Brain stem gliomas and current landscape Wummer, Brandon; Woodworth, Delaney; Flores, Catherine
Journal of neuro-oncology,
2021/1, Letnik:
151, Številka:
1
Journal Article
Recenzirano
Purpose
CNS malignancies are currently the most common cause of disease related deaths in children. Although brainstem gliomas are invariably fatal cancers in children, clinical studies against this ...disease are limited. This review is to lead to a succinct collection of knowledge of known biological mechanisms of this disease and discuss available therapeutics.
Methods
A hallmark of brainstem gliomas are mutations in the histone H3.3 with the majority of cases expressing the mutation K27M on histone 3.3. Recent studies using whole genome sequencing have revealed other mutations associated with disease. Current standard clinical practice may merely involve radiation and/or chemotherapy with little hope for long term survival. Here we discuss the potential of new therapies.
Conclusion
Despite the lack of treatment options using frequently practiced clinical techniques, immunotherapeutic strategies have recently been developed to target brainstem gliomas. To target brainstem gliomas, investigators are evaluating the use of broad non-targeted therapy with immune checkpoint inhibitors. Alternatively, others have begun to explore adoptive T cell strategies against these fatal malignancies.
Abstract
BACKGROUND
Mutated neoantigens have shown promise as targets for cancer immunotherapy but embryonal pediatric brain tumors with notoriously low mutational burden have more limited ...opportunities for neoantigen directed therapies. Evidence suggests that embryonal brain tumors such as medulloblastoma (MB) and brain stem gliomas (BSG) arise from the aberrant reactivation of fetal developmental programming. We explored the hypothesis that neonatal mouse cerebellum and brainstem express developmentally regulated proteins that could serve as potent tumor rejection antigens for a preclinical model of Group 3 MB (NSC) and H3.3K27M positive BSG (K2), respectively. We thus generated tumor-reactive T cells by using P5 cerebellum and P4 brain stem RNA as sources of antigens. P5-cerebellum-specific T cells (cDevAg-T cells) and P4-brain stem-specific T cells (bsDevAg-T cells) demonstrated effector function against respective MB and BSG tumor cells with exquisite specificity.
METHODS
RNA was isolated from P5 cerebellum and P4 brain stem and pulsed into bone marrow-derived dendritic cells. These were then used to in vitro activate splenocytes from previously immunized mice, generating either cDevAg-T cells or bsDevAg-T cells. In vitro functionality assays against tumor targets were conducted to determine reactivity and specificity. DevAg-T cells were used in adoptive cellular therapy in orthotopic models to determine therapeutic efficacy of DevAg-specific T cells in vivo. Results and
CONCLUSIONS
DevAg-T cells produce high levels of Th1-type cytokines that recognize distinct subtypes of MB and BSG, show no cross-reactivity with normal brain. Adoptive cellular therapy employing DevAg-specific T cells demonstrate a significant survival benefit in orthotopic models of established Group 3 NSC MB and H3.3K27M mutation positive BSG. Our studies demonstrate that RNA encoding non-mutated and organ-specific developmental antigens can serve as novel tumor rejection antigens for pediatric brain cancers.
Abstract
INTRODUCTION
Adoptive cellular therapy is demonstrably efficacious in two preclinical models of brain stem glioma (BSG), OB1 (wildtype H3.3), and K2 (H3.3K27M mutation). The survival benefit ...of adoptive cellular therapy is significantly enhanced by concomitant transfer of bone marrow derived hematopoietic stem cells (HSC) with tumor-reactive T cells. We demonstrate in orthotopic models that HSC-derived cells differentiate into dendritic cells within the tumor microenvironment and cross-prime adoptively transferred T lymphocytes in BSG. Using a novel method of 3D printing to fabricate microtumors using OB1 and K2 cells, we interrogate the BSG tumor microenvironment and demonstrate direct activation of tumor-reactive T cells in situ by HSC-derived dendritic cells.
METHODS
We employ orthotopic K2 and OB1 BSGs as well as an in vitro system using an innovative technique where 3Dtumoroids are fabricated using K2 and OB1 cells into engineered medium that allows in situ imaging over >30 days. Tumor-reactive T cells and HSCs are also applied to the system. T cells were generated using mice with fluorescent reporters. High resolution imaging is used for visualization of cell-to-cell interactions. Flowcytometry and immunofluorescence is used to confirm T cell and HSC immunophenotypes and activation status. RESULTS &
CONCLUSION
In orthotopic models of K2 and OB1, we found that HSCs are required for T cell infiltration to BSGs. T cell infiltration into BSG is an impactful observation in this tumor type. 3D models of BSG, tumor-reactive T cell infiltration was significantly increased in the presence of HSCs. Using T cells generated from GREAT mice which have YFP reporter on the IFNγ promoter, we visualized direct activation of tumor-reactive T cells in situ. These studies are unique in that the in situ interrogation of BSG is not possible due to location. Here were are able to bypass this limitation with this technology to make key immunological observations.
Abstract
INTRODUCTION
The T cell repertoire of brain tumor bearing hosts has been previously described to be skewed to have increased regulatory phenotype relative to healthy hosts (Woroniecka et al ...2018). We have found that hematopoietic stem cells (HSCs) isolated from tumor bearing mice are inefficient at engraftment and reconstitution of the hematopoietic compartment, giving rise to less live cells than HSCs derived from healthy controls. We found that CD4+ splenocytes and CD8+ bone marrow-derived cells and splenocytes that arise from HSCs of tumor bearing hosts are polarized towards a terminal memory phenotype relative to HSCs derived from healthy hosts. We believe that this dysregulation in T cell reconstitution is a major player in mounting immune responses against CNS malignancies.
METHODS
Lineage negative HSCs were isolated from GFP transgenic healthy donors or DsRed transgenic tumor-bearing mice and adoptively transferred into C57BL/6 recipient cohort of lethally irradiated mice. HSCs are derived from DsRed or GFP transgenic mice to allow for tracking of HSC-derived populations. One month after transfer, mice are sacrificed and spleen, bone marrow, and blood are harvested and stained for flow cytometry. RESULTS &
CONCLUSIONS
T cells derived from TB HSCs have a distinct phenotype compared to T cells from healthy HSCs, demonstrating intracranial brain tumors likely have an impact on HSC differentiation outcomes.
Studies suggest that pregnant women might be at increased risk for severe illness associated with coronavirus disease 2019 (COVID-19) (1,2). This report provides updated information about symptomatic ...women of reproductive age (15-44 years) with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19. During January 22-October 3, CDC received reports through national COVID-19 case surveillance or through the National Notifiable Diseases Surveillance System (NNDSS) of 1,300,938 women aged 15-44 years with laboratory results indicative of acute infection with SARS-CoV-2. Data on pregnancy status were available for 461,825 (35.5%) women with laboratory-confirmed infection, 409,462 (88.7%) of whom were symptomatic. Among symptomatic women, 23,434 (5.7%) were reported to be pregnant. After adjusting for age, race/ethnicity, and underlying medical conditions, pregnant women were significantly more likely than were nonpregnant women to be admitted to an intensive care unit (ICU) (10.5 versus 3.9 per 1,000 cases; adjusted risk ratio aRR = 3.0; 95% confidence interval CI = 2.6-3.4), receive invasive ventilation (2.9 versus 1.1 per 1,000 cases; aRR = 2.9; 95% CI = 2.2-3.8), receive extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases; aRR = 2.4; 95% CI = 1.5-4.0), and die (1.5 versus 1.2 per 1,000 cases; aRR = 1.7; 95% CI = 1.2-2.4). Stratifying these analyses by age and race/ethnicity highlighted disparities in risk by subgroup. Although the absolute risks for severe outcomes for women were low, pregnant women were at increased risk for severe COVID-19-associated illness. To reduce the risk for severe illness and death from COVID-19, pregnant women should be counseled about the importance of seeking prompt medical care if they have symptoms and measures to prevent SARS-CoV-2 infection should be strongly emphasized for pregnant women and their families during all medical encounters, including prenatal care visits. Understanding COVID-19-associated risks among pregnant women is important for prevention counseling and clinical care and treatment.
Introduction
Public health responses often lack the infrastructure to capture the impact of public health emergencies on pregnant women and infants, with limited mechanisms for linking pregnant women ...with their infants nationally to monitor long-term effects. In 2019, the Centers for Disease Control and Prevention (CDC), in close collaboration with state, local, and territorial health departments, began a 5-year initiative to establish population-based mother–baby linked longitudinal surveillance, the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET).
Objectives
The objective of this report is to describe an expanded surveillance approach that leverages and modernizes existing surveillance systems to address the impact of emerging health threats during pregnancy on pregnant women and their infants.
Methods
Mother–baby pairs are identified through prospective identification during pregnancy and/or identification of an infant with retrospective linking to maternal information. All data are obtained from existing data sources (e.g., electronic medical records, vital statistics, laboratory reports, and health department investigations and case reporting).
Results
Variables were selected for inclusion to address key surveillance questions proposed by CDC and health department subject matter experts. General variables include maternal demographics and health history, pregnancy and infant outcomes, maternal and infant laboratory results, and child health outcomes up to the second birthday. Exposure-specific modular variables are included for hepatitis C, syphilis, and Coronavirus Disease 2019 (COVID-19). The system is structured into four relational datasets (maternal, pregnancy outcomes and birth, infant/child follow-up, and laboratory testing).
Discussion
SET-NET provides a population-based mother–baby linked longitudinal surveillance approach and has already demonstrated rapid adaptation to COVID-19. This innovative approach leverages existing data sources and rapidly collects data and informs clinical guidance and practice. These data can help to reduce exposure risk and adverse outcomes among pregnant women and their infants, direct public health action, and strengthen public health systems.
Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness and might be at risk for preterm birth (1-3). The full impact of infection with SARS-CoV-2, the virus ...that causes COVID-19, in pregnancy is unknown. Public health jurisdictions report information, including pregnancy status, on confirmed and probable COVID-19 cases to CDC through the National Notifiable Diseases Surveillance System.* Through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET), 16 jurisdictions collected supplementary information on pregnancy and infant outcomes among 5,252 women with laboratory-confirmed SARS-CoV-2 infection reported during March 29-October 14, 2020. Among 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019 (4). Among 610 infants (21.3%) with reported SARS-CoV-2 test results, perinatal infection was infrequent (2.6%) and occurred primarily among infants whose mother had SARS-CoV-2 infection identified within 1 week of delivery. Because the majority of pregnant women with COVID-19 reported thus far experienced infection in the third trimester, ongoing surveillance is needed to assess effects of infections in early pregnancy, as well the longer-term outcomes of exposed infants. These findings can inform neonatal testing recommendations, clinical practice, and public health action and can be used by health care providers to counsel pregnant women on the risks of SARS-CoV-2 infection, including preterm births. Pregnant women and their household members should follow recommended infection prevention measures, including wearing a mask, social distancing, and frequent handwashing when going out or interacting with others or if there is a person within the household who has had exposure to COVID-19.
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Background
The US Zika Pregnancy and Infant Registry (USZPIR) monitors infants born to mothers with confirmed or possible Zika virus infection during pregnancy. The surveillance case definition for ...Zika‐associated birth defects includes microcephaly based on head circumference (HC).
Methods
We assessed birth and follow‐up data from infants with birth HC measurements <3rd percentile and birthweight ≥10th percentile to determine possible misclassification of microcephaly. We developed a schema informed by literature review and expert opinion to identify possible HC measurement inaccuracy using HC growth velocity and longitudinal HC measurements between 2 and 12 months of age. Two or more HC measurements were required for assessment. Inaccuracy in birth HC measurement was suspected if growth velocity was >3 cm/month in the first 3 months or HC was consistently >25th percentile during follow‐up.
Results
Of 6,799 liveborn infants in USZPIR, 351 (5.2%) had Zika‐associated birth defects, of which 111 had birth HC measurements <3rd percentile and birthweight ≥10th percentile. Of 84/111 infants with sufficient follow‐up, 38/84 (45%) were classified as having possible inaccuracy of birth HC measurement, 19/84 (23%) had HC ≥3rd percentile on follow‐up without meeting criteria for possible inaccuracy, and 27/84 (32%) had continued HC <3rd percentile. After excluding possible inaccuracies, the proportion of infants with Zika‐associated birth defects including microcephaly decreased from 5.2% to 4.6%.
Conclusions
About one‐third of infants in USZPIR with Zika‐associated birth defects had only microcephaly, but indications of possible measurement inaccuracy were common. Implementation of this schema in longitudinal studies can reduce misclassification of microcephaly.
Background
Spontaneous cerebrospinal fluid (sCSF) leaks develop from pressure erosion due to idiopathic intracranial hypertension, treatment of which is paramount to preventing recurrence. Direct ...measurements of intracranial pressure (ICP) for monitoring response to treatment via lumbar drain (LD) or ventriculostomy are invasive and have risks. The objectives of this study are to determine whether ultrasonographic measurements of optic nerve sheath diameter (ONSD) correlate with LD ICP in patients with sCSF leaks undergoing treatment, and whether ONSDs are larger in patients with sCSF leaks than controls.
Methods
Subjects with sCSF leaks and controls were prospectively recruited. ONSD, sex, and body mass index (BMI) were analyzed. For sCSF leak subjects, ultrasonography was performed at the time of LD opening and each pressure check postoperatively, including the acetazolamide response. In control patients, measurements were obtained at the time of surgery. Pearson's correlation between ONSD and ICP was performed.
Results
Subjects with sCSF leaks (n = 9, age 52.4 ± 9.5, all female) and controls (n = 8, age 60.1 ± 14.8, two females) had significantly different BMIs, 38.4 ± 8.1 vs. 29.2 ± 4.8, t(15) = 2.793, p = 0.014. ONSD was strongly correlated with ICP measurements (r = 0.583, p = 0.002). However, percentage change in ONSD and ICP measurements were more strongly correlated (r = 0.733, p < 0.001). Patients with sCSF leaks had significantly higher ONSDs than controls, 0.63 cm ± 0.044 vs. 0.56 cm ± 0.074, t(15) = 2.329, p = 0.034.
Conclusion
ONSD significantly correlated with ICP in sCSF leak patients and was wider in sCSF leak subjects than controls. Ultrasonography has utility in monitoring the ICP response to acetazolamide.
Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and ...optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.
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