Palpable Lumps after Mastectomy: Radiologic-Pathologic Review of Benign and Malignant Masses.

Patients who have undergone mastectomy, with or without reconstruction, are not universally screened with mammography or US. Therefore, clinical breast examination by the physician and patient-detected palpable abnormalities are crucial for detecting breast cancer or recurrence. Diagnostic US is the first-line modality for evaluation of postmastectomy palpable masses, with occasional adjunct use of diagnostic mammography for confirming certain benign masses. In the setting of a negative initial imaging evaluation with continued clinical concern, diagnostic MRI may aid in improving sensitivity. Knowledge of the typical multimodality imaging appearances and locations of malignant palpable abnormalities-such as invasive carcinoma recurrence, cancer in residual breast tissue, radiation-induced sarcoma, and metastatic disease-is crucial in diagnosis and treatment of these entities. In addition, familiarity with the range of benign palpable postmastectomy processes-including fat necrosis, fat graft, seroma, granuloma, neuroma, fibrosis, and infection-may help avoid unnecessary biopsies and reassure patients. The authors review common and rare benign and malignant palpable masses in mastectomy patients, describe multimodality diagnostic imaging evaluation of each entity, review radiologic and pathologic correlation, and acquaint the radiologist with management when these findings are encountered. ©RSNA, 2021.

Collaboration, Collegiality, and Sharing of Resources: Benefits of a Visiting Professor Exchange Program in Breast Imaging.

The role of a visiting professor (VP) has long been used as a model to share medical knowledge and new advances between different teaching institutions. As with all subspecialties, breast imaging has institution-specific differences in resources and faculty. Sharing of resources between programs can have a profound impact on enriching educational experiences for learners. Our conceptual design of a VP lecture exchange program was between two academic medical centers, Virginia Commonwealth University Health System (VCU) and MedStar Georgetown University Hospital University (MGUH), in the subspecialty of breast imaging. The program was designed to supplement potential areas of weakness in the breast imaging educational curriculum at each respective institution. The program also sought to create opportunities for long-term mentorship and collaboration between institutions. Three faculty members from VCU and three faculty members from MGUH participated for a total of six lectures (three lectures at each site). Participating residents and faculty completed anonymous surveys following each lecture regarding the lecture exchange program experience. The survey responses showed that the VP exchange was well received at both institutions. The VP exchange process was relatively easy to arrange, benefits both institutions, and could even be expanded to the virtual environment.

Biosensors Show the Pharmacokinetics of S-Ketamine in the Endoplasmic Reticulum.

The target for the "rapid" (<24 h) antidepressant effects of S-ketamine is unknown, vitiating programs to rationally develop more effective rapid antidepressants. To describe a drug's target, one must first understand the compartments entered by the drug, at all levels-the organ, the cell, and the organelle. We have, therefore, developed molecular tools to measure the subcellular, organellar pharmacokinetics of S-ketamine. The tools are genetically encoded intensity-based S-ketamine-sensing fluorescent reporters, iSKetSnFR1 and iSKetSnFR2. In solution, these biosensors respond to S-ketamine with a sensitivity, S-slope = delta(F/F0)/(delta[S-ketamine]) of 0.23 and 1.9/µM, respectively. The iSKetSnFR2 construct allows measurements at <0.3 µM S-ketamine. The iSKetSnFR1 and iSKetSnFR2 biosensors display >100-fold selectivity over other ligands tested, including R-ketamine. We targeted each of the sensors to either the plasma membrane (PM) or the endoplasmic reticulum (ER). Measurements on these biosensors expressed in Neuro2a cells and in human dopaminergic neurons differentiated from induced pluripotent stem cells (iPSCs) show that S-ketamine enters the ER within a few seconds after appearing in the external solution near the PM, then leaves as rapidly after S-ketamine is removed from the extracellular solution. In cells, S-slopes for the ER and PM-targeted sensors differ by <2-fold, indicating that the ER [S-ketamine] is less than 2-fold different from the extracellular [S-ketamine]. Organelles represent potential compartments for the engagement of S-ketamine with its antidepressant target, and potential S-ketamine targets include organellar ion channels, receptors, and transporters.

Determining the pharmacokinetics of nicotinic drugs in the endoplasmic reticulum using biosensors.

Nicotine dependence is thought to arise in part because nicotine permeates into the endoplasmic reticulum (ER), where it binds to nicotinic receptors (nAChRs) and begins an "inside-out" pathway that leads to up-regulation of nAChRs on the plasma membrane. However, the dynamics of nicotine entry into the ER are unquantified. Here, we develop a family of genetically encoded fluorescent biosensors for nicotine, termed iNicSnFRs. The iNicSnFRs are fusions between two proteins: a circularly permutated GFP and a periplasmic choline-/betaine-binding protein engineered to bind nicotine. The biosensors iNicSnFR3a and iNicSnFR3b respond to nicotine by increasing fluorescence at [nicotine] <1 µM, the concentration in the plasma and cerebrospinal fluid of a smoker. We target iNicSnFR3 biosensors either to the plasma membrane or to the ER and measure nicotine kinetics in HeLa, SH-SY5Y, N2a, and HEK293 cell lines, as well as mouse hippocampal neurons and human stem cell-derived dopaminergic neurons. In all cell types, we find that nicotine equilibrates in the ER within 10 s (possibly within 1 s) of extracellular application and leaves as rapidly after removal from the extracellular solution. The [nicotine] in the ER is within twofold of the extracellular value. We use these data to run combined pharmacokinetic and pharmacodynamic simulations of human smoking. In the ER, the inside-out pathway begins when nicotine becomes a stabilizing pharmacological chaperone for some nAChR subtypes, even at concentrations as low as ∼10 nM. Such concentrations would persist during the 12 h of a typical smoker's day, continually activating the inside-out pathway by >75%. Reducing nicotine intake by 10-fold decreases activation to ∼20%. iNicSnFR3a and iNicSnFR3b also sense the smoking cessation drug varenicline, revealing that varenicline also permeates into the ER within seconds. Our iNicSnFRs enable optical subcellular pharmacokinetics for nicotine and varenicline during an early event in the inside-out pathway.