Identification of an mRNP complex regulating tumorigenesis at the translational elongation step.

Transcript-selective translational regulation of epithelial-mesenchymal transition (EMT) by transforming growth factor-ß (TGF-ß) is directed by the hnRNP E1-containing TGF-ß-activated-translational (BAT) mRNP complex. Herein, eukaryotic elongation factor-1 A1 (eEF1A1) is identified as an integral component of the BAT complex. Translational silencing of Dab2 and ILEI, two EMT transcripts, is mediated by the binding of hnRNP E1 and eEF1A1 to their 3'UTR BAT element, whereby hnRNP E1 stalls translational elongation by inhibiting the release of eEF1A1 from the ribosomal A site. TGF-ß-mediated hnRNP E1 phosphorylation, through Akt2, disrupts the BAT complex, thereby restoring translation of target EMT transcripts. Attenuation of hnRNP E1 expression in two noninvasive breast epithelial cells (NMuMG and MCF-7) not only induced EMT but also enabled cells to form metastatic lesions in vivo. Thus, translational regulation by TGF-ß at the elongation stage represents a critical checkpoint coordinating the expression of EMT transcripts required during development and in tumorigenesis and metastatic progression.

Cystic neutrophilic granulomatous mastitis: The Cleveland Clinic experience with diagnosis and management.

Granulomatous mastitis is an uncommon inflammatory disease that typically presents with painful breast lesions. Recent publications have brought to light a specific subset of granulomatous mastitis patients with a distinct histological pattern of disease termed, "cystic neutrophilic granulomatous mastitis" (CNGM). Although many cases of granulomatous lobular mastitis have been thought to be idiopathic, this rare subset of an uncommon disease has been linked to infections with Corynebacterium species. Herein, a cohort of CNGM patients from a large, tertiary care, North-American, academic medical center is presented. Correlative demographic, clinical, radiographic, pathologic, microbiologic, management, and outcomes data are provided. Collaborative communication between specialists to accurately diagnose and manage these patients is essential to decreasing potential morbidity.

Sunscreen Application, Safety, and Sun Protection: The Evidence.

Recently in Canada, there has been an effort to create consistent messaging about sun safety as there is a lack of up-to-date evidence-based guidelines regarding sun-protection measures. This review aimed to provide updated, evidence-based recommendations on sunscreen application, safety, and sun protection regarding the following topics for which there is clinical uncertainty: physical barriers, sunscreen properties, sunscreen application, and risk-benefit analysis.

Periductal Stromal Tumor of the Breast: One Institution's Review of 6 Tumors Over a 22 Year Period With Immunohistochemical Analysis.

Introduction. Periductal stromal tumor (PST) of the breast is a rare fibroepithelial neoplasm with controversial pathogenesis. Methods. A retrospective search of our Pathology database from 2000 to 2021 identified 6 PST, all evaluated according to the Armed Forces Institute of Pathology (AFIP) criteria. Immunohistochemistry for CD10, CD34, KIT, GATA3, p63, SOX10, ER, PR, HER2, smooth muscle actin (SMA), beta-catenin, and myogenin was performed as well. Results. All 6 patients were female and age ranged from 29 to 55 years (mean 40 years). Tumor size ranged from 2.9 to 5.9 cm (mean 3.0 cm). Data showed absence of leaf-like architecture (0/6), at least moderate hypercellularity (6/6), lack of a circumscribed border (5/6), coalescing nodules with intermixed adipose tissue (4/6), at least moderate stromal atypia (4/6), and an elevated mitotic activity ≥3mitotic figures/10 HPF (6/6). The stromal cells were positive for CD10 (4/4), CD34 (4/4), KIT (3/4), and SMA (3/4), and negative for GATA3 (0/6), p63 (0/6), SOX10 (0/6), ER (0/4), PR (0/4), HER2 (0/4), nuclear beta-catenin (0/5), and myogenin (0/4). No patient had a PST recurrence or metastasis (average follow-up of 91 months). Conclusion. We confirm that PST shares morphologic and immunophenotypic similarities with phyllodes tumor (PT). However, PST can be reliably differentiated from PT using the AFIP criteria. Additionally, PST's immunoprofile of positive KIT and CD34 stromal expression alongside the negative GATA3, p63, and SOX10 reactivity can aid the pathologist in excluding metaplastic carcinoma. All 6 of our PST behaved as benign neoplasms akin to benign PT.

Assessment of Glucagon-like Peptide-1 Receptor Agonists in Veterans Taking Basal/Bolus Insulin Regimens.

Background: Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is well established as add-on therapy to oral medications and basal insulin. However, there is little published data regarding the use of GLP-1 RAs for longer than 12 months in patients taking basal/bolus insulin regimens. The primary goal of our study was to assess the long-term efficacy of GLP-1 RAs as add-on therapy to basal/bolus insulin regimens. Methods: This study was a retrospective record review of all patients on basal/bolus insulin regimens who received additional therapy with a GLP-1 RA. The primary outcome was the change in glycosylated hemoglobin A1c (HbA1c) at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and total daily dose (TDD) of insulin and incidence of hypoglycemia and other adverse effects (AEs). Results: Ninety-two patient records were reviewed. Mean glycemic control changed from baseline -1.1% (95% CI, -1.3 to -0.8; P < .001) at 3 months; -1.0% (95% CI, -1.3 to -0.7; P < .001) at 6 months; -0.9% (95% CI, 1.3 to -0.6; P < .001) at 12 months; -0.9% (95% CI, -1.4 to -0.3; P = .002) at 18 months; and -0.7 (95% CI, -1.4 to 0.1; P = .07) at 24 months. A significant decrease in weight was also observed from baseline through 18 months, and a significant decrease in TDD of insulin was identified from baseline through 12 months. Hypoglycemia was documented in 29.8% of patients at any point during GLP-1 RA therapy, and gastrointestinal AEs were documented in 18.3% of patients. Conclusions: Adding GLP-1 RAs to complex insulin regimens may help achieve glycemic control while decreasing insulin requirements and mitigating undesirable AEs, such as weight gain.

Implementation of a Pharmacist-Managed Transitions of Care Tool.

PURPOSE: To improve, expand, and sustain a pharmacist-based transitions of care (TOC) program and to assess interventions targeting veterans at high risk for adverse outcomes. METHODS: A TOC program was developed and piloted at the Richard L. Roudebush Veterans Affairs Medical Center (RLRVAMC). Following success of the pilot project, targeted interventions were identified to improve and expand the program. Patients deemed high risk for readmission by an acute care pharmacist were identified and referred for continued postdischarge follow-up. The study population included patients discharged to the community with primary care established within the RLRVAMC system. Eligible patients were entered into a TOC database by the referring acute care pharmacist. A pharmacist in the primary care clinic reviewed then contacted the patient within 1 week of discharge. Appropriate documentation of each visit was completed in the electronic health record. Data collection included background information, time to follow-up, medication discrepancies, pharmacist interventions, emergency department visits, and hospital readmissions. RESULTS: A total of 139 patients were included, of which 99 patients were reached for pharmacist follow-up. There were 43 medication-related discrepancies among all patients. The most common discrepancy was taking the wrong dose of a prescribed medication. Additional counseling was provided to 75% of patients. The subset of patients who were reached by a pharmacist had decreased index (5.1% vs 15.0%; P = .049) and all-cause readmissions (8.1% vs 27.5%; P = .03) at 30 days compared with those who did not received pharmacist follow-up, respectively. CONCLUSIONS: This study demonstrated that implementation and expansion of a pharmacist-based TOC process is effective in communicating high-risk patients and intervening on medication-related issues postdischarge.

Mammary ductoscopy and ductal washings for the evaluation of patients with pathologic nipple discharge.

The majority of breast diseases result from lesions of the ductal epithelium. Mammary ductoscopy allows for visualization of intraductal abnormalities, and ductoscopic lavage provides thousands of cells for analysis. We reviewed our experience of 89 cases of patients with pathologic nipple discharge (PND) undergoing ductoscopy-directed duct excision and collection of ductal washings. Patients undergoing ductoscopy-directed duct excision with ductal washings had an 88% abnormal pathology rate. Most abnormalities were benign (71% papillomas), but the atypia rate for this group was 62%. The combination of visualization and pathologic analysis of washings provided the highest predictive value for the diagnosis of papilloma. Cellular yields for this technique were excellent with most specimens yielding >5,000 epithelial cells per high powered field and with evaluable ductal cells in 82% of specimens. Mammary ductoscopy offers the advantage of a high lesion localization rates with intraoperative guidance. The most accurate tool was the combination of ductal washings and ductoscopic visualization, but preoperative use of these techniques is not helpful in most cases. Greater than 90% of patients with PND are found to have a lesion on pathologic examination when using this technique for directed duct excision. Of interest, ductal washings obtained from symptomatic patients with benign diseases are often atypical.

Mammary mesenchymal and fibroepithelial lesions: An illustrated cytomorphologic update with differential diagnoses.

The Uniform Approach to Breast Fine Needle Aspiration Biopsy was put forward by a learned group of breast physicians in 1997. This landmark manuscript focused predominantly on diagnosis and reporting of mammary epithelial lesions. Today, most American practitioners turn initially to core biopsy rather than aspiration biopsy for the first line diagnosis of solid breast lesions; however, recent efforts from the International Academy of Cytology have produced a system called the Standardized Reporting of Breast Fine Needle Aspiration Biopsy Cytology (colloquially labeled in 2017 as the "Yokohama System"), suggesting a new interest in breast fine needle aspiration (FNA), especially in resource limited settings or clinical practice settings with experienced breast cytopathologists. Fibroepithelial lesions of the breast comprise a heterogeneous group of biphasic tumors with epithelial and stromal elements. Mesenchymal lesions of the breast include a variety of neoplasms of fibroblastic, myofibroblastic, endothelial, neural, adipocytic, muscular, and osteo-cartilaginous derivations. The cytology of mesenchymal breast lesions is infrequently described in the literature and is mainly limited to case reports and small series. This illustrated review highlights the cytologic features of fibroepithelial and mesenchymal mammary proliferations and discusses differential diagnoses and histomorphologic correlates.

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.

Does Identifying Whether Pseudoangiomatous Stromal Hyperplasia (PASH) Is Focal or Diffuse on Core Biopsy Correlate With a PASH Nodule on Excision?

AIMS: Pseudoangiomatous stromal hyperplasia (PASH) diagnosed on core needle biopsy is generally excised. As a consequence, PASH as an incidental finding, may lead to unnecessary excisions. This study categorized PASH in biopsies as diffuse versus focal to determine if this correlates with the presence of a mass. METHODS: In a 10-year period, 253 biopsies were identified and 159 met inclusion criteria. Of these, 47 biopsies had excisions. Biopsies and excisions were classified as diffuse, involving 2 adjacent lobules, or focal PASH in a single lobule or noncontiguous lobules. The diffuse or focal category on biopsy was correlated to the category on excision. Fibroadenomas with PASH were defined as concordant with diffuse PASH on biopsy. The category was correlated to the presence/absence of a mass determined from radiographic/clinical data for the 159 biopsies. RESULTS: The biopsies were classified as diffuse (105, 66%) and focal (54, 34%). A total of 67% of biopsies with focal PASH showed either focal or no PASH on excision. Diffuse PASH on biopsy, had diffuse PASH in 93% of excisions. Concordance of this classification between biopsy and excision, using a Fisher's exact test (2-tailed P value is <.0001), is statistically significant. A mass was present in 102/105 (97%) of biopsies with diffuse PASH. In biopsies with focal PASH, 78% had a mass lesion. CONCLUSIONS: Classification of diffuse versus focal PASH on biopsy was concordant with findings on excision. We found that diffuse PASH on biopsy showed strong correlation with a mass lesion. Quantifying PASH may assist with clinical-pathologic correlation and reduce unnecessary excisions.

Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR.

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry. This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Identification of breast cancer in patients with pathologic nipple discharge: does ductoscopy predict malignancy?

OBJECTIVE: The purpose of the current study was to review characteristics of patients with nipple discharge who underwent ductoscopy-assisted excisional biopsy who had a final diagnosis of carcinoma. METHODS: A retrospective review was performed of patients presenting with pathologic nipple discharge (PND) who underwent ductoscopy-assisted excisional biopsy and had a final diagnosis of carcinoma. RESULTS: A total of 14 (7%) of 188 patients who underwent ductoscopy-assisted excision had a final pathology of ductal carcinoma-in-situ (DCIS) (12/14, 86%) or invasive breast cancer with DCIS (2/14, 14%). Duct wall irregularities or intraluminal growths were visualized during ductoscopy in 8 of the 14 (57%) breast cancer patients. There were no visual abnormalities noted during ductoscopy that accurately predicted a final diagnosis of malignancy. CONCLUSIONS: Although occult malignancies can be identified in patients undergoing ductoscopy-assisted biopsy for PND, no clear morphologic changes visualized during ductoscopy definitively indicated the presence of malignancy.

Assisted primary screening using the automated ThinPrep Imaging System.

We report the clinical trial studies for the ThinPrep Imaging System (TIS; Cytyc, Boxborough, MA). Between December 2000 and July 2001, 10,742 ThinPrep specimens were collected at 4 US clinical sites representative of the normal clinical population of the laboratories, including screening patients and referred patients. After nonstudy screening diagnoses were completed, the vials were relabeled and randomized, and study slides were prepared and stained. TIS-trained cytotechnologists and pathologists screened the slides twice, first manually, then TIS-assisted after an appropriate interval. Afterward, 3 independent pathologists performed an adjudication study to determine definitive diagnoses for the nonnegative slides and 5% of the negative slides; the adjudicated diagnoses served as the "gold standard" for subsequent sensitivity and specificity analyses. TIS-assisted screening was statistically more sensitive than manual screening for atypical squamous cells of undetermined significance (ASCUS) or higher (+) and statistically equivalent for low- (LSIL)+ and high-grade squamous intraepithelial lesion (HSIL)+ diagnoses. TIS-assisted screening had equivalent specificity for ASCUS+ and LSIL+ and significantly higher specificity for HSIL+. Average cytologists' daily screening rates doubled with TIS-assisted screening. The sensitivity of the TIS-assisted screening system equals or exceeds the sensitivity of manual primary screening without adversely affecting specificity, and TIS-assisted screening can improve cervical cancer screening productivity. Cost issues require further study.

Invasive squamous-cell carcinoma in ThinPrep specimens: diagnostic clues in the cellular pattern.

Despite the increasing utilization of the ThinPrep Pap Test (TP), limited data exist regarding the cytomorphologic features and patterns of invasive squamous-cell carcinoma in TP specimens. We analyzed a series of TP specimens from patients with histologically confirmed invasive squamous carcinomas of the cervix. Patients with biopsy-proven invasive squamous-cell carcinoma of the cervix with a TP cervical cytologic specimen within the previous 2 mo were identified. The TP slides were analyzed for overall cellularity (percent circle coverage by epithelial cells), tumor cellularity, tumor diathesis, inflammation, coexistent dysplasia, and keratinization. Tumor cellularity was defined as <5%, 5-50%, and >50% of slide cellularity. In all 13 cases that were identified, a cytologic diagnosis of either invasive squamous-cell carcinoma or suspicious for invasive squamous-cell carcinoma was made. In 7/13 cases (54%), epithelial cells covered <40% of the slide circle. Epithelial cells covered >40% of the slide circle in 6/13 cases (46%). Tumor cellularity covered <5% of the slide circle in 4/13 cases (31%), 5-50% in 7/13 cases (54%), and >50% in 2/13 cases (15%). A tumor diathesis was present in 12/13 cases (92%). Inflammation was absent in 1/13 cases (8%), mild in 8/13 cases (62%), moderate in 2/13 cases (15%), and severe in 1/13 cases (8%). Coexistent dysplasia was identified in 12/13 cases (92%). Keratinization was identified in 9/13 specimens (69%). In the vast majority of patients, a diagnosis of squamous-cell carcinoma was rendered on the TP cervical specimen, despite a pattern of decreased cell coverage. It could be hypothesized that tumor diathesis and inflammation may be the etiology for decreased cellularity by blocking filter coverage by epithelial cells. This cellular pattern with diathesis in the ThinPrep smear may be a useful clue to look carefully for diagnostic cells of squamous-cell carcinoma.