Breast MRI for Extent of Disease: Association of Demographic Factors and Biopsy Compliance on Surgical Decisions in Patients with BI-RADS 4 and 5 Findings.

BACKGROUND: The decision to pursue bilateral mastectomy without pathological confirmation of additional preoperative MRI lesions is likely multifactorial. We investigated the association of demographic factors and biopsy compliance following preoperative breast MRI with changes in surgical management in patients with newly diagnosed breast cancer. METHODS: A retrospective review of BI-RADS 4 and 5 MRIs performed across a health system from March 2018 to November 2021 for assessment of disease extent and preoperative planning. Patient characteristics, including demographics, Tyrer-Cuzick risk score, pathology from index cancer and biopsy of MRI findings, and pre- and post-MRI surgical plans were recorded. Analysis compared patients who underwent biopsy with those who did not. RESULTS: The final cohort included 323 patients who underwent a biopsy and 89 who did not. Of patients who underwent a biopsy, 144/323 (44.6%) had additional cancer diagnoses. MRI did not change management in 179/323 patients (55.4%) who underwent biopsy and in 44/89 patients (51.7%) who did not. Patients with a biopsy were more likely to have additional breast conservation surgery (P < .001) and patients without a biopsy were more likely to have a change in management to bilateral mastectomy P = .009). Patients without a biopsy who underwent a management change to bilateral mastectomy were significantly younger (47.2 vs 58.6; P < .001) and more likely to be white (P = .02) compared to those choosing bilateral mastectomy after biopsy. DISCUSSION: Biopsy compliance is associated with changes in surgical decisions, and younger, white women are more likely to pursue aggressive surgical management without definitive pathologic diagnoses.

Mapping cortical activations underlying covert and overt language production using high-density diffuse optical tomography.

Gold standard neuroimaging modalities such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and more recently electrocorticography (ECoG) have provided profound insights regarding the neural mechanisms underlying the processing of language, but they are limited in applications involving naturalistic language production especially in developing brains, during face-to-face dialogues, or as a brain-computer interface. High-density diffuse optical tomography (HD-DOT) provides high-fidelity mapping of human brain function with comparable spatial resolution to that of fMRI but in a silent and open scanning environment similar to real-life social scenarios. Therefore, HD-DOT has potential to be used in naturalistic settings where other neuroimaging modalities are limited. While HD-DOT has been previously validated against fMRI for mapping the neural correlates underlying language comprehension and covert (i.e., "silent") language production, HD-DOT has not yet been established for mapping the cortical responses to overt (i.e., "out loud") language production. In this study, we assessed the brain regions supporting a simple hierarchy of language tasks: silent reading of single words, covert production of verbs, and overt production of verbs in normal hearing right-handed native English speakers (n = 33). First, we found that HD-DOT brain mapping is resilient to movement associated with overt speaking. Second, we observed that HD-DOT is sensitive to key activations and deactivations in brain function underlying the perception and naturalistic production of language. Specifically, statistically significant results were observed that show recruitment of regions in occipital, temporal, motor, and prefrontal cortices across all three tasks after performing stringent cluster-extent based thresholding. Our findings lay the foundation for future HD-DOT studies of imaging naturalistic language comprehension and production during real-life social interactions and for broader applications such as presurgical language assessment and brain-machine interfaces.

Fertility after Transcatheter Arterial Embolization for Obstetric Hemorrhage: An Urban Health Care System Observational Study.

OBJECTIVE: This study aimed to investigate pregnancy rate, pregnancy outcomes, and resumption of menses after transcatheter arterial embolization (TAE) for obstetric hemorrhage (OH). STUDY DESIGN: Sixty-seven patients who underwent TAE for OH from 2006 to 2020 within an urban, multihospital health care system were identified retrospectively. Selected patients were interviewed by phone to complete a survey with a primary outcome of self-reported pregnancy in those seeking pregnancy. Secondary outcomes included pregnancy outcomes and resumption of menses. Univariate testing of association of pregnancy and miscarriage rate with embolic agent was performed using Fisher's exact test. RESULTS: Thirty-three of 50 patients (66%) meeting the inclusion criteria completed the survey on fertility, a median of 47 (range, 13-123) months after TAE for OH. Of the 13 patients who attempted pregnancy, there was a pregnancy rate of 77% and miscarriage rate of 38%. Those who delivered live newborns conceived spontaneously, carried to term, and delivered a healthy newborn via cesarean section at a weight appropriate for gestational age. Thirty (91%) patients resumed menstruation, and the majority with unchanged frequency. Most patients underwent bilateral uterine artery embolization with radial artery access (54%). The most common embolic agents used were gelfoam only (30%) and glue only (24%). There was no statistically significant association between embolic agent and pregnancy or miscarriage rate. CONCLUSION: Spontaneous pregnancy with live birth and resumption of menses can occur in a majority of patients after TAE for OH. KEY POINTS: · Most patients who attempted pregnancy after TAE for OH achieved pregnancy.. · Most patients who became pregnant conceived spontaneously and delivered healthy newborns at term.. · Most patients resumed menstruation after TAE for OH.. · There was no significant association between type of embolic and pregnancy or miscarriage rate..

Embracing nanomaterials' interactions with the innate immune system.

Immunotherapy has firmly established itself as a compelling avenue for treating disease. Although many clinically approved immunotherapeutics engage the adaptive immune system, therapeutically targeting the innate immune system remains much less explored. Nanomedicine offers a compelling opportunity for innate immune system engagement, as many nanomaterials inherently interact with myeloid cells (e.g., monocytes, macrophages, neutrophils, and dendritic cells) or can be functionalized to target their cell-surface receptors. Here, we provide a perspective on exploiting nanomaterials for innate immune system regulation. We focus on specific nanomaterial design parameters, including size, form, rigidity, charge, and surface decoration. Furthermore, we examine the potential of high-throughput screening and machine learning, while also providing recommendations for advancing the field. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Prosaposin mediates inflammation in atherosclerosis.

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient (Apoe -/-) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that Psap inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of Psap -/- bone marrow to low-density lipoprotein receptor knockout (Ldlr -/-) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between PSAP expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target.

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less explored. The intrinsic interactions between nanoparticles and phagocytic myeloid cells make these materials especially suited for engaging the innate immune system. However, developing nanotherapeutics is an elaborate process. Here, we demonstrate a modular approach that facilitates efficiently incorporating a broad variety of drugs in a nanobiologic platform. Using a microfluidic formulation strategy, we produced apolipoprotein A1-based nanobiologics with favorable innate immune system-engaging properties as evaluated by in vivo screening. Subsequently, rapamycin and three small-molecule inhibitors were derivatized with lipophilic promoieties, ensuring their seamless incorporation and efficient retention in nanobiologics. A short regimen of intravenously administered rapamycin-loaded nanobiologics (mTORi-NBs) significantly prolonged allograft survival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.

Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor 64Cu-Macrin in Mice, Rabbits, and Pigs.

BACKGROUND: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases. METHODS: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer 64Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose. RESULTS: PET imaging using 64Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (VT680Macrin) primarily in tissue macrophages. In 5-day-old mice, 64Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of 64Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that 64Cu-Macrin is safe for use in humans. CONCLUSIONS: Taken together, these results indicate 64Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. 64Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition.

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging.

Ischaemic heart disease evokes a complex immune response. However, tools to track the systemic behaviour and dynamics of leukocytes non-invasively in vivo are lacking. Here, we present a multimodal hot-spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (19F-HDL) to allow myeloid cell tracking by 19F magnetic resonance imaging. The 19F-HDL nanotracer can additionally be labelled with zirconium-89 and fluorophores to detect myeloid cells by in vivo positron emission tomography imaging and optical modalities, respectively. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo 19F-HDL magnetic resonance imaging. Concurrently, using ex vivo techniques, we showed that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and at the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox, enabling the study of complex myeloid cell behaviour dynamically.