Abstract
Commonly used for Parkinson’s disease (PD), deep brain stimulation (DBS) produces marked clinical benefits when optimized. However, assessing the large number of possible stimulation ...settings (i.e., programming) requires numerous clinic visits. Here, we examine whether functional magnetic resonance imaging (fMRI) can be used to predict optimal stimulation settings for individual patients. We analyze 3 T fMRI data prospectively acquired as part of an observational trial in 67 PD patients using optimal and non-optimal stimulation settings. Clinically optimal stimulation produces a characteristic fMRI brain response pattern marked by preferential engagement of the motor circuit. Then, we build a machine learning model predicting optimal vs. non-optimal settings using the fMRI patterns of 39 PD patients with a priori clinically optimized DBS (88% accuracy). The model predicts optimal stimulation settings in unseen datasets: a priori clinically optimized and stimulation-naïve PD patients. We propose that fMRI brain responses to DBS stimulation in PD patients could represent an objective biomarker of clinical response. Upon further validation with additional studies, these findings may open the door to functional imaging-assisted DBS programming.
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low‐grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of ...known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low‐grade glial‐glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5′ of the kinase domain, while the breakpoints in the 3′ partner preserved the N‐terminal kinesin‐interacting domain and coiled‐coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non‐classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re‐resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low‐grade glial‐glioneuronal tumors. We present the associated clinical, histopathologic and molecular features.
Abstract
Background
The prognosis for Li–Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development ...of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.
Methods
In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.
Results
The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup “SHH_3” (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).
Conclusions
LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
Graphical Abstract
Graphical Abstract
Purpose of Review
Malignant embryonal brain tumors (EBTs) of childhood span a wide clinical spectrum but can share remarkably similar morphologic features. This overlap presents significant ...diagnostic challenges, particularly for tumor entities that are rarely encountered in clinical practice and for which diagnostic criteria were poorly defined. This review will provide an update on the evolving characterization and treatment of rare EBTs.
Recent Findings
Rapid advances in genomic tools have led to the discovery of robust molecular markers, and identification of novel tumor types and subtypes for almost all major categories of pediatric brain tumors. These developments have had significant impact on improving the diagnostic classification of the rare EBTs, particularly for tumors with newly recognized
C19MC
alterations, central nervous system primitive neuroectodermal tumors (CNS-PNET), and pineoblastoma (PB).
Summary
These important developments in the clinical and molecular understanding of rare EBTs are paving the way for novel therapeutic strategies and improved clinical management.
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of ...PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (
DICER1
,
DROSHA
, and
DGCR8
) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic
MYC-miR-17/92-RB1
pathway were observed in the RB and MYC sub-group, respectively, characterized by
RB1
loss with gain of
miR-17/92
, and recurrent gain or amplification of
MYC
. PB sub-groups exhibited distinct clinical features: group 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent survival (5-year OS of 68.0–100%), while Group RB and MYC PB patients were much younger (median age 1.3–1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Thermochemical energy storage using salt hydrates is a promising method for the efficient use of energy. In this study, three host matrices, expanded vermiculite, expanded clay, and expanded natural ...graphite were impregnated with a eutectic mixture of CaCl2·6H2O and bischofite (MgCl2·6H2O). These composites were subjected to various humidity conditions (30–70% relative humidity) at 20 °C over an extended hydration period to investigate their cyclability. It was shown that only expanded natural graphite could contain the deliquescent salt at high humidity over 50 cycles. Hence, the expanded natural graphite composites containing either CaCl2·6H2O or CaCl2·6H2O/bischofite eutectic mixture were placed in a lab-scale open packed bed reactor, providing energy densities of 150 and 120 kWh/m3 over 20 h, respectively. The eutectic composite showed slightly lower temperature lift, water uptake rate, and power output but at reduced cost. Using the eutectic mixture also decreased the composite’s dehydration temperature at which the maximum mass loss rate occurred around 16.2 °C to 62.3 °C, allowing recharge using less energy-intensive heating methods. The cost of storing 1 kWh of energy with expanded natural graphite composites is only USD 0.08 due to its stability. This research leveraging cost-effective composites with enhanced stability, reaction kinetics, and high thermal energy storage capabilities benefits renewable energy, power generation, and the building construction research communities and industries by providing a competitive alternative to sensible heat storage technologies.
Bipolar disorder (BD) lacks objective measures for illness activity and treatment response. Electrodermal activity (EDA) is a quantitative measure of autonomic function, which is altered in manic and ...depressive episodes. We aimed to explore differences in EDA (1) inter-individually: between patients with BD on acute mood episodes, euthymic states and healthy controls (HC), and (2) intra-individually: longitudinally within patients during acute mood episodes of BD and after clinical remission.
A longitudinal observational study. EDA was recorded using a research-grade wearable in patients with BD during acute manic and depressive episodes and at clinical remission. Euthymic BD patients and HC were recorded during a single session. We compared EDA parameters derived from the tonic (mean EDA, mEDA) and phasic components (EDA peaks per minute, pmEDA, and EDA peaks mean amplitude, pmaEDA). Inter- and intra-individual comparisons were computed respectively with ANOVA and paired t-tests.
49 patients with BD (15 manic, 9 depressed, and 25 euthymic), and 19 HC were included. Patients with bipolar depression showed significantly reduced mEDA (p = 0.003) and pmEDA (p = 0.001), which increased to levels similar to euthymia or HC after clinical remission (mEDA, p = 0.011; pmEDA, p < 0.001; pmaEDA, p < 0.001). Manic patients showed no differences compared to euthymic patients and HCs, but a significant reduction of tonic and phasic EDA parameters after clinical remission (mEDA, p = 0.035; pmEDA, p = 0.004).
Limited sample size, high inter-individual variability of EDA parameters, limited comparability to previous studies and non-adjustment for medication.
EDA ecological monitoring might provide several opportunities for early detection of depressive symptoms, and might aid at assessing early response to treatments in mania and bipolar depression.
•EDA is reduced during bipolar depression and increases after remission.•Ecological monitoring of EDA might allow early detection of depressive symptoms.•Electrodermal activity (EDA) is reduced after remission of a manic episode.•EDA might aid to asses early response to treatment in mania and bipolar depression.
Mood disorders (MDs) are among the leading causes of disease burden worldwide. Limited specialized care availability remains a major bottleneck thus hindering pre-emptive interventions. MDs manifest ...with changes in mood, sleep, and motor activity, observable in ecological physiological recordings thanks to recent advances in wearable technology. Therefore, near-continuous and passive collection of physiological data from wearables in daily life, analyzable with machine learning (ML), could mitigate this problem, bringing MDs monitoring outside the clinician's office. Previous works predict a single label, either the disease state or a psychometric scale total score. However, clinical practice suggests that the same label may underlie different symptom profiles, requiring specific treatments. Here we bridge this gap by proposing a new task: inferring all items in HDRS and YMRS, the two most widely used standardized scales for assessing MDs symptoms, using physiological data from wearables. To that end, we develop a deep learning pipeline to score the symptoms of a large cohort of MD patients and show that agreement between predictions and assessments by an expert clinician is clinically significant (quadratic Cohen's κ and macro-average F1 score both of 0.609). While doing so, we investigate several solutions to the ML challenges associated with this task, including multi-task learning, class imbalance, ordinal target variables, and subject-invariant representations. Lastly, we illustrate the importance of testing on out-of-distribution samples.
Background
More than half of children with high‐risk neuroblastoma (NB) will experience recurrence. Radiologic imaging is used for initial staging and during therapy to assess response. However, the ...role of surveillance imaging in the detection of relapse has not been well studied. Surveillance potentially results in high cumulative exposure to ionizing radiation, which may be associated with an increased risk of developing second malignancies.
Procedure
We reviewed NB cases at our institution between 2000 and 2011. We calculated radiation exposure due to imaging (during diagnosis, treatment, and posttherapy surveillance) using cumulative effective dose (CED) estimates and determined whether cross‐sectional imaging identified recurrences.
Results
Fifty of 183 patients with NB experienced a recurrence. The median time from diagnosis to relapse was 1.20 years (range: 0.18–6.66 years). Most patients had evidence of metastases and only 4 of 50 patients presented with isolated primary tumor site recurrences. The mean CED prior to relapse was 125.2 mSv (range: 24.5–259.7), 64% of which was from computed tomography (CT) scans. Thirty‐seven of 50 patients had clinically evident or measurable disease detected by X‐ray (XR), ultrasound (US), or urinary catecholamines (UCats), and the addition of metaiodobenzylguanidine (MIBG) scans identified eight additional recurrences. Thus, cross‐sectional imaging (CT/MRI, where MRI is magnetic resonance imaging) was only required to identify 10% (5/50) of cases.
Conclusion
Relapsed disease was detected in most patients by symptoms/exam, MIBG scan, UCats, and/or XR/US, supporting reduced use of CT imaging in posttherapy surveillance, thereby decreasing cumulative radiation dose. Refinement of surveillance imaging may be further guided by risk stratification, disease sites, and potentially biomolecular markers.
Abstract Background Affective states influence the sympathetic nervous system, inducing variations in electrodermal activity (EDA), however, EDA association with bipolar disorder (BD) remains ...uncertain in real‐world settings due to confounders like physical activity and temperature. We analysed EDA separately during sleep and wakefulness due to varying confounders and potential differences in mood state discrimination capacities. Methods We monitored EDA from 102 participants with BD including 35 manic, 29 depressive, 38 euthymic patients, and 38 healthy controls (HC), for 48 h. Fifteen EDA features were inferred by mixed‐effect models for repeated measures considering sleep state, group and covariates. Results Thirteen EDA feature models were significantly influenced by sleep state, notably including phasic peaks ( p < 0.001). During wakefulness, phasic peaks showed different values for mania ( M SD = 6.49 5.74, 7.23), euthymia (5.89 4.83, 6.94), HC (3.04 1.65, 4.42), and depression (3.00 2.07, 3.92). Four phasic features during wakefulness better discriminated between HC and mania or euthymia, and between depression and euthymia or mania, compared to sleep. Mixed symptoms, average skin temperature, and anticholinergic medication affected the models, while sex and age did not. Conclusion EDA measured from awake recordings better distinguished between BD states than sleep recordings, when controlled by confounders.
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