Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes.

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer.

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

Graduate Medical Education in Pathology: A Scoping Review.

CONTEXT.­: Pathologists have produced a substantial body of literature on graduate medical education (GME). However, this body of literature is diverse and has not yet been characterized. OBJECTIVE.­: To chart the concepts, research methods, and publication patterns of studies on GME in pathology. DATA SOURCES.­: This was a systematic scoping review covering all literature produced since 1980 in the PubMed and Embase databases. CONCLUSIONS.­: Research on GME in pathology is evenly dispersed across educational topics. This body of literature would benefit from research based on theory, stronger study designs, and studies that can provide evidence to support decisions on educational policies.

The next phase in patient safety education: Towards a standardized, tools-based pathology patient safety curriculum: A call to action from the Association of Pathology Chairs' Residency Program Directors Section Training Residents in Patient Safety Workgroup.

Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum.

Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics.

Obesity exerts adverse effects on breast cancer survival, but the means have not been fully elucidated. We evaluated obesity as a contributor to breast cancer survival according to tumor molecular subtypes in a population-based case-cohort study using data from the Surveillance Epidemiology and End Results (SEER) program. We determined whether obese women were more likely to be diagnosed with poor prognosis tumor characteristics and quantified the contribution of obesity to survival. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated via Cox multivariate models. The effect of obesity on survival was evaluated among 859 incident breast cancers (subcohort; 15% random sample; median survival 7.8 years) and 697 deaths from breast cancer (cases; 100% sample). Obese women had a 1.7- and 1.8-fold increased risk of stage III/IV disease and grade 3/4 tumors, respectively. Obese women with Luminal A- and Luminal B-like breast cancer were 1.8 (95% CI 1.3-2.5) and 2.2 (95% CI 0.9-5.0) times more likely to die from their cancer compared to normal weight women. In mediation analyses, the proportion of excess mortality attributable to tumor characteristics was 36.1% overall and 41% and 38% for Luminal A- and Luminal B-like disease, respectively. Obesity was not associated with breast cancer-specific mortality among women who had Her2-overexpressing or triple-negative tumors. Obesity may influence hormone-positive breast cancer-specific mortality in part through fostering poor prognosis tumors. When tumor biology is considered as part of the causal pathway, the public health impact of obesity on breast cancer survival may be greater than previously estimated.

Predicting breast cancer response to neoadjuvant chemotherapy based on tumor vascular features in needle biopsies.

In clinical breast cancer intervention, selection of the optimal treatment protocol based on predictive biomarkers remains an elusive goal. Here, we present a modeling tool to predict the likelihood of breast cancer response to neoadjuvant chemotherapy using patient specific tumor vasculature biomarkers. A semi-automated analysis was implemented and performed on 3990 histological images from 48 patients, with 10-208 images analyzed for each patient. We applied a histology-based model to resected primary breast cancer tumors (n = 30), and then evaluated a cohort of patients (n = 18) undergoing neoadjuvant chemotherapy, collecting pre- and post-treatment pathology specimens and MRI data. We found that core biopsy samples can be used with acceptable accuracy (r = 0.76) to determine histological parameters representative of the whole tissue region. Analysis of model histology parameters obtained from tumor vasculature measurements, specifically diffusion distance divided by radius of drug source (L/rb) and blood volume fraction (BVF), provides a statistically significant separation of patients obtaining a pathologic complete response (pCR) from those that do not (Student's t-test; P < 0.05). With this model, it is feasible to evaluate primary breast tumor vasculature biomarkers in a patient specific manner, thereby allowing a precision approach to breast cancer treatment.