Surgery of the primary tumor in patients with de novo metastatic breast cancer: a nationwide population-based retrospective cohort study in Belgium.

PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

The impact of erythropoiesis-stimulating agents administration concomitantly with adjuvant anti-HER2 treatments on the outcomes of patients with early breast cancer: a sub-analysis of the ALTTO study.

PURPOSE: To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC). METHODS: ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared. RESULTS: Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54 years, 39.0% premenopausal, most had tumor size > 2 cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1 years (IQR 5.3-7.0) vs. 6.9 years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41). CONCLUSION: ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes.

Evaluation of walking activity and gait to identify physical and mental fatigue in neurodegenerative and immune disorders: preliminary insights from the IDEA-FAST feasibility study.

BACKGROUND: Many individuals with neurodegenerative (NDD) and immune-mediated inflammatory disorders (IMID) experience debilitating fatigue. Currently, assessments of fatigue rely on patient reported outcomes (PROs), which are subjective and prone to recall biases. Wearable devices, however, provide objective and reliable estimates of gait, an essential component of health, and may present objective evidence of fatigue. This study explored the relationships between gait characteristics derived from an inertial measurement unit (IMU) and patient-reported fatigue in the IDEA-FAST feasibility study. METHODS: Participants with IMIDs and NDDs (Parkinson's disease (PD), Huntington's disease (HD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (PSS), and inflammatory bowel disease (IBD)) wore a lower-back IMU continuously for up to 10 days at home. Concurrently, participants completed PROs (physical fatigue (PF) and mental fatigue (MF)) up to four times a day. Macro (volume, variability, pattern, and acceleration vector magnitude) and micro (pace, rhythm, variability, asymmetry, and postural control) gait characteristics were extracted from the accelerometer data. The associations of these measures with the PROs were evaluated using a generalised linear mixed-effects model (GLMM) and binary classification with machine learning. RESULTS: Data were recorded from 72 participants: PD = 13, HD = 9, RA = 12, SLE = 9, PSS = 14, IBD = 15. For the GLMM, the variability of the non-walking bouts length (in seconds) with PF returned the highest conditional R2, 0.165, and with MF the highest marginal R2, 0.0018. For the machine learning classifiers, the highest accuracy of the current analysis was returned by the micro gait characteristics with an intrasubject cross validation method and MF as 56.90% (precision = 43.9%, recall = 51.4%). Overall, the acceleration vector magnitude, bout length variation, postural control, and gait rhythm were the most interesting characteristics for future analysis. CONCLUSIONS: Counterintuitively, the outcomes indicate that there is a weak relationship between typical gait measures and abnormal fatigue. However, factors such as the COVID-19 pandemic may have impacted gait behaviours. Therefore, further investigations with a larger cohort are required to fully understand the relationship between gait and abnormal fatigue.

Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice.

BACKGROUND: New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) privileges real-world data. As part of the ongoing HTA, this study aimed to evaluate the effectiveness of palbociclib with aromatase inhibitors (AI) and compare it with the efficacy reported in PALOMA-2. METHODS: A population-based retrospective exposure cohort study was conducted including all patients initiating treatment in Portugal with palbociclib under early access use and registered in the National Oncology Registry. The primary outcome was progression free survival (PFS). Secondary outcomes considered included time to palbociclib failure (TPF), overall survival (OS), time to next treatment (TTNT), and proportion of patients discontinuing treatment due to  adverse events (AEs). The Kaplan-Meier method was used and median, 1- and 2-year survival rates were computed, with two-sided 95% confidence intervals (95%CI). STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were used. RESULTS: There were 131 patients included. Median follow-up was 28.3 months (IQR: 22.7-35.2) and median duration of treatment was 17.5 months (IQR: 7.8-29.1). Median PFS was 19.5 months (95%CI 14.2-24.2), corresponding to a 1-year PFS rate of 67.9% (95%CI 59.2-75.2) and a 2-year PFS rate of 42.0% (95%CI 33.5-50.3). Sensitivity analysis showed median PFS would increase slightly when excluding those not initiating treatment with the recommended dose, raising to 19.8 months (95%CI 14.4-28.9). By considering only patients meeting PALOMA-2 criteria, we could observe a major difference in treatment outcomes, with a mean PFS of 28.8 months (95%CI 19.4-36.0). TPF was 19.8 months (95%CI 14.2-24.9). Median OS was not reached. Median TTNT was 22.5 months (95%CI 18.0-29.8). A total of 14 patients discontinued palbociclib because of AEs (10.7%). CONCLUSIONS: Data suggest palbociclib with AI to have an effectiveness of 28.8 months, when used in patients with overlapping characteristics to those used in PALOMA-2. However, when used outside of these eligibility criteria, namely in patients with less favorable prognosis (e.g., presence of visceral disease), the benefits are inferior, even though still favorable.

Direct oral anticoagulants vs vitamin K antagonist on dementia risk in atrial fibrillation: systematic review with meta-analysis.

Oral anticoagulation significantly reduces the incidence of dementia in atrial fibrillation patients. However, this protective effect has not been compared between Direct Oral Anticoagulants (DOAC) and Vitamin K antagonists' anticoagulants (VKA). We conducted an electronic search for potentially eligible studies through the bibliographic databases MEDLINE, CENTRAL, ClinicalTrials.gov, EMBASE and Web of Science. The outcome of interest was dementia. Random-effects meta-analysis was performed. Nine observational studies were included and 1,175,609 atrial fibrillation patients were enrolled. DOAC therapy was associated with a significant reduction when compared with patients under VKA therapy (hazard ratio 0.89; 95% confidence interval 0.80-0.99). The grade of confidence of our results was very low due to the risk of bias. DOAC therapy is associated with a significant decrease in the risk of dementia when compared with VKA therapy. However, the low certainty of the evidence along with the paucityof clinical trials dedicated to answering this important question underscores a need for global clinical research initiatives.

A Systematic Review of International Affective Picture System (IAPS) around the World.

Standardized Emotion Elicitation Databases (SEEDs) allow studying emotions in laboratory settings by replicating real-life emotions in a controlled environment. The International Affective Pictures System (IAPS), containing 1182 coloured images as stimuli, is arguably the most popular SEED. Since its introduction, multiple countries and cultures have validated this SEED, making its adoption on the study of emotion a worldwide success. For this review, 69 studies were included. Results focus on the discussion of validation processes by combining self-report and physiological data (Skin Conductance Level, Heart Rate Variability and Electroencephalography) and self-report only. Cross-age, cross-cultural and sex differences are discussed. Overall, IAPS is a robust instrument for emotion elicitation around the world.

Brewer's Spent Yeast Cell Wall Polysaccharides as Vegan and Clean Label Additives for Mayonnaise Formulation.

Brewer's spent yeast (BSY) mannoproteins have been reported to possess thickening and emulsifying properties. The commercial interest in yeast mannoproteins might be boosted considering the consolidation of their properties supported by structure/function relationships. This work aimed to attest the use of extracted BSY mannoproteins as a clean label and vegan source of ingredients for the replacement of food additives and protein from animal sources. To achieve this, structure/function relationships were performed by isolating polysaccharides with distinct structural features from BSY, either by using alkaline extraction (mild treatment) or subcritical water extraction (SWE) using microwave technology (hard treatment), and assessment of their emulsifying properties. Alkaline extractions solubilized mostly highly branched mannoproteins (N-linked type; 75%) and glycogen (25%), while SWE solubilized mannoproteins with short mannan chains (O-linked type; 55%) and (1→4)- and (ß1→3)-linked glucans, 33 and 12%, respectively. Extracts with high protein content yielded the most stable emulsions obtained by hand shaking, while the extracts composed of short chain mannans and ß-glucans yielded the best emulsions by using ultraturrax stirring. ß-Glucans and O-linked mannoproteins were found to contribute to emulsion stability by preventing Ostwald ripening. When applied in mayonnaise model emulsions, BSY extracts presented higher stability and yet similar texture properties as the reference emulsifiers. When used in a mayonnaise formulation, the BSY extracts were also able to replace egg yolk and modified starch (E1422) at 1/3 of their concentration. This shows that BSY alkali soluble mannoproteins and subcritical water extracted ß-glucans can be used as replacers of animal protein and additives in sauces.

Personalised Gait Recognition for People with Neurological Conditions.

There is growing interest in monitoring gait patterns in people with neurological conditions. The democratisation of wearable inertial sensors has enabled the study of gait in free living environments. One pivotal aspect of gait assessment in uncontrolled environments is the ability to accurately recognise gait instances. Previous work has focused on wavelet transform methods or general machine learning models to detect gait; the former assume a comparable gait pattern between people and the latter assume training datasets that represent a diverse population. In this paper, we argue that these approaches are unsuitable for people with severe motor impairments and their distinct gait patterns, and make the case for a lightweight personalised alternative. We propose an approach that builds on top of a general model, fine-tuning it with personalised data. A comparative proof-of-concept evaluation with general machine learning (NN and CNN) approaches and personalised counterparts showed that the latter improved the overall accuracy in 3.5% for the NN and 5.3% for the CNN. More importantly, participants that were ill-represented by the general model (the most extreme cases) had the recognition of gait instances improved by up to 16.9% for NN and 20.5% for CNN with the personalised approaches. It is common to say that people with neurological conditions, such as Parkinson's disease, present very individual motor patterns, and that in a sense they are all outliers; we expect that our results will motivate researchers to explore alternative approaches that value personalisation rather than harvesting datasets that are may be able to represent these differences.

Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis.

OBJECTIVE: Bone marrow-derived myeloid cells accumulate in the liver as monocytes and macrophages during the progression of obesity-related non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). Myeloid cells comprise heterogeneous subsets, and dietary overnutrition may affect macrophages in the liver and bone marrow. We therefore aimed at characterising in depth the functional adaptations of myeloid cells in fatty liver. DESIGN: We employed single-cell RNA sequencing to comprehensively assess the heterogeneity of myeloid cells in the liver and bone marrow during NAFLD, by analysing C57BL/6 mice fed with a high-fat, high-sugar, high-cholesterol 'Western diet' for 16 weeks. We also characterised NAFLD-driven functional adaptations of macrophages in vitro and their functional relevance during steatohepatitis in vivo. RESULTS: Single-cell RNA sequencing identified distinct myeloid cell clusters in the liver and bone marrow. In both compartments, monocyte-derived populations were largely expanded in NASH-affected mice. Importantly, the liver myeloid compartment adapted a unique inflammatory phenotype during NAFLD progression, exemplarily characterised by downregulated inflammatory calprotectin (S100A8/A9) in macrophage and dendritic cell subsets. This distinctive gene signature was also found in their bone marrow precursors. The NASH myeloid phenotype was principally recapitulated by in vitro exposure of bone marrow-derived macrophages with fatty acids, depended on toll-like receptor 4 signalling and defined a characteristic response pattern to lipopolysaccharide stimulation. This imprinted and stable NASH myeloid immune phenotype functionally determined inflammatory responses following acute liver injury (acetaminophen poisoning) in vivo. CONCLUSION: Liver myeloid leucocytes and their bone marrow precursors adapt a common and functionally relevant inflammatory signature during NAFLD progression.

Pharmacokinetics and pharmacodynamics of antibody-drug conjugates for the treatment of patients with breast cancer.

INTRODUCTION: Currently three antibody-drug-conjugates (ADC) are approved by the European Medicines Agency (EMA) for treatment of breast cancer (BC) patient: trastuzumab-emtansine, trastuzumab-deruxtecan and sacituzumab-govitecan. ADC are composed of a monoclonal antibody (mAb) targeting a specific antigen, a cytotoxic payload and a linker. Pharmacokinetics (PK) and pharmacodynamics (PD) distinguish ADC from conventional chemotherapy and must be understood by clinicians. AREAS COVERED: Our review delineates the PK/PD profiles of ADC approved for the treatment of BC with insight for future development. This is an expert opinion literature review based on the EMA's Assessment Reports, enriched by a comprehensive literature search performed on Medline in August 2023. EXPERT OPINION: All three ADC distributions are described by a two-compartment structure: tissue and serum. Payload concentration peak is immediate but remains at low concentration. The distribution varied for all ADC only with body weight. mAb will be metabolised firstly by the saturable complex formation of ADC/Tumour-Receptor and secondly by binding of FcgRs in immune cells. They are all excreted in the bile and faeces with minimal urine elimination. Dose adjustments, apart from weight, are not recommended. Novel ADC are composed of cleavable linkers with various targets/payloads with the same PK/PD properties, but novel structures of ADC are in development.

The Impact of Initial Tumor Response on Survival Outcomes of Patients With HER2-Positive Advanced Breast Cancer Treated With Docetaxel, Trastuzumab, and Pertuzumab: An Exploratory Analysis of the CLEOPATRA Trial.

INTRODUCTION: The CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease re-evaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD). METHODS: We performed an exploratory analysis of the CLEOPATRA study to address this question. RESULTS: Out of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on survival was observed for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR. CONCLUSIONS: Our findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research.

Progression-free survival assessment by local investigators versus blinded independent central review in randomized clinical trials in metastatic breast cancer: A systematic review and meta-analysis.

INTRODUCTION: In randomized clinical trials (RCTs), blinded independent central review (BICR) is used to minimize heterogeneity and bias associated with radiological response evaluation by local investigators. However, BICR adds costs and complexity to the trial management. We assessed the discrepancy index between progression-free survival (PFS) assessment by local investigators and by BICR in RCTs conducted in patients with metastatic breast cancer (MBC). METHODS: A systematic search of PubMed, Embase, Cochrane databases and conference proceedings (ASCO, SABCS, ESMO) was performed up to January 4, 2023 (PROSPERO: CRD42021229865). All RCTs published from 2000 to 2022, including MBC patients treated in first- or second-line, and reporting PFS assessed by local investigators and BICR were included. A discrepancy index between BICR-assessed and investigator-assessed HR was calculated for each trial and an overall combined DI was obtained using a fixed-effects model. The agreement between hazard ratios (HR) of PFS assessed by local investigators and BICR was measured using intraclass correlation coefficient (ICC). RESULTS: We analyzed 24 studies including 13,168 patients. Among them, 19 (79%) were in first-line, 18 (75%) were phase III trials and 23 (96%) had PFS as primary endpoint. The overall combined discrepancy index was 0.97 (95%CI 0.85-1.10; ICC 0.831, p < 0.001) suggesting no statistically significant difference in PFS assessment between local investigators and BICR. This result was consistent across all analyzed subgroups. CONCLUSIONS: The good concordance between local investigator and BICR assessments supports the reliability of local investigator-assessed PFS as primary endpoint for RCTs in MBC and questions the practical utility of implementing BICR in all RCTs.

Intake of added sugar, fruits, vegetables, and legumes of Portuguese preschool children: Baseline data from SmartFeeding4Kids randomized controlled trial participants.

Introduction: The SmartFeeding4Kids (SF4K) program is an online self-guided intervention for parents with the propose of changing parental feeding practices and children's dietary intake, focusing on the intake of added sugars, fruit, vegetables, and legumes. This paper aims to describe children's dietary pattern at baseline through a 24-h food recall, the SmartKidsDiet24. Methods: Overall, 89 participants recorded at least one meal of the 3-day food recall. Mean age was 36.22 ± 6.05 years and 53.09 ± 15.42 months old for parents and children, respectively. Of these, 22 participants were considered to have 2 days of near complete 24-h food recalls. Children's dietary intake are reported for these 22 participants based on parents reports and, thus, represent estimations only, as it remains unknown whether children consumed other non-reported foods. Results: Fruit was the group with the highest daily intake among children (mean 1.77 ± 1.10 portions/day), followed by added sugar foods (mean 1.48 ± 0.89 portions/day), vegetables [median 1.27 (1.64) portions/day] and legumes [median 0.12 (0.39) portions/day]. Fruit intake was positively correlated with vegetable intake (p = 0.008). Regarding Dietary Reference Values accomplishment, 13.6% of children exceeded the daily safe and adequate intake of sodium, 77.3% did not meet potassium and fiber recommendations, and 31.8% did not meet vitamin C recommendations. Discussion: All children did not meet calcium, vitamin B12 and vitamin D intake recommendations. Our findings further justify the need for dietary interventions in this field, to improve young children's diets. Clinical trial registration: ClinicalTrials.gov, identifier NCT04591496.

Adjuvant Chemotherapy De-Escalation with Genomic Assay Protocol in Patients with Early Breast Cancer: A Single-Centre Prospective Cohort Study.

INTRODUCTION: Genomic assays are useful tools for tailoring adjuvant treatment in early breast cancer. We aimed to analyse the role of an institutional protocol of a genomic assay for chemotherapy de-escalation. MATERIAL AND METHODS: Prospective cohort study of all consecutive women diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-negative early breast cancer, tested with the 21-gene Recurrence Score (RS) assay from August 2015 to July 2018 at a Portuguese cancer centre. For being tested, patients should meet at least one of the pre-defined inclusion criteria: i) luminal A-like, pT2pN0; ii) luminal A-like, 1 - 3 positive nodes and comorbidities with higher risk of chemotherapy-induced toxicity; iii) pT1-2pN0, progesterone receptor ≤ 20% and/or Ki67 14% - 40%. Adjuvant treatment was de-escalated to isolated endocrine therapy if RS was less than 18. We measured the reduction in chemotherapy prescribing and its clinical impact, the RS association with pathologic features, and the protocol feasibility. RESULTS: We tested 154 women with a median age of 61 years old (range: 25 - 79), 69% postmenopausal. Tumours were mainly pT1 (55%), pN0 (82%), invasive ductal (73%), G2 (86%), luminal B-like (69%) and stage IA (85%). We obtained a RS less than 18 in 60% of women, with an overall adjuvant chemotherapy reduction of 65%. Seven (95% confidence interval: 5 - 10) patients needed to be screened with the 21-gene RS assay to prevent one clinically relevant adverse event during the first six months of adjuvant treatment. Considering the currently used RS cut-off, only 9% of node-negative and 11% of node-positive patients had RS over 25. We found no relevant associations between RS and pathologic features. The protocol was feasible and did not compromise the adequate timing for adjuvant treatment. CONCLUSION: These criteria allowed the de-escalation of adjuvant systemic treatment in at least six out of ten women.

NeuroAIreh@b: an artificial intelligence-based methodology for personalized and adaptive neurorehabilitation.

Cognitive impairments are a prevalent consequence of acquired brain injury, dementia, and age-related cognitive decline, hampering individuals' daily functioning and independence, with significant societal and economic implications. While neurorehabilitation represents a promising avenue for addressing these deficits, traditional rehabilitation approaches face notable limitations. First, they lack adaptability, offering one-size-fits-all solutions that may not effectively meet each patient's unique needs. Furthermore, the resource-intensive nature of these interventions, often confined to clinical settings, poses barriers to widespread, cost-effective, and sustained implementation, resulting in suboptimal outcomes in terms of intervention adaptability, intensity, and duration. In response to these challenges, this paper introduces NeuroAIreh@b, an innovative cognitive profiling and training methodology that uses an AI-driven framework to optimize neurorehabilitation prescription. NeuroAIreh@b effectively bridges the gap between neuropsychological assessment and computational modeling, thereby affording highly personalized and adaptive neurorehabilitation sessions. This approach also leverages virtual reality-based simulations of daily living activities to enhance ecological validity and efficacy. The feasibility of NeuroAIreh@b has already been demonstrated through a clinical study with stroke patients employing a tablet-based intervention. The NeuroAIreh@b methodology holds the potential for efficacy studies in large randomized controlled trials in the future.

Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment.

Antibody-drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these 'off-target effects', such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.

Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with ER-positive/HER2-negative early breast cancer: a systematic review and meta-analysis.

BACKGROUND: Neoadjuvant treatment discriminates responders, but pathologic complete response is uncommon in oestrogen receptor (ER)-positive/HER2-negative early breast cancer. We aimed to assess the prognostic value of Ki-67 index after neoadjuvant endocrine therapy (NET). METHODS: We conducted a systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings up to 22nd August 2023 to identify studies reporting the association of Ki-67 index after NET with recurrence-free survival (RFS) and/or overall survival (OS) in women with ER-positive/HER2-negative early breast cancer. We combined RFS and OS hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Twelve studies including 7897 patients were analysed. Most studies were clinical trials (n = 7547) including only postmenopausal women (n = 3953) treated with aromatase inhibitor (n = 3359). Three studies evaluated Ki-67 in a preplanned core biopsy at 2-4 weeks of NET (n = 3348), while nine evaluated Ki-67 in the surgical specimen (n = 4549) after 2-24 weeks of NET. Median follow-up ranged between 37 and 95 months for RFS and 62-84 months for OS. High Ki-67 index after NET was significantly associated with worse RFS (HR 2.48, 95% CI 1.86-3.30) and OS (HR 2.66, 95% CI 1.65-4.28). A sensitivity analysis including three studies that measured Ki-67 in a preplanned core biopsy showed similar association with RFS (HR 2.41, 95% CI 1.77-3.30). CONCLUSIONS: High Ki-67 after NET is associated with worse survival outcomes, even after a short course of NET, emphasising the prognostic value of this biomarker in women with ER-positive/HER2-negative early breast cancer.

Identification of Fatigue and Sleepiness in Immune and Neurodegenerative Disorders from Measures of Real-World Gait Variability.

Current assessments of fatigue and sleepiness rely on patient reported outcomes (PROs), which are subjective and prone to recall bias. The current study investigated the use of gait variability in the "real world" to identify patient fatigue and daytime sleepiness. Inertial measurement units were worn on the lower backs of 159 participants (117 with six different immune and neurodegenerative disorders and 42 healthy controls) for up to 20 days, whom completed regular PROs. To address walking bouts that were short and sparse, four feature groups were considered: sequence-independent variability (SIV), sequence-dependant variability (SDV), padded SDV (PSDV), and typical gait variability (TGV) measures. These gait variability measures were extracted from step, stride, stance, and swing time, step length, and step velocity. These different approaches were compared using correlations and four machine learning classifiers to separate low/high fatigue and sleepiness.Most balanced accuracies were above 50%, the highest was 57.04% from TGV measures. The strongest correlation was 0.262 from an SDV feature against sleepiness. Overall, TGV measures had lower correlations and classification accuracies.Identifying fatigue or sleepiness from gait variability is extremely complex and requires more investigation with a larger data set, but these measures have shown performances that could contribute to a larger feature set.Clinical relevance- Gait variability has been repeatedly used to assess fatigue in the lab. The current study, however, explores gait variability for fatigue and daytime sleepiness in real-world scenarios with multiple gait-impacted disorders.

Immune response to anti-SARS-CoV-2 prime-vaccination in patients with cancer: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the immune response to anti-SARS-CoV-2 prime-vaccination in patients with cancer. METHODS: We performed a systematic literature search using PubMed, Embase, and Cochrane Library until 28/09/2021, and conference proceedings from ASCO and ESMO 2021 annual meetings. We screened for observational or interventional studies including subjects ≥ 16 years old with cancer diagnosis who were vaccinated against SARS-CoV-2. Prime-vaccination was defined as one dose of Ad26.COV2-S vaccine or two doses of BNT162b2, mRNA-1273, ChAdOx1-S or inactivated SARS-CoV-2 vaccine. The outcomes were humoral and adaptive immune responses (proportion of subjects with positive titers of antibody anti-SARS-CoV-2 spike protein and anti-SARS-CoV-2 cellular responses, respectively). RESULTS: We included 89 records reporting data from 30,183 subjects. The overall seropositive rate within the first month after complete anti-SARS-CoV-2 prime-vaccination was 80% [95% confidence interval (CI), 72-86%], 60% (95%CI, 53-67%) in patients with hematological malignancies (HM) versus 94% (95%CI, 88-97%) in patients with solid malignancies (SM). The diagnosis of HM was significantly associated with a lower seropositive rate on multivariate meta-regression (odds ratio 0.35, 95% CI 0.18-0.69, HM versus both, p = 0.002). The overall humoral response was 49% (95% CI, 42-56%) after incomplete prime-vaccination and 79% (95% CI, 70-86%) at 2 months after complete prime-vaccination. These responses were also lower in patients with HM at these time points. The overall cellular response rate at any time after vaccination was 61% (95% CI, 44-76%). CONCLUSION: This meta-analysis provides compelling evidence of humoral and adaptive immune responses against SARS-CoV-2 in patients with cancer, which last for at least 2 months following complete prime-vaccination.