Disturbi del sonno in bambini con tumore cerebrale e loro correlazione con i deficit neurocognitivi

Sleep is a complex neurological process essential for life. Several parts of the brain are involved in the regulation of this mechanism. Different brain damages, like injuries or brain surgery, could produce sleep alteration. According to some studies, sleep disturbances are common problems in different developmental ages, reaching an incidence up to 37% in children attending primary school, and 25% among adolescents. Brain tumours represent the more frequent solid tumours in children and their survival has been improving. The therapeutic approach comprises surgery, followed by chemotherapy and/or radiotherapy, according to subtypes and treatment protocols. Some studies showed a relationship between the outcomes of paediatric brain tumour survivors and the different therapeutic approach. They described behavioural problems, memory deficiency, fatigue, and psychological and neurocognitive consequences, as late effects. Only few studies evaluated the prevalence of sleep disorders (SD) in children treated for brain tumours, failing to fully understand the involved mechanisms. Some Authors suggested an alteration in the regulatory pathway of sleep, due to the presence of the tumour itself or as an effect of treatments. A disturbed sleep produces important consequences on daytime performance, as memory defects, attention deficits, and alteration of psychosocial functioning, thus impacting on patients\u2019 quality of life. Furthermore, sleep is critical for neural recovery and tissue repair. The aim of the present study is to evaluate the prevalence and type of sleep disorder among children treated for brain tumours. The first part of the study analysed the prevalence of sleep disorders with a Sleep Questionnaire, comparing children treated for brain tumour to healthy population. Our study revealed a trend toward SD in children with brain tumor when compared to healthy population. A significant difference was obtained only for parasomnia and night awakenings. In the second part Polysomnography (PSG) was performed in children treated for brain tumour. We found a significant higher prevalence of central apnea in children with subtentorial tumour, compared with sovratentorial localization. Moreover, PSG showed a sleep night organization\u2019s alteration. In the third part neurocognitive performances in children treated for brain tumour were analyzed confirming deficits in some fields, as described in literature. On the other side, our study failed to find a direct correlation between SD and the worsening of daily performances. The small sample size, mainly due to the relatively low incidence of brain tumour and to the exclusion criteria, does not allow to draw definitive conclusions. The main aim of this studies is to highlight the role of sleep follow up in patients treated for brain tumour, to potentially set up a behavioural of pharmacological therapy to improve children\u2019s quality of life.Il sonno \ue8 un sistema neurologico complesso essenziale per la vita, legato a diversi meccanismi biologici di controllo localizzati a livello del Sistema Nervoso Centrale. Vari meccanismi di danno a tale livello possono interferire con i processi fisiologici del sonno. I disturbi del sonno rappresentano un comune problema dell\u2019et\ue0 evolutiva. Secondo diversi studi si stima che circa il 37% dei bambini delle scuole elementari e il 25% degli adolescenti presentino problematiche relative al sonno. Le neoplasie cerebrali rappresentano la seconda neoplasia in et\ue0 pediatrica dopo la Leucemia Linfoblastica Acuta e la prima neoplasia solida per frequenza. Il primo approccio terapeutico nella cura dei tumori del SNC \ue8 rappresentato dall\u2019intervento neurochirurgico di asportazione seguito dalla radioterapia e dalla chemioterapia. La radioterapia \ue8 responsabile di diverse alterazioni a livello del SNC legate a effetti endocrini e neurocognitivi. Il trend di sopravvivenza \ue8 in aumento; per i casi diagnosticati pi\uf9 recentemente raggiunge sopravvivenze a 5, 10 e 15 anni di 79%, 75% e 74% rispettivamente, secondo i dati ISTAT. Con l\u2019aumento della sopravvivenza si presenteranno sempre pi\uf9 problematiche relative alla qualit\ue0 di vita complessiva dei pazienti oncologici, in particolare di tipo neurocognitivo. La prevalenza dei disturbi del sonno nei bambini con tumore cerebrale \ue8 stata poco studiata in letteratura. Le cause di tali disturbi, collegate sia ad un meccanismo diretto della neoplasia sui centri di controllo del sonno, sia agli effetti dei trattamenti, chirurgici e/o chemio e radioterapici, non sono tuttora completamente comprese. La presenza di un sonno disturbato pu\uf2 avere conseguenze rilevanti sulle performance diurne. Nei soggetti dell\u2019et\ue0 evolutiva questo aspetto si traduce in problematiche di natura emozionale e comportamentale oltre che in difficolt\ue0 scolastiche, legate in particolare ad alterazione delle capacit\ue0 mnemoniche, esecutive e a deficit dell\u2019attenzione, che possono andare ad aggiungersi alle problematiche note legate ai trattamenti. Lo studio proposto ha lo scopo di individuare la presenza di disturbi del sonno nella popolazione pediatrica con neoplasia cerebrale, di caratterizzare eventuali disturbi ed associarli ad eventuali deficit neurocognitivi. Dalla prima parte dello studio \ue8 stata individuata, attraverso un questionario, una prevalenza dei disturbi del sonno tendenzialmente maggiore nella popolazione con tumore cerebrale rispetto alla popolazione sana di controllo. In particolare, parasonnie e risvegli notturni hanno presentato una prevalenza significativamente superiore rispetto alla popolazione di controllo. Nella seconda parte, caratterizzata dallo studio polisonnografico della popolazione di bambini con neoplasia cerebrale, \ue8 emerso come ci sia una prevalenza di disturbi respiratori (OSAS) di tipo centrale nei bambini con localizzazione sottotentoriale e come ci sia una modifica della struttura elettroencefalografica del sonno. Nella terza parte abbiamo valutato le capacit\ue0 neurocognitive dei bambini trattati per tumore cerebrale, evidenziando la presenza di deficit nei domini relativi alla elaborazione visuo-spaziale, alla memoria e apprendimento e alla attenzione e funzioni esecutive senza per\uf2 riscontrarne una chiara correlazione con la qualit\ue0 del sonno. La limitata numerosit\ue0 campionaria, dovuta principalmente all\u2019incidenza relativamente bassa di tali neoplasie e ai criteri di esclusione dello studio, non permette comunque di trarre conclusioni definitive. Tale percorso vuole quindi sottolineare l\u2019importanza del monitoraggio del sonno nel follow up dei bambini trattati per tumore cerebrale, per poter eventualmente avviare trattamenti comportamentali e/o farmacologici per migliorarne la qualit\ue0 della vita

Elena Zambelli, Sexscapes of pleasure. Women, sexuality and the whore stigma in Italy, New York-Oxford, Berghahn Books, 2023, pp. 184

Recensione di Elena Zambelli, Sexscapes of pleasure. Women, sexuality and the whore stigma in Italy, New York-Oxford, Berghahn Books, 2023, pp. 184

Role of mTOR signaling in tumor microenvironment. An overview

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy

Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU

Diencephalic syndrome in child with NF-1 and hypothalamic tumour

We describe a 20 month old boy with neuro-fibromatosis type 1 (NF-1) who presented with diencephalic syndrome due to a large hypothalamic tumour and developed massive necrosis after chemotherapy associated with severe encephalopathy. We report this case because of rapid progression of presenting symptoms, the rare association with diencephalic syndrome in NF-1, chemotherapy induction of “tumour lysis” associated with encephalopathy, reduced toxicity and sustained improvement with vinblastine, the therapeutic benefit of tumour drainage signs of resolution of diencephalic syndrome and then restoration of visual movements and function associated with developmental recovery. The presentation of tumour in this case highlights the importance for parents and doctor to known and recognize the precocious symptoms, and justifies sharing these features as an indicator with parents and GP’s to justify early / urgent specialist review, particularly in the first two years of life. Early recognition could offer a reduced risk of brain injury

Diencephalic syndrome in child with NF-1 and hypothalamic tumour

We describe a 20 month old boy with neuro-fibromatosis type 1 (NF-1) who presented with diencephalic syndrome due to a large hypothalamic tumour and developed massive necrosis after chemotherapy associated with severe encephalopathy.We report this case because of rapid progression of presenting symptoms, the rare association with diencephalic syndrome in NF-1, chemotherapy induction of “tumour lysis” associated with encephalopathy, reduced toxicity and sustained improvement with vinblastine, the therapeutic benefit of tumour drainage signs of resolution of diencephalic syndrome and then restoration of visual movements and function associated with developmental recovery. The presentation of tumour in this case highlights the importance for parents and doctor to known and recognize the precocious symptoms, and justifies sharing these features as an indicator with parents and GP’s to justify early / urgent specialist review, particularly in the first two years of life. Early recognition could offer a reduced risk of brain injury

A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

Summary: LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes. : Through biophysical, biochemical, and structural studies, including cryo-EM, Marabelli et al. describe how NPAC promotes LSD2 productive interaction with the nucleosome in a rapid and flexible manner. Their findings provide a molecular mechanism for LSD2 activity in the context of H3K4me2 demethylation during Pol II transcriptional elongation. Keywords: histone demethylation, cryoelectron microscopy, chromatin reader, flavoenzyme, epigenetics, evolution of protein function, molecular recognitio

Exceptional Response in BRAF p.V600E-Mutant Enteric-Type Adenocarcinoma of the Lung With Cutaneous Spread: A Case Report

Background: Enteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis. Case presentation: An 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing. Conclusions: We reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation

Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

Innovative therapeutic agents have significantly improved outcomes, with an acceptable safety profile, in a substantial proportion of non-small cell lung cancer (NSCLC) patients in whom the malignant phenotype of the disease is determined by oncogenic molecular alterations. However, the benefit seen with these treatment models has not translated well to NSCLCs with KRAS mutations or squamous cell histology. Although efforts have been made to develop precision medicine approaches, KRAS mutant NSCLC and lung squamous cell carcinoma (LSCC) continue to display resistance to therapy. Recently, based on the results of the Phase III SQUIRE trial, the EGFR monoclonal antibody necitumumab received FDA authorization in combination with cisplatin and gemcitabine for first line treatment of patients with metastatic LSCC. Among the molecular compounds tested in KRAS mutant NSCLC patients, the MEK inhibitor, selumentinib, combined with docetaxel in second line setting, determined a progression-free survival improvement, but no overall survival advantage. Better understanding is needed in regard to signaling pathways which cooperate to induce oncogene transformation in LSCC and KRAS mutant NSCLC and could determine intrinsic or acquired resistance to necitumumab and selumetinib. Greater understanding of such pathways will provide a molecular base upon which to improve the scant clinical benefit with these compounds

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting \u3b2-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid