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Atrial arrhythmogenic substrate is a key determinant of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a noninvasive method to assess such electrophysiologic substrate is not available to date. This study aimed to noninvasively assess regional conduction velocities and their association with arrhythmia-free survival after PVI. A consecutive 52 patients scheduled for AF ablation (PVI only) and 19 healthy controls were prospectively included and received electrocardiographic imaging (ECGi) to noninvasively determine regional atrial conduction velocities in sinus rhythm. A novel ECGi technology obviating the need of additional computed tomography or cardiac magnetic resonance imaging was applied and validated by invasive mapping. Mean ECGi-determined atrial conduction velocities were significantly lower in AF patients than in healthy controls (1.45 ± 0.15 m/s vs 1.64 ± 0.15 m/s; P <.0001). Differences were particularly pronounced in a regional analysis considering only the segment with the lowest average conduction velocity in each patient (0.8 ± 0.22 m/s vs 1.08 ± 0.26 m/s; P <.0001). This average conduction velocity of the "slowest" segment was independently associated with arrhythmia recurrence and better discriminated between PVI responders and nonresponders than previously proposed predictors, including left atrial size and late gadolinium enhancement (magnetic resonance imaging). Patients without slow-conduction areas (mean conduction velocity <0.78 m/s) showed significantly higher 12-month arrhythmia-free survival than those with 1 or more slow-conduction areas (88.9% vs 48.0%; P =.002). This is the first study to investigate regional atrial conduction velocities noninvasively. The absence of ECGi-determined slow-conduction areas well discriminates PVI responders from nonresponders. Such noninvasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be a step toward personalized AF therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Ophthalmology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In modern manufacturing, machining remains a vital process for complex mechanical components. In particular, the aerospace industry extensively employs high-feed milling techniques to machine complex geometries from nickel-based superalloys. This study focuses on the analysis and modeling of high-feed milling for Inconel 718 in 2.5-axis machining. Its objective is to develop a generalized model of high-feed milling that enables the prediction of surface topography. The proposed model integrates crucial geometric parameters of the tool and its exact kinematic within the machine, along with tool and machine deflections caused by cutting forces. A key novelty of this research lies in its capability to determine surface topography and its quality based on a generalized model, representing significant progress in the field of high-feed milling. To validate the model, experimental efforts are measured to characterize the cutting forces and system deflections during machining. The developed approach demonstrates its ability to model surface topography and to predict surface roughness. It also highlights the influence of tool and machine deflection on surface quality. This research contributes to the advancement of the application of high-feed milling in aerospace manufacturing by enhancing machining capabilities and improving part quality. [ABSTRACT FROM AUTHOR]

Endoscopic resection is standard treatment for adenomatous colorectal lesions. Depending on lesion morphology and resection technique, recurrence can occur. Scarred adenomas are challenging to resect and may require surgical management. This study evaluated the safety and effectiveness of an endoscopic powered resection (EPR) system for scarred adenomatous colorectal lesions. This single-arm, prospective, multicenter study was conducted from January 2018 to January 2021 at 12 sites. Patients with persistent flat or sessile colorectal lesions were enrolled. Primary end points were technical success (the ability of the device to resect the lesion[s] without use of other resection devices without device-related serious adverse events [AEs]) and safety (the occurrence of AEs through 90 days). Secondary end points included endoscopic confirmation of resection completeness, occurrence of colon stenosis, disease persistence, and diagnostic value of resected specimens. Sixty-five patients were in the intention-to-treat/safety analysis population. Primary analysis was performed on 45 per-protocol (PP) patients with 48 lesions. All PP patients were solely treated by using the EPR device. Technical success was achieved in 44 (98%) patients. Three (5%) serious AEs occurred: 2 delayed self-limited bleeds and 1 perforation. Nonserious AEs included 4 (6%) cases of mild intraprocedural bleeding. Completeness of resection and histopathologic diagnosis of tissue specimens were achieved in all patients. Twenty-one (46.7%) patients had disease persistence after the first treatment, and there was no colon stenosis. EPR is safe and effective for benign, persistent, large (>20 mm), scarred colorectal adenomas and should be considered as an alternative treatment in lieu of surgery. A persistence rate of 46.7% indicates that >1 treatment is necessary for effective endoscopic treatment. (Clinical trial registration number: NCT04203667.) [ABSTRACT FROM AUTHOR]

[Display omitted] • PACIFIC-PRESERVED is a prospective multicentre observational cohort study. • Study designed to perform multidimensional deep phenotyping of patients with HFpEF. • Patients with HFrEF and subjects without overt HF also enrolled as comparators. • Ratio of HFpEF:HFrEF:no overt HF = 3:2:1. • HFpEF defined as LVEF ≥ 50%; HFrEF defined as LVEF ≤ 40%. • Platform study to enable standard and innovative measurements in enrolled patients. • Will foster development of innovative strategies for HFpEF diagnosis/stratification. • Aim is to redefine phenotypic spectrum of HFpEF using machine-learning techniques. Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is poorly defined, reflecting an incomplete understanding of its pathophysiology. To redefine the phenotypic spectrum of HFpEF. The PACIFIC-PRESERVED study is a prospective multicentre cohort study designed to perform multidimensional deep phenotyping of patients diagnosed with HFpEF (left ventricular ejection fraction ≥ 50%), patients with heart failure with reduced ejection fraction (left ventricular ejection fraction ≤ 40%) and subjects without overt heart failure (3:2:1 ratio). The study proposes prospective investigations in patients during a 1-day hospital stay: physical examination; electrocardiogram; performance-based tests; blood samples; cardiac magnetic resonance imaging; transthoracic echocardiography (rest and low-level exercise); myocardial shear wave elastography; chest computed tomography; and non-invasive measurement of arterial stiffness. Dyspnoea, depression, general health and quality of life will be assessed by dedicated questionnaires. A biobank will be established. After the hospital stay, patients are asked to wear a connected garment (with digital sensors) to collect electrocardiography, pulmonary and activity variables in real-life conditions (for up to 14 days). Data will be centralized for machine-learning-based analyses, with the aim of reclassifying HFpEF into more distinct subgroups, improving understanding of the disease mechanisms and identifying new biological pathways and molecular targets. The study will also serve as a platform to enable the development of innovative technologies and strategies for the diagnosis and stratification of patients with HFpEF. PACIFIC-PRESERVED is a prospective multicentre phenomapping study, using novel analytical techniques, which will provide a unique data resource to better define HFpEF and identify new clinically meaningful subgroups of patients. [ABSTRACT FROM AUTHOR]

Nutritional complications have an impact in both short- and long-term morbidity of patients with congenital diaphragmatic hernia (CDH). We aimed to compare time to full enteral tube feeding depending on route -gastric (GT) or transpyloric (TPT)- in newborns with left CDH (L-CDH). Retrospective cohort study of L-CDH patients admitted to a referral tertiary care NICU between January 2007 and December 2014. Lethal chromosomal abnormalities and death before initiation of enteral nutrition were exclusion criteria. 37 patients were fed through GT, 46 by TPT. TPT children took 11.0 (6.8) days to reach full enteral tube feeding and spent 16.6 (8.1) days on parenteral nutrition vs 16.8 (14.7) days (p = 0.041) and 22.7 (13.5) days (p = 0.020) of GT patients. TPT children had 3.9 (2.4) days of fasting due to GI issues and 20% had episodes of decreased rates of enteral nutrition for extra-GI complications vs 11.4 (11.1) days (p = 0.028) and 49% (p = 0.006). According to the best fitting model (R2 0.383, p < 0.001), the TPT-group achieved full enteral feeding 8.4 days earlier than the GT-group (95% CI -14.76 to - 2.02 days), after adjustment by severity of illness during the first days, o/e LHR_liver and class of diaphragmatic defect. There were no differences in growth outcomes and length of stay between survivors of GT and TPT groups. TPT shortens time to full enteral nutrition, especially in the most severe L-CDH patients. We propose that placement of a TPT at the end of the surgical repair procedure should be considered, especially in higher-risk patients. Treatment study, Level III. Retrospective comparative, case–control study. [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Cardiología (18855857) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

"Cup-shaped power reamers" and "flat cuts" (FC) are common joint preparation techniques in first metatarsophalangeal (MTP) joint arthrodesis. However, the third option of an "in situ" (IS) technique has rarely been studied. This study aims to compare the clinical, radiographic, and patient-reported outcomes (PROMs) of the IS technique for various MTP pathologies with other MTP joint preparation techniques. A single-center retrospective review was performed for patients who underwent primary MTP joint arthrodesis between 2015 and 2019. In total, 388 cases were included in the study. We found higher nonunion rates in the IS group (11.1% vs 4.6%, p =.016). However, the revision rates were similar between the groups (7.1% vs 6.5%, p =.809). Multivariate analysis revealed that diabetes mellitus was associated with significantly higher overall complication rates (p <.001). The FC technique was associated with transfer metatarsalgia (p =.015) and a more first ray shortening (p <.001). Visual analog scale, PROMIS-10 physical, and PROMIS-CAT physical scores significantly improved in IS and FC groups (p <.001, p =.002, p =.001, respectively). The improvement was comparable between the joint preparation techniques (p =.806). In conclusion, the IS joint preparation technique is simple and effective for first MTP joint arthrodesis. In our series, the IS technique had a higher radiographic nonunion rate that did not correlate with a higher revision rate, and otherwise similar complication profile to the FC technique while providing similar PROMs. The IS technique resulted in significantly less first ray shortening when compared to the FC technique. [ABSTRACT FROM AUTHOR]

Acute cholangitis (AC) is an infection of the biliary tract secondary to biliary obstruction requiring biliary drainage through endoscopic retrograde cholangiopancreatography. This study aims to compare the outcome between the early and delayed ERCP in patients with severe AC. Patient with severe AC due to choledocholithiasis admitted to intensive care unit were included. Early ERCP was defined was as ERCP performed within 24 h following hospital admission. Propensity-score matching was used to reduce the imbalance between groups. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay, onset or persistent organ failure. The delayed ERCP group had a higher mortality rate at 30 days (45,5 versus 13%, <0.001) and at 1 year (59,7% versus 15,6%, p <0.001). Delayed ERCP had also a higher rate of respiratory adverse events (54,5 versus 27,8%, p = 0,002), longer ICU (7.41 versus 4.61, p = 0,004) and hospital (11,88 versus 9,22, p = 0,042) length of stay. Predictors of delayed ERCP were cardiac arrythmias, liver disease, creatinine value and white blood cell count at baseline. Delays in ERCP for patients with severe AC appear to be associated with higher mortality rate and prolonged ICU and hospital stays. [ABSTRACT FROM AUTHOR]

Valve-sparing aortic root replacement with the David procedure is an alternative to the Bentall procedure in patients with aortic root aneurysm. The aim of this study was to describe our long-term experience with this technique and the predictive factors of late failure. Between January 1998 and August 2019, 300 consecutive patients underwent a David procedure. Clinical and echocardiographic early- and long-term outcomes were analyzed. Median follow-up was 7.0 years (range, 4.1-11.5), with 98.3% complete. Early mortality was 1%. No early valve-related reoperations occurred. There were 9 cardiac-related deaths and 22 reinterventions (19 valve-related). All patients survived reoperation. In 3 patients reintervention consisted of transcatheter aortic valve implantation. Overall survival rates were 95.3% (95% confidence interval [CI], 92.0-97.2), 91.1% (95% CI, 86.5-94.2), and 82.9% (95% CI, 75.3-88.4) at 5, 10, and 15 years, respectively. Freedom from postoperative aortic insufficiency (AI) grade ≥ 2 was 84.8% (95% CI, 79.9-88.6) and 74.3% (95% CI, 67.4-79.9) at 5 and 10 years, respectively. Freedom from reintervention for aortic valve disease was 97.1% (95% CI, 94.2-98.5), 92.9% (95% CI, 88.2-95.7), and 92.5% (95% CI, 87.1-95.7) at 5, 10, and 15 years, respectively. Preoperative AI ≥ 2 (hazard ratio, 1.782; 95% CI, 1.352-2.350) and a ventriculoaortic junction ≥ 29 mm (hazard ratio, 3.379; 95% CI, 1.726-6.616) were predictive factors for postoperative AI ≥ 2 in a multivariate analysis (P <.001). Preoperative AI ≥ 2 and a ventriculoaortic junction ≥ 29 mm were identified as risk factors for late postoperative AI ≥ 2. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Cardiología (18855857) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Española de Cardiología (18855857) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Sarcopenia, a loss of muscle mass, quality and function, which is particularly evident in respiratory muscles, has been associated with many clinical adverse outcomes. In this study, we aimed at evaluating the role of reduced muscle mass and quality in predicting ventilation weaning, complications, length of intensive care unit (ICU) and of hospital stay and mortality in patients admitted to ICU for SARS-CoV-2-related pneumonia. This was an observational study based on a review of medical records of all adult patients admitted to the ICU of a tertiary hospital in Milan and intubated for SARS-CoV-2-related pneumonia during the first wave of the COVID-19 pandemic. Muscle mass and quality measurement were retrieved from routine thoracic CT scans, when sections passing through the first, second or third lumbar vertebra were available. A total of 81 patients were enrolled. Muscle mass was associated with successful extubation (OR 1.02, 95% C.I. 1.00–1.03, p = 0.017), shorter ICU stay (OR 0.97, 95% C.I. 0.95–0.99, p = 0.03) and decreased hospital mortality (HR 0.98, 95% C.I. 0.96–0.99, p = 0.02). Muscle density was associated with successful extubation (OR 1.07, 95% C.I. 1.01–1.14; p = 0.02) and had an inverse association with the number of complications in ICU (Β −0.07, 95% C.I. −0.13 - −0.002, p = 0.03), length of hospitalization (Β −1.36, 95% C.I. −2.21 - −0.51, p = 0.002) and in-hospital mortality (HR 0.88, 95% C.I. 0.78–0.99, p = 0.046). Leveraging routine CT imaging to measure muscle mass and quality might constitute a simple, inexpensive and powerful tool to predict survival and disease course in patients with COVID-19. Preserving muscle mass during hospitalisation might have an adjuvant role in facilitating remission from COVID-19. • Routine CT scans are useful to characterise muscle mass, density and quality. • Preserved muscle mass and density predicted successful extubation in patients with SARS-CoV-2-related pneumonia. • Low muscle mass and density predicted a fatal and/or complicated COVID-19 course. [ABSTRACT FROM AUTHOR]

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions.Methods and Results: A total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/m2 and a diagnosis of diabetes mellitus. Carotid ultrasonography was performed to measure markers of atherosclerosis and arterial stiffness. Cardiac remodeling was analyzed using echocardiography. The prevalence of subclinical and overt atherosclerosis was significantly higher in the NAFLD + HT patients as compared to the other two groups (atherosclerotic plaques: 43.1%, 10.9%, and 22.4% (p < 0.001) in NAFLD + HT, NAFLD, and HT groups, respectively). No differences were found among indices of arterial stiffening and cardiac remodeling across the three groups. In multivariate regression analysis, the coexistence of NAFLD and HT was an independent risk factor for overt atherosclerosis (OR = 4.88, CI 95% 1.14-20.93), while no association was found when either NAFLD or HT was considered alone.Conclusion: Overt atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT. [ABSTRACT FROM AUTHOR]

• Young age at diagnosis is associated with poor outcomes among breast cancer patients. • Young patients' tumors have unique biological characteristics, including mutations and genomic signatures. • Only a handful of trials testing gene-expression platforms have included young patients. • The lack of effective treatment strategies in this subset warrants further investigation. The incidence of breast cancer in ≤ 40 yr-old women (YWBC) has been steadily increasing in recent decades. Although this group of patients represents less than 10 % of all newly diagnosed BC cases it encompasses a significant burden of disease. Usually underrepresented in clinical trials, YWBCs are also characterized by late diagnoses and poorly differentiated, aggressive-subtype disease, partly explaining its poor prognosis along with a high recurrence risk, and high mortality rates. On the other hand, YWBC treatment poses unique challenges such as preservation of fertility, and long-term toxicity and adverse events. Herein, we summarize the current evidence in hormone receptor-positive YWBC including specific risk factors, clinicopathologic and genomic features, and available evidence on response to chemotherapy and endocrine therapy. Overall, we advocate for a more comprehensive multidisciplinary healthcare model to improve the outcomes and the quality of life of this subset of younger patients. [ABSTRACT FROM AUTHOR]

Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights. [ABSTRACT FROM AUTHOR]

An altered gut microbiome characterized by reduced abundance of butyrate producing bacteria and reduced gene richness is associated with type 2 diabetes (T2D). An important complication of T2D is increased risk of cognitive impairment and dementia. The biguanide metformin is a commonly prescribed medication for the control of T2D and metformin treatment has been associated with a significant reduction in the risk of dementia and improved cognition, particularly in people with T2D. To investigate the associations of metformin use with cognition exploring potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. We explored two independent cohorts: an observational study (Aging Imageomics) and a phase IV, randomized, double-blind, parallel-group, randomized pilot study (MEIFLO). From the two studies, we analyzed four study groups: (1) individuals with no documented medical history or medical treatment (n = 172); (2) people with long-term T2D on metformin monotherapy (n = 134); (3) people with long-term T2D treated with oral hypoglycemic agents other than metformin (n = 45); (4) a newly diagnosed T2D subjects on metformin monotherapy (n = 22). Analyses were also performed stratifying by sex. Several bacterial species belonging to the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated with metformin treatment, while bacterial species belonging to the Firmicutes phylum (Romboutsia timonensis , Romboutsia ilealis) were negatively associated. Due to the consistent increase in A. muciniphila and decrease in R.ilealis in people with T2D subjects treated with metformin, we investigated the association between this ratio and cognition. In the entire cohort of metformin-treated T2D subjects, the A.muciniphila / R.ilealis ratio was not significantly associated with cognitive test scores. However, after stratifying by sex, the A.muciniphila / R. ilealis ratio was significantly and positively associated with higher memory scores and improved memory in men. Metformin treatment was associated with an enrichment of microbial pathways involved in the TCA cycle, and butanoate, arginine, and proline metabolism in both cohorts. The bacterial genes involved in arginine metabolism, especially in production of glutamate (astA, astB, astC, astD, astE, putA), were enriched following metformin intake. In agreement, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in the metabolism of glutamate. The beneficial effects of metformin may be mediated by changes in the composition of the gut microbiota and microbial-host-derived co-metabolites. • Metformin's beneficial effects may be mediated by changes in gut microbiota composition and functionality. • Metformin was associated with an increase in E. coli and A. muciniphila and a decrease in R. ilealis. • A. muciniphila / R. ilealis ratio was associated with improved memory scores in men, but not in women. • Metformin was associated with an enrichment of pathways involved in the arginine, and proline metabolism. • The bacterial functions of arginine metabolism (astA, astB, astC, astD, astE, putA) were involved in glutamate synthesis. [ABSTRACT FROM AUTHOR]

There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH. We retrospectively included patients with biopsy-verified AH. Clinical, laboratory and outcome data were collected. CPA and five AH scores were calculated: Maddrey's DF, MELD, GAHS, ABIC, and the Lille Model. Predictors of short and long-term all-cause mortality were assessed using Cox regression analysis. We included 140 patients with AH. In total, 67 (48%) patients died after a median follow-up of 66 (IQR 102) months, with 17 (12%) dying within the first 90-days. CPA was not a predictor of 90-days mortality and had no additional value to the prognostic AH scores on short-term mortality. However, CPA predicted long-term mortality independently of prognostic AH scores. Importantly, CPA and abstinence from alcohol were independent predictors of long-term mortality in patients alive 90 days after the biopsy. CPA predicts long-term mortality in patients with AH independently of abstinence from alcohol but has no prognostic value on short-term mortality. [ABSTRACT FROM AUTHOR]

• Triple-positive Breast Cancer (TPBC) display different biological features and gene expression profiles. • For some TPBC, endocrine therapy with anti-HER2 agents may avoid the use of chemotherapy. • CDK4/6 inhibitors may represent a valuable option, particularly in Luminal-subtype TPBC. • The expression of hormone receptors may represent the rationale for Antibody-drug conjugates combinations. Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes. [ABSTRACT FROM AUTHOR]

Background: Early results from the Micra investigational trial and Micra Post-Approval Registry (PAR) demonstrated excellent safety and device performance; however, outcomes based on anticoagulation (AC) status at implant have not been evaluated.Objective: The purpose of this study was to report implant characteristics, perforation rate, and vascular-related events based on perioperative oral AC strategy in patients undergoing Micra implant.Methods: We compared procedure characteristics, major complications, and vascular events, including pericardial effusion, stratified by any adverse event (including major complications, minor complications, and observations) or major complication only according to AC status in the Micra PAR.Results: Among 1795 patients with AC status available, 585 were not on AC, 795 had AC interrupted, and 415 had AC continued during Micra implant. Non-AC patients tended to be younger, with less history of atrial fibrillation and chronic obstructive pulmonary disease, and more history of dialysis than interrupted and continued patients. The implant success rate was similar for all groups (99.1%-99.8%). Through 30 days postimplant, the overall major complication rate was 3.1% for the non-AC group, 2.6% for the interrupted group, and 1.5% for the continued group. The combined rate for any vascular or pericardial effusion adverse event did not differ significantly among AC strategies (6.5%, 4.8%, and 3.6%, respectively).Conclusion: Implant of Micra seems to be safe and feasible regardless of an interrupted or continued periprocedural oral AC strategy, with no increased risk of perforation or vascular complications. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on cancer diagnosis and treatment. Most patients newly diagnosed with digestive system cancer are aged 65 and over. We performed a retrospective, observational, multicentre cohort study based on prospectively collected electronic health records. All adults aged 65 or over and having been newly treated for a digestive system cancer between January 2018 until August 2020 were enroled. Data on 7882 patients were analysed. The first COVID-19 lockdown period led to a 42.4% decrease in newly treated digestive system cancers, and the post-lockdown period was associated with a 17% decrease. The decrease in newly treated digestive system cancer did not differ as a function of age, sex, comorbidities, primary tumour site, and disease stage. The proportion of patients admitted to an emergency department increased during the lockdown period. We do not observe a higher 3-month mortality rate in 2020, relative to the corresponding calendar periods in 2018 and 2019. To avoid a decrease in newly treated cancers during future lockdown periods, access to healthcare will have to be modified. Although 3-month mortality did not increase in any of the patient subgroups, the 2020 cohort must be followed up for long-term mortality. [ABSTRACT FROM AUTHOR]

• Self-collected nasal and saliva samples can be used for SARS-CoV-2 screening. • Self-collected nasal and saliva specimens had a 99% and 90% sensitivity, respectively. • Nasopharyngeal swab viral loads correlate better with nasal than saliva. • Viral load correlations are poorer at day 7, when lower viral loads are observed. [ABSTRACT FROM AUTHOR]

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease. • Almost 50 % of HER2+ breast cancer (BC) are molecularly HER2-Enriched (HER2-E). • Most relevant mutations are found in ERBB2 (∼4 %) and PI3K/AKT/mTOR pathway (>30 %). • Tumor infiltrating lymphocytes are frequent, predictive and prognostic in HER2+ BC. • HER2 heterogeneity and HER2 low status are gaining therapeutic relevance. • New treatments need to consider HER2+ molecular and microenvironmental complexity. [ABSTRACT FROM AUTHOR]

Background: Scar characteristics analyzed by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) are related with ventricular arrhythmias. Current guidelines are based only on the left ventricular ejection fraction to recommend an implantable cardioverter-defibrillator (ICD) in primary prevention.Objectives: Our study aims to analyze the role of imaging to stratify arrhythmogenic risk in patients with ICD for primary prevention.Methods: From 2006 to 2017, we included 200 patients with LGE-CMR before ICD implantation for primary prevention. The scar, border zone, core, and conducting channels (CCs) were automatically measured by a dedicated software.Results: The mean age was 60.9 ± 10.9 years; 81.5% (163) were men; 52% (104) had ischemic cardiomyopathy. The mean left ventricular ejection fraction was 29% ± 10.1%. After a follow-up of 4.6 ± 2 years, 46 patients (22%) reached the primary end point (appropriate ICD therapy). Scar mass (36.2 ± 19 g vs 21.7 ± 10 g; P < .001), border zone mass (26.4 ± 12.5 g vs 16.0 ± 9.5 g; P < .001), core mass (9.9 ± 8.6 g vs 5.5 ± 5.7 g; P < .001), and CC mass (3.0 ± 2.6 g vs 1.6 ± 2.3 g; P < .001) were associated with appropriate therapies. Scar mass > 10 g (25.31% vs 5.26%; hazard ratio 4.74; P = .034) and the presence of CCs (34.75% vs 8.93%; hazard ratio 4.07; P = .003) were also strongly associated with the primary end point. However, patients without channels and with scar mass < 10 g had a very low rate of appropriate therapies (2.8%).Conclusion: Scar characteristics analyzed by LGE-CMR are strong predictors of appropriate therapies in patients with ICD in primary prevention. The absence of channels and scar mass < 10 g can identify patients at a very low risk of ventricular arrhythmias in this population. [ABSTRACT FROM AUTHOR]

• Participatory processes are key in river management but remain scarce in temporary rivers. • Despite their ecological importance, temporary rivers are socially considered in low esteem. • Raising awareness on temporary rivers is key to increase stakeholders' engagement. • Involving stakeholders also in the diagnosis of rivers increased their knowledge. • Our approach can contribute to adapt current participatory processes to future management needs. The European Water Framework Directive (WFD) mandates to incorporate the participation of stakeholders and the general public in the development and updating of the river basin management plans. So far, the WFD implementation has been mainly focused on perennial rivers without considering temporary rivers properly, neither in biomonitoring programs nor participatory processes. This paper aims at adapting participatory processes in river basin management to enhance the inclusion of ecosystems with poor or no social recognition such as temporary rivers. To do so, we examined previous experiences of participatory processes conducted in the WFD and adapted them to propose and implement an approach for promoting stakeholders' engagement in temporary rivers. The approach is based on a collaborative leadership, includes multiple participatory engagement mechanisms, uses future global change scenarios and the concept of ecosystem services at different stages of the process, and aims at involving stakeholders not only in the proposal of measures stage but in the diagnosis of the ecological status. It also includes an evaluation of participants' satisfaction on the process. We tested our approach in temporary rivers from the Mediterranean region. We found that the combination of environmental education and citizen science activities, together with the inclusion of the ecosystem services concept, was the most useful way to raise awareness on the biodiversity and ecological value of temporary rivers and to promote stakeholders' engagement. Workshops conducted during the diagnosis stage played an important role in both including stakeholders' suggestions and increasing their knowledge on temporary rivers. Further, envisaging climate-related future scenarios allowed participants to incorporate measures that could tackle new and emerging pressures on these ecosystems. As future environmental changes will increase the proportion of rivers with temporary flow regimes, our approach can contribute to adapt current participatory processes to future needs. [ABSTRACT FROM AUTHOR]

Background: Mass testing for early identification and isolation of infectious COVID-19 individuals is efficacious for reducing disease spread. Antigen-detecting rapid diagnostic tests (Ag-RDT) may be suitable for testing strategies; however, benchmark comparisons are scarce.Methods: We used 286 nasopharyngeal specimens from unexposed asymptomatic individuals collected between December 2020 and January 2021 to assess five Ag-RDTs marketed by Abbott, Siemens, Roche Diagnostics, Lepu Medical, and Surescreen.Results: For the overall sample, the performance parameters of Ag-RDTs were as follows: Abbott assay, sensitivity 38.6% (95%CI 29.1-48.8) and specificity 99.5% (97-100%); Siemens, sensitivity 51.5% (41.3-61.6) and specificity 98.4% (95.3-99.6); Roche, sensitivity 43.6% (33.7-53.8) and specificity 96.2% (92.4-98.5); Lepu, sensitivity 45.5% (35.6-55.8) and specificity 89.2% (83.8-93.3%); Surescreen, sensitivity 28.8% (20.2-38.6) and specificity 97.8% (94.5-99.4%). For specimens with cycle threshold (Ct) <30 in RT-qPCR, all Ag-RDT achieved a sensitivity ≥70%. The modelled negative- and positive-predictive value for 1% prevalence were >99% and <50%, respectively.Conclusions: When screening unexposed asymptomatic individuals, two Ag-RDTs achieved sensitivity ≥80% for specimens with Ct<30 and specificity ≥96%. The estimated negative predictive value suggests the suitability of Ag-RDTs for mass screenings of SARS-CoV-2 infection in the general population. [ABSTRACT FROM AUTHOR]

New evidence has emerged on the impact of frailty on prognosis in colon cancer, but the findings are not always consistent and conclusive. The aim of this systematic review was to assess the effect of frailty on postoperative complications and mortality in patients with non-metastatic colon cancer (CC) aged 65 years and older. We systematically searched for original studies published in the PubMed and Web of Science databases up to June 2021. Two independent reviewers selected the studies and extracted predefined data. A meta-analysis was performed using the random effects model to assess the effect of frailty on 30-day, 3- to 6-month and 1-year mortality, survival, and postoperative complications. The search yielded 313 articles, of which 14 were included in this systematic review. The meta-analysis showed an effect for frailty on 30-day, 3- to 6-month, and 1-year mortality with respective pooled odds ratios (ORs) of 3.67 (95% confidence interval [CI] 1.53–8.79, p = 0.004), 8.73 (95% CI 4.03–18.94, p < 0.0001), and 3.99 (95% CI 2.12–7.52, p < 0.0001). Frailty also had an effect on survival, with a pooled hazard ratio of 2.99 (95% CI 1.70–5.25. p < 0.0001), and on overall and severe postoperative complications with pooled ORs of 2.34 (95% CI 1.75–3.15; p < 0.0001) and 2.43 (95% CI 1.72–3.43; p < 0.0001), respectively. Frailty in older patients with CC is a risk factor for postoperative complications and mortality in the short term (30 days), medium term (3–6 months), and long term (1 year). [ABSTRACT FROM AUTHOR]

• Ki-67/MIB-1 index and Simpson grading are both independent predictors of recurrence in meningiomas. • Ki-67/MIB-1values =>3% increases rate of recurrence. • Meningiomas grade I with Ki-67/MIB-1 >=3% and meningiomas grade II have similar recurrence. Simpson grading of resection has been used as a predictor of intracranial meningioma (IM) recurrence. Histopathological findings, like the Ki-67/MIB-1 labeling index, may be useful in the assessment risk of recurrence. Our objective was to analyze the predictive value of meningioma recurrence using both parameters. We retrospectively studied 322 consecutive patients with histopathological diagnosis of IM WHO grade I and 43 patients with IM WHO grade II in a 13-year period. Multivariate survival analysis was performed. In the WHO grade I IM group, recurrence was observed in 28 patients (8.69%). The Cox regression model for WHO grade I IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3 (HR = 36.35, p < 0.001) and Simpson's grading resection, grade II (HR = 2.03, p = 0.045), grade III (HR = 3.41, p = 0.034) and grade IV (HR = 19.75, p ≥ 0.001). In the WHO grade II IM group, recurrence was observed in 10 patients (23.25%). The Cox regression model for WHO grade II IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3% (HR = 1.66, p < 0.001) and Simpson's grading resection grade III (HR = 3.96, p = 0.027). The Kaplan–Meier survival curve showed a similar distribution of survival between WHO grade I IM with Ki-67/MIB-1 ≥3% and WHO grade II IM. In WHO grade I meningiomas, the Ki-67/MIB-1 index and Simpson grading were both independent predictors of recurrence. A similar management protocol should be advisable for WHO grade I with Ki-67/MIB-1 ≥3% and WHO grade II meningiomas. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate children in middle childhood with clubfoot treated with Ponseti method vs posterior-only release and to compare their results to a control group with 4 modules (physical examination, gait study, radiographic measurements, and questionnaires). From 01/01/2004 until 01/01/2009, 31 children (45 feet) were treated with the posterior-only release protocol and 22 patients (34 feet) were treated with the Ponseti method. In 2016, patients were evaluated and compared with 25 children without neuromuscular disorders. Parents completed 3 outcome questionnaires. Radiographs evaluated residual deformity and osteoarthritis. A physical examination and a 3-dimensional gait analysis were performed to evaluate range of motion, kinematic, and kinetic data. Recurrence rate was similar between treatment groups; however, type of surgery to treat residual deformity was more aggressive in the posterior-only release (91% required major surgery), p =.024. Radiographic examination showed similar residual deformity with greater hindfoot varus in posterior-only release (68%), p =.02. Reduced cadence, increased stance dorsiflexion, calcaneus gait and forced eversion prior to swing were the main characteristics of gait in posterior-only release. Four (11%) feet treated with posterior-only release vs 11 (33%) feet treated with Ponseti method had a normal gait, p =.016. Our study showed that biomechanical function and long-term outcomes of children in middle childhood treated with the Ponseti method more closely compare with healthy individuals than those treated using posterior-only surgical technique. [ABSTRACT FROM AUTHOR]

The best valvular substitute remains controversial in young adults with active aortic valve endocarditis. The Ross procedure has gained interest because of its theoretical resistance to infection. We aimed to report our long-term outcomes of the Ross procedure in this indication. Between March 1992 and January 2019, 511 patients underwent a Ross procedure in our institution. Among them, we included 38 patients who suffered from an active aortic valve infective endocarditis. The mean age was 33.9 ± 8.1 years. Six patients had emergent procedures and 17 patients had perivalvular involvement. A pulmonary autograft was implanted using the full root technique in 78.9% of patients. Median follow-up was 12 (interquartile range, 1.75-16.25) years. The hospital mortality rate was 5.3%. Estimated overall survival was 84.2% ± 6.6% at 10 years. There were 2 cases of recurrent endocarditis, both requiring reoperation. Six other patients required reoperation on an autograft or homograft. Estimated freedom from recurrent endocarditis or reoperation was 89.4% ± 5.9% at 10 years. In experienced centers, the Ross procedure is a reliable alternative to prosthetic or homograft valve replacement in young adults experiencing active aortic valve endocarditis, with a low operative risk and good long-term results. [ABSTRACT FROM AUTHOR]

Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P =.005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT. [ABSTRACT FROM AUTHOR]

Background: In adults, the most common cause of out-of-hospital cardiac arrests (OHCA) is acute coronary artery occlusion. If an immediate coronary angiogram (CAG) is recommended for survivors presenting a ST segment elevation on the electrocardiogram (ECG) performed after resuscitation, there is still a debate regarding the best strategy in patients without ST segment elevation.Hypothesis: Performing an immediate CAG after an OHCA without ST segment elevation on the post-resuscitation ECG and no obvious non-cardiac cause of arrest could lead to a better 180-day survival rate with no or minimal neurological sequel as compared with a delayed CAG performed 48 to 96 hours after the arrest.Design: The EMERGE trial is a prospective national, randomized, open and parallel group trial, in which 970 survivors of OHCA will be randomized (1:1) to either immediate (as soon as possible after return of spontaneous circulation) or delayed (48 to 96 h) CAG. Participants will be OHCA patients with no ST segment elevation on the post resuscitation ECG and no obvious non-cardiac cause of arrest. The primary endpoint of the study is the 180-day survival rate with no or minimal neurological sequel corresponding to Cerebral Performance Category (CPC) 1 or 2. The secondary endpoints are: occurrence of shock during the first 48 hours, ventricular tachycardia and/or fibrillation during the first 48 hours, change in left ventricular ejection fraction between baseline and 180 days assessed by echocardiogram, neurological status evaluated by the CPC score at intensive care unit (ICU) discharge and day 90 neurological status assessed by the Glasgow Outcome Scale Extended score (GOSE) at 90 and 180 days, overall survival rate, and hospital length of stay.Summary: The EMERGE trial is a prospective, multicenter, randomized, controlled trial that will assess the 180-day survival rate with no or minimal neurologic sequel in patients resuscitated from an OHCA without ST segment elevation and who will be managed with either immediate or delayed CAG. [ABSTRACT FROM AUTHOR]

Factors associated with rectal NENs prognosis are poorly investigated. To evaluate the prognostic role of the ENETs staging and grading systems in rectal NENs. Tertiary referral, multicenter, retrospective study. Factors associated with OS and PFS were investigated by Cox-regression analysis, with best size cut-offs calculated by ROC analysis. Of 100 patients (mean age 55, 45% male, mean size 16.2 mm) 62, 5, 10 and 23 were TNM stage 1 to 4, and 63, 15 and 22 were G1, G2 and G3. Primary treatment was endoscopic snare resection in 62%, endoscopic mucosal resection/endoscopic submucosal dissection in 10%, surgery in 20% and medical treatment in 8%. The best size cut-offs to predict OS and PFS were 10 and 12 mm. During a mean follow-up of 40.7 months 12% died and 26% progressed. The 5-year OS and PFS were 79.5% and 65.2%. Stage IV and G3 were associated with worse OS (HR 8.16; p = 0.002; HR 15.57; p = 0.0004) and PFS (HR 14.26 p < 0.0001; HR 6.42; p = 0.0007). Both staging and grading accurately predict rectal NENs prognosis. Size alone has limited accuracy as 26% of patients with stage IV and 16% with G3 have a primary tumour≤10 mm. [ABSTRACT FROM AUTHOR]

There are strong suggestions for a link between pulmonary tuberculosis (TB) and air quality. Diesel exhaust is one of the main contributors to pollution and it is reported to be able to modify susceptibility to lung infections. In this study we exposed THP-1 human macrophages and Mycobacterium bovis BCG to diesel exhaust particles (DEPs). High cytotoxicity and activation of apoptosis was found in THP-1 cells at 3 and 6 days, but no effect was found on the growth of M. bovis BCG. Infection of THP-1 cells exposed to a non-cytotoxic DEP concentration showed a limited capacity to engulf latex beads. However, M. bovis BCG infection of macrophages did not result in an increase in the bacterial burden, but it did result in an increase in the bacteria recovered from the extracellular media, suggesting a poor contention of M. bovis BCG. We also observed that DEP exposure limited the production of cytokines. Using the Galleria mellonella model of infection, we observed that larvae exposed to low levels of DEPs were less able to survive after infection with M. bovis BCG and had a higher internal bacterial load after 4 days of infection. Unraveling the links between air pollution and impairment of human antimycobacterial immunity is vital, because pollution is rapidly increasing in areas where TB incidence is extremely high. [Display omitted] • Diesel exhaust particles (DEPs) are highly toxic to human macrophages, avidly internalized and increase the apoptosis • DEPs limit the ability of macrophages to engulf latex beads • DEPs difficult the contention of M. bovis BCG inside human macrophages • DEPs impairs the production of cytokines TNF-α, IL-8, IL-1β and GM-CSF. • DEPs decrease the survival in M. bovis BCG infected G. mellonella at non-toxic concentrations. [ABSTRACT FROM AUTHOR]

• AXL drives resistance to HER2 blockade in HER2+ cancers. • AXL expression predicts worse prognosis and associates with metastasis in HER2+ breast cancer. • AXL inhibitors are currently being evaluated in clinical trials in solid tumors. • Dual inhibition of AXL and HER2 is a promising therapeutic strategy for HER2+ tumors. HER2 is a driver in solid tumors, mainly breast, oesophageal and gastric cancer, through activation of oncogenic signaling pathways such as PI3K or MAPK. HER2 overexpression associates with aggressive disease and poor prognosis. Despite targeted anti-HER2 therapy has improved outcomes and is the current standard of care, resistance emerge in some patients, requiring additional therapeutic strategies. Several mechanisms, including the upregulation of receptors tyrosine kinases such as AXL, are involved in resistance. AXL signaling leads to cancer cell proliferation, survival, migration, invasion and angiogenesis and correlates with poor prognosis. In addition, AXL overexpression accompanied by a mesenchymal phenotype result in resistance to chemotherapy and targeted therapies. Preclinical studies show that AXL drives anti-HER2 resistance and metastasis through dimerization with HER2 and activation of downstream pathways in breast cancer. Moreover, AXL inhibition restores response to HER2 blockade in vitro and in vivo. Limited data in gastric and oesophageal cancer also support these evidences. Furthermore, AXL shows a strong value as a prognostic and predictive biomarker in HER2+ breast cancer patients, adding a remarkable translational relevance. Therefore, current studies enforce the potential of co-targeting AXL and HER2 to overcome resistance and supports the use of AXL inhibitors in the clinic. [ABSTRACT FROM AUTHOR]

Preclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2–) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2− breast cancer. Here, we report outcomes from the safety run-in phase. Patients with histologically confirmed, untreated ER+/HER2− breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation. At safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [ n = 6], grade 3 febrile neutropaenia [ n = 1], grade 1 pneumonitis [ n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [ n = 1]). Consequently, the study was closed early. Neoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2− breast cancer. • CheckMate 7A8 assessed neoadjuvant nivolumab plus palbociclib plus anastrozole. • Patients had ER+/HER2− breast cancer with primary tumour ≥2 cm. • Of the 21 patients in the safety run-in phase, 9 discontinued due to toxicity. • The study was closed early due to grade 3/4 hepatotoxicity. • Nivolumab combined with CDK4/6 inhibitors should not be pursued in this setting. [ABSTRACT FROM AUTHOR]