prevalence of the practice to be modified, the severity of its potential risks and the ease with which it could be modified. Proposals and evaluations were both made by members of working groups of the Sociedad Española de Cuidados Intensivos Pediátricos (SECIP, Spanish Society of Paediatric Intensive Care), coordinated by email. The initial set of DNDRs was reduced based on the coefficient of variation (<80%) of the corresponding evaluations. RESULTS: A total of 182 DNDRs were proposed by 30 intensivists. The 14 Delphi evaluators managed to pare down the initial set to 85 DNDRs and, after a second round, to the final set of 26 DNDRs. The care quality dimensions most represented in the final set are clinical effectiveness and patient safety. CONCLUSIONS: This study allowed the selection by consensus of a series of recommendations to avoid unsafe, inefficient or ineffective practices in paediatric intensive care in Spain, which could be useful for improving the quality of clinical care in our field.

HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.

Aquaporin-4-Positive Triple-Negative Breast Cancer Presenting with Paraneoplastic Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory central nervous system disorder that preferentially affects the optic nerve and the spinal cord. Although NMOSD is more commonly an idiopathic autoimmune condition associated with antibodies against aquaporin-4 (AQP4)-IgG, the disease may also occur as a paraneoplastic syndrome in rare instances. In these cases, the expression of AQP4 by the tumor is likely the trigger of the autoimmune response. CASE PRESENTATION: We describe the case of a 32-year-old woman who presented with progressive tetraparesis, cranial involvement, respiratory failure, and spinal cord MRI compatible with longitudinally extensive transverse myelitis, few days after being diagnosed with a T3N1M0 triple-negative right breast cancer. Due to the history of concurrent breast cancer and after ruling out metastatic spinal cord involvement, the possibility of a paraneoplastic origin was raised. AQP4-IgG were found in the serum and CSF by cell-based assay, confirming the diagnosis of NMOSD. The patient was treated with corticosteroids, plasma exchange, and rituximab. Concomitantly, breast cancer therapy was started with an adapted neoadjuvant chemotherapy scheme based on carboplatin and paclitaxel. An initial slight improvement slowed down; so, a right mastectomy with lymphadenectomy was performed. Expression of AQP4 was demonstrated in the tumor. The patient presented a significant neurological improvement after combined treatment regaining muscular balance and strength in upper and lower extremities. CONCLUSION: NMOSD may have a paraneoplastic origin associated with breast cancer and the importance of its early detection since the combination of tumoral and immunosuppressive therapy may improve the patient's prognosis.

Gene expression profiles of breast cancer metastasis according to organ site.

In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry-based groups. Second, HER2-low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype-related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ-specific and subtype-independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.