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BACKGROUND Asthma is a chronic respiratory disease with significant heterogeneity in its clinical presentation and pathobiology. There is need for improved understanding of respiratory lipid metabolism in asthma patients and its relation to observable clinical features. OBJECTIVE To perform a comprehensive, prospective, cross-sectional analysis of the lipid composition of induced sputum supernatant obtained from asthma patients with a range of disease severities, as well as healthy controls. METHODS Induced sputum supernatant was collected from 211 asthmatic adults and 41 healthy individuals enrolled in the U-BIOPRED study. Sputum lipidomes were characterised by semi-quantitative shotgun mass spectrometry, and clustered using topological data analysis to identify lipid phenotypes. RESULTS Shotgun lipidomics of induced sputum supernatant revealed a spectrum of nine molecular phenotypes, highlighting not just significant differences between the sputum lipidomes of asthmatics and healthy controls, but within the asthmatic population as well. Matching clinical, pathobiological, proteomic and transcriptomic data informed on the underlying disease processes. Sputum lipid phenotypes with higher levels of non-endogenous, cell-derived lipids were associated with significantly worse asthma severity, worse lung function, and elevated granulocyte counts. CONCLUSION We propose a novel mechanism of increased lipid loading in the epithelial lining fluid of asthmatics, resulting from the secretion of extracellular vesicles by granulocytic inflammatory cells, which could reduce the ability of pulmonary surfactant to lower surface tension in asthmatic small airways, as well as compromise its role as an immune regulator. CLINICAL IMPLICATION Immunomodulation of extracellular vesicle secretion in the lungs may provide a novel therapeutic target for severe asthma.

Background Patients with difficult-to-control asthma consume 50–60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called ‘T2-low asthma’ and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy. Methods/design Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers. Discussion Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct. Trial registration ClinicalTrials.gov, NCT02717689. Registered on 16 March 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2384-7) contains supplementary material, which is available to authorized users.

Many people with asthma do not achieve disease control, despite bronchodilators and inhaled corticosteroid therapy. People with uncontrolled asthma are at higher risk of an asthma attack and death, with mortality rates estimated at 1000 deaths/year in England and Wales. The recent National Review of Asthma Deaths (NRAD) report, ‘Why asthma still kills’, recommended that patients at step 4 or 5 of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidance must be referred to a specialist asthma service. This article reviews the 2014 evidence base for therapy of asthma patients at BTS/SIGN step 4 of the treatment cascade, in response to key findings of the NRAD report and lack of preferred treatment option at this step.

To retrospectively determine the degree of underestimation of breast carcinoma diagnosis in papillary lesions initially diagnosed at core-needle biopsy.Institutional review board approval and waiver of informed consent were obtained for this HIPAA-compliant study. Mammographic database review (1994-2003) revealed core biopsy diagnoses of benign papilloma (n=38), atypical papilloma (n=15), sclerotic papilloma (n=6), and micropapilloma (n=4) in 57 women (mean age, 57 years). Excisional or mammographic follow-up (or=2 years) findings were available. Patients with in situ or invasive cancer in the same breast or patients without follow-up were excluded. Findings were collected from mammography, ultrasonography, core technique, core biopsy, excision, and subsequent mammography. Reference standard was excisional findings or follow-up mammogram with no change at 2 years. Associations were examined with regression methods.In 38 of 63 lesions, surgical excision was performed; in 25 additional lesions (considered benign), follow-up mammography (24-month minimum) was performed, with no interval change. In 15 lesions, 14-gauge core needle was used; in 48, vacuum assistance (mean cores per lesion, 8.7). Carcinoma was found at excision in 14 of 38 lesions. Core pathologic findings associated with malignancy were benign papilloma (n=1), sclerotic papilloma (n=1), micropapilloma (n=2), and atypical papilloma (n=10). Frequency of malignancy was one (3%) of 38 benign papillomas, 10 (67%) of 15 atypical papillomas, two (50%) of four micropapillomas, and one (17%) of six sclerotic papillomas. Excisional findings included lobular carcinoma in situ (n=2), ductal carcinoma in situ (n=7), papillary carcinoma (n=2), and invasive ductal carcinoma (n=3). Low-risk group (micropapillomas and sclerotic and benign papillomas) was compared with high-risk atypical papilloma group. Core findings were associated with malignancy at excision for atypical papilloma (P=.006). Lesion location, mammographic finding, core number, or needle type were not associated (P.05) with underestimation of malignancy at excision.Benign papilloma diagnosed at core biopsy is infrequently (3%) associated with malignancy; mammographic follow-up is reasonable. Because of the high association with malignancy (67%), diagnosis of atypical papilloma at core biopsy should prompt excision for definitive diagnosis.

The lactiferous duct system of the breast is the site of development of various benign and malignant lesions. Asymptomatic patients may have incidental diagnosis of ductal dilation on mammography. A mass or area of calcifications identified on mammography as suspicious and subsequently biopsied may represent a lesion of a primary lactiferous duct. The smaller terminal ducts are the site of development of most cancers and hyperplasias. In patients who present with the symptom of nipple discharge, a clinical assessment is made to determine the potential significance of the finding. In patients with uniorificial, spontaneous and suspicious discharge, further evaluation with galactography is recommended. In this article we will review the benign and malignant lesions of the main lactiferous ducts, the assessment of asymptomatic patients with ductal dilation on mammography, and the assessment of patients with abnormal nipple discharge.

The American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) defines four different types of asymmetric breast findings: asymmetric breast tissue, densities seen in one projection, architectural distortion, and focal asymmetric densities. These lesions are frequently encountered at screening and diagnostic mammography and are significant because they may indicate a neoplasm, especially if an associated palpable mass is present. Once these lesions are detected at standard mammography, supplementary breast imaging with additional mammographic views and ultrasonography (US) can be a key aspect of work-up. The role of US in this setting has not been clearly defined. However, a positive US finding such as a solid mass or an area of focal shadowing increases the level of suspicion for malignancy. A thorough knowledge of the patient's clinical history, along with a fundamental understanding of the ACR BI-RADS lexicon and the role and limitations of supplementary breast imaging, will allow more accurate interpretation of these potentially perplexing soft-tissue findings.

We report on some extensions and further developments of a well-known microcalcification detection algorithm based on adaptive noise equalization. Tissue equivalent phantom images with and without labeled microcalcifications were subjected to this algorithm, and analyses of results revealed some shortcomings in the approach. Particularly, it was observed that the method of estimating the width of distributions in the feature space was based on assumptions which resulted in the loss of similarity preservation characteristics. A modification involving a change of estimator statistic was made, and the modified approach was tested on the same phantom images. Other modifications for improving detectability such as downsampling and use of alternate local contrast filters were also tested. The results indicate that these modifications yield improvements in detectability, while extending the generality of the approach. Extensions to real mammograms and further directions of research are discussed.

Stereotactic core needle biopsy (SCNB) has become a popular method for diagnosis of occult breast abnormalities. There are few large series of SCNB from a single institution. Data on patients undergoing SCNB for mammographic abnormalities were collected prospectively over 43 months at a university hospital. Mammographic findings were categorized as benign, probably benign, indeterminate, suspicious or malignant. For lesions with SCNB pathology that were non-diagnostic, showed atypical hyperplasia or malignancy (in situ or invasive), or were discordant with the pre-biopsy mammogram findings, surgical excision was recommended. Subsequent surgical pathology was reviewed. All remaining lesions were followed mammographically after SCNB. SCNB was performed on 692 lesions in 607 patients. There were 79 malignancies, for a positive SCNB rate of 11.4%. The 349 SCNB performed for benign, probably benign and indeterminate lesions on mammography had a positive SCNB rate of only 4%. Surgery was recommended for 127 (18.3%) lesions, while 565 (81.6%) were followed mammographically after SCNB. A compliance rate of 61 % for at least one follow-up mammogram was obtained, with a median follow-up of 17.2 months and with no cancers found. The sensitivity for malignancy with SCNB was 93%. SCNB provides a minimally invasive method to assess mammographic abnormalities. Abnormalities considered radiographically to be other than malignant or suspicious yielded few cancers. In this series a low positive SCNB rate resulted in no false negatives on mammographic follow-up. The optimal positive biopsy rate for SCNB is debatable.

1From the Department of Radiology, University of Arkansas for Medical Sciences, Slot 581, 4301 W Markham, Little Rock, AR 72205-7199 (T.L.A.); the Department of Radiology, Medical College of Virginia, Richmond (E.S.P.); private practice, Women’s Imaging Center, Denver, Colo (K.A.M.); and the Department of Radiology, University of California, San Francisco (H.H.). Presented as a refresher course at the 1998 RSNA scientific assembly. Received and accepted May 3, 1999. Address reprint requests to T.L.A.

Detection and management of breast abnormalities that develop during pregnancy and lactation is difficult for both the clinician and the radiologist. This article reviews the hormonal and physiologic effects on the breast during pregnancy and lactation. Breast masses that occur in pregnant or lactating patients, including pregnancy-associated breast cancer, are discussed and the corresponding ultrasound and mammographic findings are presented. Finally, a rationale for the imaging evaluation and management of the pregnant or lactating patient with a breast mass are presented.

The capability to provide histologic diagnoses of nonpalpable lesions by performance of percutaneous needle biopsy has revolutionized breast imaging in the past decade. The radiologist who performs percutaneous breast biopsies assumes an increased level of responsibility for the patient regarding patient selection, lesion selection, performance of the biopsy procedure, interpretation of results, and patient follow-up. With variable and increasingly numerous options for the biopsy of breast lesions, careful attention must be paid to the selection of patients and types of lesions for different procedures. Critical technical considerations affect whether biopsy of a lesion can be optimally performed percutaneously, and these considerations must be factored into the recommendations for patient treatment. In addition, a limited preprocedural clinical assessment of the patient will allow a safer procedure to be performed expeditiously. Most breast abnormalities classified by using the ACR Lexicon as 4 (suggestive) or 5 (highly suggestive, likely malignant) are suitable for either percutaneous breast needle biopsy or needle localization and excisional biopsy. In general, those lesions classified as 3 (probably benign) carry a recommendation for early follow-up and not biopsy, because the likelihood of malignancy is small. A particular advantage of percutaneous biopsy is in the diagnosis of multicentric breast cancer. Core biopsy is less invasive and less costly than surgical biopsy, and it can be used to demonstrate multicentric disease, saving the patient a two-step surgery. However, several lesions are better treated by excision than by percutaneous biopsy. Among these are architectural distortion or loosely arranged, segmental or regional microcalcifications. For nonpalpable breast lesions visualized on mammography, sonography, or both, imaging-guided localization is required for precise needle placement either for wire localization or for percutaneous breast biopsy. The selection of which modality to use for guidance depends on (1) the adequacy of visualization of the lesion by the modality used, (2) the position of the lesion, (3) the ease of positioning the patient, (4) the skill of the operator, (5) the need to reduce radiation exposure, (6) the overall patient condition, and (7) size of the lesion. Fine-needle aspiration biopsy (FNAB) has a high sensitivity and specificity in the diagnosis of palpable breast lesions when the procedure is properly performed and interpreted. Variable results have been achieved with FNAB of nonpalpable breast lesions under imaging guidance. Three critical components are necessary to achieve reliable results by using FNAB. These include the following: (1) accuracy in needle placement, (2) skill in performance of FNAB, and (3) expert cytopathologic analysis. Accurate preoperative needle localization of nonpalpable breast lesions allows the radiologist to guide the surgeon performing an open biopsy and helps to ensure that the surgical procedure can be performed quickly and can be accomplished with the best possible cosmetic result for the patient. Lesions selected for needle localization and biopsy should undergo a complete tailored imaging evaluation before the needle localization is scheduled. Specimen radiography should be performed for all nonpalpable lesions. Once the lesion has been identified on specimen radiography, the radiologist can assist the pathologist in identifying the lesion microscopically by marking the lesion within the surgical specimen. We cover the technical and interpretative aspects of percutaneous breast biopsy and needle localization for surgical biopsy.

The purpose of routine screening mammography is to detect unsuspected cancer that has the potential to be cured. Abnormalities detected on the screening examination often necessitate additional radiologic workup before a definitive result or diagnosis can be given. This workup (diagnostic mammography) may include specialized views, such as spot compression to evaluate the margins of a nodule, or magnification views to determine the features of microcalcifications. Additional evaluation with mammographic views, breast ultrasound, and, at times, interventional procedures such as fine needle aspiration or core biopsy are performed to complete the radiologic evaluation of a patient with an abnormal mammogram. Signs of malignancy include nodules (most often poorly defined), microcalcifications, and, less commonly, areas of architectural distortion, asymmetry, or focal ductal dilatation. A comprehensive approach to breast imaging will help to potentiate the early detection of subtle malignancies and avoid the performance of some biopsies for benign lesions.

Because of advances in mammography and a concomitant rise in the number of breast biopsies being performed for mammographically detected abnormalities, increasing numbers of columnar cell lesions (CCLs) are being described by pathologists. However, these lesions can be challenging to manage, since their classification has changed over time and only limited research has been conducted regarding their clinical significance. CCLs may be characterized by a single layer of columnar cells (columnar cell change [CCC]), multiple layers with stratification and apical tufting (columnar cell hyperplasia [CCH]), or monomorphic cells with cytologic atypia (flat epithelial atypia [FEA]). The differentiation between CCC, CCH, and FEA is clinically significant: CCC and CCH are considered benign lesions, whereas FEA can be associated with, and even a precursor to, low-grade ductal carcinoma in situ and atypical ductal hyperplasia. Therefore, the identification of FEA at core biopsy should prompt excision of the remaining portion of the lesion.

Este artículo muestra evidencias del diseño, implementación y evaluación de una estrategia pedagógica orientada por maestros directores de curso de los grados sexto y séptimo de la educación básica secundaria en la elaboración de reglas pro-ambientales mediante los procesos de socialización y aprendizaje concernientes a la solución de problemáticas ambientales para el cuidado y conservación del ambiente natural y social de su aula de clase. La estrategia basada en la acción comunicativa permitió mejorar los conocimientos ambientales, las actitudes ambientales, y los comportamientos pro-ambientales de los agentes educativos, inicialmente en los maestros, a través de la aplicación de conocimientos ambientales para la construcción de una frase que posteriormente se trasformó en una regla pro-ambiental cuyos enunciados corresponden a la realidad, logrando mediante procesos metacognitivos efectos positivos en el grupo de estudiantes, mejorando las condiciones ambientales del espacio escolar, de las relaciones interpersonales entre maestros y estudiantes y ayudando a la consolidación de una cultura ambiental escolar.

Fibroepithelial lesions of the breast are commonly seen in clinical practice. The masses are composed of a combination of prominent stroma and varying glandular elements. Fibroadenomas, benign lesions that derive from the terminal duct lobular unit, are the most common and are often identified at clinical examination or mammography as circumscribed masses. Benign mesenchymal tumors include focal fibrosis, pseudoangiomatous stromal hyperplasia, and fibromatosis or desmoid tumor. Phyllodes tumor, which is similar to fibroadenoma but has increased cellularity in the stroma, is typically benign but has malignant potential. Diabetic fibrous mastopathy, a stromal proliferation found in patients with juvenile-onset insulin-dependent diabetes, is a reactive fibrous lesion. Most of these lesions manifest as masses at clinical and/or mammographic examination. Some (eg, fibroadenomas) may be associated with calcifications. Except for fibromatosis and phyllodes tumor, fibroepithelial lesions need not be excised if the diagnosis is confirmed by the results of histologic analysis at percutaneous biopsy. To correctly differentiate between fibrous breast lesions that are benign and those that should be resected, the physician must be familiar with the correlated radiologic-pathologic findings in the various lesion types.

As the breast imager has evolved as a breast interventionalist, the clinical responsibility associated with breast imaging has increased. The radiologist not only performs the biopsy procedure but also is responsible for correctly selecting the best procedure for the patient preoperatively and for communicating the results afterwards. The breast interventionalist must understand the indications and techniques for performing procedures, the selection of the appropriate procedure for the patient, and the risks, contraindications, and limitations of each procedure. Percutaneous breast biopsy developed in the late 1980s and 1990s to become a widely acceptable and utilized method for diagnosis of a nonpalpable breast lesion. The purpose of performing a percutaneous biopsy rather than an open or excisional biopsy is to obtain a diagnosis with a less invasive and less costly procedure. The roles of percutaneous breast biopsy are the following: (1) to confirm a benign diagnosis for lesions that are indeterminate by mammography and to avoid surgical biopsy of these lesions, and (2) to diagnose a highly suspicious lesion as malignant, thus avoiding a two-step surgical procedure for diagnosis and treatment. The technique is also utilized to sample palpable breast masses with or without imaging guidance. Methods of guidance include, primarily, mammography with stereotactic guidance or sonographic direction. In many cases, either technique is acceptable for a particular lesion or patient, and it is the operator who decides the method of preference. In other cases the choice of technique is determined by the characteristics of the lesion or the patient that allows either visualization of or access to the lesion by only one method. Clinical aspects of percutaneous breast biopsy relate to the proper assessment of the patient prior to the procedure to avoid unnecessary risk to her, and monitoring her during and after the procedure for any potential complication. Management of the patient after the procedure includes not only clinical follow-up but also obtaining the biopsy results and establishing a plan for patient management. Postprocedural assessment may involve a follow-up clinical visit with the patient for discussion of her results and for developing a management plan. The time spent by the breast imaging team before and after the procedure usually is greater than the time spent in the technical aspects of performing the biopsy. In this chapter the selection of patients and lesions for breast biopsy and the clinical parameters involved in preand postprocedure care of the patient are discussed.

The utilization of charged-coupled device detectors (CCD) for digital mammography is an area of active investigation. Smaller field detectors are commercially available and are increasingly utilized on mammographic units to guide stereotactic breast biopsies. Advantages of digital mammography include the following: a wide dynamic range, improved contrast, increased signal to noise ratio, and improved efficiency in image acquisition through a near real-time operation (1,2,3).

The role of the diagnostic radiologist in breast cancer has expanded during the eight-decade history of breast imaging. The radiologist's role now encompasses both breast cancer diagnosis and treatment. This article traces the expansion of the radiologist's role through the history of mammography. The current roles of the radiologist in breast cancer diagnosis are discussed, including screening mammography in the asymptomatic patient, problem-solving breast imaging, breast ultrasound, and galactography. The radiologist's roles in breast cancer treatment that are discussed include preoperative needle localization, percutaneous breast biopsy, and evaluation of the postoperative breast.

During an 8-year period, 74 breast cancers were diagnosed in 66 patients 35 years of age and younger who underwent preoperative mammography. Mammograms and clinical data in these women were reviewed retrospectively to evaluate the mammographic findings and the efficacy of mammography. In 58 cases the cancer was detected by means of both clinical examination and mammography; in eight cases, mammography alone enabled readers to find the lesion; in seven cases, the lesion was found by means of clinical examination, but mammograms were negative; and in one case a cancer was found by means of incidental biopsy of the contralateral breast. Although 34 patients (52%) had dense breasts, mammography demonstrated the lesion in 66 cases (89%); the most common mammographic finding was microcalcifications, with or without associated masses (n = 28 [38%]). The authors do not suggest that screening of women younger than 35 years be performed routinely, but they believe that mammography can be valuable in screening young women at high risk for breast cancer or in confirming and suggesting prompt biopsy of a suspicious lesion.

The authors retrospectively reviewed 118 well defined breast masses. Over 9% proved to be neoplastic or to represent lesions that are associated with a greater than normal risk of developing carcinoma. Thirty four examples of well defined masses representing a great variety of lesions are illustrated. The authors conclude that well defined breast masses warrant more careful examination and followup than they presently receive because of the greater than expected incidence of carcinoma and premalignant states.

Background: Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective treatment in animal models of inflammation, but has not been tested in experimental colitis. Aim: To investigate the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis. Method: Interleukin 10-deficient (IL10(-/-)) mice and wild-type mice were kept in ultra-barrier facilities (UBF) or conventional housing, and used for experimental conditions. Dextran sodium sulphate (DSS)-treated mice were used as a model of acute colitis. Mice were treated with ATN-161 or its scrambled peptide ATN-163. Mucosal neoangiogenesis and mean vascular density (MVD) were assessed by CD31 staining. A Disease Activity Index (DAI) was determined, and the severity of colitis was determined by a histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell proliferation by thymidine incorporation. Result: MVD increased in parallel with disease progression in IL10(-/-) mice kept in conventional housing, but not in IL10(-/-) mice kept in UBF. Angiogenesis also occurred in DSS-treated animals. IL10(-/-) mice with established disease treated with ATN-161, but not with ATN-163, showed a significant and progressive decrease in DAI. The histological colitis score was significantly lower in ATN-161-treated mice than in scrambled peptide-treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN-161-treated mice than in ATN-163-treated mice. No therapeutic effects were observed in the DSS model of colitis. ATN-161 showed no direct immunomodulatory activity in vitro. Conclusion: Active angiogenesis occurs in the gut of IL10(-/-) and DSS-treated colitic mice and parallels disease progression. ATN- 161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in IL10(-/-) mice but not in the DDS model of inflammatory bowel disease (IBD). The results provide the rational basis for considering anti- angiogenic strategies in the treatment of IBD in humans.