Incidence of Pathologic Nodal Disease in Clinically Node-Negative, Microinvasive or T1a Breast Cancers.

BACKGROUND: Axillary staging in early-stage breast cancer can impact adjuvant treatment options but also has associated morbidity. The incidence of pathologic nodal positivity (pN+) in patients with microinvasive or T1a disease is poorly characterized and the value of sentinel node biopsy remains controversial. METHODS: Women with cN0 and pathologic microinvasive or T1a cancer who underwent upfront surgery were identified from the National Cancer Database. Pathologic nodal stage at the time of surgery was the primary outcome. Multivariable logistic modeling was used to assess predictors of pN+. RESULTS: Overall, 141,840 women were included; 139,206 had pathologic node-negative (pN0) disease and 2634 had pN+ disease. Rates of pN+ disease differed by receptor status, with the highest rates in hormone receptor-negative/human epidermal growth factor receptor 2-positive (HR-/HER2+) disease compared with triple-negative breast cancer (TNBC), HR-positive/HER2-negative (HR+/HER2-), and triple positive breast cancer. Rates of pN+ were also higher with lobular histology compared with ductal histology. Multivariable analysis demonstrated that compared with White women, Black women had higher odds of pN+ disease, and compared with women <50 years of age, women >70 years of age had higher odds of pN+ disease. Compared with women with HR+/HER2- disease, women with TNBC, triple-positive breast cancer, and HR-/HER2+ all had lower odds, and women with invasive lobular disease had higher odds compared with women with invasive ductal disease. Women with significant comorbidities also had higher odds of node positivity. CONCLUSION: Over 90% of patients with clinically node-negative, microinvasive and T1a breast cancer remain pathologically node-negative following axillary staging. However, higher rates of nodal disease were found among Black patients, older patients, and patients with lobular cancer and significant comorbidities.

National Patterns of Hospital Admission Versus Home Recovery Following Mastectomy for Breast Cancer.

BACKGROUND: We examined national patterns of care and perioperative outcomes for women after mastectomy, comparing home recovery (HR) with hospital admission. PATIENTS AND METHODS: Using Martketscan data (2017-2019), women ≥ 18 years old who underwent mastectomy ± reconstruction were identified and classified as either home recovery (same calendar day discharge) or hospital admission (stays > 1 calendar day). Comorbidities and receipt of chemo/immunotherapy 6 months prior to surgery and post-surgical 30-day complications were measured. Logistic regression calculated the odds of any complication by encounter type, adjusting for age, accompanying lymph node (LN) procedure, reconstruction, neoadjuvant chemo- and/or immunotherapy, and select comorbidities. RESULTS: Of 11,789 mastectomy encounters (N = 11,659 women), 4751 (40%) cases utilized HR while 7038 (60%) had hospital admission. HR patients were older (53.6 years old vs. 51.8 years old) with lower rates of reconstruction (60.2 vs. 74.5%, p < 0.001). Rates of neoadjuvant chemotherapy (19.6 vs. 20.9%, p = 0.099) and immunotherapy (3.6 vs. 3.9%, p = 0.445) were similar between groups. Complication rates were lower among HR patients with fewer postoperative hematomas (0.6 vs. 1.3%, p < 0.001) and decreased wound complications (8.5 vs. 9.8%, p = 0.019). In a multivariable analysis, the odds of any complication were approximately 20% lower for HR patients compared with admission patients (aOR 0.81, 95% CI 0.72-0.91, p < 0.001). Unplanned emergency room visits were similar between groups (6.7 vs. 7.2%, p = 0.374); yet fewer hospital re-admissions (2.5 vs. 3.5%, p = 0.003) occurred in women recovering at home. CONCLUSION: HR is a safe option compared with in-hospital admission for clinically appropriate women after mastectomy as they are less likely to experience postoperative complications, emergency department (ED) visits, or hospitalization.

Heart Healthy Routines in Young Children with Sesame Workshop®: A Qualitative Study of Latina Mothers with Economic Hardship.

OBJECTIVE: To explore how Sesame Workshop® resources are perceived by Latino families with economic hardship and to highlight approaches for early heart healthy routine promotion. METHODS: We performed purposive sampling of Latina mothers (n=40) with young children experiencing economic hardship. Using an interview guide informed by the Consolidated Framework for Implementation Research, we recorded Spanish and English semi-structured interviews which were translated and transcribed verbatim. Partnering with Sesame Workshop®, we iteratively incorporated Sesame Resources® into interviews to query for acceptability. Using reflexive thematic analysis, we coded transcripts through textual analysis until saturation, prioritizing in vivo coding to capture participant voices. RESULTS: We constructed three themes. Parents connected with resources that 1) Reflect lived and multicultural experiences containing recognizable family scenes that can serve as tools to transfer a parent's own early routines or cultural rituals to their child. They appreciated resources that 2) Engage caregivers and children together featuring elements for both children and adult caregivers with activities to highlight important caregivers and encourage shared play. Participants also reflected on how 3) Routines amplify family strengths and foster resilient reactions with feelings of decreased stress when daily practices become routines, promoting resilient reactions and supporting long-term goals even when facing setbacks. CONCLUSION: An interdisciplinary partnership leveraged strengths of pediatric practitioners and Sesame Workshop® to align future initiatives with the values and priorities of mothers of young children at risk for early obesity. Resultant themes inform strategies to promote heart healthy routines and relational health in young children with economic hardship.

Fungal Keratitis, Epidemiology and Outcomes in a Tropical Australian Setting.

BACKGROUND: Fungal keratitis is an ophthalmic emergency that can cause visual impairment and blindness. We reviewed the epidemiology and clinical features of fungal keratitis in a tropical Australian setting. OBJECTIVES: To document the clinical and microbiological characteristics of fungal keratitis in an Australian tropical setting. METHODS: A retrospective cohort study of patients with fungal keratitis from October 2014 to December 2022 was conducted at Royal Darwin Hospital, Northern Territory, Australia. We reviewed all patients with culture-proven fungal keratitis and their outcomes. RESULTS: There were 31 patients identified. Aboriginal and Torres Strait Islander (ATSI) patients were of a significantly younger median age (28 years) compared to non-ATSI patients (42 years), and they also presented later to health care. Contact lens use and ocular trauma were the most common predisposing factors. Most patients presented with a corneal infiltrate and corneal epithelial defect, and the central visual axis was affected in 54% of patients. Curvularia spp. and Fusarium spp. were the commonest causative fungi (39% and 30% respectively). CONCLUSIONS: Our series is different and reveals a wider range of fungal species identified over the 7 years of the study, in particular, a range of Curvularia spp. were detected. Access to eye health services in rural and remote settings is important, particularly for ATSI patients, as morbidity remains high.

Core Needle Biopsies as an Alternative Source for Ex Vivo Expanded TIL for Adoptive Cell Therapy in Triple-Negative Breast Cancer.

Adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TILs) have produced long-term response in metastatic cancers. TILs have traditionally been expanded from surgically resected specimens. Ultrasound-guided core needle biopsy (CNB) is an alternative method that avoids the morbidity of surgery and have added benefits which may include patients not amenable to surgery as well as the potential to produce TILs from multiple lesions in the same patient. We assessed the ability to produce and expand TILs from primary triple-negative breast cancer tumors from CNB (n=7) and demonstrate comparable expansion, phenotype and cytokine secretion after phorbol myristate acetate-ionomycin stimulation to TILs expanded from surgery (n=6). T cell Receptor clonality and diversity were also comparable between the two cohorts throughout the TIL culture. CNB is a safe and feasible method to obtain tumor tissue for TIL generation in patients with triple-negative breast cancer.

Supporting early childhood routines to promote cardiovascular health across the life course.

Optimal cardiovascular health is an essential component of human health and well-being across the life course. Heart healthy practices around diet, physical activity, and sleep early in childhood have the potential to greatly improve lifespan and quality (Mehta et al., 2020). Early childhood routines, defined as functional practices that are predictable and repeatable, predict positive growth and development across the lifecourse (Fiese et al., 2002; Ferretti and Bub, 2017; Spagnola and Fiese, 2007). The American Heart Association has identified key heart healthy routines, such as daily regular activities including diet, physical activity, and sleep that promote cardiovascular health (Lloyd-Jones et al., 2022). Integrating the strength-based relational aspects of routines with the acquisition of cardiovascular health development capabilities allows children to establish their own optimal cardiovascular health trajectory early on. A systematic life course approach to supporting heart healthy routines in early childhood would inform clinical, research, and policy strategies to promote long-term cardiovascular health, and contribute to reducing inequalities in cardiovascular outcomes.

Neoadjuvant Immunotherapy in Early, Triple-Negative Breast Cancers: Catching Up with the Rest.

Despite breast cancer being long thought to be "immunologically cold," within early, triple-negative breast cancer (TNBC), there has been exciting advances with the use of immune checkpoint modulation combined with neoadjuvant chemotherapy. We review the major trials that have investigated combination immunochemotherapy in the neoadjuvant setting, reviewing both the pathological complete response rates and the maturing data regarding event-free and overall survival. Strategies to deescalate adjuvant therapy in patients with preserving excellent clinical outcome, as well as exploration of combinatorial adjuvant therapies to improve outcome in those with extensive residual are the next-generation challenges. In addition to refinement of existing biomarkers, such as PD-L1, TILs, and tumor mutational burden (TMB), exploration of topics like the microbiome as both a biomarker and a therapeutic has shown promise in other cancer types, which motivates investigating these in breast cancer.

Breast Cancer Screening: Is There Room for De-escalation?

Purpose of Review: Breast cancer screening is highly controversial and different agencies have widely varying guidelines. Yet it is currently used extensively in the USA and frequently the thought is "the more, the better." The purpose of this review is to objectively assess the risks and benefits of screening mammography and consider whether there may be areas where it could be de-escalated. Recent Findings: Over the past few years, there have been several meta-analyses that are concordant, and it is now agreed that the main benefit of screening mammography is about a 20% reduction in breast cancer mortality. This actually benefits about 5% of patients with mammographically detected tumors. We now appreciate that the main harm of screening is overdiagnosis, i.e. detection of a cancer that will not cause the patient any harm and would not have ever been detected without the screening. This currently represents about 20 to 30% of screening detected cancers. Finding extra cancers with more intense screening is not always good, because in this situation, the risk of overdiagnosis increases and the benefit decreases. In some groups, the risk of overdiagnosis approaches 75%. Summary: Our goal should be not only to find more cancers, but to avoid finding cancers that would never have caused the patient any harm and lead to unnecessary treatment. The authors suggest some situations where it may be reasonable to de-escalate screening.

Pilot Study: The Queen Square Screening Test for Visual Deficits in Dementia.

The Queen Square Screening Test for Visual Deficits (QS test) screens for changes in visual processing. Our pilot study aimed to review the applicability of the QS test in individuals with dementia compared with those with normal cognition. Participants with major and minor neurocognitive disorder scored 50/71 (n=12) and 61/71 (n=10) respectively on the QS test, compared to 65/71 for age-matched healthy controls (n=11). The QS test score correlated with cognitive impairment as measured using the Rowland Universal Dementia Assessment Scale (r = 0.74). The QS test is an affordable and easy bedside screening test for visual processing changes.

Association of Protein Z with Prediabetes and Type 2 Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease. Early detection of prediabetes is important to reduce the risk of T2DM. Some cytokines are known to be associated with T2DM. Therefore, we aimed to identify cytokines as novel biomarkers of glucose dysmetabolism. METHODS: The first stage of the study included 43 subjects (13 subjects with newly diagnosed T2DM, 13 with prediabetes, and 16 with normoglycemia) for cytokine microarray analysis. Blood samples of the subjects were assessed for 310 cytokines to identify potential indicators of prediabetes. The second stage included 142 subjects (36 subjects with T2DM, 35 with prediabetes, and 71 with normoglycemia) to validate the potential cytokines associated with prediabetes. RESULTS: We identified 41 cytokines that differed by 1.5-fold or more in at least one out of the three comparisons (normoglycemia vs. prediabetes, normoglycemia vs. T2DM, and prediabetes vs. T2DM) among 310 cytokines. Finally, we selected protein Z (PROZ) and validated this finding to determine its association with prediabetes. Plasma PROZ levels were found to be decreased in patients with prediabetes (1,490.32±367.19 pg/mL) and T2DM (1,583.34±465.43 pg/mL) compared to those in subjects with normoglycemia (1,864.07±450.83 pg/mL) (P<0.001). There were significantly negative correlations between PROZ and fasting plasma glucose (P=0.001) and hemoglobin A1c (P=0.010). CONCLUSION: PROZ levels were associated with prediabetes and T2DM. We suggest that PROZ may be a promising biomarker for the early detection of prediabetes. Further large-scale studies are needed to evaluate the relationship and mechanism between PROZ and prediabetes and T2DM.

Ferroportin 3 is a dual-targeted mitochondrial/chloroplast iron exporter necessary for iron homeostasis in Arabidopsis.

Mitochondria and chloroplasts are organelles with high iron demand that are particularly susceptible to iron-induced oxidative stress. Despite the necessity of strict iron regulation in these organelles, much remains unknown about mitochondrial and chloroplast iron transport in plants. Here, we propose that Arabidopsis ferroportin 3 (FPN3) is an iron exporter that is dual-targeted to mitochondria and chloroplasts. FPN3 is expressed in shoots, regardless of iron conditions, but its transcripts accumulate under iron deficiency in roots. fpn3 mutants cannot grow as well as the wild type under iron-deficient conditions and their shoot iron levels are lower compared with the wild type. Analyses of iron homeostasis gene expression in fpn3 mutants and inductively coupled plasma mass spectrometry (ICP-MS) measurements show that iron levels in the mitochondria and chloroplasts are increased relative to the wild type, consistent with the proposed role of FPN3 as a mitochondrial/plastid iron exporter. In iron-deficient fpn3 mutants, abnormal mitochondrial ultrastructure was observed, whereas chloroplast ultrastructure was not affected, implying that FPN3 plays a critical role in the mitochondria. Overall, our study suggests that FPN3 is essential for optimal iron homeostasis.

GSK3B induces autophagy by phosphorylating ULK1.

Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis.

Trends in Real-World Neovascular AMD Treatment Outcomes in the UK.

PURPOSE: To report trends in real-world outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD) in the United Kingdom (UK) over the last decade. DESIGN: Systematic review. METHODS: Medline, PubMed, and Embase databases were searched from 9 April 2010 to 8 April 2020 for publications that met the inclusion criteria: treatment-naïve eyes, UK-only data and ≥1 year of follow-up. ICHOM (International Consortium for Health Outcome Measures) outcomes and study quality were assessed. Visual acuity (VA) trends were assessed in studies with ≥100 eyes at baseline. RESULTS: Twenty-six studies (n=25,761 eyes) were included, meeting 14-17 out of 20 Institute of Health Economics Quality Appraisal of Case Series checklist domains. Only ranibizumab and aflibercept outcome data were available. The mean injection number in the first year of treatment was 5.9 in publications from 2010 to 2015 and 7.1 from 2015 to 2020. Average baseline VA and mean one-year, two-year and three-year VA gains gradually improved over the last decade. Longer-term studies reported that the visual gains achieved in the first year of treatment were rarely maintained, with under-treatment a likely contributing factor. CONCLUSION: UK real-world outcomes have improved over the last decade with improved service delivery and the adoption of more proactive treatment regimens but are still not always as impressive as registration clinical trial results. Access to longer-acting anti-VEGF therapies would reduce the treatment burden for patients, carers, and the healthcare system, potentially making replication of clinical trial results possible in the NHS.

Intensive care management of a rare case of pyrexia of unknown origin (Kikuchi-Fujimoto disease).

Kikuchi-Fujimoto disease is a rare, benign cause of necrotising lymphadenitis often presenting with fever. We describe a case of a 17-year-old boy with non-verbal autism presenting to our intensive care unit with prolonged fever of unknown cause. This case highlights the role of the intensive care unit in cases of diagnostic dilemma. The critical care community should be aware of Kikuchi-Fujimoto disease as although it is usually benign, it can rarely lead to acute airway compromise.