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Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer 1,2 . Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system., (© 2024. The Author(s).)

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8 + T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8 + T cells, follicular helper T cells and shorter distances between tumor and CD8 + T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 ., Competing Interests: Competing interests R.M.M. reports research grants from Siemens Healhtineers, Bayer Healthcare, Screenpoint Medical, Beckton & Dickinson, PA Imaging, Lunit and Koning, and is an advisory board member for Screenpoint, Bayer, Siemens and Guerbet, all outside the scope of this work. E. Kalashnikova is an employee of Natera. G.S.S. reports research funding to the institute from Merck, Agendia, AstraZeneca, Roche and Novartis and a consulting role for Novartis, Seattle Genetics and Biovica, outside the submitted work. S.C.L. reports research funding to the institute from Roche/Genentech, AstraZeneca, BMS, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia and Novartis and a consulting role and travel grant from Daiichi Sankyo, outside this work. C.U.B. has received research grants from Novartis, BMS and NanoString, is a paid advisory board member for BMS, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab and Pierre Fabre and holds ownership interest in Uniti Card, Neon Therapeutics and Forty Seven, all outside this submitted work. K.E.d.V. reports research funding from Roche and is a consultant for Macomics, outside the scope of this work. R.S. reports nonfinancial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche and personal fees from Roche, BMS and Exact Sciences for advisory boards, all outside the scope of this paper. L.F.A.W. reports funding to the institute from Genmab BV. T.N.S. is an advisor for Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Bio, Cell Control, Celsius, Merus and Scenic Biotech; and is venture partner at Third Rock Ventures, all outside of the current work. M.K. reports research funding to the institute from BMS, Roche and AstraZeneca/MedImmune and an advisory role/speakers’ fee (all compensated to the institute) for Alderaan, BMS, Domain Therapeutics, Medscape, Roche, MSD and Daiichi Sankyo, outside the submitted work. Natera provided nonfinancial support to this study. The other authors declare no competing interests., (© 2024. The Author(s).)

Ageing in a non-native land brings numerous challenges that may complicate adaptation and health for older Latin American immigrants in Australia. While religiosity emerges as a protective factor for mental health, there is scarce research focused on exploring the multifaceted dimensions of religiosity in this population. As part of a broad Constructivist Grounded Theory study, the aim of this qualitative descriptive analysis was to explore and understand this population's religious practices and experiences, focusing on the impact on their mental health. Following ethical approval, 23 Spanish-speaking Latin American immigrants aged 60 and older living in Australia were interviewed. Data analysis was performed on a constant comparative basis and concurrent with data collection to understand the findings. Three key categories were identified: "Being involved in religious groups and communities," "Connecting with God," and "Changing how one lives one's faith." Regardless of their religious practices, all participants engaged in social activities that helped them integrate into their communities. Several barriers to religious practices were identified. The findings add to the field of religiosity as a protective factor in older Latin American immigrants' mental health. Future research should identify barriers to religious practices and targeted interventions.

Positive remodeling (PR) is an atherosclerotic plaque feature defined as an increase in arterial caliber at the level of an atheroma, in response to increasing plaque burden. The mechanisms that lead to its formation are incompletely understood, but its role in coronary atherosclerosis has major clinical implications. Indeed, plaques with PR have elevated risk of provoking acute cardiac events. Hence, PR figures among the high-risk plaque features that cardiac imaging studies should report. This review aims to provide an overview of the current literature on coronary PR. It outlines the pathophysiology of PR, the different techniques used to assess its presence, and the imaging findings associated to PR, on both noninvasive and invasive studies. This review also summarizes clinical observations, trials, and studies, focused on the impact of PR on clinical outcome.

Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), hold notable significance due to their pharmaceutical relevance. Obtaining PUFAs from diverse sources like vegetables, fish oils, and algae poses challenges due to the mixed fatty acid (FA) composition. Therefore, focusing on particular FAs necessitates purification and resolution processes. To address this, we propose a continuous assay for screening lipases selective for ethyl EPA (E-EPA) or ethyl DHA (E-DHA). Utilizing microplate spectrophotometry, the method enables quantification of liberated fatty acids from ethyl esters (E-EPA or E-DHA). This involves assessing enzyme selectivity by measuring the release of FAs through p-nitrophenolate protonation, either separately for each substrate or in competition with a reference substrate, resorufin acetate. Ten lipases underwent screening, revealing Burkholderia cepacia lipase's (BCL) preference for ethyl DHA hydrolysis (E-EPA/E-DHA = 0.82 ± 0.07 and the lipase selectivity ratio (S) for E-EPA/E-DHA = 0.13 ± 0.04) and Candida antarctica lipase B's (CALB) high specific activity towards both E-EPA and E-DHA (531.14 ± 37.76 and 281.79 ± 2.79 U/mg, respectively) and E-EPA preference (E-EPA/E-DHA = 1.86 ± 0.15 and S E-EPA/E-DHA = 2.59±0.15). Candida rugosa recombinant isoform 4 (rCRLip4) and commercial Candida rugosa lipase (CRL) exhibited significant preference for E-EPA hydrolysis (E-EPA/E-DHA = 2.18 ±0.51 and 2.26 ±0.36, respectively; and S E-EPA/E-DHA = 7.59 ± 1.59 and 7.88 ± 2.13, respectively). Docking analyses of rCRLip4, BCL, and CALB demonstrated no statistically significant differences in activation energies or distances to the catalytic serine; however, they agreed with the experimental results. These findings suggest potential mutagenesis or directed evolution strategies for CALB to enhance E-EPA selectivity, with rCRLip4 emerging as a promising candidate for further investigation. This assay offers a valuable tool for identifying lipases with desired substrate selectivity, with broad implications for pharmaceutical and biotechnological applications., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4 + T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity., (© 2024. The Author(s).)

The databases provided for two meteorological stations installed in the Alqueva reservoir (the largest artificial lake in Europe), one located on a floating platform and the other on the shore (approximately 1 km away in a straight line), cover a period of 6 years, from 2018 to 2023. The data available are, the hourly accumulated precipitation as well as the hourly averages of surface water temperature (0.25 m of depth), soil temperature, and meteorological parameters (wind intensity and direction, relative humidity, upward/downward solar radiation, air temperature, and relative humidity). Additionally, daily maximum and minimum values of the air temperature and relative humidity are provided, together with the time at which they were recorded. These data can potentially be used for various purposes, including hydrometeorological analysis, monitoring and assessing local environmental conditions, analysing local meteorological patterns, integrating or validating results from high-resolution numerical model simulations, or gaining a better understanding of changes in water quality or microalgae blooms in large reservoirs. The percentage of failures/gaps per parameter for each hour and day is provided to give users the flexibility to choose their own requirements regarding the maximum acceptable limit., (© 2024 The Authors.)

Purpose To determine the prevalence of clinically relevant extracardiac findings at cardiac CT and MRI examinations from a multicenter, multinational MR/CT registry and the relationship of prevalence with examination indications and patient characteristics. Materials and Methods This was a retrospective analysis of data from the European Society of Cardiovascular Radiology MR/CT Registry. Data from 208 506 cardiac CT examinations (median patient age, 66 years [IQR, 55-77]; 121 617 [58.33%] male patients) and 228 462 cardiac MRI examinations (median patient age, 57 years [IQR, 42-69]; 145 792 [63.81%] male patients) entered into the registry between January 2011 and November 2023 were analyzed. Clinically relevant extracardiac findings were defined as findings requiring follow-up examinations or influencing clinical management. The association of examination indication and patient characteristics, including age, with prevalence of extracardiac findings was evaluated using incidence rate ratios (IRRs) derived from multivariable Poisson regression models. Results The prevalence of clinically relevant extracardiac findings was 3.28% (6832 of 208 506) at cardiac CT and 1.50% (3421 of 228 462) at cardiac MRI examinations. Extracardiac findings were more common at CT examinations performed for transcatheter aortic valve replacement (IRR, 2.07; P < .001) and structural heart disease (IRR, 1.44; P < .001) compared with CT performed for coronary artery disease (IRR, 1; reference). Extracardiac findings were more common at MRI examinations performed for myocarditis (IRR, 1.36; P < .001) and structural heart disease (IRR, 1.16; P < .001) than for coronary artery disease. Older patient age was also significantly associated with higher prevalence of extracardiac findings, with an IRR for both CT and MRI examinations of 1.02 ( P < .001). Conclusion Data from the multicenter, multinational MR/CT registry indicate that clinically relevant extracardiac findings are present at cardiovascular CT and MRI examinations, and the prevalence of these findings is associated with examination indication and patient age. Keywords: Cardiac Imaging Techniques, Incidental Findings, MRI, CT Angiography, CT, Heart Disease Supplemental material is available for this article. © RSNA, 2024.

Takotsubo syndrome (TS) is a temporary form of left ventricular (LV) dysfunction characterized by a distinct pattern of LV impairment, often triggered by a physical or emotional stressful event. Historically, TS was considered a benign condition due to its prompt restoration of myocardial function and generally excellent outcomes. However, recent studies have shown that complications similar to those seen after myocardial infarction can occur, necessitating careful monitoring of these patients. Among noninvasive imaging techniques, cardiovascular magnetic resonance (CMR) is becoming increasingly important in evaluating patients with TS. CMR offers a unique ability to noninvasively assess myocardial tissue characteristics, allowing for detecting the typical features of TS, such as specific wall motion abnormalities and myocardial edema. Beyond its well-established diagnostic utility in the clinical management of TS, CMR has also proven valuable in prognosis and risk stratification for these patients. Advances in CMR, including myocardial strain and parametric mapping have expanded its role in the diagnosis, prognosis, and follow-up of these patients. This review aims to provide a comprehensive overview of the potential applications of CMR in the diagnostic and prognostic evaluation of TS patients. It explores the emerging use of novel CMR imaging biomarkers that may enhance diagnosis, improve prognostic accuracy, and contribute to the overall management of these patients., (© 2024 Wiley Periodicals LLC.)

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution., (© 2024. The Author(s).)

Stable chest pain is a common symptom with multiple potential causes. Non-invasive imaging has an important role in diagnosis and guiding management through the assessment of coronary stenoses, atherosclerotic plaque, myocardial ischaemia or infarction, and cardiac function. Computed tomography (CT) provides the anatomical evaluation of coronary artery disease (CAD) with the assessment of stenosis, plaque type and plaque burden, with additional functional information available from CT fractional flow reserve (FFR) or CT myocardial perfusion imaging. Stress magnetic resonance imaging, nuclear stress myocardial perfusion imaging, and stress echocardiography can assess myocardial ischaemia and other cardiac functional parameters. Coronary CT angiography can be used as a first-line test for many patients with stable chest pain, particularly those with low to intermediate pre-test probability. Functional testing may be considered for patients with known CAD, where the clinical significance is uncertain based on anatomical testing, or in patients with high pre-test probability. This practice recommendations document can be used to guide the selection of non-invasive imaging for patients with stable chest pain and provides brief recommendations on how to perform and report these diagnostic tests. KEY POINTS: The selection of non-invasive imaging tests for patients with stable chest pain should be based on symptoms, pre-test probability, and previous history. Coronary CT angiography can be used as a first-line test for many patients with stable chest pain, particularly those with low to intermediate pre-test probability. Functional testing can be considered for patients with known CAD, where the clinical significance of CAD is uncertain based on anatomical testing, or in patients with high pre-test probability. KEY RECOMMENDATIONS: Non-invasive imaging is an important part of the assessment of patients with stable chest pain. The selection of non-invasive imaging test should be based on symptoms, pre-test probability, and previous history. (Level of evidence: High). Coronary CT angiography can be used as a first line test for many patients with stable chest pain, particularly those with low to intermediate pre-test probability. CT provides information on stenoses, plaque type, plaque volume, and if required functional information with CT fractional flow reserve or CT perfusion. (Level of evidence: High). Functional testing can be considered for patients with known CAD, where the clinical significance of CAD is uncertain based on anatomical testing, or in patients with high pre-test probability. Stress MRI, SPECT, PET, and echocardiography can provide information on myocardial ischemia, along with cardiac functional and other information. (Level of evidence: Medium)., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: In this study, we aimed to explore if the combination of tumor infiltrating lymphocytes (TILs) and change in tumor load on dynamic contrast-enhanced magnetic resonance imaging leads to better assessment of response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, compared to either alone., Methods: In 190 NAC treated patients, MRI scans were performed before and at the end of treatment. The percentage of stromal TILs (%TILs) was assessed in pre-NAC biopsies according to established criteria. Prediction models were developed with linear regression by least absolute shrinkage and selection operator and cross validation (CV), with residual cancer burden as the dependent variable. Discrimination for pathological complete response (pCR) was evaluated using area under the receiver operating characteristic curves (AUC). We used Cox regression analysis for exploring the association between %TILs and recurrence-free survival (RFS)., Results: Fifty-one patients reached pCR. In all patients, the %TILs model and change in MRI tumor load model had an estimated CV AUC of 0.69 (95% confidence interval (CI) 0.53-0.78) and 0.69 (95% CI 0.61-0.79), respectively, whereas a model combining the variables resulted in an estimated CV AUC of 0.75 (95% CI 0.66-0.83). In the group with tumors that were ER positive and HER2 negative (ER+/HER2-) and in the group with tumors that were either triple negative or HER2 positive (TN&HER2+) separately, the combined model reached an estimated CV AUC of 0.72 (95% CI 0.60-0.88) and 0.70(95% CI 0.59-0.82), respectively. A significant association was observed between pre-treatment %TILS and RFS (hazard ratio (HR) 0.72 (95% CI 0.53-0.98), for every standard deviation increase in %TILS, p = 0.038)., Conclusion: The combination of TILs and MRI is informative of response to NAC in patients with both ER+/HER2- and TN&HER2+ tumors., (© 2024. The Author(s).)

Objective: Our study aimed to explore with cardiovascular magnetic resonance (CMR) the impact of left atrial (LA) and left ventricular (LV) myocardial strain in patients with acute pericarditis and to investigate their possible prognostic significance in adverse outcomes., Method: This retrospective study performed CMR scans in 36 consecutive patients with acute pericarditis (24 males, age 52 [23-52]). The primary endpoint was the combination of recurrent pericarditis, constrictive pericarditis, and surgery for pericardial diseases defined as pericardial events. Atrial and ventricular strain function were performed on conventional cine SSFP sequences., Results: After a median follow-up time of 16 months (interquartile range [13-24]), 12 patients with acute pericarditis reached the primary endpoint. In multivariable Cox regression analysis, LA reservoir and LA conduit strain parameters were all independent determinants of adverse pericardial diseases. Conversely, LV myocardial strain parameters did not remain an independent predictor of outcome. With receiving operating characteristics curve analysis, LA conduit and reservoir strain showed excellent predictive performance (area under the curve of 0.914 and 0.895, respectively) for outcome prediction at 12 months., Conclusion: LA reservoir and conduit mechanisms on CMR are independently associated with a higher risk of adverse pericardial events. Including atrial strain parameters in the management of acute pericarditis may improve risk stratification., Clinical Relevance Statement: Atrial strain could be a suitable non-invasive and non-contrast cardiovascular magnetic resonance parameter for predicting adverse pericardial complications in patients with acute pericarditis., Key Points: • Myocardial strain is a well-validated CMR parameter for risk stratification in cardiovascular diseases. • LA reservoir and conduit functions are significantly associated with adverse pericardial events. • Atrial strain may serve as an additional non-contrast CMR parameter for stratifying patients with acute pericarditis., (© 2024. The Author(s).)

Rationale: To provide an overview of the current status of cardiac multimodality imaging practices in Europe and radiologist involvement using data from the European Society of Cardiovascular Radiology (ESCR) MRCT-registry., Materials and Methods: Numbers on cardiac CT and MRI examinations were extracted from the MRCT-registry of the ESCR, entered between January 2011 and October 2023 (n = 432,265). Data collection included the total/annual numbers of examinations, indications, complications, and reporting habits., Results: Thirty-two countries contributed to the MRCT-registry, including 29 European countries. Between 2011 and 2022, there was a 4.5-fold increase in annually submitted CT examinations, from 3368 to 15,267, and a 3.8-fold increase in MRI examinations, from 3445 to 13,183. The main indications for cardiac CT were suspected coronary artery disease (CAD) (59%) and transcatheter aortic valve replacement planning (21%). The number of patients with intermediate pretest probability who underwent CT for suspected CAD showed an increase from 61% in 2012 to 82% in 2022. The main MRI indications were suspected myocarditis (26%), CAD (21%), and suspected cardiomyopathy (19%). Adverse event rates were very low for CT (0.3%) and MRI (0.7%) examinations. Reporting of CT and MRI examinations was performed mainly by radiologists (respectively 76% and 71%) and, to a lesser degree, in consensus with non-radiologists (19% and 27%, respectively). The remaining examinations (4.9% CT and 1.7% MRI) were reported by non-radiological specialties or in separate readings of radiologists and non-radiologists., Conclusions: Real-life data on cardiac imaging in Europe using the largest available MRCT-registry demonstrate a considerable increase in examinations over the past years, the vast majority of which are read by radiologists. These findings indicate that radiologists contribute to meeting the increasing demands of competent and effective care in cardiac imaging to a relevant extent., Clinical Relevance Statement: The number of cardiac CT and MRI examinations has risen over the past years, and radiologists read the vast majority of these studies as recorded in the MRCT-registry., Key Points: • The number of cardiac imaging examinations is constantly increasing. • Radiologists play a central role in providing cardiac CT and MR imaging services to a large volume of patients. • Cardiac CT and MR imaging examinations performed and read by radiologists show a good safety profile., (© 2024. The Author(s).)

Objective: This work aimed to derive a machine learning (ML) model for the differentiation between ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM) on non-contrast cardiovascular magnetic resonance (CMR)., Methods: This retrospective study evaluated CMR scans of 107 consecutive patients (49 ICM, 58 NICM), including atrial and ventricular strain parameters. We used these data to compare an explainable tree-based gradient boosting additive model with four traditional ML models for the differentiation of ICM and NICM. The models were trained and internally validated with repeated cross-validation according to discrimination and calibration. Furthermore, we examined important variables for distinguishing between ICM and NICM., Results: A total of 107 patients and 38 variables were available for the analysis. Of those, 49 were ICM (34 males, mean age 60 ± 9 years) and 58 patients were NICM (38 males, mean age 56 ± 19 years). After 10 repetitions of the tenfold cross-validation, the proposed model achieved the highest area under curve (0.82, 95% CI [0.47-1.00]) and lowest Brier score (0.19, 95% CI [0.13-0.27]), showing competitive diagnostic accuracy and calibration. At the Youden's index, sensitivity was 0.72 (95% CI [0.68-0.76]), the highest of all. Analysis of predictions revealed that both atrial and ventricular strain CMR parameters were important for the identification of ICM patients., Conclusion: The current study demonstrated that using a ML model, multi chamber myocardial strain, and function on non-contrast CMR parameters enables the discrimination between ICM and NICM with competitive diagnostic accuracy., Clinical Relevance Statement: A machine learning model based on non-contrast cardiovascular magnetic resonance parameters may discriminate between ischemic and non-ischemic cardiomyopathy enabling wider access to cardiovascular magnetic resonance examinations with lower costs and faster imaging acquisition., Key Points: • The exponential growth in cardiovascular magnetic resonance examinations may require faster and more cost-effective protocols. • Artificial intelligence models can be utilized to distinguish between ischemic and non-ischemic etiologies. • Machine learning using non-contrast CMR parameters can effectively distinguish between ischemic and non-ischemic cardiomyopathies., (© 2024. The Author(s).)

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

Aims: Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study we evaluated the performance of a deep-learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells' staining intensity and completeness of membrane staining., Methods and Results: We trained a DL model on a multicentric cohort of breast cancer cases with HER2-IHC scores (n = 299). The model was validated on two independent multicentric validation cohorts (n = 369 and n = 92), with all cases reviewed by three senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. The model's concordance with the ground truth (ICC = 0.77 [0.68-0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the three senior pathologists (ICC = 0.45 [0.17-0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93% - 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumours, respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumour-infiltrating lymphocytes, and necrosis, whilst some artefacts such as nonspecific background cytoplasmic stain in the cytoplasm of tumour cells also cause discrepancy., Conclusion: Deep learning can support pathologists' interpretation of difficult HER2-low cases. Morphological variables and some specific artefacts can cause discrepant HER2-scores between the pathologist and the DL model., (© 2024 John Wiley & Sons Ltd.)

Association of stromal tumor-infiltrating lymphocytes (sTILs) with survival outcomes among patients with metastatic breast cancer (MBC) remains unclear. The primary objective was to evaluate the association of sTILs with progression-free survival in randomized phase III trial CALGB 40502. sTILs were associated with progression-free and overall survival in chemotherapy-treated MBC when controlling for treatment arm; however, this effect did not remain significant after additional adjustment for hormone receptor status. CALGB is now part of the Alliance for Clinical Trials in Oncology. Trial Registration: ClinicalTrials.gov: NCT00785291., (© 2024. The Author(s).)

Cardiovascular imaging is exponentially increasing in the diagnosis, risk stratification, and therapeutic management of patients with cardiovascular disease. The European Society of Cardiovascular Radiology (ESCR) is a non-profit scientific medical society dedicated to promoting and coordinating activities in cardiovascular imaging. The purpose of this paper, written by ESCR committees and Executive board members and approved by the ESCR Executive Board and Guidelines committee, is to codify a standardized approach to creating ESCR scientific documents. Indeed, consensus development methods must be adopted to ensure transparent decision-making that optimizes national and global health and reaches a certain scientific credibility. ESCR consensus documents developed based on a rigorous methodology will improve their scientific impact on the management of patients with cardiac involvement. CRITICAL RELEVANCE STATEMENT: This document aims to codify the methodology for producing consensus documents of the ESCR. These ESCR indications will broaden the scientific quality and credibility of further publications and, consequently, the impact on the diagnostic management of patients with cardiac involvement. KEY POINTS: Cardiovascular imaging is exponentially increasing for diagnosis, risk stratification, and therapeutic management. The ESCR is committed to promoting cardiovascular imaging. A rigorous methodology for ESCR consensus documents will improve their scientific impact., (© 2024. The Author(s).)

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology., (© 2024. Springer Nature Limited.)

Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking., Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs., Design, Setting, and Participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023., Main Outcomes and Measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients., Results: Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater., Conclusions and Relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.

Objective: Using a salutogenic approach, this study aimed to identify similarities in the protective factors of nurses' psychological Quality of Life (QoL) and professional wellbeing (PWB) in four countries and to assess their variability over time during the COVID-19 pandemic., Methods: This multicentric study used a longitudinal design with three measurements points: Autumn 2021, spring 2022, and autumn 2022. The study consisted in a self-administered online questionnaire addressed to nurses working in hospitals. Across all measurement times, 3,310 observations were collected in France, 603 in Switzerland, 458 in Portugal, and 278 in Canada. The outcomes were psychological QoL and PWB, and several potential protective factors were used as determinants., Results: Analyses revealed few changes over time in the outcomes. Across all countries, psychological QoL was associated positively with resilience and perceived social support, whereas PWB was associated positively with the ability to provide quality work and support from colleagues and superiors., Conclusion: The findings of this study highlighted the potential of several factors protective of nurses' psychological QoL and PWB. These should be fostered through policies and measures to support nurses., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Jubin, Martin, Kabwiku, Delmas, Gilles, Oulevey Bachmann, Huber, Loiselle, Rassy, Sampaio, Salgado and Ortoleva Bucher.)

Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. To improve reproducibility, the International Immuno-oncology Working Group recently released recommendations for the computational assessment of TILs that build on visual scoring guidelines. However, existing resources do not adequately address these recommendations due to the lack of annotation datasets that enable joint, panoptic segmentation of tissue regions and cells. Moreover, existing deep-learning methods focus entirely on either tissue segmentation or cell nuclei detection, which complicates the process of TILs assessment by necessitating the use of multiple models and reconciling inconsistent predictions. We introduce PanopTILs, a region and cell-level annotation dataset containing 814,886 nuclei from 151 patients, openly accessible at: sites.google.com/view/panoptils . Using PanopTILs we developed MuTILs, a neural network optimized for assessing TILs in accordance with clinical recommendations. MuTILs is a concept bottleneck model designed to be interpretable and to encourage sensible predictions at multiple resolutions. Using a rigorous internal-external cross-validation procedure, MuTILs achieves an AUROC of 0.93 for lymphocyte detection and a DICE coefficient of 0.81 for tumor-associated stroma segmentation. Our computational score closely matched visual scores from 2 pathologists (Spearman R = 0.58-0.61, p < 0.001). Moreover, computational TILs scores had a higher prognostic value than visual scores, independent of TNM stage and patient age. In conclusion, we introduce a comprehensive open data resource and a modeling approach for detailed mapping of the breast tumor microenvironment., (© 2024. The Author(s).)

Physical inactivity represents a global challenge in public health, being the second most significant factor contributing to mortality. In Latin America, the prevalence of physical inactivity and sedentary behaviour is notable, affecting medical students as well, who play a crucial role as behavioural role models for the population. This study addresses the prevalence of physical activity and sedentary behaviour among medical students in Latin America during the year 2023. A total of 864 participants from 12 institutions across eight countries were surveyed using the Global Physical Activity Questionnaire. Significant variations in physical activity and sedentary behaviour were observed according to sex, age, body mass index, academic year, and country. Notably, Costa Rica exhibited the highest levels of moderate physical activity in leisure time (90 min/day). Strength training was more common among men (60 min/day) and in Argentina (60 min/day). Sedentary behaviour was higher in women (420 min/day) and during the first academic year (485 min/day). Uruguay stood out with high levels of sedentary behaviour (600 min/day). Correlations indicated positive moderate associations between academic year and moderate leisure-time PA (r:0,128, p:0,007). In conclusion, there are associations between the level of physical activity and sedentary behaviour with the variables studied in this research, with the main findings being that the female sex has more time spent in sedentary behaviour (minutes/day) and less time spent in strength training (minutes/day). Additionally, there are higher levels of sedentary behaviour in the early years of medical study compared to the later years of the program., (© 2024. The Author(s).)

Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis., Significance: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)

This position statement guides cardiovascular magnetic resonance (CMR) imaging program directors and learners on the key competencies required for Level II and III CMR practitioners, whether trainees come from a radiology or cardiology background. This document is built upon existing curricula and was created and vetted by an international panel of cardiologists and radiologists on behalf of the Society for Cardiovascular Magnetic Resonance (SCMR)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancers (TNBCs) exhibit heightened T cell infiltration, contributing to an enhanced response to immune checkpoint blockade (ICB) compared with other subtypes. An immune-rich immune microenvironment correlates with improved prognosis in early and advanced TNBC. Combination chemotherapy and ICB is now the standard of care in early- and late-stage TNBC. Although programmed death ligand-1 (PD-L1) positivity predicts ICB response in advanced stages, its role in early-stage disease remains uncertain. Despite neoadjuvant ICB becoming common in early-stage TNBC, the necessity of adjuvant ICB after surgery remains unclear. Understanding the molecular basis of the immune response in breast cancer is vital for precise biomarkers for ICB and effective combination therapy strategies., Competing Interests: Declaration of interests S.L. receives research funding to institution from Novartis, Bristol Myers Squibb, MSD, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca/Daiichi Sankyo, and Seattle Genetics. S.L. has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, MSD, AstraZeneca/Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies, and Roche-Genentech. S.L. has acted as a consultant (paid to institution) to Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca/Daiichi Sankyo, Pfizer, Gilead Therapeutics, Seattle Genetics, MSD, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. V.C.R. has received honoraria from AstraZeneca and has received travel and education funding from MSD. R.S. serves on an advisory board and/or has a consultancy role for BMS, Roche, and Owkin. R.S. has received research funding by Roche, Puma, and Merck. R.S. has received travel and congress registration support from Roche, Merck, and AstraZeneca., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Purpose: Stromal tumor-infiltrating lymphocytes (sTIL) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in the setting of anthracycline-based chemotherapy. The impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known., Experimental Design: This is a pooled analysis of two studies where patients with stage I (T>1 cm)-III TNBC received carboplatin (AUC 6) plus docetaxel (75 mg/m2; CbD) NAC. sTILs were evaluated centrally on pre-treatment hematoxylin and eosin slides using standard criteria. Cox regression analysis was used to examine the effect of variables on event-free survival (EFS) and overall survival (OS)., Results: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range, 1%-95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR, 2.08; P = 0.007), nodal status (OR, 1.64; P = 0.035), and sTILs (OR, 1.10; P = 0.011) were associated with pCR. On multivariate analysis, nodal status (HR, 0.46; P = 0.008), pCR (HR, 0.20; P < 0.001), and sTILs (HR, 0.95; P = 0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, with 5-year OS 86% versus 57% in ≥30% versus <30% sTILs (HR, 0.29; P = 0.014), and numeric trend in stage II, with 5-year OS 93% versus 89% in ≥30% versus <30% sTILs (HR, 0.55; P = 0.179). Among stage II-III patients with pCR, EFS was better in those with ≥30% sTILs (HR, 0.16; P, 0.047)., Conclusions: sTILs density was an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond tumor-node-metastasis (TNM) stage and pathologic response. These findings highlight the role of sTILs in patient selection and stratification for neo/adjuvant escalation and de-escalation strategies., (©2024 American Association for Cancer Research.)

A growing body of research supports stromal tumour-infiltrating lymphocyte (TIL) density in breast cancer to be a robust prognostic and predicive biomarker. The gold standard for stromal TIL density quantitation in breast cancer is pathologist visual assessment using haematoxylin and eosin-stained slides. Artificial intelligence/machine-learning algorithms are in development to automate the stromal TIL scoring process, and must be validated against a reference standard such as pathologist visual assessment. Visual TIL assessment may suffer from significant interobserver variability. To improve interobserver agreement, regulatory science experts at the US Food and Drug Administration partnered with academic pathologists internationally to create a freely available online continuing medical education (CME) course to train pathologists in assessing breast cancer stromal TILs using an interactive format with expert commentary. Here we describe and provide a user guide to this CME course, whose content was designed to improve pathologist accuracy in scoring breast cancer TILs. We also suggest subsequent steps to translate knowledge into clinical practice with proficiency testing., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100-100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99-1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50-1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis., (© 2024. The Author(s).)

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear., Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy., Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy., Exposure: TIL abundance in breast tissue from resected primary tumors., Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center., Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6)., Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

This work puts forth and demonstrates the utility of a reporting framework for collecting and evaluating annotations of medical images used for training and testing artificial intelligence (AI) models in assisting detection and diagnosis. AI has unique reporting requirements, as shown by the AI extensions to the Consolidated Standards of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklists and the proposed AI extensions to the Standards for Reporting Diagnostic Accuracy (STARD) and Transparent Reporting of a Multivariable Prediction model for Individual Prognosis or Diagnosis (TRIPOD) checklists. AI for detection and/or diagnostic image analysis requires complete, reproducible, and transparent reporting of the annotations and metadata used in training and testing data sets. In an earlier work by other researchers, an annotation workflow and quality checklist for computational pathology annotations were proposed. In this manuscript, we operationalize this workflow into an evaluable quality checklist that applies to any reader-interpreted medical images, and we demonstrate its use for an annotation effort in digital pathology. We refer to this quality framework as the Collection and Evaluation of Annotations for Reproducible Reporting of Artificial Intelligence (CLEARR-AI)., (Published by Elsevier Inc.)

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08-1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00-1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies., (© 2024. The Author(s).)

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Person-centred decision-making approaches in mental health care are crucial to safeguard the autonomy of the person. The use of these approaches, however, has not been fully explored beyond the clinical and policy aspects of shared and supported decision-making. The main goal is to identify and collate studies that have made an essential contribution to the understanding of shared, supported, and other decision-making approaches related to adult mental health care, and how person-centred decision-making approaches could be applied in clinical practice. A scoping review of peer-reviewed primary research was undertaken. A preliminary search and a main search were undertaken. For the main search, eight databases were explored in two rounds, between October and November 2022, and in September 2023, limited to primary research in English, Spanish or Portuguese published from October 2012 to August 2023. From a total of 12,285 studies retrieved, 21 studies were included. These research articles, which had mixed quality ratings, focused on therapeutic relationships and communication in decision-making (30%), patients' involvement in treatment decision-making (40%), and interventions for improving patients' decision-making engagement (30%). While there is promising evidence for shared decision-making in mental health care, it is important that healthcare providers use their communicational skills to enhance the therapeutic relationship and engage patients in the process. More high-quality research on supported decision-making strategies and their implementation in mental health services is also required.

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported., Materials and Methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models., Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status., Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials., Competing Interests: Disclosure PJvD has advisory relationships with Paige, Pantarei and Samantree, paid to the institution, and research grants paid to the institute from Pfizer. NS received institutional research funding from Pfizer. ZV has a consulting role for Roche. CHMvD received institutional research funding from AstraZeneca/Daiichi Sankyo. SMW has a consulting role for Roche, and received institutional research funding from Roche, Pfizer, Bayer, MSD, AstraZeneca/Merck and Amgen. SMW has a consulting role for IDDI, Sensorion, Biophytis, Servier, Yuhan, Amaris Consulting and Roche. JW received institutional research funding from Cancer Research UK and KWF Dutch Cancer Society. AR has a consulting role for MSD Oncology, Amgen, Roche, AstraZeneca/Daiichi Sankyo and Bristol Myers Squibb/Pfizer. SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SCL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. MK is an advisory board member and/or received speakers’ fee for/from Alderaan, Bristol Myers Squibb (BMS), Domain Therapeutics, Gilead, Roche, Medscape, MSD and AZ/Daiichi and received institutional research support from AstraZeneca/Daiichi, BMS and Roche outside the submitted work. RS reports non-financial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. IRK received research grants from Novartis and Gilead. RHTK is an advisory board member for Amgen, AstraZeneca, Bayer, BMS, MSD, Novartis, Pfizer, Pierre Fabre Sante, Sanofi and Servier. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A significant gap in exposure data for most livestock and zoonotic pathogens is common for several Latin America deer species. This study examined the seroprevalence against 13 pathogens in 164 wild and captive southern pudu from Chile between 2011 and 2023. Livestock and zoonotic pathogen antibodies were detected in 22 of 109 wild pudus (20.18%; 95% CI: 13.34-29.18) and 17 of 55 captive pudus (30.91%; 95% CI: 19.52-44.96), including five Leptospira interrogans serovars (15.38% and 10.71%), Toxoplasma gondii (8.57% and 37.50%), Chlamydia abortus (3.03% and 12.82%), Neospora caninum (0.00% and 9.52%), and Pestivirus (8.00% and 6.67%). Risk factors were detected for Leptospira spp., showing that fawn pudu have statistically significantly higher risk of positivity than adults. In the case of T. gondii , pudu living in "free-range" have a lower risk of being positive for this parasite. In under-human-care pudu, a Pestivirus outbreak is the most strongly suspected as the cause of abortions in a zoo in the past. This study presents the first evidence of Chlamydia abortus in wildlife in South America and exposure to T. gondii , L. interrogans , and N. caninum in wild ungulate species in Chile. High seroprevalence of livestock pathogens such as Pestivirus and Leptospira Hardjo in wild animals suggests a livestock transmission in Chilean template forest.

Importance: Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed., Objective: To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC., Design, Setting, and Participants: This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022., Intervention or Exposure: Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles., Main Outcomes and Measures: Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay., Results: Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group., Conclusions and Relevance: The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC., Trial Registration: ClinicalTrials.gov Identifier: NCT03639948.

(1) Objective : Myocarditis can be associated with ventricular arrhythmia (VA), individual non-invasive risk stratification through cardiovascular magnetic resonance (CMR) is of great clinical significance. Our study aimed to explore whether left atrial (LA) and left ventricle (LV) myocardial strain serve as independent predictors of VA in patients with myocarditis. (2) Methods: This retrospective study evaluated CMR scans in 141 consecutive patients diagnosed with myocarditis based on the updated Lake Louise criteria (29 females, mean age 41 ± 20). The primary endpoint was VA; this encompassed ventricular fibrillation, sustained ventricular tachycardia, nonsustained ventricular tachycardia, and frequent premature ventricular complexes. LA and LV strain function were performed on conventional cine SSFP sequences. (3) Results: After a median follow-up time of 23 months (interquartile range (18-30)), 17 patients with acute myocarditis reached the primary endpoint. In the multivariable Cox regression analysis, LA reservoir (hazard ratio [HR] and 95% confidence interval [CI]: 0.93 [0.87-0.99], p = 0.02), LA booster (0.87 95% CI [0.76-0.99], p = 0.04), LV global longitudinal (1.26 95% CI [1.02-1.55], p = 0.03), circumferential (1.37 95% CI [1.08-1.73], p = 0.008), and radial strain (0.89 95% CI [0.80-0.98], p = 0.01) were all independent determinants of VA. Patients with LV global circumferential strain > -13.3% exhibited worse event-free survival compared to those with values ≤ -13.3% ( p < 0.0001). (4) Conclusions: LA and LV strain mechanism on CMR are independently associated with VA events in patients with myocarditis, independent to LV ejection fraction, and late gadolinium enhancement location. Incorporating myocardial strain parameters into the management of myocarditis may improve risk stratification.

Climate change, competent vectors, and reservoir animals are the main factors for developing vector-borne zoonotic diseases. These diseases encompass a significant and widespread category of pathogens (e.g., viruses, bacteria, protozoa, and helminths) transmitted by blood-feeding arthropods, including ticks, fleas, lice, triatomines, mosquitoes, sandflies, and blackflies. In Chile, several studies have explored the role of dogs as reservoirs of vector-borne pathogens; however, there is a lack of research investigating the presence of pathogens in arthropods. Specifically, within the order Diptera, limited knowledge exists regarding their roles as carriers of pathogens. This study aimed to examine the presence of zoonotic filarial nematodes in mosquitoes and dogs within a previously unstudied semi-rural area of Central Chile. Two hundred samples of dog blood and seven hundred and twenty-four mosquitoes were collected during 2021-2022 and studied for filarial nematodes by PCR. The prevalence of microfilaremic dogs detected by Knott's test was 7.5%, with Acanthocheilonema reconditum being the only species identified. Aedes ( Ochlerotatus ) albifasciatus was the most abundant mosquito species collected, and 15 out of 65 pools were positive for filarial nematodes. Among these pools, 13 tested positive for Acanthocheilonema reconditum , and two tested positive for Setaria equina through PCR. Additionally, five Culex pipiens specimens were positive for Acanthocheilonema reconditum . Despite the absence of zoonotic filarial species, these findings underscore the significance of monitoring pathogens in mosquitoes and animal hosts and continued research into the dynamics of vector-borne diseases, particularly in unexplored regions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cancino-Faure, González, Piñeiro González, Pinochet, Bustos, Morchón, Piñeiro Cazaux, Quezada Aguilar, Salas Espinoza, Acevedo Salgado, Barra Díaz, Segovia, Lozada-Yavina and Álvarez Rojas.)

Seasonal variations in cardiorespiratory diseases may be influenced by air pollution and meteorological factors. This work aims to highlight the relevance of a complete seasonal characterization of the pollutant-meteorological factors and cardio-respiratory mortality in Portugal and the relationships between health outcomes and environmental risk factors. To this end, air pollution and meteorological variables along with health outcomes were analyzed at national level and on a monthly basis for the period of 2011-2020. It was found that cardiorespiratory mortality rates during winter were 44% higher than during the summer. Furthermore, particulate matter with aerodynamic diameters of 10 and 2.5 μm (μm) or smaller (PM 10 and PM 2.5 ), carbon monoxide (CO) and nitrogen dioxide (NO 2 ) showed a seasonal variability with the highest concentrations during winter while ozone (O 3 ) presented higher concentrations during spring and summer. PM 10 , PM 2.5 and NO 2 , showed a positive correlation between seasons, indicating similar patterns of behavior. Canonical correlation analysis (CCA) applied to pollutant-meteorological and cardiorespiratory mortality data indicates a strong linear correlation between pollutant-meteorological factors and health outcomes. The first canonical correlation was 0.889, and the second was 0.545, both statistically significant (p-value < 0.001). The CCA results suggest that there is a strong association between near-surface temperature, relative humidity, PM 10 , PM 2.5 , CO and NO 2 and health outcomes. The results of this study provide important information of the seasonal variability of air pollutants and meteorological factors in Portugal and their associations with cardiorespiratory mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The aim of this review was to identify, assess, collate, and analyze existing research that has made a direct contribution to aiding understanding of the ethical and decision-making issues related to the use of advance care directives for people with dementia and/or other major neurocognitive disorders and/or their surrogate decision-makers on treatment. The Web of Science, Scopus, PubMed, CINAHL, Academic Search Ultimate, and MEDLINE databases were searched between August and September 2021 and July to November 2022 limited to primary studies written in English, Spanish, or Portuguese. Twenty-eight studies of varying quality that addressed related thematic areas were identified. These themes being support for autonomy in basic needs (16%), making decisions ahead/planning ahead and upholding these decisions (52%), and support in decision-making for carers (32%). Advance care directives are an important mechanism for documenting treatment preferences in patient care planning. However, the available literature on the topic is limited in both quantity and quality. Recommendations for practice include involving decision makers, promoting educational interventions, exploring how they are used and implemented, and promoting the active involvement of social workers within the healthcare team.