The first Canadian experience with the Afirma® gene expression classifier test

Abstract Background Thyroid nodules are common and often benign, although prove to be malignant upon surgical pathology in 5–15% of cases. When assessed with ultrasound-guided fine-needle aspiration (USFNA), 15–30% of the nodules yield an indeterminate result. The Afirma® gene expression classifier (AGEC) was developed to improve management of indeterminate thyroid nodules (ITNs) by classifying them as “benign” or “suspicious.” Objectives were (1) to assess the performance of the AGEC in two Canadian academic medical centres (2), to search for inter-institutional variation and (3) to compare AGEC performance in Canadian versus American institutions. Methods We undertook a retrospective cohort study of patients with indeterminate cytopathology (Bethesda Class III or IV) as per USFNA who underwent AGEC testing. We reviewed patient demographics, cytopathological results, AGEC data and, if the patient underwent surgery, results from their final pathology. Results In total, we included 172 patients with Bethesda Class III or IV thyroid nodules underwent AGEC testing, 109 in Montreal, Quebec and 63 in St. John’s, Newfoundland, in this study. Among the nodules sent for testing, 55% (60/109) in Montreal and 46% (29/63) in St. John’s returned as “benign.” None of these patients underwent surgery. On the other hand, 45% (49/109) nodules in Montreal and 54% (34/63) in St. John’s were found to be “suspicious,” for a total of 83 specimens. Seventy seven of these patients underwent surgery. Both in Montreal and St. John’s, the final pathology yielded malignant thyroid disease in approximately 50% of the specimens categorized as “suspicious.” Since 2013, no patient diagnosed with a benign nodule as per AGEC testing was found to harbor a malignant thyroid nodule on follow-up. Conclusions Molecular analysis is increasingly used in the management of indeterminate thyroid nodules. This study highlights the experience of two Canadian centres with AGEC testing. We found inter-institutional variability in the rate of nodules returning as “benign,” however we found similar rates of confirmed malignancy in nodules returning as “suspicious.” According the literature, results for AGEC testing in two Canadian institutions align with results reported in American centres

Corticosteroid therapy for sepsis: a clinical practice guideline

Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients’ values and preferences may guide this decision-making process. This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: • ADRENAL (3658 patients who had septic shock) found no statistically significant difference in 90 day mortality between the hydrocortisone and placebo groups.1 • APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality.2 The trials are incorporated into a linked systematic review comparing corticosteroids with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. C urrently most guidelines advise against WHAT YOU NEED TO KNOW • Sepsis is a syndrome of life threatening infection with organ dysfunction, and most guidelines do not advise use of corticosteroids to treat it in the absence of refractory shock • Two new trials of corticosteroid treatment for sepsis came to differing conclusions • Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular weakness by a small amount, but the evidence is not definitive • This guideline makes a weak recommendation for corticosteroids in patients with sepsis; both steroids and no steroids are reasonable management options • Fully informed patients who value avoiding death over quality of life and function would likely choose corticosteroids No commercial reuse: See rights and reprints http://www.bmj.com/permissions giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction. The box below shows publications linked in this Rapid Recommendation package. The main infographic provides an overview of the absolute benefits and harms. The table at the end of the article shows any evidence that has emerged since the publication of this guideline.This guideline was not funded

Classification of agents using Syrian hamster embryo (SHE) cell transformation assay (CTA) with ATR-FTIR spectroscopy and multivariate analysis

The Syrian hamster embryo (SHE) cell transformation assay (pH 6.7) has a reported sensitivity of 87% and specificity of 83%, and an overall concordance of 85% with in vivo rodent bioassay data. To date, the SHE assay is the only in vitro assay that exhibits multistage carcinogenicity. The assay uses morphological transformation, the first stage towards neoplasm, as an endpoint to predict the carcinogenic potential of a test agent. However, scoring of morphologically transformed SHE cells is subjective. We treated SHE cells grown on low-E reflective slides with 2,6-diaminotoluene, N-nitroso-N-ethylnitroguanidine, N-nitroso-N-methylurea, N-nitroso-N-ethylurea, EDTA, dimethyl sulphoxide (DMSO; vehicle control), methyl methanesulfonate, benzoepyrene, mitomycin C, ethyl methanesulfonate, ampicillin or five different concentrations of benzoapyrene. Macroscopically visible SHE colonies were located on the slides and interrogated using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy acquiring five spectra per colony. The acquired IR data were analysed using Fisher?s linear discriminant analysis (LDA) followed by principal component analysis (PCA)-LDA cluster vectors to extract major and minor discriminating wavenumbers for each treatment class. Each test agent vs. DMSO and treatment-induced transformed cells vs. corresponding non-transformed were classified by a unique combination of major and minor discriminating wavenumbers. Alterations associated with Amide I, Amide II, lipids and nucleic acids appear to be important in segregation of classes. Our findings suggest that a biophysical approach of ATR-FTIR spectroscopy with multivariate analysis could facilitate a more objective interrogation of SHE cells towards scoring for transformation and ultimately employing the assay for risk assessment of test agents

Socially transferred materials: why and how to study them

When biological material is transferred from one individual's body to another, as in ejaculate, eggs, and milk, secondary donor-produced molecules are often transferred along with the main cargo, and influence the physiology and fitness of the receiver. Both social and solitary animals exhibit such social transfers at certain life stages. The secondary, bioactive, and transfer-supporting components in socially transferred materials have evolved convergently to the point where they are used in applications across taxa and type of transfer. The composition of these materials is typically highly dynamic and context dependent, and their components drive the physiological and behavioral evolution of many taxa. Our establishment of the concept of socially transferred materials unifies this multidisciplinary topic and will benefit both theory and applications

Corticosteroid therapy for sepsis: A clinical practice guideline

Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients’ values and preferences may guide this decision-making process. This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: • ADRENAL (3658 patients who had septic shock) found no statistically significant difference in 90 day mortality between the hydrocortisone and placebo groups.1 • APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality.2 The trials are incorporated into a linked systematic review comparing corticosteroids with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. C urrently most guidelines advise against WHAT YOU NEED TO KNOW • Sepsis is a syndrome of life threatening infection with organ dysfunction, and most guidelines do not advise use of corticosteroids to treat it in the absence of refractory shock • Two new trials of corticosteroid treatment for sepsis came to differing conclusions • Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular weakness by a small amount, but the evidence is not definitive • This guideline makes a weak recommendation for corticosteroids in patients with sepsis; both steroids and no steroids are reasonable management options • Fully informed patients who value avoiding death over quality of life and function would likely choose corticosteroids No commercial reuse: See rights and reprints http://www.bmj.com/permissions giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction. The box below shows publications linked in this Rapid Recommendation package. The main infographic provides an overview of the absolute benefits and harms. The table at the end of the article shows any evidence that has emerged since the publication of this guideline

BRAFV600E Mutation Is Associated with Preferential Sensitivity to Mitogen-Activated Protein Kinase Kinase Inhibition in Thyroid Cancer Cell Lines

Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors