Trends in Acute Lymphoblastic Leukemia Incidence in the United States by Race/Ethnicity From 2000 to 2016.

Incidence trends in acute lymphoblastic leukemia (ALL) demonstrate disparities by race and ethnicity. We used data from the Surveillance, Epidemiology, and End Results Registry to evaluate patterns in ALL incidence from 2000 to 2016, including the association between percentage of people born in a foreign country at the county level and ALL incidence. Among 23,829 persons of all ages diagnosed with ALL, 8,297 (34.8%) were Latinos, 11,714 (49.2%) were non-Latino (NL) Whites, and 1,639 (6.9%) were NL Blacks. Latinos had the largest increase in the age-adjusted incidence rate (AAIR) of ALL during this period compared with other races/ethnicities for both children and adults: The AAIR was 1.6 times higher for Latinos (AAIR = 2.43, 95% confidence interval (CI): 2.37, 2.49) than for NL Whites (AAIR = 1.56, 95% CI: 1.53, 1.59) (P < 0.01). The AAIR for all subjects increased approximately 1% per year from 2000 to 2016 (annual percent change = 0.97, 95% CI: 0.67, 1.27), with the highest increase being observed in Latinos (annual percent change = 1.18, 95% CI: 0.76, 1.60). In multivariable models evaluating the contribution of percentage of county residents who were foreign-born to ALL risk, a positive association was found for percentage foreign-born for NL Whites (P for trend < 0.01) and NL Blacks (P for trend < 0.01), but the reverse was found for Latinos (P for trend < 0.01); this is consistent with tenets of the "Hispanic paradox," in which better health outcomes exist for foreign-born Latinos.

The endoscope-assisted supraorbital "keyhole" approach for anterior skull base meningiomas: an updated meta-analysis.

INTRODUCTION: The gold-standard treatment for symptomatic anterior skull base meningiomas is surgical resection. The endoscope-assisted supraorbital "keyhole" approach (eSKA) is a promising technique for surgical resection of olfactory groove (OGM) and tuberculum sellae meningioma (TSM) but has yet to be compared with the microscopic transcranial (mTCA) and the expanded endoscopic endonasal approach (EEA) in the context of existing literature. METHODS: An updated study-level meta-analysis on surgical outcomes and complications of OGM and TSM operated with the eSKA, mTCA, and EEA was conducted using random-effect models. RESULTS: A total of 2285 articles were screened, yielding 96 studies (2191 TSM and 1510 OGM patients). In terms of effectiveness, gross total resection incidence was highest in mTCA (89.6% TSM, 91.1% OGM), followed by eSKA (85.2% TSM, 84.9% OGM) and EEA (83.9% TSM, 82.8% OGM). Additionally, the EEA group had the highest incidence of visual improvement (81.9% TSM, 54.6% OGM), followed by eSKA (65.9% TSM, 52.9% OGM) and mTCA (63.9% TSM, 45.7% OGM). However, in terms of safety, the EEA possessed the highest cerebrospinal fluid leak incidence (9.2% TSM, 14.5% OGM), compared with eSKA (2.1% TSM, 1.6% OGM) and mTCA (1.6% TSM, 6.5% OGM). Finally, mortality and intraoperative arterial injury were 1% or lower across all subgroups. CONCLUSIONS: In the context of diverse study populations, the eSKA appeared not to be associated with increased adverse outcomes when compared with mTCA and EEA and offered comparable effectiveness. Case-selection is paramount in establishing a role for the eSKA in anterior skull base tumours.

Trends in cerebrospinal fluid leak rates following the extended endoscopic endonasal approach for anterior skull base meningioma: a meta-analysis over the last 20 years.

OBJECTIVE: The extended endoscopic approach provides unimpaired visualization and direct access to ventral skull base pathology, but is associated with cerebrospinal fluid (CSF) leak in up to 25% of patients. To evaluate the impact of improved surgical techniques and devices to better repair skull base defects, we assessed published surgical outcomes of the extended endoscopic endonasal approach in the last two decades for a well-defined homogenous group of tuberculum sellae and olfactory groove meningioma patients. METHODS: Random-effects meta-analyses were performed for studies published between 2004 (first publications) and April 2020. We evaluated CSF leak as primary outcome. Secondary outcomes were gross total resection, improvement in visual outcomes in those presenting with a deficit, intraoperative arterial injury, and 30-day mortality. For the main analyses, publications were pragmatically grouped based on publication year in three categories: 2004-2010, 2011-2015, and 2016-2020. RESULTS: We included 29 studies describing 540 patients with tuberculum sellae and 115 with olfactory groove meningioma. The percentage patients with CSF leak dropped over time from 22% (95% CI: 6-43%) in studies published between 2004 and 2010, to 16% (95% CI: 11-23%) between 2011 and 2015, and 4% (95% CI: 1-9%) between 2016 and 2020. Outcomes of gross total resection, visual improvement, intraoperative arterial injury, and 30-day mortality remained stable over time CONCLUSIONS: We report a noticeable decrease in CSF leak over time, which might be attributed to the development and improvement of new closure techniques (e.g., Hadad-Bassagasteguy flap, and gasket seal), refined multilayer repair protocols, and lumbar drain usage.

Fibrinolytics and Intraventricular Hemorrhage: A Systematic Review and Meta-analysis.

Intraventricular hemorrhage (IVH) is an independent poor prognostic factor in subarachnoid and intra-parenchymal hemorrhage. The use of intraventricular fibrinolytics (IVF) has long been debated, and its exact effects on outcomes are unknown. A systematic review and meta-analysis were performed in accordance with the PRISMA guidelines to assess the impact of IVF after non-traumatic IVH on mortality, functional outcome, intracranial bleeding, ventriculitis, time until clearance of third and fourth ventricles, obstruction of external ventricular drains (EVD), and shunt dependency. Nineteen studies were included in the meta-analysis, totaling 1020 patients. IVF was associated with lower mortality (relative risk [RR] 0.58; 95% confidence interval [CI] 0.47-0.72), fewer EVD obstructions (RR 0.41; 95% CI 0.22-0.74), and a shorter time until clearance of the ventricles (median difference [MD] - 4.05 days; 95% CI - 5.52 to - 2.57). There was no difference in good functional outcome, RR 1.41 (95% CI 0.98-2.03), or shunt dependency, RR 0.93 (95% CI 0.70-1.22). Correction for publication bias predicted an increased risk of intracranial bleeding, RR 1.67 (95% CI 1.01-2.74) and a lower risk of ventriculitis, RR 0.68 (95% CI 0.45-1.03) in IVH patients treated with IVF. IVF was associated with improved survival, faster clearance of blood from the ventricles and fewer drain obstructions, but further research is warranted to elucidate the effects on ventriculitis, long-term functional outcomes, and re-hemorrhage.

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

Longer genotypically-estimated leukocyte telomere length is associated with increased meningioma risk.

PURPOSE: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls. METHODS/PATIENTS: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates. RESULTS: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10-5]. CONCLUSION: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.

Randomized controlled trials comparing surgery to non-operative management in neurosurgery: a systematic review.

BACKGROUND: A randomized controlled trial (RCT) remains the pinnacle of clinical research design. However, RCTs in neurosurgery, especially those comparing surgery to non-operative treatment, are rare and their relevance and applicability have been questioned. This study set out to assess trial design and quality and identify their influence on outcomes in recent neurosurgical trials that compare surgery to non-operative treatment. METHODS: From 2000 to 2017, PubMed and Embase databases and four trial registries were searched. RCTs were evaluated for study design, funding, adjustments to reported outcome measures, accrual of patients, and academic impact. RESULTS: Eighty-two neurosurgical RCTs were identified, 40 in spine disorders, 19 neurovascular and neurotrauma, 11 functional neurosurgery, ten peripheral nerve, and two pituitary surgery. Eighty-four RCTs were registered, of which some are ongoing. Trial registration rate differed per subspecialty. Funding was mostly from non-industry institutions (58.5%), but 25.6% of RCTs did not report funding sources. 36.4% of RCTs did not report a difference between surgical and non-operative treatment, 3.7% favored non-operative management. Primary and secondary outcome measures were changed in 13.2% and 34.2% of RCTs respectively and varied by subspecialty. 41.9% of RCTs subtracted ≥ 10% of the anticipated accrual and 12.9% of RCTs added ≥ 10%. 7.3% of registered RCTs were terminated, mostly due to too slow recruitment. Subspecialty, registration, funding, masking, population size, and changing outcome measures were not significantly associated with a reported benefit of surgery. High Jadad scores (≥ 4) were negatively associated with a demonstration of surgical benefit (P < 0.05). CONCLUSIONS: Neurosurgical RCTs comparing surgical to non-operative treatment often find a benefit for surgical treatment. Changes to outcome measurements and anticipated accrual are common and funding sources are not always reported.

A nationwide analysis of 30-day adverse events, unplanned readmission, and length of hospital stay after peripheral nerve surgery in extremities and the brachial plexus.

BACKGROUND: Little is known on adverse events and their timing after peripheral nerve surgery in extremities. The aim of this study is to identify predictors and typical timing of complications, unplanned readmission, and length of hospital stay for patients undergoing peripheral nerve surgery in the extremities. METHODS: Data were extracted from the National Surgical Quality Improvement Program (NSQIP) registry from 2005 to 2015. Adult patients undergoing peripheral nerve surgery in the extremities were included. A subgroup analysis was performed for brachial plexus operations. Multivariable logistic regression was performed to identify predictors of any complication, surgical site infection, unplanned readmission, and reoperation. RESULTS: A total of 2,840 patients were identified; 628 were brachial plexus operations. Overall complications were 4.4% and 7.0%, respectively. Median time for occurrence of any complication was 8 days. The most common complications were wound-related (1.7%), which occurred at a median of 15 days postoperatively. Reoperation occurred in 1.8% of all cases; most commonly for musculoskeletal repair (16.7%). Unplanned readmissions occurred in 2.3% and were most often due to wound-related problems (24.1%). Preoperatively contaminated wounds, inpatient procedures, and longer operative time seemed to have the most influence on all adverse events. In brachial plexus pathology, insulin-dependent diabetes and emergency cases also negatively affected outcomes. CONCLUSIONS: Complications usually occur one to two weeks postoperatively. Preoperatively contaminated wounds, inpatient procedures, and longer operative times influence outcome. Anatomical level of operation results in significantly different lengths of hospital stay; brachial plexus pathology has the longest length of stay.

Venous thromboembolism and intracranial hemorrhage after craniotomy for primary malignant brain tumors: a National Surgical Quality Improvement Program analysis.

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), frequently complicates the postoperative course of primary malignant brain tumor patients. Thromboprophylactic anticoagulation is commonly used to prevent VTE at the risk of intracranial hemorrhage (ICH). We extracted all patients who underwent craniotomy for a primary malignant brain tumor from the National Surgical Quality Improvement Program (NSQIP) registry (2005-2015) to perform a time-to-event analysis and identify relevant predictors of DVT, PE, and ICH within 30 days after surgery. Among the 7376 identified patients, the complication rates were 2.6, 1.5, and 1.3% for DVT, PE, and ICH, respectively. VTE was the second-most common major complication and third-most common reason for readmission. ICH was the most common reason for reoperation. The increased risk of VTE extends beyond the period of hospitalization, especially for PE, whereas ICH occurred predominantly within the first days after surgery. Older age and higher BMI were overall predictors of VTE. Dependent functional status and longer operative times were predictive for VTE during hospitalization, but not for post-discharge events. Admission two or more days before surgery was predictive for DVT, but not for PE. Preoperative steroid usage and male gender were predictive for post-discharge DVT and PE, respectively. ICH was associated with various comorbidities and longer operative times. This multicenter study demonstrates distinct critical time periods for the development of thrombotic and hemorrhagic events after craniotomy. Furthermore, the VTE risk profile depends on the type of VTE (DVT vs. PE) and clinical setting (hospitalized vs. post-discharge patients).

Oversight in Surgical Innovation: A Response to Ethical Challenges.

BACKGROUND: Surgical innovation has advanced outcomes in the field, but carries inherent risk for surgeons and patients alike. Oversight mechanisms exist to support surgeon-innovators through difficulties associated with the innovation process. METHODS: A literature review of ethical risks and oversight mechanisms was conducted. RESULTS: Oversight mechanisms range from the historical concept of surgical exceptionalism to departmental, hospital, and centralized committees. These fragmentary and non-standardized oversight mechanisms leave surgeon-innovators and patients open to significant risk of breaching the ethical principles at the core of surgical practice. A systematized approach that mitigates these risks while maintaining the independence and dignity of the surgical profession is necessary. We propose an oversight framework that incorporates multiple structures tailored toward the ethical risk introduced by different forms of innovation. DISCUSSION: We summarize ethical risks and current regulatory structures, and we then use these findings to outline an oversight framework that may be applied to surgical practice.

Gross total resection of pituitary adenomas after endoscopic vs. microscopic transsphenoidal surgery: a meta-analysis.

BACKGROUND: Microscopic transsphenoidal surgery (mTSS) is a well-established method to address adenomas of the pituitary gland. Endoscopic transsphenoidal surgery (eTSS) has become a viable alternative, however. Advocates suggest that the greater illumination, panoramic visualization, and angled endoscopic views afforded by eTSS may allow for higher rates of gross total tumor resection (GTR). The aim of this meta-analysis was to determine the rate of GTR using mTSS and eTSS. METHODS: A meta-analysis of the literature was conducted using PubMed, EMBASE, and Cochrane databases through July 2017 in accordance with PRISMA guidelines. RESULTS: Seventy case series that reported GTR rate in 8257 pituitary adenoma patients were identified. For all pituitary adenomas, eTSS (GTR=74.0%; I2 = 92.1%) was associated with higher GTR as compared to mTSS (GTR=66.4%; I2 = 84.0%) in a fixed-effect model (P-interaction < 0.01). For functioning pituitary adenomas (FPAs) (n = 1170 patients), there was no significant difference in GTR rate between eTSS (GTR=75.8%; I2 = 63.9%) and mTSS (GTR=75.5%; I2 = 79.0%); (P-interaction = 0.92). For nonfunctioning pituitary adenomas (NFPAs) (n = 2655 patients), eTSS (GTR=71.0%; I2 = 86.4%) was associated with higher GTR as compared to mTSS (GTR=60.7%; I2 = 87.5%) in a fixed-effect model (P-interaction < 0.01). None of the associations were significant in a random-effect model (all P-interaction > 0.05). No significant publication bias was identified for any of the outcomes. CONCLUSION: Among patients who were not randomly allocated to either approach, eTSS resulted in a higher rate of GTR as compared to mTSS for all patients and for NFPA patients alone, but only in a fixed-effect model. For FPA, however, eTSS did not seem to offer a significantly higher rate of GTR. These conclusions should be interpreted with caution because of the nature of the included non-comparative studies.

The endoscopic endonasal approach is not superior to the microscopic transcranial approach for anterior skull base meningiomas-a meta-analysis.

OBJECT: In the past decade, the endonasal transsphenoidal approach (eTSA) has become an alternative to the microsurgical transcranial approach (mTCA) for tuberculum sellae meningiomas (TSMs) and olfactory groove meningiomas (OGMs). The aim of this meta-analysis was to evaluate which approach offered the best surgical outcomes. METHODS: A systematic review of the literature from 2004 and meta-analysis were conducted in accordance with the PRISMA guidelines. Pooled incidence was calculated for gross total resection (GTR), visual improvement, cerebrospinal fluid (CSF) leak, intraoperative arterial injury, and mortality, comparing eTSA and mTCA, with p-interaction values. RESULTS: Of 1684 studies, 64 case series were included in the meta-analysis. Using the fixed-effects model, the GTR rate was significantly higher among mTCA patients for OGM (eTSA: 70.9% vs. mTCA: 88.5%, p-interaction < 0.01), but not significantly higher for TSM (eTSA: 83.0% vs. mTCA: 85.8%, p-interaction = 0.34). Despite considerable heterogeneity, visual improvement was higher for eTSA than mTCA for TSM (p-interaction < 0.01), but not for OGM (p-interaction = 0.33). CSF leak was significantly higher among eTSA patients for both OGM (eTSA: 25.1% vs. mTCA: 10.5%, p-interaction < 0.01) and TSM (eTSA: 19.3%, vs. mTCA: 5.81%, p-interaction < 0.01). Intraoperative arterial injury was higher among eTSA (4.89%) than mTCA patients (1.86%) for TSM (p-interaction = 0.03), but not for OGM resection (p-interaction = 0.10). Mortality was not significantly different between eTSA and mTCA patients for both TSM (p-interaction = 0.14) and OGM resection (p-interaction = 0.88). Random-effect models yielded similar results. CONCLUSION: In this meta-analysis, eTSA was not shown to be superior to mTCA for resection of both OGMs and TSMs.

Visual outcomes after endoscopic endonasal pituitary adenoma resection: a systematic review and meta-analysis.

PURPOSE: Patients with pituitary adenomas often present with visual deficits. While the aim of endoscopic endonasal transsphenoidal surgery (EETS) is to improve these deficits, permanent worsening is a possible outcome. The aim of this meta-analysis was to evaluate the effect of EETS for pituitary adenomas on visual outcomes. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Pooled prevalence was calculated for complete recovery, improvement, and deterioration of visual field deficits, visual acuity and unspecified visual function in fixed- and random-effect models, including assessment of heterogeneity (I2) and publication bias (Begg's test). RESULTS: Out of 2636 articles, 35 case series were included in the meta-analysis. Results are described for fixed-effect models. For patients with impaired visual acuity, only one study reported complete recovery (27.2%). Pooled prevalence for improvement was 67.5% (95% CI = 59.1-75.0%), but with considerable heterogeneity (I2: 86.0%), and 4.50% (95% CI = 1.80-10.8%) for patients experiencing deterioration. For patients with visual field deficits, the prevalence was 40.4% (95% CI = 34.8-46.3%) for complete recovery, 80.8% (95% CI = 77.7-83.6%) for improvement, and 2.3% (95% CI = 1.1-4.7%) for deterioration. For the unspecified visual outcomes, pooled prevalence of complete recovery was 32.9% (95% CI: 28.5-37.7%), but with considerable heterogeneity (I2 = 84.2%). The prevalence was 80.9% (95% CI = 77.9-83.6) for improvement and 2.00% (95% CI = 1.10-3.40%) for deterioration. Random-effect models yielded similar results. Publication bias was non-significant for all the outcomes. CONCLUSION: While visual deficits improved after EETS in the majority of patients, complete recovery was only achieved in less than half of the patients and some patients even suffered from visual deterioration.

Defensive medicine among neurosurgeons in the Netherlands: a national survey.

OBJECTIVE: In defensive medicine, practice is motivated by legal rather than medical reasons. Previous studies have analyzed the correlation between perceived medico-legal risk and defensive behavior among neurosurgeons in the United States, Canada, and South Africa, but not yet in Europe. The aim of this study is to explore perceived liability burdens and self-reported defensive behaviors among neurosurgeons in the Netherlands and compare their practices with their non-European counterparts. METHODS: A survey was sent to 136 neurosurgeons. The survey included questions from several domains: surgeon characteristics, patient demographics, type of practice, surgeon liability profile, policy coverage, defensive practices, and perception of the liability environment. Survey responses were analyzed and summarized. RESULTS: Forty-five neurosurgeons filled out the questionnaire (response rate of 33.1%). Almost half (n = 20) reported paying less than 5% of their income to annual malpractice premiums. Nearly all respondents view their insurance premiums as a minor or no burden (n = 42) and are confident that in their coverage is sufficient (n = 41). Most neurosurgeons (n = 38) do not see patients as "potential lawsuits". CONCLUSIONS: Relative to their American peers, Dutch neurosurgeons view their insurance premiums as less burdensome, their patients as a smaller legal threat, and their practice as less risky in general. They are sued less often and engage in fewer defensive behaviors than their non-European counterparts. The medico-legal climate in the Netherlands may contribute to this difference.

Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results.

BACKGROUND: Fluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma. METHODS: We searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events. RESULTS: The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified. CONCLUSIONS: 5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.

Accelerated epigenetic aging in newborns with Down syndrome.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.

Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.

Background: The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. Methods: We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity. Results: Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20). Conclusions: The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States. Funding: This work was supported by the V Foundation for funding this work (Grant FP067172).

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

Visual Outcomes after Endoscopic Endonasal Transsphenoidal Resection of Pituitary Adenomas: Our Institutional Experience.

Objectives Visual dysfunction in patients with pituitary adenomas is a clear indication for endoscopic endonasal transsphenoidal surgery (EETS). However, the visual outcomes vary greatly among patients and it remains unclear what tumor, patient, and surgical characteristics contribute to postoperative visual outcomes. Methods One hundred patients with pituitary adenomas who underwent EETS between January 2011 and June 2015 in a single institution were retrospectively reviewed. General patient characteristics, pre- and postoperative visual status, clinical presentation, tumor characteristics, hormone production, radiological features, and procedural characteristics were evaluated for association with presenting visual signs and visual outcomes postoperatively. Suprasellar tumor extension (SSE) was graded 0 to 4 following a grading system as formulated by Fujimoto et al. Results Sixty-six (66/100) of all patients showed visual field defects (VFD) at the time of surgery, of whom 18% (12/66) were asymptomatic. VFD improved in 35 (35%) patients and worsened in 4 (4%) patients postoperatively. Mean visual acuity (VA) improved from 0.67 preoperatively to 0.84 postoperatively ( p = 0.04). Nonfunctioning pituitary adenomas (NFPAs) and Fujimoto grade were independent predictors of preoperative VFD in the entire cohort ( p = 0.02 and p < 0.01 respectively). A higher grade of SSE was the only factor independently associated with postoperative improvement of VFD ( p = 0.03). NFPA and Fujimoto grade 3 were independent predictors of VA improvement (both p = 0.04). Conclusion EETS significantly improved both VA and VFD for most patients, although a few patients showed deterioration of visual deficits postoperatively. Higher degrees of SSE and NFPA were independent predictors of favorable visual outcomes.