Mouse-INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy.

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p > 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p > 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Emerging Trends in Smartphone Photo Documentation of Child Physical Abuse.

ABSTRACT: Photo documentation of injuries on children is universally recommended in cases of suspected child physical abuse. As technology improves, the ability to document physical examination findings through smartphone photography is increasingly accessible and practical. The quality of images captured on smartphones now rivals traditional photography and the integration of photo capture within the electronic medical record has led to a variety of fields adopting smartphone photo documentation for diagnosis, consult, and follow-up. However, in cases of child physical abuse, practitioners have been hesitant to adopt smartphones as a primary means of photo documentation because of concerns around image quality, privacy, and security. In this article, we discuss the technology of available smartphone cameras and current evidence regarding their use for photo documentation, use existing guidelines to propose a workflow to improve the yield of smartphone photo documentation in child physical abuse, and discuss common medicolegal concerns.

Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion.

INTRODUCTION: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated ß-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. METHODS: Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. RESULTS: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. CONCLUSION: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.

NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802-13. ©2017 AACR.

Abusive head trauma in Maine infants: medical, child protective, and law enforcement analysis.

OBJECTIVE: To collect and compare the results of medical, child protective, and law enforcement evaluation of a sample of Maine children who were victims of abusive head trauma (AHT) in order to describe the clinical and evaluative characteristics as they relate to victims, families and perpetrators of such trauma and to improve the professional response to AHT in Maine. METHOD: Retrospective chart review of medical, child protective, and law enforcement records of all AHT victims admitted to two tertiary care hospitals in Maine or seen by the state medical examiner from 1991 to 1994. RESULTS: Nineteen children (age range 2 weeks to 17 months) were identified as victims of AHT (out of a total of 94 head trauma admissions) accounting for 20 hospitalizations during the study period. There was a history of prior injury in 30%, history of prior medical evaluations for possibly abuse related problems in 65%, while, on presentation, 75% had evidence or history of prior injury. The hospitals notified child protective services (CPS) in all 20 cases and correctly identified abuse in 18 (90%). Parental risk factors for abuse identified in CPS records included substance abuse (53%), domestic violence (42%), criminal history (32%), unrealistic expectations (42%), and attachment problems (32%). However, risk factors were inadequately assessed in 53% of homes. Law enforcement identified a likely perpetrator in 79% of cases and in the majority the identified suspect was the father. In the 15 cases where a perpetrator was identified by law enforcement, that person was alone with the child at symptom onset in 14 (93%). CONCLUSIONS: The medical response, at least at the inpatient level, was generally well done with regard to suspicion and reporting. Cases are possibly being missed at the outpatient level. Child protective risk assessment was limited overall yet in a third of the homes where AHT occurred, few if any risk factors were present to aid in identification and prevention. Law enforcement results suggest that a primary suspect for AHT is the caretaker alone with the child at the time of symptom onset.

Development and preliminary psychometric properties of the multidimensional neglectful behavior scale-child report.

This article describes the development and psychometric properties of the Multidimensional Neglectful Behavior Scale-Child Report (MNBS-CR). The measure is broadly conceptualized to tap child neglect across four core domains: cognitive, emotional, physical and supervisory neglect, and it assesses exposure to violence, alcohol-related neglect, abandonment, and children's appraisals of parenting. Features include pictorial items, audio computer-assisted testing, and programming by age and gender of the child and caregiver. A clinical sample of 144 children, age 6 to 15 years, and a comparison sample of 87 children were tested. Results showed that the MNBS-CR has high reliability, with higher reliability found for older children (alpha = .94) than for younger children (alpha = .66). Among older children, the MNBS-CR Supervisory scale was significantly associated with the Child Behavior Check List (CBCL), and total MNBS-CR scores were significantly associated with clinician reports of behavioral disorders. Younger and older neglected children scored significantly higher on the MNBS-CR than community children.