Breast cancer (BC) cells (BCCs) can retain cellular quiescence for decades, a phenomenon referred to as dormancy. BCCs show preference for the bone marrow (BM) where they can remain dormant for decades. Targeting BCCs within the BM is a challenge since the dormant BCCs reside within BM stroma, also residence for hematopoietic stem cells (HSCs). Dormant BCCs could behave as cancer stem cells (CSCs). The CSCs and HSCs are similar by function and also, by commonly expressed genes. The method by which dormant BCCs transition into clinically metastatic cells remains unclear. This study tested the hypothesis that macrophages (MΦs) within BM stroma, facilitates dormancy or reverse this state into metastatic cells. MΦs exhibiting an M2 phenotype constitute ~10% of cultured BM stroma. The M2 MΦs form gap junctional intercellular communication (GJIC) with CSCs, resulting in cycling quiescence, reduced proliferation and carboplatin resistance. In contrast, MΦs expressing the M1 phenotype reversed BC dormancy. Activation of M2a MΦs via the toll-like receptor 4 (TLR4) switched to M1 phenotype. The switch can occur by direct activation of M2a MΦs, or indirectly through activation of mesenchymal stem cells. M1 MΦ-derived exosomes activated NFкB to reverse quiescent BCCs to cycling cells. Using an in vivo model of BC dormancy, injected Mi MOs sensitized BCCs to carboplatin and increased host survival. In summary, we have shown how BM stromal MΦs, through exosomes, regulate the behavior of BCCs, by either inducing or reversing dormancy.

Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic and pro-inflammatory niche is described during organotro-pism and in lymphatic-mediated metastasis. Second, tumor-derived exosomes can transfer molecular signals that induce cell cycle arrest, dormancy, and survival pathways in disseminated cells, promoting a dormant state are reviewed. Third, several studies highlight exosome involvement in maintaining cellular dormancy in the bone marrow endosteum. Finally, the clinical implications of exosomes as biomarkers or diagnostic tools for cancer progression are also outlined. Understanding the complex interplay between tumor-derived exosomes and the pre-metastatic niche is crucial for developing novel therapeutic strategies to target metastasis and prevent cancer recurrence. To that end, several examples of how exosomes or other nanocarriers are used as a drug delivery system to inhibit cancer metastasis are discussed. Strategies are discussed to alter exosome cargo content for better loading capacity or direct cell targeting by integrins. Further, pre-clinical models or Phase I clinical trials implementing exosomes or other nanocarriers to attack metastatic cancer cells are highlighted.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by the diffuse loss of adipose tissue resulting in hyperglycemia, severe insulin resistance, and sequelae of metabolic disease. Here, we report the case of a 32-year-old woman who developed uncontrolled hyperglycemia and significant weight loss within 2 months postpartum. Upon endocrine evaluation, she was found to have generalized loss of adiposity, hypoleptinemia, and persistent hyperglycemia despite aggressive insulin administration. Glycemic response was obtained with U-500 intramuscular insulin, pioglitazone, and metformin-sitagliptin. At 14 months postpartum, the patient achieved spontaneous remission with normoglycemia off medication and restoration of adipose tissue deposition. Autoimmune workup revealed positive antinuclear antibodies (ANA) and anti-U1-ribonucleoprotein (anti-U1-RNP) titers, suggestive of an autoimmune etiology to her condition. This case of AGL represents the first reported case of spontaneous remission and the first to develop in the postpartum period.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading inherited cause of sudden cardiac death in young athletes. Rarely, ARVC may present with acute myocardial injury and troponin elevation, mimicking myocarditis and delaying diagnosis. A 20-year-old competitive female cross-country runner presented with exertional presyncope and emesis during a race and was found to have marked troponin elevation. Electrocardiography demonstrated T-wave inversions in leads V₁ to V₃ and premature ventricular contractions. Evaluations for coronary and pulmonary embolism were negative. Transthoracic echocardiography demonstrated mild right ventricular dilation and dysfunction. Cardiac magnetic resonance revealed severe right ventricular dilation with an ejection fraction of 27% and extensive late gadolinium enhancement of the right ventricular free wall without left ventricular involvement. Genetic testing confirmed a pathogenic plakophilin-2 (PKP2) variant. A subcutaneous implantable cardioverter-defibrillator was placed, and competitive athletics was discontinued. This case represents an atypical "hot-phase" presentation of PKP2-mediated ARVC with isolated right ventricular involvement and myocardial injury, distinct from the more common DSP-associated left-dominant phenotype. ARVC should be considered in young athletes presenting with exertional syncope and troponin elevation. Cardiac magnetic resonance is critical for distinguishing ARVC from myocarditis.

Bicuspid aortic valve represents a rare but important cause of sudden cardiac death in athletes. A 48-year-old runner with a bicuspid aortic valve with significant mixed aortic valve disease experienced a pulseless electrical activity arrest after a race and underwent a Ross procedure. Fifteen months after surgery, he presented to clinic for guidance on return to training. After reassuring cardiopulmonary exercise testing and shared decision-making, he has returned to training without complications. This case highlights considerations of the Ross procedure in the adult athletic population, the complex nature of aortic valve disease in athletes, and guideline-directed postarrest evaluation and return to sport. While the Ross procedure offers unique advantages, further data are needed to assess durability in adult athletes. Athletes with at least moderate aortic valve disease warrant formal exercise testing and consideration of sport-specific stressors.

Background and Clinical Significance: Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly. Such patients are unlikely to survive adulthood without a major surgical correction. Case Presentation: We report a 30-year-old female with a lifelong murmur who presented to the sports cardiology clinic with progressively reduced exercise tolerance. She was eventually diagnosed with ALCAPA and underwent successful Takeuchi repair. Conclusions: Surgical correction is strongly recommended upon diagnosis to mitigate the associated risks and improve the prognosis for affected individuals.