Hyperechoic malignancies of the breast: Underlying pathologic features correlating with this unusual appearance on ultrasound

Hyperechogenicity in the breast on ultrasound (US) is usually regarded as a benign feature with only rare hyperechoic malignancies reported to date. In this study, we evaluated the pathologic findings on core needle biopsy of hyperechoic lesions and investigated the histologic features in malignancies that give rise to an echogenic pattern. A total of 163 core needle biopsies (CNB) were performed for “hyperechoic” or “echogenic” lesions between 1/1/05 and 7/31/17. Lesions were classified based on the proportion of hyperechoic areas identified. We found that all lesions with a homogenous hyperechoic pattern (>90% hyperechoic) were benign (n = 17), regardless of the type of margins. Malignancies were found in 21% (7/34, six invasive carcinomas and one lymphoma) of heterogenous lesions with ≥50% hyperechoic areas (all with noncircumscribed margins) and in 31% of lesions with <50% hyperechoic areas (19/61, 14 invasive carcinomas, two lymphomas, and three metastases), including five with circumscribed margins (one invasive carcinoma, one lymphoma, and three metastases). Two major US patterns were identified in malignant lesions, those with a hypoechoic center and hyperechoic rim, corresponding to a central tumor area with dense stroma and tumor cells infiltrating adipose tissue at the periphery (“rim pattern”), and a second “dispersed pattern” with hyperechoic areas distributed throughout the lesion. Hyperechoic malignancies were found to be comprised of a complex intermixture of elements of differing echogenicity including tumor cells, adipose tissue, and fluid (in tubules, stromal clefts, or blood vessels). Our findings support the importance of radiologists specifying the echogenic pattern of hyperechoic lesions, as heterogenous lesions are associated with a higher risk of malignancy and pathologists should be alert to the associated pathologic findings.     

Multi-laboratory comparison of three heparin-Mn2+ precipitation procedures for estimating cholesterol in high-density lipoprotein.

Plasma high-density lipoprotein is commonly estimated by measuring the cholesterol remaining in plasma supernatant solutions after other lipoproteins, which contain apolipoprotein B, are precipitated with heparin and Mn2+. The method (method I) now in use by the Lipid Research Clinics, in which Mn2+ is at 46 mmol/liter final concentration, is reasonably accurate, but precipitation and sedimentation of lipoproteins other than high-density lipoproteins is often incomplete. We evaluated two modifications of method I. In method II, the Mn2+ concentration was doubled; the second modification (method III) included the increased Mn2+ concentration in a combined heparin Mn2+ reagent, decreased sample volume (2 ml), and a shorter incubation time (10 min at room temperature). The percentages of samples with turbid supernates (i.e., incomplete sedimentation) by methods I, II, and III were 9, 3, and 2%, respectively. Among non-turbid supernates, the percentages of samples containing measurable apolipoprotein B (incomplete precipitation) were 79, 19, and 16%, respectively. We conclude that method III is the most convenient and accurate of the three procedures.     

Career Placement of Doctor of Pharmacy Graduates at Eight U.S. Midwestern Schools

Objective. To characterize postgraduation placement plans of 2013 doctor of pharmacy (PharmD) graduates.Methods. A cross-sectional survey of PharmD graduates from 8 midwestern colleges of pharmacy was designed to capture a comprehensive picture of graduating students’ experiences and outcomes of their job search.Results. At graduation, 81% of 2013 respondents had postgraduate plans, with approximately 40% accepting jobs and 40% accepting residencies or fellowships. Eighty-four percent of graduates reported being pleased with offers received, and 86% received placement in their preferred practice setting. Students perceived that securing residencies was more difficult than securing jobs. Students who participated in key activities had a nearly sevenfold increase in successful residency placement.Conclusion. While the demand for pharmacists decreased in recent years, responses indicated successful placement by the majority of 2013 graduates at the time of graduation.     

ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma

Melanomas are characterized by activating “driver” mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative (“pan-negative”) patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.     

Comparison of the treatment results of knee osteoarthritis using adipose tissue mesenchymal stromal cells derived through enzymatic digestion and mechanically fragmented adipose tissue

Introduction:Knee osteoarthritis is a common condition that affects daily functioning and decreases the quality of life. There are many ways of treatment depending on the stage of the disease. Advanced cases are qualified for arthroplasty, which is an extensive and demanding surgical procedure. Less advanced stages are treated in various ways: from rehabilitation, through oral and intra-articular pharmacotherapy, to surgical treatment (arthroscopy, osteotomy). Because surgical treatment is risky, scientists focus on less invasive therapeutic methods. The most valuable management is based on regeneration. Mesenchymal stromal cells (MSC) derived from the adipose tissue have a great regenerative and anti-inflammatory potential, therefore an attempt is being made to take advantage of them in knee osteoarthritis treatment.The study aims to compare the clinical effects of treatment of knee osteoarthritis using adipose tissue MSC obtained by an enzymatic method with the outcomes of the therapy with the mechanically fragmented adipose tissue.Methods:One hundred adults with primary knee osteoarthritis will undergo lipoaspiration under sterile conditions. The collected lipoaspirates will be further processed, depending on the randomly assigned group-enzymatically with the use of collagenase or mechanically using the Lipogems system. The preparations will be administered to the patients’ knee joints in the operating room under ultrasound control.The results of treatment will be assessed using Knee Injury and Osteoarthritis Outcome Score, measuring the flexibility of the knee joint, evaluating joint gap in X-ray and the quality of cartilage in magnetic resonance T2-mapping during 1 year after treatment.Discussion/conclusion:Identification and functional analysis of the regenerative capacity of adipose-derived MSC depending on three variables (body weight, sex, and age) will help to develop a targeted therapy for different groups of patients and will determine the effectiveness of both methods of treatment. An attempt will be made to identify groups of patients with the greatest regenerative potential of the adipose tissue, and thus indicate those with the most probable improvement of the joint condition.Trial registration:This study protocol has been approved by the Ethics Committee of Medical University of Warsaw and registered on www.clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT04675359","term_id":"NCT04675359"}}NCT04675359 (06 Jan 2021)     

Lung biopsy in diffuse interstitial lung disease (simple technique)

A simple, safe, easily reproducible and quick method of taking lung biopsy in diffuse interstitial lung disease is described.     

Functions of ascending thin limb of Henle's loop with special emphasis on mechanism of NaCl transport.

Major controversy concerning the ascending thin limb of Henle's loop (ATL) centers on the urine concentration mechanism based on the countercurrent multiplier system in the inner medulla of the kidney. This renal tubular segment has specific transport properties which function to dilute the urine without any movement of water across the epithelium. This segment is fundamentally impermeable to water, moderately permeable to urea, and highly permeable to Na+ and Cl-. Whether NaCl is reabsorbed actively in the ATL has long been an important question. While mathematical modelling studies have failed to explain completely how the osmotic gradient in the inner medulla is generated without active NaCl transport in the ATL, the experimental data support the view that active NaCl reabsorption is absent. Recently, we succeeded in measuring the intracellular Na+ concentration by using the fluorescent Na+ indicator sodium-binding benzofuran isophthalate in the in vitro microperfused ATL. Our data suggest that the ATL maintains a low intracellular Na+ concentration by the ouabain-sensitive Na+/K+ ATPase in the basolateral membrane, and that the luminal membrane of the ATL has furosemide-insensitive Na+ permeability. Active Na+ reabsorption estimated in our study amounts to only a few per cents of the net Na+ reabsorption in the ATL. It is therefore suggested that the major role of Na+ extrusion in the ATL cells is to maintain a low cellular Na+ concentration against ambient hyperosmolarity, although small but substantial amount of Na+ is reabsorbed by the furosemide-insensitive Na+ permeability and ouabain-sensitive Na+/K+ ATPase.     

Chronic asymptomatic pseudocyst with sludge aggregates masquerading as mucinous cystic neoplasm of the pancreas

Pseudocyst of the pancreas is sometimes difficult to distinguish from mucinous cystic neoplasm of the pancreas. A 37-year-old asymptomatic Japanese man was diagnosed with hypertension. He had a 20-years history of habitual drinking of alcohol, but no history of pancreatitis or abdominal trauma. During examinations to ascertain the cause of hypertension, ultrasonography and computed tomography incidentally demonstrated a huge cyst in the head of the pancreas. Laboratory data were within normal limits, including serum levels of amylase, carcinoembryonic antigen, and carbohydrate antigen 19-9. Imaging studies showed a huge unilocular cyst, measuring 7 cm, in the head-to-body of the pancreas, and two small unilocular cysts, measuring 1.4 and 1.5 cm, in the tail and head of the pancreas, respectively. A mural nodule was suspected in the largest cyst. Endoscopic retrograde cholangiopancreatography demonstrated communication of the main pancreatic duct with the two small cysts in the head and tail of the pancreas but not with the huge cyst. There were no ductal changes suggesting chronic pancreatitis. Laparotomy was performed under the tentative diagnosis of potentially malignant mucinous cystic neoplasms of the pancreas. However, inflammatory adhesion was dense around the pancreas and the mural nodule suspected preoperatively was found to be sludge aggregates in a pseudocyst. The diagnosis of an intraoperative frozen section of the cyst wall was pseudocyst of the pancreas. Cystojejunostomy was performed. We report this case because the pre-operative diagnosis was mucinous cystic neoplasm of the pancreas, but the diagnosis changed with careful intraoperative examinations, to pseudocyst of the pancreas. We discuss the differential diagnosis of the two conditions. (Received Oct. 1, 1997; accepted Jan. 23, 1998)     

Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.