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.

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.

Intra-operative Radiation Therapy versus Whole Breast External Beam Radiotherapy: A Comparison of Patient-Reported Outcomes.

INTRODUCTION: This project sought to compare patient-reported outcomes between patients who received intra-operative radiation therapy (IORT) and those who qualified for IORT but received whole-breast external beam radiation therapy (EBRT) following breast-conserving surgery (BCS). METHODS: Three scales from the BREAST-Q Breast Cancer BCT Module Version 2.0 questionnaire were used to collect patient-reported outcomes regarding post-operative physical well-being of the chest, post-operative satisfaction with breast cosmesis, and post-operative adverse effects of radiation. RESULTS: Patients who received EBRT travelled farther on average than patients who received IORT to complete treatment. Respondents who received IORT reported better physical well-being of the chest than those who received EBRT. Regression revealed that the respondent's age was the determining factor in the difference between IORT and EBRT post-operative physical well-being scores, where younger patients report poorer well-being. There was no difference in patient-reported outcomes regarding post-operative satisfaction with breast cosmesis or adverse effects of radiation. CONCLUSIONS: Patients who received IORT reported better physical well-being of the chest than patients who received EBRT. There appeared to be a relationship between age and physical well-being of chest. This study suggested that there was no difference in patient-reported outcomes concerning post-operative satisfaction with breast cosmesis or post-operative adverse effects of radiation between patients who received IORT and those who received EBRT.

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.

Influence of fibrin glue on seroma formation after breast surgery.

BACKGROUND: This study was designed to determine the effectiveness of Hemaseel APR fibrin sealant versus conventional drain placement in the prevention of seromas after breast procedures. METHODS: A prospective, randomized, controlled study of subjects who were randomized into control (drain) and experimental (fibrin) groups was conducted. RESULTS: Analysis of 82 patients showed similarly matched groups. Seroma formation rate was 45.5% in the control group and 36.8% in the fibrin glue group (P = 0.43). The rate of wound complications was similar. Aspirate volumes were significantly greater in the fibrin glue group. Drain placement saved patients >366 US dollars over fibrin glue. CONCLUSIONS: Although use of fibrin sealant resulted in a nonsignificant decrease in seroma formation rate compared with that of drain placement, the higher cost involved, cumbersome technique, and higher aspirate volumes tend to indicate that there is no advantage to using fibrin glue over drain placement with the technique described.

An evaluation of resident training in breast procedures.

BACKGROUND: The purpose of this study was to determine if senior residents are participating in advanced level breast cases. METHODS: A retrospective review of 1,583 breast procedures on 1,213 patients over 2 years was performed. Each case was evaluated for the type of case: (1) junior level (PGY 1 and 2)--core needle biopsy, fine needle aspirate, excisional biopsy, needle localized biopsy, lumpectomy, partial mastectomy, and simple mastectomy; and (2) senior level--stereotactic breast biopsy, sentinel lymph node biopsy, axillary dissection, and modified radical mastectomy. All cases were reviewed for level of resident involved. RESULTS: Overall, seniors performed 31% of the cases, junior residents performed 42%, and 27% were unattended by any resident. Senior level breast cases were specifically examined to compare whether a senior or junior was present. Overall, 891 defined senior cases were performed. A senior level resident attended 34% of these, leaving 66% covered by junior residents or uncovered altogether. CONCLUSIONS: It is clear when evaluating breast procedures that senior residents are less involved than junior residents. Furthermore, the fact that many of the reported cases (28%) and, more significantly, senior level cases (26%) have no resident involved leads us to conclude that senior level residents are not taking advantage of the opportunity to gain experience in performing advanced level breast procedures in our surgical program.

Do medical student's surgical examination scores correlate with performance markers?

BACKGROUND: Some medical school training consists of oral examinations. METHODS: We conducted a 9-year review of third-year medical student examinations including oral examinations, National Board of Medical Examiners Surgery Subject Examination (SSE, ie, shelf), and United States Medical Licensing Examinations Step 1 and Step 2. RESULTS: Step 1 showed a moderate to strong association with Period 1 orals (Somers' D = .297, P < .001), but not Period 2 orals (Somers' D = .048, P = .053). Period 1 orals (percentage) had a strong association with SSE (Somers' D = .356, P < .001) and Step 2 (Somers' D = .368, P < .001). Period 2 orals (pass/fail) suggested a positive, but not statistically significant, association with SSE (Somers' D = .334, P = .085) and Step 2 (Somers' D = .370, P = .055). Step 1 shows a strong association with SSE (Somers' D = .490, P < .001). SSE showed a strong association with Step 2 (Somers' D = .506, P < .001). CONCLUSIONS: Orals can be used to identify students who may have difficulty passing the SSE. Step 1 can be used to identify students at risk of poor performance on the SSE, and SSE can be used to identify students at risk for poor performance on Step 2.

Evaluation of changes in breast architecture after preoperative chemotherapy for breast cancer.

BACKGROUND: Although use of preoperative chemotherapy for breast cancer is increasing, resultant changes in breast architecture have not been described. The purpose of this study was to examine breast architecture changes in response to chemotherapy by the placement of 4 peripheral clips. METHODS: In a prospective case-series of breast cancer patients selected to undergo preoperative chemotherapy, 4 clips were placed peripherally to each mass using sonographic guidance. Mammograms documented tumor size and clip locations both before chemotherapy and after chemotherapy. Percentage reduction in area was calculated based on the tumor dimensions and distances between clips. RESULTS: In 16 participants, 87.5% of lesions had a significant response to chemotherapy. Changes in clip measurements varied widely from significant reduction to significant increase and did not correlate with changes in tumor size. The Pearson correlation coefficient comparing changes in tumor size and clip measurements was .036 (P = .895). CONCLUSIONS: There was no correlation between reduction in tumor size and change in clip measurements. Further research should be conducted using noncompression breast imaging modalities to eliminate possible distortion caused by mammographic compression.

Do strong resident teachers help medical students on objective examinations of knowledge?

BACKGROUND: Despite a lack of formal training, surgical residents at our institution have an integral role instructing medical students on their general surgery clerkship. It is unknown how the instruction provided by surgical residents affects the students' testable knowledge base and performance on standardized surgical examinations. The purpose of this survey study was to evaluate the impact of surgical resident teachers on medical student performance on the National Board of Medical Examiners surgery shelf examination. STUDY DESIGN: Surveys were provided to all third-year medical students completing an 8-week clerkship in general surgery. Students were asked to rate the quality and quantity of instruction received from surgical residents. Resident instruction was evaluated in several categories using a 5-point Likert scale. Analyses were conducted to evaluate the impact of survey responses on student percentile scores on the surgery shelf examination. RESULTS: Seventy-five of 110 (67.3%) students completed the surveys over a period of 22 months. Forty-two individual residents were evaluated in several categories, and an overall teaching evaluation was completed. The mean shelf percentile score by the medical students was 48.1 ± 31.4 (range, 1st to 98th percentile). Using univariate analyses, no individual resident factors or overall factors had a significant effect on student performance. A regression analysis revealed that overall quality of instruction had a significantly positive impact on student performance (p = 0.038). Individual residents and increasing PGY level had a significantly negative impact on the students' shelf performance (p < 0.001). The model R(2) showed our model to predict only 13.8% of the student's examination score variability. CONCLUSIONS: A statistically significant relationship exists between student performance on the shelf examination and their perception of the overall quality of instruction that they receive from surgical residents. However, this seems to account only for a small portion of the variability in student percentile scores.

Do topical anesthetics reduce periareolar injectional pain before sentinel lymph node biopsy?

BACKGROUND: Topical anesthetics have been used in various procedures. The purpose of this study was to evaluate efficacy of lidocaine/prilocaine cream in decreasing the pain of injection for sentinel lymph node biopsy. METHODS: A prospective, randomized, placebo-controlled study was conducted on female breast cancer patients undergoing periareolar injection for sentinel lymph node isolation. Subjects applied lidocaine/prilocaine cream or a placebo cream before injection and completed a survey postoperatively. RESULTS: Twenty treatment and 19 control patients were studied. There was a trend for control subjects to indicate that the injection was "painful" or "extremely painful" more often than treatment subjects (52.6% vs 25.0%, respectively, P = .074). The treatment group was more likely to recommend the cream to other cancer patients (70.0% vs 42.1%), with a trend toward significance (P = .076). CONCLUSIONS: This study showed no statistically significant reduction in pain scores in subjects receiving the topical anesthetic. Further studies targeting patients with low pain tolerance may prove more effective.