Chimeric antigen receptors (CARs) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the non-tumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 107 or 3 × 108 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in two and four patients, respectively. mRNA c-Met-CAR T cells cell injections were well tolerated, as none of the patients had study drug–related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors.

The teaching of gross anatomy has, for centuries, relied on the dissection of human cadavers, and this formative experience is known to evoke strong emotional responses. The authors hypothesized that the phenomenon of cadaver naming is a coping mechanism used by medical students and that it correlates with other attitudes about dissection and body donation. The authors developed a 33-question electronic survey to which 1,156 medical students at 12 medical schools in the United States voluntarily responded (November 2011-March 2012). They also surveyed course directors from each institution regarding their curricula and their observations of students' coping mechanisms. The majority of students (574, 67.8%) named their cadaver. Students most commonly cited the cadaver's age as the reason they chose a particular name for the cadaver. A minority of the students who did not name the cadaver reported finding the practice of naming disrespectful. Almost all students indicated that they would have liked to know more about their donor, particularly his or her medical history. Finally, students who knew the birth name of the donor used it less frequently than predicted. The authors found that the practice of naming cadavers is extremely prevalent among medical students and that inventive naming serves as a beneficial coping mechanism. The authors suggest that developing a method of providing students with more information about their cadaver while protecting the anonymity of the donor and family would be useful.

The Ts65Dn mouse is the most-studied of murine models for Down syndrome. Homology between the triplicated murine genes and those on human chromosome 21 correlates with shared anomalies of Ts65Dn mice and Down syndrome patients, including congenital heart defects. Lethality is associated with inheritance of the T65Dn chromosome, and anomalies such as right aortic arch with Kommerell's diverticulum and interrupted aortic arch were found in trisomic neonates. The incidence of gross vascular abnormalities was 17% in the trisomic population. Histological analyses revealed interventricular septal defects and broad foramen ovale, while immunohistochemistry showed abnormal muscle composition in the cardiac valves of trisomic neonates. These findings confirm that the gene imbalance present in Ts65Dn disrupts crucial pathways during cardiac development. The candidate genes for congenital heart defects that are among the 104 triplicated genes in Ts65Dn mice are, therefore, implicated in the dysregulation of normal cardiogenic pathways in this model. Developmental Dynamics 237:426 -435, 2008.

We demonstrated, for the first time, that breast cancer subtype distribution varied significantly according to BMI status. Our results suggested that obesity might activate molecular pathways other than the well-known obesity/estrogen circuit in the pathogenesis of breast cancer. Future studies are needed to understand the molecular mechanisms that drive the variation in subtype distribution across BMI subgroups.

Background Philadelphia and its suburbs were an epicenter for the initial COVID-19 outbreak. Accordingly, alterations were made in breast cancer care at a community hospital. Methods The authors developed a prospective database of all the patients with invasive or in situ breast cancer between March 1 and June 15 at their breast center. Any change in a breast cancer plan due to the pandemic was documented, and the patients were grouped into two cohorts according to whether a change was made (CTX) or no change was made (NC) in their care. The patients were asked a series of questions about their care, including those in the Generalized Anxiety Disorder two-item questionnaire (GAD-2), via telephone. Results The study enrolled 73 patients: 41 NC patients (56%) and 32 CTX patients (44%). The two cohorts did not differ in terms of age, race, or stage. Changes included delay in therapy (15.1%) and use of neoadjuvant endocrine therapy (NET, 28.8%). The median time to surgery was 24 days (interequartile range [IQR], 16–45 days) for the NC patients and 82 day s (IQR, 52–98 days) for the CTX patients ( p ≤ 0.001). The median duration of NET was 78 days. The GAD-2 showed anxiety positivity to be 29.6% for the CTX patients and 32.4% for the NC patients ( p = 1.00). More than half (55.6%) of the CTX patients believed COVID-19 affected their treatment outlook compared with 25.7% of the NC patients ( p = 0.021). Conclusions A prospective database captured changes in breast cancer care at a community academic breast center during the initial phase of the COVID-19 pandemic. 44% of patients experienced a change in breast cancer care due to COVID-19. The same level of anxiety and depression was seen in both change in therapy (CTX) and no change (NC). 55.6% of CTX cohort believed COVID-19 affected their treatment outlook.

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BackgroundIntegration of evidence into practice is suboptimal. Clinical pathways, defined as multidisciplinary care plans, are a method for translating evidence into local settings and have been shown to improve the value of patient care.ObjectiveTo describe the development of a clinical pathways programme across a large academic healthcare system.MethodsWe use a 10-step framework (grounded in the Knowledge-to-Action framework and ADAPTE Collaboration methodology for guideline adaptation) to support pathway development and dissemination, including facilitating clinical owner and stakeholder engagement, developing pathway prototypes based on rapid reviews of the existing literature, developing tools for dissemination and impact assessment. We use a cloud-based technology platform (Dorsata, Washington, DC) to assist with development and dissemination across our geographically distributed care settings and providers. Content is viewable through desktop and mobile applications. We measured programme adoption and penetration by examining number of pathways developed as well as mobile application use and pathway views.ResultsFrom 1 February 2016 to 30 April 2018, a total of 202 pathways were disseminated. The three most common clinical domains represented were oncology (46.5%, n=94), pulmonary/critical care (8.9%, n=18) and cardiovascular medicine (7.4%, n=15). Users opting to register for a personal account totalled 1279; the three largest groups were physicians (45.1%, n=504), advanced practice providers (19.5%, n=245) and nurses (19.1%, n=240). Pathway views reached an average of 2150 monthly views during the last 3 months of the period. The majority of pathways reference at least one evidence-based source (93.6%, n=180).ConclusionsA healthcare system can successfully use a framework and technology platform to support the development and dissemination of pathways across a multisite institution.

Background. Several studies have proven that neoadjuvant endocrine therapy (NET) has a similar beneficial therapeutic effect in estrogen-positive (ER ?) breast cancer (BC) with improved breast conservation rate in patients undergoing NET versus neoadjuvant chemotherapy (NAC). The impact of axillary complete pathologic response (pCR) is less clear. We evaluate the impact of NET on axillary downstaging and surgical management. Methods. Using the National Cancer Database (NCDB), we identified all patients with node positive (N ?), ER ? , HER 2-BC undergoing NET and performed a systemic review of literature using PRISMA guidelines. Results. The literature review identified 1479 clinically N ? patients in four studies, 148 of whom had axillary pCR (10.0%). In the two studies of patients with invasive lobular carcinoma (ILC), 7.8% (69/883) of clinically N ? patients had axillary pCR. The NCDB query identified 4580 female patients with clinically N ? ER ? HER 2-BC who underwent NET from 2010 to 2016 with mean age of 61.4 years. Patients who achieved a pCR were more likely to have N1 disease (p 0.008), moderately differentiated tumors (p 0.003), and ductal histology (p 0.04). There was no statistically significant difference in race, comorbidity score, education, income, hospital setting, or clinical tumor stage. Of the 4580 total patients, 663 (14.48%) had an axillary pCR (pN0) after NET, and 3917 (85.52%) remained pN?. Conclusions. We found that patients who underwent NET for N ? disease had a higher axillary pCR than previously reported (10%) in smaller studies. Although NET is not a common treatment option for women with N ? ER ? HER 2-BC, it may be a suitable option for axillary downstaging, which is currently underutilized. In 2019, approximately 268,600 new cases of invasive breast cancer (IBC) and 48,100 cases of ductal carcinoma in situ (DCIS) were diagnosed among U.S. women, and more than 80% of breast cancers (BC) were diagnosed among women aged C 50 years. 1 Hormone receptor-positive (HR ?)/human epidermal growth factor receptor 2 (HER2)-negative BC is by far the most common subtype. 1 In patients with HR ? breast cancer, the innate exposure to endogenous estrogen results in dimerization of the estrogen receptor (ER) promoting estrogen gene transcription. 2 Multiple endocrine therapies have been developed for adjuvant use, such as selective ER downregulators, aromatase inhibitors (AIs), and luteinizing hormone releasing agonists. 3 The role of neoadjuvant endocrine therapy (NET) in the setting of HR ? breast cancer in the US is underutilized, typically being reserved for elderly patients,