Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Association of family characteristics with health status and needs among children with congenital heart disease.

INTRODUCTION: Low socio-economic status is associated with poorer quality of life among children with congenital heart disease (CHD), but this finding is based on disparities among children remaining under cardiology follow-up. We used a population-based health survey data set to analyse the impact of socio-economic status on health and functional status among children with CHD. MATERIALS AND METHODS: We used 2007-2018 National Health Interview Survey data, selecting children 2-17 years of age who had been diagnosed with CHD. Outcomes included caregiver-rated general health, presence of functional limitations, number of missed school days, need for special education, and need for special equipment related to the child's health conditions. Socio-economic status measures included maternal educational attainment, food stamp programme participation, poverty status, and insurance coverage. RESULTS: Based on a sample of 233 children with CHD, 10% had fair or poor health, 38% reported having any health-related limitation on their usual activities, 11% needed special equipment, and 27% received special education services. On multivariable analysis, lower maternal educational attainment was correlated with worse caregiver-rated health, and children without insurance were especially likely to experience functional limitations. Black children with CHD had significantly worse caregiver-rated health compared to White children (ordered logit odds ratio: 0.19; 95% confidence interval: 0.08, 0.45; p < 0.001). CONCLUSIONS: In a population-based survey of children with CHD, race and several measures of socio-economic status disadvantage were associated with worse health outcomes. Further evaluation of social determinants of health during cardiology follow-up may help improve outcomes for children with CHD in socio-economically disadvantaged families.

Two Cases of Cerebral Infarcts Caused by Topical Hemostatic Agent Embolism.

ABSTRACT: Resorbable topical hemostatic agents are widely used in surgical procedures to control intraoperative bleeding. There have been multiple reports of complications from use of these agents, including pulmonary vasculature thromboembolism, cerebral venous sinus occlusion, and postoperative inflammatory mass lesions each containing the hemostatic agent. We report 2 cases of inadvertent intra-arterial embolization of hemostatic agent. Both cases followed elective surgical cervical spinal procedures, during which gelatin-based local hemostatic agents were used to control unanticipated bleeding. Postoperatively, both patients exhibited neurologic defects and were found to have infarcts of the brain. At autopsy, vertebrobasilar thromboemboli containing foreign material grossly and microscopically consistent with hemostatic matrix material were found in both cases. These are the first reports of hemostatic agent embolization resulting in cerebral infarcts and leading to death.

Metastatic atypical meningioma to the parotid gland - A cytopathological correlation.

The tumors involving the parotid gland are mainly primary, with metastatic lesions comprising only 5% of malignant salivary gland neoplasms. We are presenting a rare case of metastatic meningioma to the parotid in a 51-year-old male with a past medical history of recurrent atypical meningioma involving the frontal lobe. For the past 1.5 years, routine imaging showed parotid lesions with interval growth including a 2.0 cm dominant tender preauricular parotid mass. The chronicity and the number of lesions made malignancy unlikely. The differential diagnosis included non-specific lesions such as intraparotid lymph nodes and benign neoplasms. Fine needle aspiration of the parotid mass was performed to show loosely cohesive fragments and singly scattered neoplastic cells with mild nuclear pleomorphism and oncocytic cytoplasm. The main cytomorphologic differential diagnosis included oncocytic and myoepithelial-rich tumors. The neoplastic cells were immunoreactive to p63, calponin and SSTR2A and were negative for cytokeratins, progesterone receptor, S100, DOG-1, EMA, synaptophysin, and chromogranin. The cytology slides and the parotid gland mass resection were compared to the previous meningioma resection specimen which showed a similar morphology of the oncocytic tumor cells in some areas. The overall morphologic and immunohistochemical findings of the parotid tumor were consistent with metastatic meningioma. Extracranial metastases from intracranial tumors are extremely rare. Meningiomas arise from the dura matter, constitute 15% of primary brain tumors, and metastasize at an estimated rate of 0.1%. Despite how uncommon metastatic meningioma is, our case emphasizes the critical role of clinical history when evaluating parotid gland lesions.

Spatial discrimination of glioblastoma and treatment effect with histologically-validated perfusion and diffusion magnetic resonance imaging metrics.

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

Amorphous Mixed-Metal Oxide Thin Films from Aqueous Solution Precursors with Near-Atomic Smoothness.

Thin films with tunable and homogeneous composition are required for many applications. We report the synthesis and characterization of a new class of compositionally homogeneous thin films that are amorphous solid solutions of Al2O3 and transition metal oxides (TMOx) including VOx, CrOx, MnOx, Fe2O3, CoOx, NiO, CuOx, and ZnO. The synthesis is enabled by the rapid decomposition of molecular transition-metal nitrates TM(NO3)x at low temperature along with precondensed oligomeric Al(OH)x(NO3)3-x cluster species, both of which can be processed from aq solution. The films are dense, ultrasmooth (Rrms < 1 nm, near 0.1 nm in many cases), and atomically mixed amorphous metal-oxide alloys over a large composition range. We assess the chemical principles that favor the formation of amorphous homogeneous films over rougher phase-segregated nanocrystalline films. The synthesis is easily extended to other compositions of transition and main-group metal oxides. To demonstrate versatility, we synthesized amorphous V0.1Cr0.1Mn0.1Fe0.1Zn0.1Al0.5Ox and V0.2Cr0.2Fe0.2Al0.4Ox with Rrms ≈ 0.1 nm and uniform composition. The combination of ideal physical properties (dense, smooth, uniform) and broad composition tunability provides a platform for film synthesis that can be used to study fundamental phenomena when the effects of transition metal cation identity, solid-state concentration of d-electrons or d-states, and/or crystallinity need to be controlled. The new platform has broad potential use in controlling interfacial phenomena such as electron transfer in solar-cell contacts or surface reactivity in heterogeneous catalysis.

Spinal osteoblastic meningioma with hematopoiesis: radiologic-pathologic correlation and review of the literature.

Spinal meningiomas associated with bone formation and hematopoiesis are rare tumors with only 3 prior case reports in the literature. We describe a case report of a woman who presented with back pain and an isolated event of urinary incontinence. A calcified spinal canal mass at T8 was identified on computed tomographic and magnetic resonance imaging. A gross total resection of the tumor was performed and pathologic examination showed a meningioma, World Health Organization grade 1, containing bone and bone marrow elements. A review of previously reported cases and a discussion of possible mechanisms of bone and hematopoiesis development in meningioma are presented.

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics.

Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNα was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM.

Hypervalence in monoxides and dioxides of superalkali clusters.

F2Li3, a superalkali cluster, is characterized as having a lower adiabatic ionization energy than its elemental alkali counterpart and, coupled with the presence of complex molecular orbitals, suggests promise for novel bonding possibilities. CBS-QB3 composite method was used to study three distinct cluster isomers, as well as their cationic (+1) and anionic (-1) species, to identify energetic trends and observe geometric changes. Oxides were then generated from these clusters, of which three distinct monoxides and nine dioxides were obtained upon structure optimization. Identical calculations were performed for the oxide species and their charged counterparts. Some of the most stable oxides produced appear to possess hypervalent lithium and oxygen atoms, forming unique structures with exceptional stability.

Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma.

Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.

Social Determinants of Outcomes Disparity among Pediatric Patients with Solid Tumor.

BACKGROUND: Socioeconomic factors have a significant impact on healthcare outcomes. Metrics such as area deprivation index (ADI) are used to quantify the anticipated influence of these factors. Here, we sought to assess the impact of socioeconomic factors on clinical outcomes among pediatric patients with solid tumor in our region. STUDY DESIGN: We identified 3,863 pediatric patients who were diagnosed with a malignant solid tumor in the Texas Cancer Registry between 1995 and 2019. ADI was used to quantify socioeconomic determinants of health. These outcome variables were determined: stage of disease at diagnosis, time between diagnosis and treatment initiation, and overall mortality. Statistical analysis was performed using logistic regression, linear regression, Cox proportional hazards regression, and Kaplan-Meier survival curves. RESULTS: A total of 53.5% of patients were male and the average age at diagnosis was 4.5 years. Forty-seven percent of patients were White, 13.3% were Black, 36.2% were Hispanic, 1.7% were Asian, and other rare minority groups made up 1.8%. On multivariable analysis, increased risk of death was associated with Black race, rare minority race, residence in a border county, and increasing ADI score, with the risk of death at 5 years rising 4% with each increasing ADI point. CONCLUSIONS: Social determinants of health are associated with disparate outcomes among pediatric patients with solid tumor. Our results suggest that patients who are part of racial minority groups and those who reside in socioeconomically disadvantaged neighborhoods or regions near the Texas-Mexico border are at an increased risk of death. This information may be useful in strategizing outreach and expanding resources to improve outcomes in at-risk communities.

Modeling protective action decision-making in earthquakes by using explainable machine learning and video data.

Earthquakes pose substantial threats to communities worldwide. Understanding how people respond to the fast-changing environment during earthquakes is crucial for reducing risks and saving lives. This study aims to study people's protective action decision-making in earthquakes by leveraging explainable machine learning and video data. Specifically, this study first collected real-world CCTV footage and video postings from social media platforms, and then identified and annotated changes in the environment and people's behavioral responses during the M7.1 2018 Anchorage earthquake. By using the fully annotated video data, we applied XGBoost, a widely-used machine learning method, to model and forecast people's protective actions (e.g., drop and cover, hold on, and evacuate) during the earthquake. Then, explainable machine learning techniques were used to reveal the complex, nonlinear relationships between different factors and people's choices of protective actions. Modeling results confirm that social and environmental cues played critical roles in affecting the probability of different protective actions. Certain factors, such as the earthquake shaking intensity and number of people shown in the environment, displayed evident nonlinear relationships with the probability of choosing to evacuate. These findings can help emergency managers and policymakers design more effective protective action recommendations during earthquakes.

A unified perspective of seismicity and fault coupling along the San Andreas Fault.

The San Andreas Fault (SAF) showcases the breadth of possible earthquake sizes and occurrence behavior; in particular, the central SAF is a microcosm of such diversity. This section also exhibits the spectrum of fault coupling from locked to creeping. Here, we show that the observations of aseismic slip, temporal clustering of seismicity, and spatial variations in earthquake size distributions are tightly connected. Specifically, the creep rate along the central SAF is shown to be directly proportional to the fraction of nonclustered earthquakes for the period 1984-2020. This relationship provides a unified perspective of earthquake phenomenology along the SAF, where lower coupling manifests in weaker temporal clustering, with repeating earthquakes as an end-member. This new paradigm provides additional justification for characterizing the northwest ∼75 kilometers of the creeping segment as a transition zone, with potential implications for seismic hazard.

The in-utero diagnosis of choledochal cyst: can postnatal imaging predict benefit from early surgical intervention?

BACKGROUND: Infants prenatally suspected of having a choledochal cyst (CDC) typically undergo ultrasound imaging shortly after birth. This study sought to evaluate features on the initial postnatal ultrasound (IPU) that could identify newborns at risk for early complications. METHODS: Following IRB approval, patients from four US fetal centers with prenatal suspicion for CDC and postnatal imaging from 2000 to 2017 were reviewed. Imaging and clinical courses were assessed. RESULTS: Forty-two patients had prenatal ultrasounds suspicious for CDC. Nineteen (45.2%) were excluded due to diagnostic revision (n = 9), cyst resolution (n = 5), lack of IPU measurements (n = 3), or lack of follow-up (n = 2). The 23 remaining patients were included in the study. Of these, five (21.7%) developed symptoms at a median age of 16.5 days (IQR 16-19 days), and 18 (78.3%) remained asymptomatic throughout the first year after birth. Five patients (21.7%) had cysts ≥ 4.5 cm on IPU (Symptomatic: n = 3; Asymptomatic: n = 2). Eighteen patients (78.3%) had cysts < 4.5 cm on IPU (Symptomatic: n = 2; Asymptomatic: n = 16). An IPU cyst size ≥ 4.5 cm was associated with neonatal symptom manifestation (p = 0.048), with 88.9% specificity (95% CI 65.3-98.6%) and 60% sensitivity (95% CI 14.7-94.7%). CONCLUSIONS: In newborns with prenatally diagnosed CDC, a cyst size ≥ 4.5 cm on IPU is associated with symptom development during the first month after birth and therefore early cyst excision is recommended.

Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma.

Background: Pulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect. Methods: We performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps. Results: The median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%). Conclusion: This case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation.

Intracranial Capillary Hemangiomas: A Peripartum Presentation and Review of the Literature.

BACKGROUND: Intracranial capillary hemangiomas (ICHs) are rare vascular tumors composed of a bed of many narrow thin-walled vessels. Within the confines of the skull, these tumors can lead to serious neurologic deficits including cranial nerve dysfunction, mood/personality disturbances, and signs of intracranial mass effect. METHODS: We report the case of a 23-year-old, 5-week postpartum woman with a history of progressive painful ophthalmalgia of the right eye presenting with rapid onset of ptosis, diplopia, and right-sided facial pain and hypesthesia. Imaging demonstrated a small extraaxial mass within the right cavernous sinus. She underwent 2 operations via an endoscopic endonasal approach for biopsy followed by complete resection. Histology showed a highly mitotic capillary hemangioma, which was negative for both estrogen and progesterone receptors. RESULTS: We review cases of ICH reported in the literature and provide an updated summary of the presentation, diagnosis, and treatment of ICH. We then present a brief analysis of the reported cases with respect to age and sex. CONCLUSIONS: We conclude that, in experienced hands, the endoscopic endonasal approach can be used to access the cavernous sinus for complete resection of ICHs of the cavernous sinus. We also suggest that further attention be paid to such cases in pregnant and peripartum women as these tumors may progress more quickly in this subpopulation.

Investigation of the physical, optical, and chemical properties of phase segregated AlCoOx thin films from a novel hexol-type cluster.

The use of a novel inorganic nanoscale cluster (Al[(µ-OH)2Co(NH3)4]3(NO3)6) was investigated for its utility as a precursor for AlCoOx films. Mixed-metal aluminum and cobalt oxide thin films were solution deposited from the novel cluster solution via the spin-coating method on Si (100) and quartz substrates. The films were annealed at increasing temperatures up to 800 °C, and characterization of these films via TEM and XRD confirms binary Co3O4 crystalline phase present in an amorphous Al2O3 network. Films are relatively smooth (Rrms < 4 nm), polycrystalline, and demonstrate a tunable optical response dominated by Co3O4 with two electronic transitions.

Magnetic Resonance Imaging Mapping of Brain Tumor Burden: Clinical Implications for Neurosurgical Management: Case Report.

BACKGROUND AND IMPORTANCE: Distinction of brain tumor progression from treatment effect on postcontrast magnetic resonance imaging (MRI) is an ongoing challenge in the management of brain tumor patients. A newly emerging MRI biomarker called fractional tumor burden (FTB) has demonstrated the ability to spatially distinguish high-grade brain tumor from treatment effect with important implications for surgical management and pathological diagnosis. CLINICAL PRESENTATION: A 58-yr-old male with glioblastoma was treated with standard concurrent chemoradiotherapy (CRT) after initial resection. Throughout follow-up imaging, the distinction of tumor progression from treatment effect was of concern. The surgical report from a redo resection indicated recurrent glioblastoma, while the tissue sent for pathological diagnosis revealed no tumor. Presurgical FTB maps confirmed the spatial variation of tumor and treatment effect within the contrast-agent enhancing lesion. Unresected lesion, shown to be an active tumor on FTB, was the site of substantial tumor growth postresection. CONCLUSION: This case report introduces the idea that a newly developed MRI biomarker, FTB, can provide information of tremendous benefit for surgical management, pathological diagnosis as well as subsequent treatment management decisions in high-grade glioma.

Intravascular Papillary Endothelial Hyperplasia of the Pineal Region: A Case Report and Review of the Literature.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular lesion that is uncommon in the central nervous system. To our knowledge, there has been only one previous report of occurrence in the pineal region. We present a second case and a review of the literature. CASE DESCRIPTION: A 28-year-old woman presented with 1 month of headaches and visual auras. Brain magnetic resonance imaging scan demonstrated a 2.6- × 1.8- × 1.3-cm nonenhancing T1-hypointense, T2-/fluid-attenuated inversion recovery-hyperintense pineal region mass with cerebral aqueduct obstruction and hydrocephalus. She underwent placement of a right extraventricular drain followed by complete surgical resection. Histologic analysis was consistent with IPEH. CONCLUSIONS: Although rare, IPEH is an entity that should be considered in the differential diagnosis for intracranial masses with radiographic features characteristic of vascular lesions. Tissue sampling is imperative for distinction from more malignant entities. Complete resection is curative and is the standard of care when feasible. Given the risk of local progression and neurologic compromise with subtotal resection of central nervous system lesions, further study regarding adjuvant treatment options is warranted.

3D fault architecture controls the dynamism of earthquake swarms.

The vibrant evolutionary patterns made by earthquake swarms are incompatible with standard, effectively two-dimensional (2D) models for general fault architecture. We leverage advances in earthquake monitoring with a deep-learning algorithm to image a fault zone hosting a 4-year-long swarm in southern California. We infer that fluids are naturally injected into the fault zone from below and diffuse through strike-parallel channels while triggering earthquakes. A permeability barrier initially limits up-dip swarm migration but ultimately is circumvented. This enables fluid migration within a shallower section of the fault with fundamentally different mechanical properties. Our observations provide high-resolution constraints on the processes by which swarms initiate, grow, and arrest. These findings illustrate how swarm evolution is strongly controlled by 3D variations in fault architecture.