Perceptions of sleep health among African American mothers regarding their preschool-aged children: A qualitative study to decrease sleep health disparities.

OBJECTIVES: African American children are documented as having poor sleep health due to shorter sleep duration, sleep timing, and sleep behaviors compared to White peers, contributing to child health disparities. Identifying cultural-environmental, and societal factors impacting a child's sleep among African American families is essential for developing interventions for this population. This study evaluated holistically why African American children may have poorer sleep health by examining sleep duration, timing, and behaviors. This was assessed by examining sleep-related beliefs, barriers, and facilitators to sleep schedules and routines. We also explored parental ideas for a sleep intervention. METHODS: African American mothers of preschool-aged children (2-5years) were recruited using local partnerships and social media. Individual semistructured interviews were conducted by phone. Interviews were transcribed, coded, and analyzed thematically using grounded-theory. RESULTS: Eighteen African American mothers completed the study. Five themes related to sleep emerged: The importance of adequate nighttime sleep, the influence of family and friends on parental sleep practices, the relationship between environmental and home dynamics on child sleep duration, the impact of acute and chronic societal-level stressors on family sleep health, and considerations for culturally tailored interventions to improve child sleep health. CONCLUSIONS: Good sleep health was important among African American mothers. Cultural-environmental and societal factors significantly impact children's sleep health. Clinicians and researchers should be aware of financial resources and home dynamics leading to challenges with adequate sleep health when developing or adapting sleep interventions. Identifying cultural-environmental, and societal factors must be considered for targeted efforts to improve sleep health in African American children.

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior.

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

Cytologic features of differentiated high-grade thyroid carcinoma: A multi-institutional study of 40 cases.

BACKGROUND: Differentiated high-grade thyroid carcinoma (DHGTC) is recently recognized by the World Health Organization (WHO) as a subgroup of thyroid carcinomas with high-grade features while retaining the architectural and/or cytologic features of well-differentiated follicular-cell-derived tumors. The cytomorphology of DHGTC is not well documented despite potential implications for patient triage and management. METHODS: The pathology archives of six institutions were searched for cases diagnosed on resection as "high-grade thyroid carcinoma" using WHO criteria. The fine-needle aspiration (FNA) cohort represents a 10-year period (2013-2023); all were reviewed to confirm DHGTC classification. The corresponding FNAs were assessed for 32 cytomorphologic features. RESULTS: Forty cases of DHGTC with prior FNA were identified. The mean patient age was 64.2 years. The average lesion size was 4.9 cm, and the majority demonstrated a TI-RADS score of 4 or 5 (95.2%). Three main high-grade subsets of DHGTC based on corresponding histology included papillary thyroid carcinoma (65%), follicular carcinoma (22.5%), and oncocytic carcinoma (12.5%). Over 97% of FNA cases were classified as Bethesda category IV or above. Approximately 25% of DHGTC showed cytologic features that included marked cytologic atypia, increased anisonucleosis, large oval nuclei, mitotic activity, or necrosis (p < .05); 68% of DHGTC cases were associated with high-risk molecular alterations. TERT mutations occurred in 41%, of which 89% of these were associated with a second mutation, usually RAS or BRAF p.V600E. CONCLUSIONS: Cytology has a low sensitivity for DHGTC, although a subset of DHGTCs have cytologic features raising the possibility of a high-grade thyroid carcinoma. Other findings include high-risk molecular changes and clinicopathologic features such as older patient age and larger lesion size.

Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

Utility of the Milan System for Reporting Salivary Gland Cytopathology in fine needle aspiration cytology of minor salivary gland lesions.

INTRODUCTION: Salivary gland lesions are routinely evaluated by fine-needle aspiration cytology (FNAC) preoperatively. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has standardized salivary gland FNAC reporting. Its application in major salivary glands (MSGs) has been well-established; however, its utility in minor salivary glands (MiSGs) is not well-known. We studied the utility of MSRSGC in MiSG FNAC. MATERIALS AND METHODS: A retrospective search of MiSG FNACs from 2 academic institutions (2006-2023) was performed. FNACs were classified using the MSRSGC. Histologic data were reviewed and recorded. The risk of malignancy (ROM), risk of neoplasia (RON), diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: The series included 43 MiSG FNAC (24 males and 18 females), with a mean age of 55 years (range 10-92). Aspirated sites included the following: palate, buccal space, floor of mouth, lip, tongue, and maxillary sinus. FNACs were classified as nondiagnostic (1), nonneoplastic (3), atypia of undetermined significance (6), benign neoplasm (9), salivary gland neoplasm of uncertain malignant potential (15), suspicious for malignancy, (2) and malignant (7). The risk of neoplasia and risk of malignancy were 87% and 39%. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 100%, respectively. CONCLUSIONS: Milan System for Reporting Salivary Gland Cytopathology offers valuable information for stratifying MiSG lesions. However, the distribution and the range of diagnostic entities encountered differ somewhat from those in MSGs. For instance, mucinous cyst contents may warrant unique consideration in MiSG; while an atypical classification is recommended in MSGs, the high prevalence of mucoceles in MiSG may tilt this group toward benignity.

Disparities in Smoking and Heavy Drinking Behaviors by Disability Status and Age of Disability Onset: Secondary Analysis of National Health Interview Survey Data.

OBJECTIVES: People with childhood-onset disabilities are living into adulthood, and the prevalence of smoking and illicit drug use among adults with disabilities is high. We evaluated the relationship between disability status and age of disability onset, current cigarette smoking status, and heavy alcohol drinking. METHODS: We conducted a secondary data analysis of the National Health Interview Survey (NHIS), a US survey on illness and disability. Among 2020 NHIS participants aged 22-80 years (n = 28 225), we compared self-reported prevalence of current cigarette smoking and heavy alcohol drinking among those with and without disabilities and among those with childhood- versus adult-onset disabilities. We used adjusted logistic regression analysis to calculate the adjusted odds ratios (AORs) of current smoking and heavy alcohol drinking based on disability status and age of disability onset. RESULTS: Compared with adults without disabilities, adults with disabilities were significantly more likely to report current smoking (23.5% vs 11.2%; P < .001) and significantly less likely to report heavy alcohol drinking (5.3% vs 7.4%; P = .001). The prevalence of these behaviors did not vary significantly by age of disability onset. In adjusted logistic regression models, adults with disabilities had significantly higher odds of current smoking (AOR = 1.76; 95% CI, 1.53-2.03) and similar odds of heavy alcohol drinking (AOR = 0.82; 95% CI, 0.65-1.04) compared with adults without disabilities. The odds of these health behaviors did not vary significantly by age of disability onset. CONCLUSIONS: Adults with disabilities overall may be at high risk for these unhealthy behaviors, particularly smoking, regardless of age of disability onset. Routine screening and cessation counseling related to smoking and unhealthy alcohol use are important for all people with disabilities.

Abnormality of Early White Matter Development in Tuberous Sclerosis Complex and Autism Spectrum Disorder: Longitudinal Analysis of Diffusion Tensor Imaging Measures.

Background: Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Methods: Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months. Positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months was used. Linear mixed effects models were fine-tuned separately for fractional anisotropy values (using fractional anisotropy corpus callosum as test outcome) and mean diffusivity values (using mean diffusivity right posterior limb internal capsule as test outcome). Fixed effects included participant age, within-participant longitudinal age, and autism spectrum disorder diagnosis. Results: Analysis included data from n = 78. After selecting separate optimal models for fractional anisotropy and mean diffusivity values, we applied these models to fractional anisotropy and mean diffusivity of all 27 white matter tracts. Fractional anisotropy corpus callosum was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = 0.0093, P = .0612), and mean diffusivity right inferior cerebellar peduncle was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = -0.00002071, P = .0445), though these findings were not statistically significant after multiple comparisons correction. Conclusion: These optimized linear mixed effects models possibly implicate corpus callosum and cerebellar pathology in development of autism spectrum disorder in tuberous sclerosis complex, but future studies are needed to replicate these findings and explore contributors of heterogeneity in these models.

Forward and Back is Not Enough: Applying Best Practices for Translation of Pediatric Sleep Questionnaires.

Cultural differences in the experience of sleep warrant consideration in the measurement of sleep across populations. This requires careful attention to both language and culture when translating survey measures. While forward and back translation is the most commonly used approach, it has numerous limitations if used as an isolated method. Best practice guidelines recommend a multi-step team-based approach for translating questionnaires. We present our recent experience applying best practices in a study with both Spanish and English-speaking Mexican American mothers of toddlers. This work is part of a larger project that will measure parental sleep-related beliefs and parenting practices in Mexican American parents of toddlers. We utilized a team-based approach to translation and cultural adaptation, assembling a diverse, bilingual, and bicultural team. The translation process started with items and measures that we had selected, revised as needed, or created. New items were based on constructs identified in semi-structured interviews and focus groups used to explore parental sleep-related beliefs and parenting practices in the target population. Following this, our translation process included forward and back translation, harmonization and decentering, cognitive interviewing, debriefing, adjudication, and proofreading. We outline details of our process and the rationale for each step. We also highlight how each step contributes to ensuring culturally appropriate items with conceptual equivalence across languages. To ensure inclusivity and scientific rigor within the field of sleep research, investigators must utilize best practices for translations and cultural adaptations, building on the foundation of cultural constructs often identified in qualitative work.

A Rare Case of Complete Inguinoscrotal Bladder Herniation With Ureteric Involvement: Assessing Diagnostic Challenges and Complex Surgical Management.

Inguinoscrotal hernias involving the urinary bladder are exceedingly rare, constituting a small subset of inguinal hernias. We present a case of a 47-year-old male with long-standing scrotal enlargement and obstructive uropathy due to complete herniation of the bladder with ureteric involvement. Diagnostic imaging confirmed the condition. Following an open laparotomy, the bladder was reduced, and a modified Bassini technique with orchiopexy was used for repair. Recurrence of the inguinoscrotal hernia with evidence of the bladder in the scrotal sac required additional surgery. This case underscores the rarity, diagnostic complexity, and potential complications of inguinoscrotal bladder hernias. Specialized surgical techniques and a multidisciplinary approach are crucial for successful management, especially in cases of complete bladder herniation. Future considerations should include innovative approaches to enhance primary repair outcomes for extensive hernias involving the bladder.

Group concept mapping for health professions education scholarship.

While explicit conceptual models help to inform research, they are left out of much of the health professions education (HPE) literature. One reason may be the limited understanding about how to develop conceptual models with intention and rigor. Group concept mapping (GCM) is a mixed methods conceptualization approach that has been used to develop frameworks for planning and evaluation, but GCM has not been common in HPE. The purpose of this article is to describe GCM in order to make it more accessible for HPE scholars. We recount the origins and evolution of GCM and summarize its core features: GCM can combine multiple stakeholder perspectives in a systematic and inclusive manner to generate explicit conceptual models. Based on the literature and prior experience using GCM, we detail seven steps in GCM: (1) brainstorming ideas to a specific "focus prompt," (2) preparing ideas by removing duplicates and editing for consistency, (3) sorting ideas according to conceptual similarity, (4) generating the point map through quantitative analysis, (5) interpreting cluster map options, (6) summarizing the final concept map, and (7) reporting and using the map. We provide illustrative examples from HPE studies and compare GCM to other conceptualization methods. GCM has great potential to add to the myriad of methodologies open to HPE researchers. Its alignment with principles of diversity and inclusivity, as well as the need to be systematic in applying theoretical and conceptual frameworks to practice, make it a method well suited for the complexities of contemporary HPE scholarship.

Biophysical Modeling of Frontocentral ERP Generation Links Circuit-Level Mechanisms of Action-Stopping to a Behavioral Race Model.

Human frontocentral event-related potentials (FC-ERPs) are ubiquitous neural correlates of cognition and control, but their generating multiscale mechanisms remain mostly unknown. We used the Human Neocortical Neurosolver's biophysical model of a canonical neocortical circuit under exogenous thalamic and cortical drive to simulate the cell and circuit mechanisms underpinning the P2, N2, and P3 features of the FC-ERP observed after Stop-Signals in the Stop-Signal task (SST; N = 234 humans, 137 female). We demonstrate that a sequence of simulated external thalamocortical and corticocortical drives can produce the FC-ERP, similar to what has been shown for primary sensory cortices. We used this model of the FC-ERP to examine likely circuit-mechanisms underlying FC-ERP features that distinguish between successful and failed action-stopping. We also tested their adherence to the predictions of the horse-race model of the SST, with specific hypotheses motivated by theoretical links between the P3 and Stop process. These simulations revealed that a difference in P3 onset between successful and failed Stops is most likely due to a later arrival of thalamocortical drive in failed Stops, rather than, for example, a difference in the effective strength of the input. In contrast, the same model predicted that early thalamocortical drives underpinning the P2 and N2 differed in both strength and timing across stopping accuracy conditions. Overall, this model generates novel testable predictions of the thalamocortical dynamics underlying FC-ERP generation during action-stopping. Moreover, it provides a detailed cellular and circuit-level interpretation that supports links between these macroscale signatures and predictions of the behavioral race model.

Cementoblastoma Mimicking Pathology of Endodontic Origin: A Case Report.

Interdisciplinary care in the management of complex pathology is critical to ensure patients receive predictable, evidence-based treatment. The authors report the unique case of a healthy 38-year-old female patient who presented to a private endodontics practice with a radiopaque lesion associated with the root of tooth No. 20. The patient experienced mild and occasional palpation tenderness associated with the tooth. Extraoral examination and intraoral soft tissues presented without any abnormalities. Intraoral radiographs revealed a radiopacity overlying the apex of tooth No. 20. A cone-beam computed tomography scan of the region revealed a well-delineated bulbous radiopaque lesion attached to the lingual aspect of the apical third of the root of tooth No. 20. The lesion could not be distinguished from the root outline and presented with a radiolucent halo along its periphery. The differential diagnosis at the time consisted of cementoblastoma, condensing osteitis, hypercementosis, and periapical cemento-osseous dysplasia. The patient was referred to an oral and maxillofacial surgeon for evaluation and treatment. Tooth No. 20 was subsequently treated with an excisional biopsy and concurrent extraction of the tooth. Histologic examination of the lesion supported the diagnosis of cementoblastoma.

Blind spots in medical education - International perspectives.

BACKGROUND: All individuals and groups have blind spots that can create problems if unaddressed. The goal of this study was to examine blind spots in medical education from international perspectives. METHODS: From December 2022 to March 2023, we distributed an electronic survey through international networks of medical students, postgraduate trainees, and medical educators. Respondents named blind spots affecting their medical education system and then rated nine blind spot domains from a study of U.S. medical education along five-point Likert-type scales (1 = much less attention needed; 5 = much more attention needed). We tested for differences between blind spot ratings by respondent groups. We also analyzed the blind spots that respondents identified to determine those not previously described and performed content analysis on open-ended responses about blind spot domains. RESULTS: There were 356 respondents from 88 countries, including 127 (44%) educators, 80 (28%) medical students, and 33 (11%) postgraduate trainees. At least 80% of respondents rated each blind spot domain as needing 'more' or 'much more' attention; the highest was 88% for 'Patient perspectives and voices that are not heard, valued, or understood.' In analyses by gender, role in medical education, World Bank country income level, and region, a mean difference of 0.5 was seen in only five of the possible 279 statistical comparisons. Of 885 blind spots documented, new blind spot areas related to issues that crossed national boundaries (e.g. international standards) and the sufficiency of resources to support medical education. Comments about the nine blind spot domains illustrated that cultural, health system, and governmental elements influenced how blind spots are manifested across different settings. DISCUSSION: There may be general agreement throughout the world about blind spots in medical education that deserve more attention. This could establish a basis for coordinated international effort to allocate resources and tailor interventions that advance medical education.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor With Sarcomatous Transformation: Clinicopathologic and Molecular Analysis of 4 Cases.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently described adipocytic tumor predominantly affecting the subcutaneous soft tissues of adults. Previous studies have shown that ASPLT follows a benign clinical course with a 4% to 12% local recurrence rate and no risk of dedifferentiation. Herein, we describe the clinicopathologic and molecular findings of 4 cases of ASPLT showing unequivocal sarcomatous transformation. Three patients were male and one was female, aged 65, 70, 74, and 78 years. Two cases presented as mass-forming lesions, while 1 case was incidentally discovered. The tumors measured 30, 55, 80, and 110 mm and occurred in the chest wall (n = 2) or arm (n = 2); all were subcutaneous. Microscopically, they showed a biphasic appearance comprising a low-grade ASPLT component and a high-grade sarcomatous component. The low-grade components showed features in the spectrum of either atypical pleomorphic lipomatous tumor (n = 2) or atypical spindle cell lipomatous tumor (n = 2). The high-grade components displayed leiomyosarcoma-like (n = 2), pleomorphic liposarcoma-like (n = 1) or undifferentiated sarcoma-like (n = 1) morphology. On immunohistochemistry, tumors were negative for MDM2 and showed loss of RB1 expression. In addition, the leiomyosarcoma-like areas seen in 2 cases were positive for smooth muscle actin and H-caldesmon. Single-nucleotide polymorphism array, performed in 3 cases, showed deletions of TP53, RB1, and flanking genes in both components. In contrast, the sarcomatous components showed more complex genomic profiles with rare segmental gains and recurrent loss of PTEN (n = 3), ATM (n = 2), and CDKN2A/B (n = 2) among other genes. Whole exome sequencing identified a TP53 variant in one case and an ATRX variant in another, each occurring in both tumor components. Limited clinical follow-up showed no recurrence or metastasis after 1 to 13 months (median, 7.5 months) postsurgical excision. Altogether, our data support that ASPLT can rarely develop sarcomatous transformation and offer insights into the molecular mechanisms underlying this event.

Seeing with greater clarity: Stakeholder ratings of blind spots in U.S. medical education.

BACKGROUND: Although medical education is affected by numerous blind spots, there is limited evidence to determine which blind spots to prioritize. METHODS: In summer 2022, we surveyed stakeholders from U.S. medical education who had identified 9 domains and 72 subdomains of blind spots. Respondents used 4-point Likert-type scales to rate the extent and magnitude of problems caused for each domain and subdomain. Respondents also provided comments for which we did content analysis. RESULTS: A total of 23/27 (85%) stakeholders responded. The majority of respondents rated each blind spot domain as moderate-major in both extent and problems they cause. Patient perspectives and voices that are not heard, valued, or understood was the domain with the most stakeholders rating extent (n = 20, 87%) and problems caused (n = 23, 100%) as moderate or major. Admitting and selecting learners likely to practice in settings of highest need was the subdomain with the most stakeholders rating extent (n = 21, 91%) and problems caused (n = 22, 96%) as moderate or major. Respondents' comments suggested blind spots may depend on context and persist because of hierarchies and tradition. DISCUSSION: We found blind spots differed in relative importance. These data may inform further research and direct interventions to improve medical education.

Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex.

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome-wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes.

GLI1-Altered Mesenchymal Tumors.

GLI1-altered mesenchymal tumors comprise an emerging group of neoplasms characterized by fusions or amplifications involving GLI1, a gene that encodes a key regulator of the Hedgehog signaling pathway. In recent years, tumors with GLI1 alterations have been reported across a variety of anatomic sites and a broad age range. Although these tumors can exhibit a wide morphologic spectrum and a variable immunophenotype, they frequently present with monomorphic ovoid cells arranged in distinctive nests with a rich, arborizing vascular network. Recent evidence indicates that they have the potential to metastasize, which suggests that they may be best considered a sarcoma.

Metastatic Neuroendocrine Neoplasms to the Pancreas: Two Unusual Cases and a Review of the Literature.

Neuroendocrine tumor metastases to the pancreas are rare, and they share substantial overlap with the significantly more common primary pancreatic neuroendocrine neoplasms, representing a potential diagnostic pitfall. Elucidating whether a neuroendocrine tumor within the pancreas is a primary neoplasm versus a metastasis has significant prognostic and treatment implications. Correlation with clinical history and imaging as well as incorporating an appropriate immunohistochemical panel are essential to establish the correct diagnosis. Herein, we present 2 rare neuroendocrine tumors that metastasized to the pancreas: a medullary thyroid carcinoma and an atypical carcinoid tumor of lung origin. We also provide a brief review of the literature.

Gene of the month: DDIT3.

DNA damage-inducible transcript 3 (DDIT3) gene, mapped to the human chromosome 12q13.3, encodes a protein that belongs to the CCAAT/enhancer-binding protein family of transcription factors. DDIT3 is involved in the proliferative control that responds to endoplasmic reticulum stress in normal conditions, dimerising other transcription factors with basic leucine zipper (bZIP) structural motifs. DDIT3 plays a significant role during cell differentiation, especially adipogenesis, arresting the maturation of adipoblasts. In disease, FUS/EWSR1::DDIT3 fusion is the pathogenic event that drives the development of myxoid liposarcoma. The amplification of DDIT3 in other adipocytic neoplasms mediates the presence of adipoblast-like elements. Another fusion, GLI1::DDIT3, has rarely been documented in other tumours. This paper reviews the structure and function of DDIT3, its role in disease-particularly cancer-and its use and pitfalls in diagnostic testing, including immunohistochemistry as a tissue-based marker.

GLI1-Altered Mesenchymal Tumors With ACTB or PTCH1 Fusion: A Molecular and Clinicopathologic Analysis.

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.