Search

Objective: Pilocytic astrocytomas (PAs) have a generally favorable prognosis; however, progression or recurrence after resection is possible. The prognostic value of histopathological qualifiers (defined below) or BRAF alterations is not well understood. The aim of this study was to identify the prognostic value of genetic and histopathological features of pediatric PAs., Methods: Patients treated for a WHO grade I PA at a single institution were analyzed for histopathological and genetic features and outcomes. "Histopathological qualifier" refers to designations such as "WHO grade I PA with increased proliferative index." BRAF alterations include gene fusions and point mutations. Patients with neurofibromatosis type 1 were excluded., Results: A total of 222 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (51%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were screened for in 77 patients and identified in 56 (73%). Histopathological qualifiers were present in 27 patients (14%). Resection was performed in 197 patients (89%), 41 (21%) of whom displayed tumor progression or recurrence after resection. Tumor progression or recurrence was not associated with histopathologic qualifiers (p = 0.36) or BRAF alterations (p = 0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p = 0.94). BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p < 0.0001) and younger patient age (p = 0.03). Patients in whom gross-total resection was achieved had lower rates of progression and recurrence (p < 0.0001)., Conclusions: Histopathological features/qualifiers and BRAF alterations were not associated with tumor recurrence/progression in pediatric PAs. The extent of resection was the only factor analyzed that predicted outcome.

Background: Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States., Methods: Incidence data from 2000 to 2017 were obtained from CBTRUS, which obtains data from the NPCR and SEER, and survival data from the CDC's NPCR. Age-adjusted incidence rate ratios (IRR) per 100 000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences., Results: Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI: 1.01-1.07, P = .003), increasing with age, peaking at 50-59 years (IRR: 1.56, 95% CI: 1.53-1.59, P < .001). Females had worse survival for ages 0-9 (HR: 0.93, 95% CI: 0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR: 1.36, 95% CI: 1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma., Conclusions: To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792)., Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms., Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms., Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant brain cancer in adults, and it carries a poor prognosis. Despite the current multimodality treatment, including surgery, radiation, and chemotherapy, the overall survival is still poor. Neurooncological imaging plays an important role in the initial diagnosis and prediction of the treatment response of GBM. Positron emission tomography (PET) imaging using radiotracers that target disease-specific hallmarks, which are both noninvasive and specific, has drawn much attention. C-X-C chemokine receptor 4 (CXCR4) plays an important role in neoangiogenesis and vasculogenesis, and, moreover, it is reported to be overexpressed in GBM, which is associated with poor patient survival; thus, CXCR4 can be an ideal candidate for PET imaging of GBM. Nanomaterials, which possess multifunctional capabilities, effective drug delivery, and favorable pharmacokinetics, are now being applied to improve the diagnosis and therapy of the most difficult-to-treat cancers. Herein, we engineered an ultrasmall, renal-clearable gold nanoclusters intrinsically radiolabeled with 64 Cu ( 64 Cu-AuNCs-FC131) for targeted PET imaging of CXCR4 in a U87 intracranial GBM mouse model. These targeted nanoclusters demonstrated specific binding to U87 cells with minimal cytotoxicity. The in vivo biodistribution showed favorable pharmacokinetics and efficient renal clearance. PET/computed tomography imaging of the U87 model revealed the effective delivery of 64 Cu-AuNCs-FC131 into the tumors. In vivo toxicity studies demonstrated insignificant safety concerns at various dosages, indicating its potential as a useful platform for GBM imaging and drug delivery.

Focused ultrasound combined with circulating microbubbles (FUS+MB) can transiently enhance blood-brain barrier (BBB) permeability at targeted brain locations. Its great promise in improving drug delivery to the brain is reflected by a rapidly growing number of clinical trials using FUS+MB to treat various brain diseases. As the clinical applications of FUS+MB continue to expand, it is critical to have a better understanding of the molecular and cellular effects induced by FUS+MB to enhance the efficacy of current treatment and enable the discovery of new therapeutic strategies. Existing studies primarily focus on FUS+MB-induced effects on brain endothelial cells, the major cellular component of BBB. However, bioeffects induced by FUS+MB expand beyond the BBB to cells surrounding blood vessels, including astrocytes, microglia, and neurons. Together these cell types comprise the neurovascular unit (NVU). In this review, we examine cell-type-specific bioeffects of FUS+MB on different NVU components, including enhanced permeability in endothelial cells, activation of astrocytes and microglia, as well as increased intraneuron protein metabolism and neuronal activity. Finally, we discuss knowledge gaps that must be addressed to further advance clinical applications of FUS+MB.

Background/purpose: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials., Methods: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825., Results: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males., Conclusions: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ ., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

In cancer, missense mutations in the DNA-binding domain of TP53 are common. They abrogate canonical p53 activity and frequently confer gain-of-oncogenic function (GOF) through localization of transcriptionally active mutant p53 to non-canonical genes. We found that several recurring p53 mutations exhibit a sex difference in frequency in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53 R172H , p53 Y202C , and p53 Y217C revealed unique interactions between cellular sex and p53 GOF mutations that determined each mutation's ability to transform male versus female primary mouse astrocytes. These phenotypic differences were correlated with sex- and p53 mutation- specific patterns of genomic localization to the transcriptional start sites of upregulated genes belonging to core cancer pathways. The promoter regions of these genes exhibited a sex difference in enrichment for different transcription factor DNA-binding motifs. Together, our data establish a novel mechanism for sex specific mutant p53 GOF activity in GBM with implications for all cancer., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Significant sex differences exist across cellular, tissue organization, and body system scales to serve the distinct sex-specific functions required for reproduction. They are present in all animals that reproduce sexually and have widespread impacts on normal development, aging, and disease. Observed from the moment of fertilization, sex differences are patterned by sexual differentiation, a lifelong process that involves mechanisms related to sex chromosome complement and the epigenetic and acute activational effects of sex hormones. In this mini-review, we examine evidence for sex differences in cellular responses to DNA damage, their underlying mechanisms, and how they might relate to sex differences in cancer incidence and response to DNA-damaging treatments., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM., (© 2021. The Author(s).)

Curing cancer through precision medicine is the paramount aim of the new wave of molecular and genomic therapies. Currently, whether patients with non-reproductive cancers are male or female according to their sex chromosomes is not adequately considered in patient standard of care. This is a matter of consequence because there is growing evidence that these cancer types generally initiate earlier and are associated with higher overall incidence and rates of death in males compared with females. Gender, in contrast to sex, refers to a chosen sexual identity. Hazardous lifestyle choices (notably tobacco smoking) differ in prevalence between genders, aligned with disproportionate cancer risk. These add to underlying genetic predisposition and influences of sex steroid hormones. Together, these factors affect metabolism, immunity and inflammation, and ultimately the fidelity of the genetic code. To accurately understand how human defences against cancer erode, it is crucial to establish the influence of sex. Our Perspective highlights evidence from basic and translational research indicating that including genetic sex considerations in treatments for patients with cancer will improve outcomes. It is now time to adopt the challenge of overhauling cancer medicine based on optimized treatment strategies for females and males.

Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs., Competing Interests: Financial disclosure statement No authors have an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Pain is common among patients with cirrhosis, yet managing pain in this population is challenging. Opioid analgesics are thought to be particularly high risk in patients with cirrhosis, and their use has been discouraged. We sought to understand patterns of opioid use among inpatients with cirrhosis and the risks of serious opioid-related adverse events in this population. We used the Vizient Clinical Database/Resource Manager, which includes clinical and billing data from hospitalizations at more than 500 academic medical centers. We identified all nonsurgical patients with cirrhosis hospitalized in 2017-2018 as well as a propensity score-matched cohort of patients without cirrhosis. Inpatient prescription records defined patterns of inpatient opioid use. Conditional logistic regression compared rates of use and serious opioid-related adverse events between patients with and without cirrhosis. Of 116,146 nonsurgical inpatients with cirrhosis, 62% received at least one dose of opioids and 34% had regular inpatient opioid use (more than half of hospital days), rates that were significantly higher than in patients without cirrhosis (adjusted odds ratio [AOR] for any use, 1.17; 95% confidence interval [CI], 1.13-1.21; P  < 0.001; AOR for regular use, 1.07; 95% CI, 1.02-1.11; P  = 0.002). Compared with patients without cirrhosis, patients with cirrhosis more often received tramadol ( P  < 0.001) and less commonly received opioid/acetaminophen combinations ( P  < 0.001). Rates of serious opioid-related adverse events were similar in patients with and without cirrhosis (1.6% vs. 1.9%; AOR, 0.96; P  = 0.63). Conclusion: Over half of patients with cirrhosis have pain managed with opioids during hospitalization. Patterns of opioid use differ in patients with cirrhosis compared with patients without cirrhosis, although rates of serious adverse events are similar. Future studies should further explore the safety and efficacy of opioids in patients with cirrhosis, with the goal of improving pain management and quality of life in this population., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background: Chronotherapy is an innovative approach to improving survival through timed delivery of anti-cancer treatments according to patient daily rhythms. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for glioblastoma (GBM). Whether timing of TMZ administration affects GBM patient outcome has not previously been studied. We sought to evaluate maintenance TMZ chronotherapy on GBM patient survival., Methods: This retrospective study reviewed patients with newly diagnosed GBM from January 1, 2010 to December 31, 2018 at Washington University School of Medicine who had surgery, chemoradiation, and were prescribed TMZ to be taken in the morning or evening. The Kaplan-Meier method and Cox regression model were used for overall survival (OS) analyses. The propensity score method accounted for potential observational study biases. The restricted mean survival time (RMST) method was performed where the proportional hazard assumption was violated., Results: We analyzed 166 eligible GBM patients with a median follow-up of 5.07 years. Patients taking morning TMZ exhibited longer OS compared to evening (median OS, 95% confidence interval [CI] = 1.43, 1.12-1.92 vs 1.13, 0.84-1.58 years) with a significant year 1 RMST difference (-0.09, 95% CI: -0.16 to -0.018). Among MGMT-methylated patients, median OS was 6 months longer for AM patients with significant RMST differences at years 1 (-0.13, 95% CI = -0.24 to -0.019) to 2.5 (-0.43, 95% CI = -0.84 to -0.028). Superiority of morning TMZ at years 1, 2, and 5 (all P < .05) among all patients was supported by RMST difference regression after adjusting for confounders., Conclusions: Our study presents preliminary evidence for the benefit of TMZ chronotherapy to GBM patient survival. This impact is more pronounced in MGMT-methylated patients., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI's great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982-0.986), 0.960 (0.956-0.963), 0.991 (0.990-0.993), 0.950 (0.944-0.956), 0.977 (0.973-0.981) and 0.976 (0.972-0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.

Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood-brain barrier (BBB). The objective of this study was to evaluate the capability of focused-ultrasound-mediated intranasal brain drug delivery (FUSIN) in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain. Both non-tumor mice and mice transcranially implanted with GL261 glioma cells at the brainstem were used in this study. aPD-L1 was labeled with a near-infrared fluorescence dye (IRDye 800CW) and administered to mice through the nasal route to the brain, followed by focused ultrasound sonication in the presence of systemically injected microbubbles. FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03- and 3.74-fold compared with intranasal (IN) administration alone in the non-tumor mice and glioma mice, respectively. Immunohistochemistry staining found that aPD-L1 was mainly located within the perivascular spaces after IN delivery, while FUSIN further enhanced the penetration depth and delivery efficiency of aPD-L1 to the brain parenchyma. The delivered aPD-L1 was found to be colocalized with the tumor cells after FUSIN delivery to the brainstem glioma. These findings suggest that FUSIN is a promising technique to enhance the delivery of immune checkpoint inhibitors to gliomas.

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies., (Copyright © 2020. Published by Elsevier B.V.)

Focused ultrasound-mediated intranasal (FUSIN) delivery is a recently proposed technique that bypasses the blood-brain barrier to achieve noninvasive and localized brain drug delivery. The goal of this study was to characterize FUSIN drug delivery outcome in mice with regard to its dependency on several critical experimental factors, including the time interval between IN administration and FUS sonication (T lag1 ), the FUS pressure, and the time for sacrificing the mice post-FUS (T lag2 ). Wild-type mice were treated by FUSIN delivery of near-infrared fluorescent dye-labeled bovine serum albumin (800CW-BSA, used as a model agent). 800CW-BSA was intranasally administered to the mice in vivo, followed by intravenous injection of microbubbles and FUS sonication at the brainstem. Fluorescence imaging of ex vivo mouse brain slices was used to quantify the delivery outcomes of 800CW-BSA. Major organs, along with the nasal tissue and trigeminal nerve, were harvested to assess the biodistribution of 800CW-BSA. The delivery outcome of 800CW-BSA was the highest at the brainstem when T lag1 was 0.5 h, which was on average 24.5-fold, 5.4-fold, and 21.6-fold higher than those of the IN only, T lag1  = 1.5 h, and T lag1  = 4.0 h, respectively. The FUSIN delivery outcome at the lowest pressure level, 0.43 MPa, was on average 1.8-fold and 3.7-fold higher than those at 0.56 MPa and 0.70 MPa, respectively. The mean concentration of 800CW-BSA in the brainstem after FUSIN delivery decreased from 0.5 h to 4.0 h post-FUS. The accumulation of 800CW-BSA was low in the heart, lung, spleen, kidneys, and liver, but high in the stomach and intestines. This study revealed the unique characteristics of FUSIN as a noninvasive, efficient, and localized brain drug delivery technique., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gender differences in the natural history of chronic liver disease have been well-described. Women have lower rates of chronic liver disease and slower fibrosis progression, yet higher rates of waitlist mortality. 1,2 Although previous studies have identified several clinical factors including height and creatinine that explain some of this transplant disparity, most have used data from administrative records, which are limited in their ability to identify clinically relevant differences and opportunities for intervention to reduce disparities. 3-5 Additionally, most studies have focused on the period between waitlist and transplant, failing to capture gender differences in access to transplant. 3,6 In the present study, we took advantage of a multicenter inpatient cohort with granular clinical data to characterize how women and men with cirrhosis differ, to stimulate future research aimed at reducing the well-established gender disparity in liver transplantation., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth., Methods: Male and female wild-type (WT) and JAM-A-deficient mice were transplanted intracranially with the syngeneic glioma cell lines GL261 and SB28 and were assessed for differences in survival and microglial activation in tumors and in vitro. RNA-sequencing was performed to identify differentially regulated genes among all genotypes, and differences were validated in vitro and in vivo., Results: We found that JAM-A-deficient female mice succumbed to GBM more quickly compared with WT females and JAM-A-deficient and male WT mice. Analysis of microglia in the tumors revealed that female JAM-A-deficient microglia were more activated, and RNA-sequencing identified elevated expression of Fizz1 and Ifi202b specifically in JAM-A-deficient female microglia., Conclusions: Our findings suggest that JAM-A functions to suppress pathogenic microglial activation in the female tumor microenvironment, highlighting an emerging role for sex differences in the GBM microenvironment and suggesting that sex differences extend beyond previously reported tumor cell-intrinsic differences., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters ( 64 Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for effective delivery of 64 Cu-CuNCs to pons in wildtype mice. Then the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low molecular weight, short-lived 68 Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of 64 Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of 64 Cu-CuNCs within the tumor., Competing Interests: Notes The authors declare no conflict of interest.

Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sex plays an important role in the incidence, prognosis, and mortality of cancers, but often is not considered in disease treatment., Methods: We quantified sex differences in cancer incidence using the United States Cancer Statistics (USCS) public use database and sex differences in cancer survival using Surveillance, Epidemiology, and End Results (SEER) public use data from 2001 to 2016. Age-adjusted male-to-female incidence rate ratios (IRR) with 95% confidence intervals (CI) were generated by primary cancer site, race, and age groups. In addition, age-adjusted hazard ratios with 95% CI by sex within site were generated., Results: In general, cancer incidence and overall survival were lower in males than females, with Kaposi sarcoma (IRR: 9.751; 95% CI, 9.287-10.242; P < 0.001) having highest male-to-female incidence, and thyroid cancers (HR, 1.774; 95% CI, 1.707-1.845) having largest male-to-female survival difference. Asian or Pacific Islanders had particularly high male-to-female incidence in larynx cancers (IRR: 8.199; 95% CI, 7.203-9.363; P < 0.001), relative to other races. Among primary brain tumors, germ cell tumors had the largest male-to-female incidence (IRR: 3.03; 95% CI, 2.798-3.284, P < 0.001)., Conclusions: Overall, incidence and survival of cancer vary significantly by sex, with males generally having lower incidence and survival compared with females. Male-to-female incidence differences were also noted across race and age groups. These results provide strong evidence that the fundamental biology of sex differences affects cancers of all types., Impact: This study represents the most recent and comprehensive reporting of sex differences in cancer incidence and survival in the United States. Identifying disadvantaged groups is critical as it can provide useful information to improve cancer survival, as well as to better understand the etiology and pathogenesis of specific cancers., (©2020 American Association for Cancer Research.)

Background: Women on the liver transplant waitlist are at greater risk of hospitalization compared with men, but whether this impacts length of stay (LOS) post-transplant is unknown. We aimed to evaluate gender disparities in post-transplant LOS, an important surrogate of health resource utilization post-transplant., Methods: Using the UNOS/OPTN registry, we analysed all non-Status 1 adult deceased donor liver transplant recipients without exception points from 2008 to 2017. Poisson regression associated female gender with post-transplant LOS., Results: Of 27 294 transplant recipients, 36% were women. Women were more likely to be hospitalized pretransplant than men (44% vs 39%, P < .01). Post-transplant, women were more likely to have prolonged (≥20d) LOS (25% vs 22%, P < .01). In univariable analysis, female gender was associated with longer post-transplant LOS (IRR 1.09, 95%CI 1.06-1.12, P < .01). Prolonged pretransplant admission was also associated with post-transplant LOS (IRR 1.83, 95%CI 1.77-1.89, P < .01). In multivariable analysis, female gender remained independently associated with post-transplant LOS (aIRR 1.05, 95%CI 1.02-1.08, P < .01), after adjustment for age, UNOS region, insurance type, MELDNa, cirrhosis complications, and donor risk index. Pretransplant hospitalization mediated this relationship, explaining 14.1% (95%CI 9.7%-25.4%) of the total effect., Conclusions: Women who undergo deceased donor liver transplant have increased healthcare utilization in the peritransplant period compared with men. Reducing gender disparities in liver transplantation, including the disproportionate burden of healthcare utilization by women pre- and post-transplant, will require interventions targeted at preventing hospitalization among women on the transplant waitlist and developing tools aimed at better characterizing the severity of end-stage liver disease in women., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences., Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females)., Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test)., Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related mortality in the United States and is a leading indication for liver transplantation (LT). Changes have been noted in the age of the population with chronic liver disease, but how this change affects patients with HCC is unknown. This study aims to characterize trends and transplant-associated outcomes among patients ≥65 years old listed for LT with HCC. Using the United Network for Organ Sharing database, we analyzed all patients ≥18 years old listed for LT during 2003-2017 in the United States in 2 groups (<65 or ≥65 years). Time trends between HCC and non-HCC patients were compared and stratified by disease etiology. Competing-risks and Cox proportional hazards regressions associated HCC and age with wait-list and post-LT survival. There were 161,724 LT candidates included: 14% were ≥65 years old at listing and 25% had HCC. The proportion of patients ≥65 years old rose significantly faster among those with HCC, as compared with those without HCC (Δ = 0.80; P < 0.001). Age ≥65 years was significantly associated with both wait-list mortality (adjusted subhazard ratio, 1.51; 95% confidence interval [CI], 1.40-1.64) and post-LT mortality (adjusted hazard ratio, 1.50; 95% CI, 1.41-1.60) in the multivariate analysis. There were significant interactions between age and HCC on both wait-list (P < 0.001) and post-LT mortality (P = 0.04), suggesting that older age does not impact patients with HCC as much as patients without HCC. The proportion of older adults with HCC listed for LT has nearly tripled from 2003 to 2017, and the rapidly growing population of older adults with HCC may provide an opportunity to expand LT access without compromising outcomes., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Background: The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males. The molecular mechanism of this difference has not yet been established. Iron is essential for many biological processes supporting tumor growth and its regulation is impacted by sex. Therefore, we interrogated the expression of a key component of cellular iron regulation, the HFE (homeostatic iron regulatory) gene, on sexually dimorphic survival in GBM., Methods: We analyzed TCGA microarray gene expression and clinical data of all primary GBM patients ( IDH -wild type) to compare tumor mRNA expression of HFE with overall survival, stratified by sex., Results: In low HFE expressing tumors (below median expression, n = 220), survival is modulated by both sex and MGMT status, with the combination of female sex and MGMT methylation resulting in over a 10-month survival advantage ( P < .0001) over the other groups. Alternatively, expression of HFE above the median (high HFE , n = 240) is associated with significantly worse overall survival in GBM, regardless of MGMT methylation status or patient sex. Gene expression analysis uncovered a correlation between high HFE expression and expression of genes associated with immune function., Conclusions: The level of HFE expression in GBM has a sexually dimorphic impact on survival. Whereas HFE expression below the median imparts a survival benefit to females, high HFE expression is associated with significantly worse overall survival regardless of established prognostic factors such as sex or MGMT methylation., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes., Methods: Molecular and clinical data from glioma patients were obtained from The Cancer Genome Atlas and grouped according to tumor grade and molecular subtype ( IDH1/2 mutation and 1p/19q chromosomal deletion). Sex-specific differentially methylated probes (DMPs) were identified in each subtype and further analyzed to determine if they were part of differentially methylated regions (DMRs) or associated with differentially methylated DNA transcription regulatory binding motifs., Results: Analysis of methylation data in 4 glioma subtypes revealed unique sets of both sex-specific DMPs and DMRs in each subtype. Motif analysis based on DMP position also identified distinct sex-based sets of DNA-binding motifs that varied according to glioma subtype. Downstream targets of 2 of the GBM-specific transcription binding sites, NFAT5 and KLF6 , showed differential gene expression consistent with increased methylation mediating downregulation., Conclusion: DNA methylation differences between males and females in 4 glioma molecular subtypes suggest an important, sex-specific role for DNA methylation in epigenetic regulation of gliomagenesis., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Glioma growth can cause pervasive changes in the functional connectivity (FC) of brain networks, which has been associated with re-organization of brain functions and development of functional deficits in patients. Mechanisms underlying functional re-organization in brain networks are not understood and efforts to utilize functional imaging for surgical planning, or as a biomarker of functional outcomes are confounded by the heterogeneity in available human data. Here we apply multiple imaging modalities in a well-controlled murine model of glioma with extensive validation using human data to explore mechanisms of FC disruption due to glioma growth. We find gliomas cause both local and distal changes in FC. FC changes in networks proximal to the tumor occur secondary to hemodynamic alterations but surprisingly, remote FC changes are independent of hemodynamic mechanisms. Our data strongly implicate hemodynamic alterations as the main driver of local changes in measurements of FC in patients with glioma.

Background and Aims: Gender disparities exist in outcomes among patients with cirrhosis. We sought to evaluate the role of gender on hospital course and in-hospital outcomes in patients with cirrhosis to help better understand these disparities., Study: We analyzed data from the National Inpatient Sample (NIS), years 2009 to 2013, to identify patients with any diagnosis of cirrhosis. We calculated demographic and clinical characteristics by gender, as well as cirrhosis complications. Our primary outcome was inpatient mortality. We used logistic regression to associate baseline characteristics and cirrhosis complications with inpatient mortality., Results: Our cohort included 553,017 patients with cirrhosis admitted from 2009 to 2013. Women made up 39% of the cohort; median age was 57 with 66% non-Hispanic white. Women were more likely than men to have noncirrhosis comorbidities, including diabetes and hypertension but were less likely to have most cirrhosis complications, including ascites and variceal bleeding. Women were more likely than men to have acute bacterial infections (34.9% vs. 28.2%; P<0.001), and were less likely than men to die in the hospital on univariable (odds ratio, 0.88; 95% confidence interval, 0.86-0.90; P<0.001) and multivariable (odds ratio, 0.86; 95% confidence interval, 0.83-0.88; P<0.001) analysis., Conclusions: In patients hospitalized with cirrhosis, women have lower rates of hepatic decompensating events and higher rates of nonhepatic comorbidities and infections, resulting in lower in-hospital mortality. Understanding differences in indications for and disposition following hospitalization may help with the development of gender-specific cirrhosis management programs to improve long-term outcomes in women and men living with cirrhosis.

Background: Glioblastoma (GBM) is the most common and most malignant glioma. Nonglioblastoma (non-GBM) gliomas (WHO Grades II and III) are invasive and also often fatal. The goal of this study is to determine whether sex differences exist in glioma survival., Methods: Data were obtained from the National Cancer Database (NCDB) for years 2010 to 2014. GBM (WHO Grade IV; N = 2073) and non-GBM (WHO Grades II and III; N = 2963) were defined using the histology grouping of the Central Brain Tumor Registry of the United States. Non-GBM was divided into oligodendrogliomas/mixed gliomas and astrocytomas. Sex differences in survival were analyzed using Kaplan-Meier and multivariable Cox proportional hazards models adjusted for known prognostic variables., Results: There was a female survival advantage in patients with GBM both in the unadjusted ( P = .048) and adjusted ( P = .003) models. Unadjusted, median survival was 20.1 months (95% CI: 18.7-21.3 months) for women and 17.8 months (95% CI: 16.9-18.7 months) for men. Adjusted, median survival was 20.4 months (95% CI: 18.9-21.6 months) for women and 17.5 months (95% CI: 16.7-18.3 months) for men. When stratifying by age group (18-55 vs 56+ years at diagnosis), this female survival advantage appeared only in the older group, adjusting for covariates ( P = .017). Women (44.1%) had a higher proportion of methylated MGMT (O 6 -methylguanine-DNA methyltransferase) than men (38.4%). No sex differences were found for non-GBM., Conclusions: Using the NCDB data, there was a statistically significant female survival advantage in GBM, but not in non-GBM., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes 1-3 . Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Background: Hospital admissions are common among patients with cirrhosis, but patient factors associated with hospitalization have not been well characterized. Given recent data suggesting increased liver transplant waitlist dropout among women, we hypothesized that women on the liver transplant waitlist would have increased rates of hospitalization compared with men., Aim: To evaluate the role of gender on risk of hospitalization for patients on the liver transplant waitlist, in order to help explain gender disparities in waitlist outcomes., Methods: Patients listed for liver transplant at a single center in the United States were prospectively enrolled in the Functional Assessment in Liver Transplantation Study. Patients included in this retrospective analysis included those enrolled between March 2012 and December 2014 with at least 12 mo of follow up and without hepatocellular carcinoma. The primary and secondary outcomes were hospitalization and total inpatient days within 12 mo, respectively. Logistic and negative binomial regression associated baseline factors with outcomes., Results: Of the 392 patients, 41% were female, with median (interquartile range) age 58 years (52-63) and model for end- stage liver disease 18 (15-22). Within 12 mo, 186 (47%) patients were hospitalized ≥ 1 time; 48% were readmitted, with a median of 8 (4-15) inpatient days. More women than men were hospitalized (54% vs 43%; P = 0.03). In univariable analysis, female sex was associated with an increased risk of hospitalization [odds ratios (OR) 1.6, 95% confidence interval (CI) 1.0-2.4; P = 0.03], which remained significant on adjusted multivariable analysis (OR 1.6, 95%CI: 1.1-2.6; P = 0.03). Female gender was also associated with an increased number of inpatient days within 12 mo in both univariable and multivariable regression., Conclusion: Women with cirrhosis on the liver transplant waitlist have more hospitalizations and inpatient days in one year compared with men, suggesting that the experience of cirrhosis differs between men and women, despite similar baseline illness severity. Future studies should explore gender-specific vulnerabilities to help explain waitlist disparities., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Sex differences in the incidence and outcome of human disease are broadly recognized but, in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that standard therapy is more effective in female compared with male patients with GBM. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical relevance of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together, these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches., Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms., Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females., Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p 54-63 = 1.50x10 -9 , OR 54-63 = 1.28, 95%CI 54-63 = 1.18-1.39; p 64+ = 2.14x10 -11 , OR 64+ = 1.32, 95%CI 64+ = 1.21-1.43] and rs11979158 [p 54-63 = 6.13x10 -8 , OR 54-63 = 1.35, 95%CI 54-63 = 1.21-1.50; p 64+ = 2.18x10 -10 , OR 64+ = 1.42, 95%CI 64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p 18-53 = 9.30 × 10 -11 , OR 18-53 = 1.76, 95%CI 18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.', (© 2018 UICC.)

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets., Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment., Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%)., Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered 64 Cu-alloyed AuNCs ( 64 Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the 64 Cu-AuNCs. Second, 64 Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. 64 Cu-AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution of 64 Cu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower 64 Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of 64 Cu-AuNCs and TR-AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The goal of this study was to establish the feasibility of integrating focused ultrasound (FUS)-mediated delivery of 64 Cu-integrated gold nanoclusters ( 64 Cu-AuNCs) to the pons for in vivo quantification of the nanocluster brain uptake using positron emission tomography (PET) imaging. FUS was targeted at the pons for the blood-brain barrier (BBB) disruption in the presence of systemically injected microbubbles, followed by the intravenous injection of 64 Cu-AuNCs. The spatiotemporal distribution of the 64 Cu-AuNCs in the brain was quantified using in vivo microPET/CT imaging at different time points post injection. Following PET imaging, the accumulation of radioactivity in the pons was further confirmed using autoradiography and gamma counting, and the gold concentration was quantified using inductively coupled plasma-mass spectrometry (ICP-MS). We found that the noninvasive and localized BBB opening by the FUS successfully delivered the 64 Cu-AuNCs to the pons. We also demonstrated that in vivo real-time microPET/CT imaging was a reliable method for monitoring and quantifying the brain uptake of 64 Cu-AuNCs delivered by the FUS. This drug delivery platform that integrates FUS, radiolabeled nanoclusters, and PET imaging provides a new strategy for noninvasive and localized nanoparticle delivery to the pons with concurrent in vivo quantitative imaging to evaluate delivery efficiency. The long-term goal is to apply this drug delivery platform to the treatment of pontine gliomas., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sex differences in cancer incidence and survival, including central nervous system tumors, are well documented. Multiple mechanisms contribute to sex differences in health and disease. Recently, the presence of fetal-in-maternal microchimeric cells has been shown to have prognostic significance in breast and colorectal cancers. The frequency and potential role of these cells has not been investigated in brain tumors. We therefore selected two common primary adult brain tumors for this purpose: meningioma, which is sex hormone responsive and has a higher incidence in women, and glioblastoma, which is sex hormone independent and occurs more commonly in men. Quantitative PCR was used to detect the presence of male DNA in tumor samples from women with a positive history of male pregnancy and a diagnosis of either glioblastoma or meningioma. Fluorescence in situ hybridization for the X and Y chromosomes was used to verify the existence of intact male cells within tumor tissue. Fetal microchimerism was found in approximately 80% of glioblastoma cases and 50% of meningioma cases. No correlations were identified between the presence of microchimerism and commonly used clinical or molecular diagnostic features of disease. The impact of fetal microchimeric cells should be evaluated prospectively., (© 2017 International Society of Neuropathology.)

Focused ultrasound (FUS) technology is reported to enhance the delivery of 64 Cu-integrated ultrasmall gold nanoclusters ( 64 Cu-AuNCs) across the blood-brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, 64 Cu-AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of 64 Cu-AuNCs. Quantitative PET imaging post-FUS treatment shows site-targeted brain penetration, retention, and diffusion of the negative, neutral, and positive 64 Cu-AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of 64 Cu-AuNCs into the brain. Of the three 64 Cu-AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro-oncology., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)