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INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

Study Design: Systematic review. Objectives: Spinal epidural abscesses (SEAs) are rare, but when missed or when diagnosis is delayed, SEA can lead to permanent neurological impairment or death. Limited information exists on the optimal treatment modalities for SEA, especially in the lumbar spine. We synthesize the current literature to identify the clinical features, diagnosis, management, and outcomes of lumbar SEA. Methods: Queries in 4 databases—EMBASE, MEDLINE, Scopus, and Web of Science—were performed using comprehensive search terms to locate published literature on lumbar SEA. Results: Ten articles reporting results for 600 cases of lumbar SEA were included, published between 2000 and 2017. Negative prognostic factors included diabetes, older age, methicillin-resistant Staphylococcus aureus, immune compromise, and more severe disease at presentation. Early first-line surgically treated patients responded better, specifically in terms of motor recovery, than those undergoing medical management or failing medical treatment, despite generally worse initial presentation. Elevated C-reactive protein, leukocytosis, and positive blood cultures predicted medical management failure. Conclusions: This systematic review provides guidance to neurological and orthopedic spine surgeons seeking the best treatment for lumbar-localized SEA. This study is limited by a dearth of high-quality publications to support evidenced-based management recommendations. Surgical treatment appears to provide better outcomes than medical treatment alone, especially in those who present with a motor deficit. Further investigation is needed to confirm this finding. What is clear is that early recognition and treatment remains crucial to minimizing morbidity and mortality of SEA.

Sepsis in patients with cirrhosis is associated with high mortality. An impaired immune response accounts for the increased infection risk observed in these patients. Hemodynamic and systemic changes suggestive of sepsis may be observed in patients with cirrhosis in the absence of infection; therefore, diagnosis and treatment of sepsis may be delayed. The optimal management of the critically ill patient with sepsis and cirrhosis has not been well established and is generally extrapolated from consensus guidelines and expert recommendations made for management of patients without cirrhosis with sepsis. Despite the lack of strong evidence, we propose a contemporary pragmatic approach to sepsis management in patients with cirrhosis, including the choice of fluids, vasopressors, and antibiotics.

Abstract Vitreoretinal lymphoma (VRL) management remains a challenge. We present 72 patients with VRL, diagnosed at Mayo Clinic between 1990‐2018. Three nondiffuse large B‐cell lymphoma (DLBCL) histology cases were excluded. Among 69 DLBCL, 33 patients had primary VRL (PVRL), 18 concurrent intraocular and central nervous system (CNS) or systemic disease and 18 secondary VRL. Patients received intraocular chemotherapy (intraocular injections of rituximab or metothrexate or steroids or in combination), radiotherapy, systemic or combined systemic plus intraocular treatment in 9, 10, 35, and 15 cases, respectively. Among primary and concurrent VRL, median failure free survival (FFS), CNS relapse‐free survival (CNS‐RFS) and overall survival (OS) were: 1.8, 4.9, and 4.1 years, respectively; among PVRL, median FFS, CNS‐RFS, and OS were: 2.6 year, Not Reached and 9.3 year, respectively. No CNS relapse occurred beyond 4 years in PVRL. Median OS for patients diagnosed between 1990 and 1999 vs between 2000 and 2018 was 1.5 vs 9.4 years, respectively ( P = .0002). OS was significantly higher in PVRL, as compared with concurrent VRL ( P = .04). Previous immunosuppression and poor performance status were predictive of worse outcome. In PVRL, a combined systemic and intraocular therapy showed higher FFS ( P = .002) and CNS‐RFS ( P = .003), but no differences in OS. Among 18 secondary VRL, at a median follow‐up of 1.1 year after vitreoretinal relapse, median FFS and OS were 0.3 and 1.3 years. An improvement in survival of VRL has been observed over the decades. PVRL should undergo combined systemic and intraocular chemotherapy to prevent CNS progression.

BACKGROUND: Primary colorectal lymphoma is rare, representing 0.2% to 0.6% of all colorectal cancers. Because of its low incidence and histologic variety, no treatment guidelines exist. OBJECTIVE: The purpose was to report the experience of primary colorectal lymphoma in an institutional and a national cohort. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted with institutional data composed of 3 tertiary referral centers and national data. PATIENTS: Patients with primary colorectal lymphoma were identified within the Mayo Clinic (1990–2016) and the Surveillance, Epidemiology, and End Results database (1990–2014). MAIN OUTCOME MEASURES: Primary outcomes were overall and 5-year survival. RESULTS: For the institutional cohort (N = 82), 5-year survival was 79.9%. Five-year survival was higher for rectal (88.4%) than for colon tumors (77.2%; p = 0.004). On multivariable analysis, age <50 years was associated with higher overall survival ( p = 0.04). Left-sided colon masses and aggressive histological subtypes were associated with worse survival (0.04 and 0.03). No effect of treatment modality on survival was noted. For the national cohort (N = 2942), 5-year survival was 58.4%. Five-year survival for rectal tumors was 61.0% and 57.8% for colon tumors. On multivariable analysis, factors associated with improved survival were age <70 y, ( p < 0.0001), female sex ( p = 0.005), right-sided masses ( p = 0.02), and diagnoses after 2000 compared with 1990–1999 ( p < 0.0001). Aggressive pathology ( p < 0.0001) and stage III or stage IV presentation compared with stage I ( p = 0.02 and p < 0.0001) were associated with worse survival. LIMITATIONS: The institutional cohort was limited by sample size to describe treatment effect on survival. A major limitation of the national cohort was the ability to describe treatment modalities other than surgery, including chemotherapy and/or no additional treatment. CONCLUSIONS: Poorer survival was noted in elderly patients and in those with aggressive pathology. An overall survival advantage was seen in women in the national cohort. Currently, optimal strategies should follow a patient-centered multidisciplinary approach. See Video Abstract at http://links.lww.com/DCR/A807. LINFOMA COLORECTAL PRIMARIO: EXPERIENCIA INSTITUCIONAL Y REVISIÓN DE UNA BASE DE DATOS NACIONAL ANTECEDENTES: El linfoma colorectal primario es poco frecuente, representando del 0.2% al 0.6% de todos los cánceres colorectales. Debido a su baja incidencia y variedad histológica, no existen guías de tratamiento. OBJETIVO: El propósito fue reportar la experiencia en linfoma colorectal primario en una cohorte institucional y una nacional. DISEÑO: Este fue un estudio de cohorte retrospectivo. ESCENARIO: El estudio se realizó con datos institucionales provenientes de 3 centros de referencia terciarios y datos nacionales. PACIENTES: Se identificaron pacientes con linfoma colorectal primario en la base de datos de la Clínica Mayo (1990–2016) y en la base de datos de vigilancia, epidemiología y resultados finales [Surveillance, Epidemiology, and End Results database (1990–2014)]. PRINCIPALES MEDIDAS DE RESULTADO: Los resultados primarios fueron la sobrevida general y a 5 años. RESULTADOS: Para la cohorte institucional (N = 82), la sobrevida a 5 años fue de 79.9%. La sobrevida a cinco años fue mayor en tumores rectales (88.4%) que en los de colon (77.2%; p = 0.004). En el análisis multivariable, la edad <50 años se asoció con una mayor sobrevida general (p = 0,04). Las masas de colon izquierdo y los subtipos histológicos agresivos se asociaron con una peor sobrevida (0.04 y 0.03). No se observó ningún efecto según la modalidad de tratamiento en la sobrevida. Para la cohorte nacional (N = 2942), la sobrevida a 5 años fue del 58.4%. La sobrevida a cinco años fue de 61.0% para los tumores rectales y 57.8% para los tumores de colon. En el análisis multivariable, los factores asociados con una mayor sobrevida fueron edad <70 años, (p <0.0001), sexo femenino (p = 0.005), masas derechas (p = 0.02) y los casos diagnósticados después del año 2000 comparados con los de 1990–1999 (p <0.0001). Histopatología agresiva (p <0.0001) y presentación en estadio III o estadio IV en comparación con estadio I (p = 0.02 y p <0.0001) se asociaron con una peor sobrevida. LIMITACIONES: La cohorte institucional estuvo limitada por el tamaño de la muestra para describir el efecto del tratamiento en la sobrevida. Una limitación mayor en la cohorte nacional fue la habilidad para describir modalidades de tratamiento distintas a la cirugía, incluyendo quimioterapia y/o ningún tratamiento adicional. CONCLUSIONES: Una menor sobrevida fue documentada en pacientes de edad avanzada y en aquellos con histopatología agresiva. Se observó ventaja en cuanto a sobrevida general en las mujeres de la cohorte nacional. Actualmente, las estrategias óptimas deben de seguir un abordaje multidisciplinario centrado en cada paciente. Vea el abstract en video en http://links.lww.com/DCR/A807.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss‐of‐function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation‐positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow‐growing hypothalamo‐pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.