A case series of thyroid fine needle aspiration biopsies diagnosed as follicular neoplasm with oncocytic features.

Oncocytic lesions of the thyroid are a heterogeneous group encompassing nonneoplastic and neoplastic entities ranging from benign to malignant and have traditionally been classified as separate entities in thyroid pathology. To illustrate the diversity of these thyroid lesions, we describe three cases of fine needle aspiration biopsies (FNAB) diagnosed as Bethesda Category IV: Follicular neoplasm, oncocytic type, under the 2017 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), with ThyroSeq v3 molecular testing and subsequent surgical excision.

The Effect of Simulated Patient Death on Learner's Stress and Knowledge Retention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Making the simulated patient die is one of the controversial decisions in healthcare simulation. Some experts believe that we should never make the manikin die as they believe the facilitator is deceiving the learners, whereas other groups of experts believe that there are advantages in making the simulated patient die as it provides a valuable learning experience to the learners, and it is as close to reality as possible. Hence, we undertook this review to know whether simulated patient mortality benefits the learners. A systematic literature search was performed in Embase, Scopus, PubMed Central, CENTRAL, MEDLINE, and Google Scholar. Randomized controlled trials assessing the learner's stress and knowledge retention when the simulated patient dies were eligible for inclusion. Comparative intervention effect estimates obtained from meta-analyses were represented as pooled standardized mean difference (SMD) with a 95% CI. Six studies with 384 participants (learners) were eligible for the analysis. All the studies had some concerns when the risk of bias was assessed. In the simulated patient mortality group, the learners experienced higher stress as assessed compared to the group where the simulated patient survives. The two groups' pooled mean difference for anxiety and stress levels was 0.63 (0.17-1.09). Three out of five studies showed improved knowledge retention in the simulated mortality group, one showed no difference, and one showed decreased knowledge retention in the simulated mortality group. The stress response of learners when exposed to simulated mortality during a simulation session is higher than the simulated survival group. However, this increased stress response is processed by the students differently. Some students will thrive when increased stress is presented to them, while some students perceive it negatively. Thus, this increased stress response can lead to knowledge retention if the timing of the stress response happens mainly during debriefing for select students. The role of the facilitator is also important as skilled debriefers will be able to use this increased stress to their advantage to increase knowledge retention. Thus, simulated mortality can be used as an effective stressor for increasing knowledge retention during the debriefing phase for select students by a skilled debriefer. This study would aid the simulation policymakers, simulation faculties, and simulation researchers in the impact of simulated patient death and learners' stress response. If the simulation scenario is designed well with robust pre-briefing, this increased stress response can enhance learning and knowledge retention during debriefing.

Lymphoid cell rich fine-needle aspirations of the salivary gland: What is the risk of malignancy?

Objectives: Lymphoid cell rich fine-needle aspirations (FNAs) of the salivary glands pose a diagnostic dilemma, with a wide range of differential diagnoses that include several benign and malignant entities. There is limited literature regarding the entities that are commonly encountered in this situation. Our goal was to characterize the surgical outcome in these cases and to evaluate the risk of malignancy. Material and Methods: This is a retrospective study at a tertiary care institution. Our database was queried over a 10-year period. FNAs yielding a prominent population of well-visualized lymphoid cells were included in the study. Only cases with surgical follow-up were evaluated. FNAs with epithelial cells, diagnostic features of any entity (such as granulomas or chondromyxoid stroma), history of metastatic malignancy, or scant cellularity were excluded from the study. Lymphoid cells were classified as atypical according to morphologic findings (monomorphism, irregular nuclear contours, and abnormal chromatin patterns). Statistical analysis was performed. Results: Of the 224 lymphoid cell rich FNAs identified, 29 (28%) had surgical follow-up in our data records. Twenty-two were from the parotid and seven from the submandibular gland. Ten cases (35%) were non-neoplastic (benign lymphoepithelial cyst [n = 4], reactive lymph node [n = 5] and chronic sialadenitis [n = 1]). Benign epithelial neoplasms including pleomorphic adenoma (n = 2) and Warthin's tumor (n = 1) were identified in 10% of the cases. One case with non-atypical lymphocytes proved to be a mucoepidermoid carcinoma (n = 1). Lymphomas were detected in 52% (n = 15). Of note, none of these patients had a history of lymphoid malignancy. 8/15 were low-grade and 7/15 were high-grade lymphoma. Most of these cases (11/15) had atypical lymphocytes on FNA. Ancillary studies were available in a few cases and supportive of the diagnosis of lymphoma, including cell block and immunohistochemistry (n = 7, 47%), flow cytometry (n = 3, 27%), and clonality polymerase chain reaction (PCR) (n = 1; 7%). Most of these were performed in cases with atypical lymphocytes. In cases with non-atypical lymphocytes, five cases were malignant on surgical excision (5/17). Morphology on FNA had a specificity of 92% for malignancy and sensitivity of 69%. The positive predictive value on FNA of atypical lymphocytes for malignancy was 92%. Conclusion: Lymphoid cell rich FNAs carry a 52% incidence rate lymphoma in our small study population. Specificity of FNA for malignancy is high (92%) and lymphocyte atypia is a strong predictor of malignancy. Ancillary studies may be of added value in FNAs with non-atypical lymphoid cells. FNA has a valuable role in triaging lymphoid lesions of the salivary glands.

The Emergency Medicine Education and Research by Global Experts (EMERGE) Network: Challenges and Lessons Learned.

INTRODUCTION: The Emergency Medicine Education and Research by Global Experts (EMERGE) network was formed to generate and translate evidence to improve global emergency care. We share the challenges faced and lessons learned in establishing a global research network. METHODS: We describe the challenges encountered when EMERGE proposed the development of a global emergency department (ED) visit registry. The proposed registry was to be a six-month, retrospective, deidentified, minimal dataset of routinely collected variables, such as patient demographics, diagnosis, and disposition. RESULTS: Obtaining reliable, accurate, and pertinent data from participating EDs is challenging in a global context. Barriers experienced ranged from variable taxonomies, need for language translation, varying site processes for curation and transfer of deidentified data, navigating institution- and country-specific data protection regulations, and substantial variation in each participating institution's research infrastructure including training in research-related activities. We have overcome many of these challenges by creating detailed data-sharing agreements with bilateral regulatory oversight agreements between EMERGE and participating EDs, developing relationships with and training health informaticians at each site to ensure secure transfer of deidentified data, and formalizing an electronic transfer process ensuring data privacy. CONCLUSION: We believe that networks like EMERGE are integral to providing the necessary platforms for education, training, and research collaborations for emergency care. We identified substantial challenges in data sharing and variation in local sites' research infrastructure and propose potential approaches to address these challenges.

NOR-1 (NR4A3) immunostaining on cytologic preparations for the preoperative diagnosis of acinic cell carcinoma of the salivary gland.

INTRODUCTION: Acinic cell carcinoma of the salivary gland (ACC-SG) is characterized by recurrent rearrangements in the nuclear receptor subfamily 4 group A member 3 (NR4A3). Immunostaining using an antibody targeting this rearrangement, neuron-derived orphan receptor 1 (NOR-1), has been recently studied on surgical specimens and cell block material of fine-needle aspirates for the diagnosis of ACC-SG. Our goal was to evaluate whether NOR-1 immunostaining could reliably be performed on destained cytologic preparations. MATERIALS AND METHODS: This was a retrospective multi-institutional study. Immunostaining with the NOR-1 antibody (sc-393902 [H-7], Santa Cruz Biotechnology Inc.) was performed at a titer of 1:30 on destained cytologic preparations. ACC-SG cases (n = 17) were represented by twelve cases with alcohol-fixed preparations (n = 12), including direct smears and SurePath preparations, as well as 5 cases with air-dried preparations (n = 5). These were compared to 27 mimicker lesions (n = 27): normal acini (4), chronic sialadenitis (3), oncocytoma (2), pleomorphic adenoma (6), Warthin tumor (8), mucoepidermoid carcinoma (1), secretory carcinoma (2), and salivary duct carcinoma (1). RESULTS: The positivity of NOR-1 in ACC-SG cases was 100% on destained alcohol-fixed preparations (12/12) and 60% on air-dried preparations (3/5). All 27 mimicker lesions were negative for NOR-1 (0/27). Evaluation of 2 ACC-SG cases with both types of cytologic preparations showed that NOR-1 was positive on the alcohol-fixed slides but negative on the air-dried slides. CONCLUSIONS: NOR-1 immunostaining can reliably be performed on alcohol-fixed direct smears and liquid-based preparations for the diagnosis of ACC-SG. Air-dried preparations show a lower positivity rate and may be less suitable for diagnostic immunostaining.

Case Report of CCDC149-ALK Fusion: A Novel Genetic Alteration and a Clinically Relevant Target in Metastatic Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, usually with an indolent course. ALK fusions are rare in PTC but may give rise to a more aggressive behavior. We report a novel ALK fusion, CCDC149-ALK, not previously described in PTC, detected by next-generation sequencing in a 30-year-old woman with progressive widely metastatic radioiodine-refractory (RAIR) disease to lung, muscle, and brain. The patient was started on alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor. Within eight weeks, her palpable disease had completely regressed, and the serum thyroglobulin decreased dramatically. Restaging imaging demonstrated an objective partial response. Our case highlights the role of ALK fusions in thyroid cancer and highlights its clinical significance in PTC. We recommend deep mutational sequencing in BRAFV600E-negative RAIR PTC to identify targetable genetic alterations, including gene fusions, that may result in dramatic therapeutic benefits.

Survival Impact of Aggressive Treatment and PD-L1 Expression in Oligometastatic NSCLC.

BACKGROUND: Studies have shown that aggressive treatment of non-small cell lung cancer (NSCLC) with oligometastatic disease improves the overall survival (OS) compared to a palliative approach and some immunotherapy checkpoint inhibitors, such as anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death protein 1 (PD-1), and T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitors are now part of the standard of care for advanced NSCLC. However, the prognostic impact of PD-L1 expression in the oligometastatic setting remains unknown. METHODS: Patients with oligometastatic NSCLC were identified from the patient database of the Centre hospitalier de l'Université de Montréal (CHUM). "Oligometastatic disease" definition chosen is one synchronous metastasis based on the M1b staging of the eight IASLC (The International Association for the Study of Lung Cancer) Classification (within sixth months of diagnosis) or up to three cerebral metastasis based on the methodology of the previous major phase II randomized study of Gomez et al. We compared the OS between patients receiving aggressive treatment at both metastatic and primary sites (Group A) and patients receiving non-aggressive treatment (Group B). Subgroup analysis was performed using tumor PD-L1 expression. RESULTS: Among 643 metastatic NSCLC patients, we identified 67 patients with oligometastasis (10%). Median follow-up was 13.3 months. Twenty-nine patients (43%) received radical treatment at metastatic and primary sites (Group A), and 38 patients (57%) received non-aggressive treatment (Group B). The median OS (mOS) of Group A was significantly longer than for Group B (26 months vs. 5 months, p = 0.0001). Median progression-free survival (mPFS) of Group A was superior than Group B (17.5 months vs. 3.4 months, p = 0.0001). This difference was still significant when controlled for primary tumor staging: stage I (p = 0.316), stage II (p = 0.024), and stage III (p = 0.001). In the cohort of patients who were not treated with PD-L1 inhibitors, PD-L1 expression negatively correlated with mOS. CONCLUSIONS: Aggressive treatments of oligometastatic NSCLC significantly improve mOS and mPFS compared to a more palliative approach. PD-L1 expression is a negative prognostic factor which suggests a possible role for immunotherapy in this setting.

Sebaceous Epithelial-Myoepithelial Carcinoma With Aggressive Behavior and Evidence of Preexisting Pleomorphic Adenoma.

Epithelial-myoepithelial carcinoma (EMCA) is a rare low-grade carcinoma of the salivary glands with multiple morphological variants. One such variant, sebaceous EMCA (SEMCA), has been reported in the literature. Distinguishing it from other tumors such as sebaceous carcinoma is crucial, as SEMCA typically behaves more indolently. We present a case of a SEMCA in the right parotid of a 71-year-old man that shows features of aggressive behavior such as facial nerve invasion and extraparenchymal extension. Also, we report evidence of preexisting pleomorphic adenoma within this tumor.

The 2019-2020 Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Pandemic: A Joint American College of Academic International Medicine-World Academic Council of Emergency Medicine Multidisciplinary COVID-19 Working Group Consensus Paper.

What started as a cluster of patients with a mysterious respiratory illness in Wuhan, China, in December 2019, was later determined to be coronavirus disease 2019 (COVID-19). The pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel Betacoronavirus, was subsequently isolated as the causative agent. SARS-CoV-2 is transmitted by respiratory droplets and fomites and presents clinically with fever, fatigue, myalgias, conjunctivitis, anosmia, dysgeusia, sore throat, nasal congestion, cough, dyspnea, nausea, vomiting, and/or diarrhea. In most critical cases, symptoms can escalate into acute respiratory distress syndrome accompanied by a runaway inflammatory cytokine response and multiorgan failure. As of this article's publication date, COVID-19 has spread to approximately 200 countries and territories, with over 4.3 million infections and more than 290,000 deaths as it has escalated into a global pandemic. Public health concerns mount as the situation evolves with an increasing number of infection hotspots around the globe. New information about the virus is emerging just as rapidly. This has led to the prompt development of clinical patient risk stratification tools to aid in determining the need for testing, isolation, monitoring, ventilator support, and disposition. COVID-19 spread is rapid, including imported cases in travelers, cases among close contacts of known infected individuals, and community-acquired cases without a readily identifiable source of infection. Critical shortages of personal protective equipment and ventilators are compounding the stress on overburdened healthcare systems. The continued challenges of social distancing, containment, isolation, and surge capacity in already stressed hospitals, clinics, and emergency departments have led to a swell in technologically-assisted care delivery strategies, such as telemedicine and web-based triage. As the race to develop an effective vaccine intensifies, several clinical trials of antivirals and immune modulators are underway, though no reliable COVID-19-specific therapeutics (inclusive of some potentially effective single and multi-drug regimens) have been identified as of yet. With many nations and regions declaring a state of emergency, unprecedented quarantine, social distancing, and border closing efforts are underway. Implementation of social and physical isolation measures has caused sudden and profound economic hardship, with marked decreases in global trade and local small business activity alike, and full ramifications likely yet to be felt. Current state-of-science, mitigation strategies, possible therapies, ethical considerations for healthcare workers and policymakers, as well as lessons learned for this evolving global threat and the eventual return to a "new normal" are discussed in this article.

Lymphocytic Vasculitis Associated With Mild Rejection in a Vascularized Composite Allograft Recipient: A Clinicopathological Study.

BACKGROUND: Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis. METHODS: We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada's first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters. RESULTS: Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding. CONCLUSIONS: Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.

Pleomorphic Undifferentiated Uterine Sarcoma in a Young Patient Presenting With Elevated Beta-hCG and Rare Variants of Benign Leiomyoma: A Case Report and Review of the Literature.

Leiomyosarcoma (LMS) is a malignant mesenchymal neoplasm showing smooth muscle differentiation. Uterine LMS is more frequent that nonuterine LMS, and represents 1% of all malignant neoplasms of the uterus. Pleomorphic undifferentiated uterine sarcoma is a rare entity, and is defined by high-grade sarcoma histology with loss of muscular markers. Several cases of pleomorphic undifferentiated uterine sarcoma have been reported in the literature, with worse clinical outcome when compared with conventional LMS. Here we report the first case of a pleomorphic undifferentiated uterine sarcoma in association with LMS in a 33 yr old woman. The patient presented clinically with recurrent vaginal bleeding and suspicion of a trophoblastic tumor. Ancillary testing revealed moderately elevated beta-hCG (49.7 U/L) and no metastatic disease on imaging. Gross examination of the hysterectomy specimen revealed a large heterogenous necrotic uterine mass infiltrating <50% of the myometrium. Microscopic evaluation showed pleomorphic undifferentiated uterine sarcoma adjacent to a nodule of leiomyoma with bizarre nuclei, with loss of myogenic markers in the high grade component. Other findings included a foci of conventional LMS, and diffuse uterine leiomyomatosis. Although beta-hCG dropped to normal levels during follow-up, the patient developed metastatic lesions to the lung at 6 mo postop. Initial elevation of beta-hCG may have correlated with the aggressive histology of the tumor, as reported by some groups previously. Recognition of pleomorphic undifferentiated uterine sarcoma and its distinction from conventional LMS is essential for patient prognosis and management.

Pre-radiotherapy PSA progression is a negative prognostic factor in prostate cancer patients using 5­alpha-reductase inhibitors.

OBJECTIVE: To investigate the impact of 5­alpha-reductase inhibitor (5-ARI) use on radiotherapy outcomes for localized prostate cancer. PATIENTS AND METHODS: We included 203 patients on a 5-ARI from our institutional database comprising over 2500 patients who had been treated with either external beam radiotherapy (EBRT) or brachytherapy for localized prostate cancer. Patients received a 5-ARI for urinary symptoms or active surveillance. Cancer progressions at the time of definitive treatment were analyzed according to the following criteria: (a) progression of Gleason score or increase in cancer volume on biopsy, (b) first biopsy positive for cancer after being treated for urinary symptoms with a 5-ARI, and (c) prostate-specific antigen (PSA) progression with or without a previous cancer diagnosis. Biochemical failure (BF) was defined by the Phoenix definition. Log-rank test was used for survival analysis. RESULTS: At a median follow-up of 38.2 months (standard deviation 22.2 months), 10 (4.9%) patients experienced BF. Concerning prostate cancer progression criteria, 52% of men demonstrated none, 37% showed only one criterion, and 11% showed two. Using univariate analysis, PSA progression (p = 0.004) and appearance of a positive biopsy (p < 0.001) were significant predictive factors for BF, while Gleason progression (p = 0.3) was not. In multivariate analysis adjusted for cancer aggressiveness, rising PSA (hazard ratio, HR, 5.7; 95% confidence interval, CI, 1.1-28.8; p = 0.04) and the number of cancer progression factors (HR 2.9, 95% CI 1.2-7.0, p = 0.02) remained adverse risk factors. CONCLUSION: PSA progression experienced during 5­ARI treatment before radiotherapy is predictive of worse biochemical outcome. Such details should be considered when counseling men prior to radiation therapy.

Analysis of the Cancer of the Prostate Risk Assessment to predict for biochemical failure after external beam radiotherapy or prostate seed brachytherapy.

OBJECTIVE: To analyze the value of the Cancer of the Prostate Risk Assessment (CAPRA) score to predict biochemical failure (bF) in patients with D'Amico low- or intermediate-risk prostate cancer treated with different radiation techniques. METHODS: We analyzed 744 patients treated with either external beam radiotherapy (52.7%) or permanent-seed prostate brachytherapy (47.3%) without any androgen deprivation. External beam radiotherapy dose levels were extreme hypofractionation (45 Gy in 9 fractions) in 10%, 76-79.2 Gy (in 1.8-2.0 Gy per fraction) in 32.7%, and 70.2-74 Gy in 10%. All patients had a minimum of 36-month follow-up. Cox regression analysis was used for univariate and multivariate analysis to predict for bF, as per the Phoenix definition (prostate-specific antigen-nadir + 2 ng/mL). RESULTS: Median follow-up for patients without bF was 56 months (range, 36-114 months). In univariate analysis, CAPRA score as a continuous variable was predictive of bF (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.23-1.79; P <.001), and in multivariate analysis adjusted for treatment type, the HR was 1.39 (95% CI, 1.14-1.71; P = .002). D'Amico intermediate-risk vs low-risk patients had an HR for bF of 1.93 (95% CI, 1.07-3.47; P = .029) in univariate analysis, but the difference was not statistically significant anymore after adjustment for treatment type, (P = .206). The area under the curve of the CAPRA score as a continuous variable at 3 and 5 years was 0.66 and 0.62, respectively (P = .005 for both years). CONCLUSION: The CAPRA score is predictive of bF. Each 1-point rise increased the risk of bF by 39%, which is comparable to surgical series.

The Cancer of the Prostate Risk Assessment (CAPRA) score predicts biochemical recurrence in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) dose escalation or low-dose rate (LDR) brachytherapy.

OBJECTIVE: To study the prognostic value of the University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score to predict biochemical failure (bF) after various doses of external beam radiotherapy (EBRT) and/or permanent seed low-dose rate (LDR) prostate brachytherapy (PB). PATIENTS AND METHODS: We retrospectively analysed 345 patients with intermediate-risk prostate cancer, with PSA levels of 10-20 ng/mL and/or Gleason 7 including 244 EBRT patients (70.2-79.2 Gy) and 101 patients treated with LDR PB. The minimum follow-up was 3 years. No patient received primary androgen-deprivation therapy. bF was defined according to the Phoenix definition. Cox regression analysis was used to estimate the differences between CAPRA groups. RESULTS: The overall bF rate was 13% (45/345). The CAPRA score, as a continuous variable, was statistically significant in multivariate analysis for predicting bF (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.10-1.72, P = 0.006). There was a trend for a lower bF rate in patients treated with LDR PB when compared with those treated by EBRT ≤ 74 Gy (HR 0.234, 95% CI 0.05-1.03, P = 0.055) in multivariate analysis. In the subgroup of patients with a CAPRA score of 3-5, CAPRA remained predictive of bF as a continuous variable (HR 1.51, 95% CI 1.01-2.27, P = 0.047) in multivariate analysis. CONCLUSION: The CAPRA score is useful for predicting biochemical recurrence in patients treated for intermediate-risk prostate cancer with EBRT or LDR PB. It could help in treatment decisions.