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Abstract Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients.

Background: We sought to understand the innovativeness of nurses engaging in innovative behaviors and quantify the associated characteristics that make nurses more able to innovate in practice. We first compared the innovativeness scores of our population; then we examined those who self-identified as an innovator versus those who did not to explore differences associated with innovativeness between these groups. Methods: A cross-sectional survey study of nurses in the US engaging in innovative behaviors was performed. We performed an exploratory factor analysis (EFA) to determine the correlates of innovative behavior. Results: Three-hundred and twenty-nine respondents completed the survey. Respondents who viewed themselves as innovators had greater exposure to HCD/DT workshops in the past year (55.8% vs. 36.6%, p = 0.02). The mean innovativeness score of our sample was 120.3 ± 11.2 out of a score of 140. The mean innovativeness score was higher for those who self-identified as an innovator compared with those who did not (121.3 ± 10.2 vs. 112.9 ± 14.8, p =< 0.001). The EFA created four factor groups: Factor 1 (risk aversion), Factor 2 (willingness to try new things), Factor 3 (creativity and originality) and Factor 4 (being challenged). Conclusion: Nurses who view themselves as innovators have higher innovativeness scores compared with those who do not. Multiple individual and organizational characteristics are associated with the innovativeness of nurses.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) account for 3–10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance. Results We studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions. By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort. Conclusion DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a ‘hybrid’ category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

Abstract Background Anxiety is common in older adults and social isolation is one of the leading factors associated with their anxiety. However, what is unknown is how the relationship between social isolation and anxiety differs by cognitive status. Therefore, this study was conducted to (1) compare the level of social isolation and anxiety in older adults who developed probable dementia and mild cognitive impairment (MCI) to those who maintained normal cognitive function over 5 years; and (2) determine if cognitive impairment moderates the relationship between changes in social isolation and changes in anxiety over 5 years. Methods A secondary data analysis was conducted using the National Social Life, Health, and Aging Project (NSHAP): Wave 2 (2010–2011) and Wave 3 (2015–2016). The participants were categorized into three groups: Participants who developed probable dementia over 5 years (4.3%), developed probable MCI (19.1%), or maintained normal cognitive function (76.6%). Weighted linear regression analyses with a group interaction were used to examine the moderating effect of cognitive impairment on the relationship between changes in social isolation and anxiety. Results At the 5-year follow up, there were statistically significant differences in social isolation between the three groups (p = 0.043). Regression analyses showed that increased social isolation over time was related to increased anxiety over 5 years regardless of cognitive status after controlling for covariates (p = 0.017). Conclusions The relationship between social isolation and anxiety was a universal phenomenon regardless of cognitive status. Tailored interventions targeting both people with or without cognitive impairment are needed to lessen social isolation and anxiety.

Background and purpose: Differentiating pediatric posterior fossa (PF) tumors such as medulloblastoma (MB), ependymoma (EP), and pilocytic astrocytoma (PA) remains relevant, because of important treatment and prognostic implications. Diffusion kurtosis imaging (DKI) has not yet been investigated for discrimination of pediatric PF tumors. Estimating diffusion values from whole-tumor-based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and assess DKI accuracy in discriminating among pediatric PF tumors. Materials and methods: We retrospectively analyzed 34 children (M, F, mean age 7.48 years) with PF tumors who underwent preoperative examination on a 3 Tesla magnet, including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor, the ROI of the area of maximum tumor diameter, and a small 5 mm ROI. The automated analysis pipeline included inter-observer variability, statistical, and machine learning (ML) analyses. We evaluated inter-observer variability with coefficient of variation (COV) and Bland–Altman plots. We estimated DKI metrics accuracy in discriminating among tumor histology with MANOVA analysis. In order to account for class imbalances, we applied SMOTE to balance the dataset. Finally, we performed a Random Forest (RF) machine learning classification analysis based on all DKI metrics from the SMOTE dataset by partitioning 70/30 the training and testing cohort. Results: Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14), and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics and were used for the analysis. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p < 0.001). SMOTE generated 11 synthetic observations (10 EP and 1 PA), resulting in a balanced dataset with 45 instances (34 original and 11 synthetic). ML analysis yielded an accuracy of 0.928, which correctly predicted all but one lesion in the testing set. Conclusions: VOI-based measurements presented improved repeatability compared to ROI-based measurements across all diffusion metrics. An ML classification algorithm resulted accurate in discriminating PF tumors on a SMOTE-generated dataset. ML techniques based on DKI-derived metrics are useful for the discrimination of pediatric PF tumors.

BackgroundIntracranial mesenchymal tumors are a rare type of neoplasm (0.3% of all soft tissue tumors) characterized by a fusion of a FET family gene (usually EWSR1, rarely FUS) to CREB family genes (CREB1, ATF1, and CREM) with a slow-growing and favorable prognosis. Mesenchymal tumors are most frequently localized in the subcutaneous tissue (typically in the limbs and hands) of young adults and have rarely been diagnosed in the central nervous system. Surgery is the gold standard treatment; adjuvant radiation therapy and chemotherapy with sarcoma-based regimens have been used in rare cases when complete surgical excision was not recommended. In terms of prognosis, these tumors show a tendency for local relapse. The longest patient outcomes reported in the literature are five years.Case descriptionThis case describes a 27-year-old woman with unconventional extracranial metastatic sites of myxoid intracranial mesenchymal tumor FET::CREB fusion-positive and high expression of PD-1 (40%) and PD-L1 (30%). Based on clinical, molecular, and histological characteristics, she underwent various local and systemic therapies, including surgery, proton beam therapy, the use of immune checkpoint inhibitors, and chemotherapy. These treatments led to a complete remission of the disease after eight years from tumor diagnosis.ConclusionsOur case sheds light on the importance of precision medicine and tailored therapy to explore new treatment opportunities for rare or unknown tumor entities.

The objective of this cross-sectional study was to determine the extent and nature of self-reported musical abilities in persons with mild cognitive impairment (MCI). We recruited 60 older adults with a diagnosis of MCI from the Alzheimer's disease Core Center. We evaluated self-reported musical abilities using the Goldsmiths General Musical Sophistication Index. We examined correlations between musical abilities and neuropsychological measures of verbal learning and memory, processing speed, executive function, verbal fluency, naming and visuoconstructive abilities, while controlling for key demographic and participant characteristics. Older adults with MCI reported varying degrees of musical abilities. Nearly half of participants reported that they did not engage in regular, daily practice of a musical instrument. When adjusting for key demographic and participant characteristics, we found modest associations between four musical ability subfactors (active engagement, perceptual abilities, musical training and emotional engagement with music) with three cognitive abilities: verbal fluency, executive function and verbal naming. Except for the emotional engagement with music subfactor, none of the remaining musical ability subfactors correlated with any demographic or participant characteristics. While our study findings provided further support for the relationship between musical and cognitive abilities in older adults with MCI, this relationship warrants further investigation.

BackgroundGerm cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout.Materials and methodsWe report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021.ResultsMost frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment.ConclusionsOur data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

IntroductionPediatric diffuse midline gliomas (DMG), H3 K27- altered, are the most aggressive pediatric central nervous system (CNS) malignancies. Disease outcome is dismal with a median survival of less than one year. Extra-neural metastases are an unusual occurrence in DMG and have been rarely described.Methods and resultsHere, we report on two pediatric patients affected by DMG with extra-neural dissemination. Their clinical, imaging, and molecular characteristics are reported here. An 11-year-old male 5 months after the diagnosis of diffuse intrinsic pontine glioma (DIPG) developed metastatic osseous lesions confirmed with computed tomography (CT) guided biopsy of the left iliac bone. The patient died one month after the evidence of metastatic progression. Another 11-year-old female was diagnosed with a cerebellar H3K27- altered DMG. After six months, she developed diffuse sclerotic osseous lesions. A CT-guided biopsy of the right iliac bone was non-diagnostic. She further developed multifocal chest and abdominal lymphadenopathy and pleural effusions. Droplet digital polymerase chain reaction (ddPCR) on pleural effusion revealed the presence of H3.3A mutation (c.83A>T, p.K28M). The patient died 24 months after the diagnosis of DMG and 3 months after the evidence of metastatic pleural effusion.DiscussionExtra-neural metastasis of DMG is a rare event and no standard therapy exists. An accurate and early diagnosis is necessary in order to develop a personalized plan of treatment. Further research is needed to gain further insights into the molecular pathology of DMG, H3K27- altered and improve the quality of life and the final outcome of patients with this deadly disease.

The relationship between language and thought is controversial. One hypothesis is that language fosters habits of processing information that are retained even in non-linguistic domains. In left-branching (LB) languages, modifiers usually precede the head, and real-time sentence comprehension may more heavily rely on retaining initial information in working memory. Here we presented a battery of working memory and short-term memory tasks to adult native speakers of four LB and four right-branching (RB) languages from Africa, Asia and Europe. In working memory tasks, LB speakers were better than RB speakers at recalling initial stimuli, but worse at recalling final stimuli. Our results show that the practice of parsing sentences in specific directions due to the syntax and word order of our native language not only predicts the way we remember words, but also other non-linguistic stimuli.

Abstract Background Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p

Purpose: The purpose of this qualitative study was to discover rural family dementia caregivers’ lived experience in a virtual dementia simulation and how it affected their understanding of their family members’ daily challenges. To our knowledge, this study is the first to document its impact and value in this understudied, under-reported, and under-represented population. Sample: A volunteer sample of 10 rural family caregivers of persons with AD/ADRD following participation in a rural eastern North Carolina community delivered AD/ADRD simulation. Method: In-depth interviews lasting 45-110 minutes were conducted. The Utrecht phenomenology analytic method was used to sort, analyze, and interpret data. Richness of data drove the sample size. Results: The volunteer participants were female familial caregivers ages ranged from 49 to 81. Their care recipients’ ages ranged from 62 to 93 years. Eighty percent of the caregivers provided care for their loved ones 6-7 days a week. Only one caregiver had formal (paid) assistance for care provision. The themes Now I Understand, Opened My Eyes, and Making Changes emerged from the participants' statements. Conclusion: Rural family caregivers found the AD/ADRD simulation profoundly impacted their perceptions of AD/ADRD and expressed new understandings and eye-opening epiphanies about their family members’ daily challenges with dementia and their planned changes to improve their loved ones’ quality of life. The AD/ADRD simulated experience provided participants with a unique opportunity for self-discovery about their loved ones’ daily challenges. This original study addresses the paucity of literature and research about AD/ADRD simulations for rural caregivers of persons with AD/ADRD. This study further demonstrates the value of AD/ADRD simulation to rural nursing practice and science. These findings may prompt rural health nurses to encourage family caregiver participation in person-in-context simulations to enhance their understanding of the loved ones’ lived experience. Keywords: interpretative thematic analysis, dementia simulation, family caregiver, qualitative research, neurocognitive syndrome DOI: https://doi.org/10.14574/ojrnhc.v22i1.695

Childhood malignant brain tumors remain a significant cause of death in the pediatric population, despite the use of aggressive multimodal treatments. New therapeutic approaches are urgently needed for these patients in order to improve prognosis, while reducing side effects and long-term sequelae of the treatment. Immunotherapy is an attractive option and, in particular, the use of gene-modified T cells expressing a chimeric antigen receptor (CAR-T cells) represents a promising approach. Major hurdles in the clinical application of this approach in neuro-oncology, however, exist. The peculiar location of brain tumors leads to both a difficulty of access to the tumor mass, shielded by the blood-brain barrier (BBB), and to an increased risk of potentially life-threatening neurotoxicity, due to the primary location of the disease in the CNS and the low intracranial volume reserve. There are no unequivocal data on the best way of CAR-T cell administration. Multiple trials exploring the use of CD19 CAR-T cells for hematologic malignancies proved that genetically engineered T cells can cross the BBB, suggesting that systemically administered CAR-T cell can be used in the neuro-oncology setting. Intrathecal and intra-tumoral delivery can be easily managed with local implantable devices, suitable also for a more precise neuro-monitoring. The identification of specific approaches of neuro-monitoring is of utmost importance in these patients. In the present review, we highlight the most relevant potential challenges associated with the application of CAR-T cell therapy in pediatric brain cancers, focusing on the evaluation of the best route of delivery, the peculiar risk of neurotoxicity and the related neuro-monitoring.

Development of the cerebellum is characterized by rapid proliferation of cerebellar granule cell precursors (GCPs) induced by paracrine stimulation of Sonic hedgehog (Shh) signaling from Purkinje cells, in the external granular layer (EGL). Then, granule cell precursors differentiate and migrate into the inner granular layer (IGL) of the cerebellum to form a terminally differentiated cell compartment. Aberrant activation of Sonic hedgehog signaling leads to granule cell precursors hyperproliferation and the onset of Sonic hedgehog medulloblastoma (MB), the most common embryonal brain tumor. β-arrestin1 (ARRB1) protein plays an important role downstream of Smoothened, a component of the Sonic hedgehog pathway. In the medulloblastoma context, β-arrestin1 is involved in a regulatory axis in association with the acetyltransferase P300, leading to the acetylated form of the transcription factor E2F1 (E2F1-ac) and redirecting its activity toward pro-apoptotic gene targets. This axis in the granule cell precursors physiological context has not been investigated yet. In this study, we demonstrate that β-arrestin1 has antiproliferative and pro-apoptotic functions in cerebellar development. β-arrestin1 silencing increases proliferation of Sonic hedgehog treated-cerebellar precursor cells while decreases the transcription of E2F1-ac pro-apoptotic targets genes, thus impairing apoptosis. Indeed, chromatin immunoprecipitation experiments show a direct interaction between β-arrestin1 and the promoter regions of the pro-apoptotic E2F1 target gene and P27, indicating the double role of β-arrestin1 in controlling apoptosis and cell cycle exit in a physiological context. Our data elucidate the role of β-arrestin1 in the early postnatal stages of cerebellar development, in those cell compartments that give rise to medulloblastoma. This series of experiments suggests that the physiological function of β-arrestin1 in neuronal progenitors is to directly control, cooperating with E2F1 acetylated form, transcription of pro-apoptotic genes.

Telomerase protects chromosome ends in stem cells and cancer cells. Here the authors show that Trimethylguaonsine Synthase 1 (TGS-1) – dependent trimethylguanosine capping of the RNA component of the human telomerase complex has an important role in directing telomere dependent telomere maintenance and suppressing the ALT pathway in cancer cells.

It has been suggested that due to functional similarity, sortal object individuation might be a primordial form of psychological essentialism. For example, the relative independence of identity judgment from perceived surface features is a characteristic of essentialist reasoning. Also, infants engaging in sortal object individuation pay more attention to kind than surface feature information when judging the identity of objects (e.g.). Indeed, previous research found that 14-month-old infants can judge trans-temporal identity even in complete absence of kind-specific surface features. Here, we used another more demanding non-linguistic paradigm to test the limits of these abilities in 14-, 18-, 23- and 36-month-old infants, comparing their performance to recent great ape data. Particularly, we presented infants with two food kinds, whose surface features were then fully transformed to make them look identical. If reasoning according to essentialist principles, participants should select the preferred item despite superficial manipulations. However, only 36-month-olds reliably tracked the preferred item after superficial manipulations. This suggests that, although basic psychological essentialism may emerge early in infancy, more complex forms require domain-general cognitive prerequisites, which only develop in more protracted form.

Introduction Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. Methods We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. Results Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. Conclusions In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

The importance of aldehydes in a number of industries has been well established, and therefore there is a resulting need to effectively and accurately monitor them. We report the application of a methyl acetoacetate derivatisation reaction to enable the analysis of aldehydes by HPLC-UV. This derivatisation reaction has been compared to alternative derivatisation reactions with nitrophenylhydrazines, resulting preferable since it yielded a more intense signal of the compound of interest and less interfering peaks. The derivatisation reaction was then optimised and applied for the analysis of short chained aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde and isobutyraldehyde, investigating parameters such as sensitivity, linearity, accuracy, and precision. This strategy has been successfully deployed also for determination of formaldehyde in a 25% w/w sodium methoxide solution in methanol at a target level of 200 ppm. Finally, this derivatisation reaction has been adjusted to enable the development of a robust chiral analytical method for a water sensitive aldehyde.