Subgroup-specific roles of primary cilia in medulloblastoma.

Here I discuss the study in this issue of Genes & Development by Youn et al. (pp. 737-751), which describes defined and diverse roles of primary cilia in molecularly distinct medulloblastoma subgroups, highlighting once again the importance of designing subgroup-specific therapeutic approaches for this tumor.

TAp73 is a marker of glutamine addiction in medulloblastoma.

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

Harnessing brain development to understand brain tumours.

Brain tumours are the commonest solid neoplasms in children, accounting for one quarter of all childhood cancers. Our growing knowledge of basic developmental mechanisms has significantly contributed to understanding the pathogenesis of these tumours and is beginning to impact clinical decisions on how children with these diseases are treated.

Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma.

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades Narginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib by increasing: 1) killing of human MM cells by stimulating both bortezomib mediated apoptosis and necroptosis, a process regulated by p62; and 2) preservation of bone mass by stimulating osteoblasts differentiation and inhibiting osteoclastic bone destruction. Co-administration of bortezomib and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, coadministration of bortezomib and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti-MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.

Children under 6 years with acute headache in Pediatric Emergency Departments. A 2-year retrospective exploratory multicenter Italian study.

BACKGROUND: Preschool age (i.e. children under six years of age) represents a red flag for requiring neuroimaging to exclude secondary potentially urgent intracranial conditions (PUIC) in patients with acute headache. We investigated the clinical characteristics of preschoolers with headache to identify the features associated with a greater risk of secondary "dangerous" headache. METHODS: We performed a multicenter exploratory retrospective study in Italy from January 2017 to December 2018. Preschoolers with new-onset non-traumatic headache admitted to emergency department were included and were subsequently divided into two groups: hospitalized and discharged. Among hospitalized patients, we investigated the characteristics linked to potentially urgent intracranial conditions. RESULTS: We included 1455 preschoolers with acute headache. Vomiting, ocular motility disorders, ataxia, presence of neurological symptoms and signs, torticollis and nocturnal awakening were significantly associated to hospitalization. Among the 95 hospitalized patients, 34 (2.3%) had potentially urgent intracranial conditions and more frequently they had neurological symptoms and signs, papilledema, ataxia, cranial nerves paralysis, nocturnal awakening and vomiting. Nevertheless, on multivariable logistic regression analysis, we found that only ataxia and vomiting were associated with potentially urgent intracranial conditions. CONCLUSION: Our study identified clinical features that should be carefully evaluated in the emergency department in order to obtain a prompt diagnosis and treatment of potentially urgent intracranial conditions. The prevalence of potentially urgent intracranial conditions was low in the emergency department, which may suggest that age under six should not be considered an important risk factor for malignant causes as previously thought.

Sonodynamic therapy and magnetic resonance-guided focused ultrasound: new therapeutic strategy in glioblastoma.

Glioblastoma (GB) is one of the most aggressive and difficult-to-treat brain tumors, with a poor prognosis and limited treatment options. In recent years, sonodynamic therapy (SDT) and magnetic resonance focused ultrasound (MRgFUS) have emerged as promising approaches for the treatment of GB. SDT uses ultrasound waves in combination with a sonosensitizer to selectively damage cancer cells, while MRgFUS delivers high-intensity ultrasound waves to precisely target tumor tissue and disrupt the blood-brain barrier to enhance drug delivery. In this review, we explore the potential of SDT as a novel therapeutic strategy for GB. We discuss the principles of SDT, its mechanisms of action, and the preclinical and clinical studies that have investigated its use in Gliomas. We also highlight the challenges, the limitations, and the future perspectives of SDT. Overall, SDT and MRgFUS hold promise as novel and potentially complementary treatment modalities for GB. Further research is needed to optimize their parameters and determine their safety and efficacy in humans, but their potential for selective and targeted tumor destruction makes them an exciting area of investigation in the field of brain cancer therapy.

Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.

The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities.

Epigenetic mechanisms in paediatric brain tumours: regulators lose control.

Epigenetic mechanisms are essential to regulate gene expression during normal development. However, they are often disrupted in pathological conditions including tumours, where they contribute to their formation and maintenance through altered gene expression. In recent years, next generation genomic techniques has allowed a remarkable advancement of our knowledge of the genetic and molecular landscape of paediatric brain tumours and have highlighted epigenetic deregulation as a common hallmark in their pathogenesis. This review describes the main epigenetic dysregulations found in paediatric brain tumours, including at DNA methylation and histone modifications level, in the activity of chromatin-modifying enzymes and in the expression of non-coding RNAs. How these altered processes influence tumour biology and how they can be leveraged to dissect the molecular heterogeneity of these tumours and contribute to their classification is also addressed. Finally, the availability and value of preclinical models as well as the current clinical trials exploring targeting key epigenetic mediators in paediatric brain tumours are discussed.

Benign Acute Childhood Myositis: Our Experience on Clinical Evaluation.

BACKGROUND: Benign acute childhood myositis (BACM) is a transient condition mainly affecting children of school age characterized by muscle pain, typically localized to the calf muscle with symmetrical lower extremity pain and difficulty in walking. Usually, the symptomatology is preceded by a viral infection including influenza, parainfluenza, rotavirus, and mycoplasma. METHODS: The case series was conducted in four pediatric hospitals in Catania, Italy, over a 12-year observational period. Clinical examination, laboratory data, course, treatment, and complications of the affected children were extracted from electronic medical records of each hospital. RESULTS: For the case series, 50 children diagnosed with BACM were enrolled: the mean age of affected children was 5.35 years, 86% of were males, and in 56% the affections occurred during the winter. In the affected children, the clinical picture was characterized by previous fever and/or symptoms of inflammation of the upper airways, and followed by pain in the lower extremities up to uncoordinated gait. In 17 cases the etiological agent was isolated, including the influenza virus type B as the most frequent and influenza virus type A, Mycoplasma pneumoniae, beta-hemolytic streptococcus, and herpes simplex virus. Children were treated with supportive therapy. In all the children the muscular symptomatology had a good evolution with progressive marked reduction of pain and of the high level of CKemia. Neither clinical recurrences nor sequelae were reported. CONCLUSION: BACM shows to have in most of the cases a favorable evolution, a spontaneous remission of symptoms, and a good prognosis. However, the disorder generates parental distress for the acute presentation and the striking muscle dysfunction. It is worthy a rapid and early diagnosis to avoid unnecessary diagnostic investigations and a careful follow-up necessary to exclude persistence of symptoms or creatine kinase elevation.

The role of teriflunomide in Multiple Sclerosis patient: an observational study.

Teriflunomide is a drug with immunosuppressive and selective immunomodulatory action, characterized by anti-inflammatory and antiproliferative properties. Several clinical studies have demonstrated the efficacy and safety of this drug in Multiple Sclerosis, estimating a significant improvement in cognitive performance.The aim of our study is to evaluate the effects of teriflunomide by analysing the correlation between brain atrophy and the general cognitive profile and evaluating long-term changes. The effect of teriflunomide was studied in 30 patients with multiple sclerosis and 30 control subjects. Patients underwent a full cognitive profile assessment using the Brief Repeatable Battery of Neuropsychological Tests and a neuroimaging examination with a 3.0 T working scanner.Our results suggested that treatment with teriflunomide could potentially not only slow down the accumulation of microstructural tissue damage in Grey Matter and With Matter, but also better preserve the cognitive profile, particularly by highlighting the benefits in the memory domain. Thanks to drug therapy, brain volume in our patients has remained constant, leading to improvements in memory, indicating teriflunomide as a neuroprotective potential and further strengthening the evidence of a link between loss of brain volume and cognitive impairment.

Cognitive and Speech Rehabilitation in a Patient Affected by Takotsubo Cardiomyophathy: A Case Report.

Background and Objectives: Takotsubo Syndrome (TS) constitutes one of the most recent clinical realities in modern cardiology. It is clinically similar to the acute coronary syndrome, in the absence of obstructive coronary artery disease. Case Presentation: We described a case of a female patient affected by TS and left ventricular apical thrombus. Several studies described the cardiological syndrome, overlooking the neuropsychological and psychological outcomes. We aimed to assess the advantages of an integrated, multidisciplinary and multifunctional rehabilitation. Conclusions: This specific training contributed to reducing the tolerance to frustration given by her communication's difficulty. It has favored a good therapeutic alliance and a good success of the psychotherapeutic path, guaranteeing the reduction of her anxious symptoms and an improvement in the emotive and relational status.

Neuropsychological Disability in the Case of Natalizumab-Related Progressive Multifocal Leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a viral disease characterized by progressive damage or inflammation of the cerebral white matter that can be encountered in patients with multiple sclerosis (MS). There are cases of PML caused by pharmacological agents including natalizumab. Therefore, in patients treated with this drug, early identification of PML allows changes in the treatment plan, reducing the risks of morbidity and mortality. CASE PRESENTATION: We reported the case of a 57-year-old female diagnosed with relapsing-remitting MS, who presented with PML related to natalizumab. The patient presented with change in behavioral, radiological abnormalities in the left parieto-temporal lobes. We described the longitudinal course of PML, from the diagnosis until the patient's death, documenting the progressive deterioration of her cognitive functioning, supported by changes on sequential brain scans and neurophysiological data. CONCLUSION: The neuropsychological impairment documented in this case study expands the range of treatment-related complications associated with natalizumab, and provides evidence that occurrence of "atypical" cognitive deficits in MS may support the early diagnosis of PML.

Chilblains-like lesions and SARS-CoV-2 in children: An overview in therapeutic approach.

SARS-CoV-2 (Severe Acute Respiratory Syndrome, Coronavirus, type 2) is the virus responsible for the global pandemic of Coronavirus disease 2019 (COVID-19) that began in China in December 2019. The variability of nasal olfactory symptoms in pediatric patients is interlinked with possible warning signs, including respiratory, gastrointestinal, ocular, or dermatological symptoms. Skin findings in patients with COVID-19 can range from petechiae to papulovesicular rashes to diffuse urticaria and can be confused with rashes of non-COVID-19 conditions. These lesions typically appear early during COVID-19 and are thought to be secondary to viral replication or circulating cytokines. Herein, we discuss two pediatric cases, presenting with skin lesions, which tested positive for SARS-CoV-2, thus, briefly reviewing current literature for similar reports and related management. Although these lesions heal spontaneously in most cases, an adequate "targeted" therapeutic approach can shorten the time and the discomfort of the skin disease.

Cognitive impairment in obstructive sleep apnea syndrome: a descriptive review.

PURPOSE: Obstructive sleep apnea syndrome is a clinical sleep disorder defined by total or partial airflow restraint during sleep that results in fragmented sleep and hypoxemia, impacting negatively with cognitive functioning. This review was conducted on studies investigating structural brain alteration and cognitive impairment in obstructive sleep apnea syndrome. METHOD: We searched on PubMed databases and screening references of included studies and review articles for additional citations. From initial 190 publications, only 17 met search criteria and described the cognitive impairment in obstructive sleep apnea syndrome. RESULTS: Findings showed that patients with this syndrome had worse performance than healthy controls in attention, memory, and executive functions, showing specific neuroanathomical features. Cognitive impairment is also related to the severity of pathology. Treatment could improve certain cognitive aspects. CONCLUSIONS: Cognitive deficits seem to be mainly attributable to decreased daytime vigilance and nocturnal hypoxemia.

Sutures ultrasound: useful diagnostic screening for posterior plagiocephaly.

PURPOSE: Posterior plagiocephaly (PP) is a common clinical condition in pediatric age. There are two main causes of PP: postural plagiocephaly and craniosynostosis. Early diagnosis is important, as it prevents neurological complications and emergencies. Diagnosis in the past was often made late and with imaging tests that subjected the infant to a high radiation load. Suture ultrasound does not use ionizing radiation; it is easy to perform, allows an early diagnosis, and directs toward the execution of the cranial 3D-CT scan, neurosurgical consultation, and possible intervention. The aim of the study is to describe the high sensitivity and specificity of suture ultrasound for the differential diagnosis between plagiocephaly and craniosynostosis. METHODS: We reported our prospective experience and compared it with the data in the literature through a systematic review. The systematic review was conducted on electronic medical databases (PubMed, Embase, Cochrane Library, Scopus, and Web of Science) evaluating the published literature up to November 2020. According to Preferred Reporting Items for Systematic Reviews and Meta-ANALYSES (PRISMA statement), we identified 2 eligible studies. Additionally, according to AMSTAR 2, all included reviews have been critically rated as high quality. A total of 120 infants with abnormal skull shape were examined in NICU. All underwent clinical and ultrasound examination. RESULTS: Of the total, 105 (87.5%) had plagiocephaly and 15 dolichocephaly/scaphocephaly (12.5%). None of these had associated other types of malformations and/or neurological disorders. The synostotic suture was identified ultrasonographically in 1 infant and subsequently confirmed by 3D CT scan (100%). CONCLUSION: Cranial sutures ultrasonography can be considered in infants a selective, excellent screening method for the evaluation of skull shape deformities as first technique before the 3D CT scan exam and subsequent neurosurgical evaluation. Cranial suture ultrasonography should be considered part of clinical practice especially for pediatricians.

Gibson approach and surgical hip dislocation according to Ganz in the treatment of femoral head fractures.

BACKGROUND: The purpose of the study is to evaluate clinical and radiological outcomes in those patients with femoral head fracture, treated with open reduction and internal fixation through Gibson approach and Ganz flip trochanter osteotomy. The treatment of Pipkin fractures is very challenging, especially for small trauma centers, because of the unusual fracture patterns and high-level surgical skills required. CASE PRESENTATION: Between 2017 and 2020, nine cases of Pipkin fractures came to the Emergency Department at the Trauma Center of our Hospital in Rome. Inclusion criteria were the diagnosis of femoral head fracture, the open reduction and internal fixation as surgical choice and at least 24 months follow-up. Patients older than 65 years and those treated through total hip replacement or combined hip procedure (CHP) were excluded. Thus, five patients were included in our case series. The clinical outcome was evaluated according to Western Ontario and McMaster Universities Arthritis Index, Vail Hip score, modified Harris Hip score and Merle D'Aubignè Postel score. Radiographic assessment was scored according to Epstein-Thompson classification and heterotopic ossification was assessed through Brooker classification. The mean follow-up was 24 months (range 12-24). Average modified Harris Hip score was 92.1 points (range 75.9-100), and the average Vail score was 81.8 (range 55-95). WOMAC score was assessed in three different subscales, pain (A), stiffness (B) and physical condition (C), with the following results: 1.4 A (range 0-7), 1.2 B (range 0-6) and 6.4 C (range 0-22). Merle d'Aubignè Postel score resulted excellent for four patients and good for one patient. According to Epstein-Thompson score of the radiological outcome, four patients showed a good result and one a fair result. No mechanical or infective complications occurred in the five patients. CONCLUSIONS: Gibson's approach and surgical hip dislocation through Ganz trochanteric flip osteotomy allow a good exposure of the femoral head and acetabulum, giving us the possibility to perform an anatomical reduction of the fracture. In our case series, satisfactory clinical and radiological short-term results were obtained without significant complications.

Anterior intrapelvic approach and suprapectineal quadrilateral surface plate for acetabular fractures with anterior involvement: a retrospective study of 34 patients.

BACKGROUND: The purpose of the study is to evaluate the use of the suprapectineal quadrilateral surface (QLS) plates associated with the anterior intrapelvic approach (AIP) to the acetabulum in the surgical treatment of acetabular fractures with anterior involvement. METHODS: We did a retrospective study of patients surgically treated with QLS plates and AIP for acetabular fractures with the involvement of the anterior column, between February 2018 and February 2020, in our Hospital. The following data were recorded: mechanism of injury, the pattern of fracture, presence of other associated injuries, the time before performing the surgery, surgical approach, position on operating table, time of surgery, intraoperative bleeding, hospitalization time, intraoperative and postoperative complications. Follow-ups were performed at 1, 3, 6, 12 months, then annually. The clinical-functional outcome was assessed with the Merle d'Aubigne Postel score (MAP) modified by Matta; while the radiological outcome with the Matta Radiological Scoring System (MRSS). A Chi-square test was utilized to examine associations between parametric variables. RESULTS: We included 34 patients, mean age 62.1, with an average follow-up of 20.7 months. The most frequent traumatic mechanism was road trauma. There were 15 isolated anterior columns and 19 associated patterns. There were 5 cases of associated visceral injuries, and 10 cases of other associated skeletal fractures. All patients were in the supine position. The surgical approach used was the AIP in all cases, with the addition of the first window of the ilioinguinal approach in 16 cases and of the Kocher-Langenbeck approach in 2 cases. The average time before performing the surgery was 8.5 days. The mean time of the surgery and the mean length of stay after surgery were 227.9 min and 8.2 days, respectively. There weren't cases of intra-operative complications, while there were postoperative complications in 5 patients. The MRSS was judged anatomical in 26 cases, imperfect in 7 cases and poor in 1 case. The average MAP value was 15.2. We observed a significant relationship between the radiological outcome and the clinical outcome (p < 0.05). CONCLUSIONS: The QLS plates in association with the AIP approach represent an effective treatment strategy for the treatment of acetabular fractures with anterior involvement.

JZL184, A Monoacylglycerol Lipase Inhibitor, Induces Bone Loss in a Multiple Myeloma Model of Immunocompetent Mice.

Multiple myeloma (MM) patients develop osteolysis characterised by excessive osteoclastic bone destruction and lack of osteoblast bone formation. Pharmacological manipulation of monoacylglycerol lipase (MAGL), an enzyme responsible for the degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced skeletal tumour burden and osteolysis associated with osteosarcoma and advanced breast and prostate cancers. MM and hematopoietic, immune and bone marrow cells express high levels of type 2 cannabinoid receptor and osteoblasts secrete 2-AG. However, the effects of MAGL manipulation on MM have not been investigated. Here, we report that treatment of pre-osteoclasts with non-cytotoxic concentrations of JZL184, a verified MAGL inhibitor, enhanced MM- and RANKL-induced osteoclast formation and size in vitro. Exposure of osteoblasts to JZL184 in the presence of MM cell-derived factors reduced osteoblast growth but had no effect on the ability of these cells to mature or form bone nodules. In vivo, administration of JZL184 induced a modest, yet significant, bone loss at both trabecular and cortical compartments of long bones of immunocompetent mice inoculated with the syngeneic 5TGM1-GFP MM cells. Notably, JZL184 failed to inhibit the in vitro growth of a panel of mouse and human MM cell lines, or reduce tumour burden in mice. Thus, MAGL inhibitors such as JZL184 can exacerbate MM-induced bone loss.

Impaired Recognition of Facial Emotion in Patients With Parkinson Disease Under Dopamine Therapy.

INTRODUCTION: Parkinson disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms. The impaired ability to recognize facial emotion expressions represents an important nonmotor symptom. The aim of this study is to investigate the ability in recognizing facial emotion expressions in patients with PD under dopamine replacement therapy. METHODS: Thirty medicated patients with PD and 15 healthy controls (HC) were enrolled. All participants performed the Ekman 60-Faces test for emotional recognition. All patients underwent a neuropsychological evaluation for global cognitive functioning, depression, and anxiety. RESULTS: Patients with PD were impaired in recognizing emotions. Significant differences between PD and HC were found in Ekman 60-Faces test scores (P < .001), and in Ekman 60-Faces test subscales, in particular, sadness, fear, disgust, anger, and surprise (P < .001). CONCLUSIONS: The nigrostriatal dopaminergic depletion seems to determine emotional information processing dysfunction. This relevant nonmotor symptom could have consequences in daily living reducing interactions and social behavioral competence.