Volume 17 - 2024 | https://doi.org/10.3389/fnmol.2024.1411360 Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists A corrigendum on Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists? by d'Amati, A., Bargiacchi, L., Rossi, S., Carai, A., Bertero, L., Barresi, V., Errico, M. E., Buccoliero, A. M., Asioli, S., Marucci, G., Del Baldo, G., Mastronuzzi, A., Miele, E., D'Antonio, F., Schiavello, E., Biassoni, V., Massimino, M., Gessi, M., Antonelli, M., and Gianno, F. (2024). Front. Mol. Neurosci. 17:1268038. doi: 10.3389/fnmol.2024.1268038 and Maura Massimino were erroneously excluded and Author contributions statement appear below Department of Precision and Regenerative Medicine and Ionian Area University of Bari “Aldo Moro” Department of Translational Biomedicine and Neuroscience (DiBraiN) Fondazione Policlinico Universitario “A Bambino Gesù Children's Hospital 6Department of Neuroscience and Neurorehabilitation 8Department of Diagnostics and Public Health 11Department of Biomedical and Neuromotor Sciences (DIBINEM) Alma Mater Studiorum University of Bologna Fondazione IRCCS Istituto Neurologico Carlo Besta 13Department of Paediatric Haematology/Oncology IRCCS Bambino Gesù Children's Hospital Fondazione IRCCS Istituto Nazionale dei Tumori d'Amati A, Bargiacchi L, Rossi S, Carai A, Bertero L, Barresi V, Errico ME, Buccoliero AM, Asioli S, Marucci G, Del Baldo G, Mastronuzzi A, Miele E, D'Antonio F, Schiavello E, Biassoni V, Massimino M, Gessi M, Antonelli M and Gianno F (2024) Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists? Front. Mol. Neurosci. 17:1268038. 10.3389/fnmol.2024.1268038 Writing – review & editing ES: Writing – review & editing VBi: Writing – review & editing MM: Writing – review & editing The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher Antonelli M and Gianno F (2024) Corrigendum: Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists? Received: 02 April 2024; Accepted: 18 April 2024; Published: 26 April 2024 Copyright © 2024 d'Amati, Bargiacchi, Rossi, Carai, Bertero, Barresi, Errico, Buccoliero, Asioli, Marucci, Del Baldo, Mastronuzzi, Miele, D'Antonio, Schiavello, Biassoni, Massimino, Gessi, Antonelli and Gianno. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Manila Antonelli, bWFuaWxhLmFudG9uZWxsaUB1bmlyb21hMS5pdA==; Antonio d'Amati, YW50b25pby5kYW1hdGlAdW5pYmEuaXQ= Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Skitchenko et al. identified four candidate somatic mutations potentially explaining the medulloblastoma (MB) onset in two pediatric patients and providing new biological insights into the mechanisms of tumor development Molecular diagnostics for two WNT-MB cases without chromosome 6 monosomy or mutations in CTNNB1 and APC are described Vallero et al. reviewed the current literature on H3K27-altered diffuse midline glioma (DMG) and addressed questions such as when additional mutations are found which one should we focus on in order to make the correct clinical decision H3K27 status has become a fundamental supplement to the histological grading of pediatric gliomas but not sufficient alone to exhaustively define the complex biological behavior of DMG in children and might not represent an indication for a unique treatment strategy across all patients each DMG case should have its own unique and precise molecular characterization The ultimate goal is to treat all patients with a personalized therapy tailored to the specific characteristics of their tumor In their review Cipri, Del Baldo et al. described the major molecular alterations detected in pediatric low-grade gliomas (pLGGs) and the molecular target therapy Having a better understanding of tumor biology and a germline and somatic genomic approach will play a central role in the therapy strategy of pLGG for the development of increasingly tailored therapies It cannot be underestimated that limitations still exist regarding the adverse effects of long-term treatment De Martino et al. reported on two pediatric patients affected by DMG with extra-neural dissemination both showing disease progression at bone sites and partial response of intracranial DMG to second-line treatment with craniospinal irradiation and systemic chemotherapy with irinotecan and bevacizumab regimen Extra-neural metastasis of DMG is a rare event and no standard therapy exists the biological mechanisms behind tumor dissemination outside the CNS of DMG have not been well-described Although improved care of patients affected by DMG is going to lead in some cases to longer survival extra-neural metastases in DMG were detected at diagnosis or relatively early after diagnosis The review of Caroleo et al. described an 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 PTEN gene variants often present in childhood with macrocephaly 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 MB the panel of genes to be tested in the presence of an MB SHH could be extended to PTEN The discovery of a PTEN germline mutation should induce the clinician to promptly provide genetic counseling in order to assess and monitor the occurrence of other PHTS clinical features and set up careful surveillance Weiser et al. explained that understanding the longitudinal overlap and glioma evolution from childhood to adulthood is an important research gap including implementation of targeted therapies starts with the adoption of appropriate molecular testing as part of the diagnostic work-up Even though the molecular features vary between pediatric and—most likely—adolescent and young adult (AYA) gliomas these tumors also share common tumorigenic pathways which should be explored for introducing new therapies in age-inclusive clinical trials To bridge this gap and offer better treatment options exchange of expertise and close collaboration between pediatric and adult neuro-oncologists—and broader multidisciplinary clinical teams—is indispensable Ensuring access to appropriate molecular testing to detect key biomarkers designing age-inclusive clinical trials for gliomas and creating multidisciplinary teams are some of the many actions needed and being implemented in several centers across the world Additional factors to be considered include the socioeconomic and mental health burden that AYA patients experience In their publication Morgacheva et al. explained a case that highlights need for the implementation of molecular methods in the diagnosis of CNS neoplasms in children Pediatric CNS tumors demonstrate clinical and biological diversity and variability in the morphological picture which can lead to misdiagnosis and wrong therapeutic strategies Diagnostic challenges can be overcome by using novel technological diagnostic approaches such as DNA and RNA sequencing They stated that their case demonstrates the complexity of diagnosing a CNS tumor in a pediatric patient which was caused by a non-specific clinical and morphologic picture of the tumor itself which twice led to misdiagnosis and a wrong therapeutic approach An additional molecular analysis allowed them to find a potential target for precision therapy which may be useful in the event of disease progression at least a complete IHC and first level molecular methods [PCR fluorescence in situ hybridization (FISH)] should be used Cipri, Fabozzi et al. demonstrated that tropomyosin receptor kinase inhibitors have showed high efficacy in pediatric patients also in CNS tumors carrying alterations in NTRK genes Additional research is necessary to help us to understand better the mechanism of action of these drugs and to identify biomarkers that can help identify patients who will benefit most from therapy d'Amati et al. summarized the major changes in the 2021 WHO CNS5 highlighting for each entity the molecular alterations and other information that are relevant for diagnostic The rationale of this “molecular classification” is also related to the effective and experimental molecular therapies targeting some cancer-specific genetic events Reclassification based on molecular investigations has allowed identification of specific entities that appear homogeneous in their response to treatment and clinical outcomes These implications highlight the necessity to adopt the new classification when considering therapeutic options (clinical trials targeted therapies) and discussing prognosis The author(s) declare that financial support was received for the research A special thank you to “Coraggio dei Bambini” Foundation The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers This had no impact on the peer review process and the final decision Advances in the classification and treatment of pediatric brain tumors New classification for central nervous system tumors: implications for diagnosis and therapy Crossref Full Text | Google Scholar Clinical updates on gliomas and implications of the 5th edition of the WHO classification of central nervous system tumors Signaling pathways in brain tumors and therapeutic interventions The 2021 WHO classification of tumors of the central nervous system: a summary Schiavello E and Carai A (2024) Editorial: 2021 WHO classification of pediatric brain tumors: a final wedding between morphology and molecular biology Received: 25 April 2024; Accepted: 29 April 2024; Published: 08 May 2024 Edited and reviewed by: Detlev Boison Copyright © 2024 Mastronuzzi, Quaglietta, Schiavello and Carai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Angela Mastronuzzi, YW5nZWxhLm1hc3Ryb251enppQG9wYmcubmV0 Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Share on FacebookShare on X (formerly Twitter)Share on PinterestShare on LinkedInHUNTSVILLE (WAFF) - It’s been five years since three people were killed on I-565 by a person driving on the wrong side of the interstate Carai Cortez was sentenced to 30 years in prison for killing Alexa Hannig, her three-year-old son Hayden and her boyfriend Ben Johnson. mother of Hannig and grandmother of Hayden but she is thankful to see so many friends and community remember her daughter Shellie Kliotas will never forget the day her own family members were killed 2016 when Carai Cortez struck their vehicle driving the wrong way his blood-alcohol level was twice the legal limit But Kioutas holds on to the last memory she had with her daughter and grandson “I feel like yesterday was harder because it was the last time I spoke to her I got to facetime her and see Hayden do his first Hannig’s friends shared precious memories and pictures on Facebook as they remember her personality laughter and reputation as a loving friend “It means a lot because you really just want your child to be remembered to know that their life had meaning and their life was meaningful to just more than you,” said Kioutas her family is still finding ways to heal and navigate through life “Her brother was only 15 when it happened so it had such a huge impact on his life Her sisters and everybody is all spread out and everyone is trying to find themselves without her and she was the oldest so she was the leader the one that everyone looked up to,” said Kioutas Kioutas said the family is taking a trip to eat and shop at some of Hannig’s favorite places to celebrate her A scholarship fund will also be set up in the fall at the YMCA in South Huntsville in Hannig’s honor to support single mothers Health System Performance Assessment (HSPA) is often lacking in data on population views and experiences – which is key to understanding efficacy Tools like the People’s Voice Survey highlight important issues raised by populations regarding their health and changing how policy-makers conceptualize performance Don’t miss this opportunity to learn how to put people at the heart of health system performance assessment Office for Quality of Care and Patient Safety World Health Organization Regional Office for Europe Susanne Carai, Office for Quality of Care and Patient Safety World Health Organization Regional Office for Europe Günther Fink Swiss Tropical and Public Health Institute MODERATORS: Dheepa Rajan & Erica Richardson (European Observatory on Health Systems and Policies) Policy-makers grapple with adapting their health systems to aging populations Doing so requires a regular performance assessment to understand where the health system bottleneck is where in the system the challenge is arising and what are the options for improvement This webinar spotlight series draws on a recent special issue of the Bulletin of the World Health Organization on health system performance Two webinars will specifically showcase 2 aspects of HSPA which are particularly important in times of permacrisis: Andrew Cunningham and Lee Hutchinson have spent decades of their lives with Robert Jordan and Brandon Sanderson's Wheel of Time books, and they previously brought that knowledge to bear as they recapped each first season episode of Amazon's new WoT TV series Now they're doing it again for season two—along with insights These recaps won't cover every element of every episode but they will contain major spoilers for the show and the book series We're going to do our best to not spoil major future events from the books but there's always the danger that something might slip out If you want to stay completely unspoiled and haven't read the books New episodes of The Wheel of Time season two will be posted for Amazon Prime subscribers every Friday We open on the Seanchan doing what they do—making imperious statements and talking about conquering things for anyone wondering when the Horn of Valere was actually going to turn up on screen hand-delivered by Padan Fain (with the requisite bit of whistling) It was also kind of fun to see Shienaran Lord Ingtar (Gregg Chilingirian) in eyeshadow and da'covale robes which are nowhere near as sheer on-screen as they are in the books The Seanchan are more or less successfully fulfilling their Book Role obviously alien invaders who immediately threaten half of our main characters by capturing and enslaving women who can channel One thing that is a lot different in the show is that it's much clearer much earlier that the Forsaken are pulling some of their strings The books would show you someone was a Darkfriend by sneaking in a one-line reference in some kind of short epilogue POV section these people show up and you just kind of see the show's main villain chilling with them on a palanquin Given that both Game of Thrones and Wheel of Time shot in Morocco some location reuse was probably inevitable whether it was intended to be overtly obvious or not so—you're absolutely right that the show has drop-kicked the plot way ahead with the way events are landing There are several specific things I want to talk about We're given more of a window into who and what they are in this episode—along with the understanding that alliances between different members of the Forsaken are somewhat But the thing that jumped out most was the mention by Lanfear about the rest of the Forsaken—and how many there may or may not be Lots of the 13 Forsaken were already sort of interchangeable as plot drivers and existed mostly to be melted by Rand and his pals in end-of-book battles and repurposing characters definitely makes it seem like it could be planning to cut some of the other less-interchangeable figures out is there a story need for Asmodean in the show universe based on some of the changes!) We've already seen the show jettison the idea that the Forsaken need to be totally reincarnated as all-new people by the Dark One; in general the idea seems to be to have fewer villains who are better-drawn Lanfear was supposed to be the most skilled within the World of Dreams (something that some of the other Forsaken take issue with She shows off a bit of that skill in her cheeky meeting with Ishamael and we see perhaps a bit more when she zaps Rand into her own little desert BDSM fantasy at the very end Rand: there is no safe-word in the World of Dreams We'll no doubt be spending a lot of time there given how central Tel'aran'rhiod is to—well to several characters (no spoilers from us about that yet—that'll likely be a season three or four thing) and it's great to know that it's not being cut I have some hope that Asmodean also makes it There were at least a couple of extended sequences in season one that were just Moiraine and one or more characters on horseback listening attentively while Moiraine delivered some worldbuilding info-dump If you wanted to do a totally faithful rendering of every single little kingdom in Randland you'd probably need a bunch more scenes like that and 20 years ago their king cut down a tree..." and on and on because in an episode filled with important stuff Perrin meeting Aviendha is one of the most important We're re-using the whole "Aiel in a cage" bit that we only obliquely got to in season one and we're mixing together a few different book bits but the encounter came off satisfying to me Aviendha dons a black veil and invites Perrin dancing—something she obviously excels at Without revealing yet to show-watchers why she's important (you'll all find out soon enough!) it's nice to have one of the last of our main characters slotting into place I believe the "Perrin frees an Aiel from a cage and befriends them" thing is pulled back from The Dragon Reborn and the first where Rand really fades into the background so that we can get closer to some other POV characters (show-Perrin also briefly meets Dain Bornhald another Whitecloak character who will become more important later) the Aiel that Perrin frees is a totally different person But what's similar is that this encounter opens us up to learn more about Aiel society—they live in a desert and they maintain a Klingon-esque understanding of honor and obligation (ji'e'toh another of Robert Jordan's many heavily apostrophe'd creations) that we get a small glimpse of here The linked nature of the sul'dam ("leash holder" in the Old Tongue) and their damane is neatly demonstrated with the simultaneous call/response thing they do when channeling My recollection is that the things utilize kind of a twisted version of the Aes Sedai/Warder bond to—well to finish up with our wayward White Tower trainees for the week Nynaeve and Elayne escape into the city of Falme seeking sanctuary in a place where there's not much to be had And are they safe with the Aes Sedai and Warder who snatch them up Ishy had a very peculiar response when Lanfear asked him about "the girls"—he notes that he has "just collected" them and that "one craves power and the other fears it." Share on FacebookShare on X (formerly Twitter)Share on PinterestShare on LinkedInMADISON COUNTY AL (WAFF) - A Huntsville man who was drunk and driving the wrong way on Interstate 565 when he struck and killed three people has been sentenced to 30 years after pleading guilty to three counts of reckless murder [READ MORE: Huntsville triple-murder suspect accused of violating bond] Carai Cortez struck a sport utility vehicle head-on in May 19 Cortez had an alcohol level twice the legal limit Cortez does not have the possibility of parole and will have to pay a $60,000 fine plus $10,000 for victim compensation There was not a dry eye in the courtroom Friday What happened almost two years ago shattered the lives of so many "I look forward to dwelling on the blessings that Alexa Ben and Hayden truly were," said Callie Brown "She had a heart the size of this state she was the epitome what an amazing single mom is like," Brown said The judge hopes the families can one day dwell on that more than the grief they feel now "The only thing that has gotten me through the past 21 months is my faith and I know I will see them again Madison County Assistant District attorney Shauna Barnett said this was the most profound emotional sentencing hearing she's ever experienced "To see that young boy in his car seat is what is going to stick with me forever and the faith of these families and the trust of these families have in our office and in me and the officers that work these wrecks I'll use the words blessing like the judge said," Barnett said Cortez pledged to spend the rest of his life talking to others about the consequences of drunk driving He has not shown any hate towards the family never shown anything but heartache and sorrow for what he did and he knew the gravity of the situation right out of the gate," said attorney Chad Morgan Cortez's attorney hopes his client now gets a chance at redemption you have everything to look forward to in your life and you make one mistake and a mistake like this can cost you your life and life behind bars and this is that case," Morgan said A message to take away is no life is worth someone drinking and driving Remember the price both these families are paying from a single terrible event Copyright 2018 WAFF Report an Error | Submit a Tip to WAFF 48 Report an Error | Submit a Tip to WAFF 48 Having eight Forsaken instead of 13 (plus various reincarnated clones territory the show may or may not decide to cover) is part of the show's modus operandi for making Jordan's world more manageable How many scary villains do we really need running around at once especially when quite a few of them are basically just Generic Bad Guys Why does Rand need a pair of unhealable holes in his gut when one hole that has properties of both will do this episode brings us to kind of the fruition of Lanfear's plan Ishy has—had!—a formal plan to bind the Dragon and his ta'veren friends It involved moving them around on the chessboard of Randland manipulating them into falling into the shadow and then getting Rand to choose darkness to save them (This also puts some more context around Mat's tea-driven vision quest last episode.) She cares about Ishamael's plan only inasmuch as it gives her the opportunity to force Rand to proclaim himself one gets the sense that the other Forsaken don't like Lanfear much because they (completely understandably and justifiably!) think she's just a bit too close to the goody-goody Dragon to be trustworthy The show has gotten a lot of mileage out of Lanfear-as-frenemy this season and it seems like we can expect that to continue for at least a while longer and the Whitecloaks show up and kick off the giant battle Geofram Bornhald (Stuart Graham) isn't necessarily a bad fellow—as he points out the Children of the Light are in Falme to save people from the Seanchan invaders and they proceed along that track with alacrity But Bornhald is the classic Paladin archetype—he and his Children are incapable of bending the rules and Chiad roll up with Perrin and Hopper in tow we variously get a bunch of happy (if rushed) reunions between our prime characters some of whom haven't seen each other in months The episode is an absolute symphony of reunions One of those reunions is Mat and village peddler/ultra-darkfriend Padan Fain—and I don't think Mat is aware that Fain is a darkfriend at first but him showing up and producing the dagger probably goes a long way to getting that message across the character currently seems to be somewhere toward the middle of book four as far as his development goes which (as in the books) summons a bunch of dead heroes to fight alongside the blower it also seems to give him the memory of his past lives that Ishamael's weird tea promised last episode and he has picked up most of his character's Signature Traits Though before I go on about Mat, I want to gush just a moment about seeing Guy Roberts back as Uno, who apparently kicked so much ass in life that upon death he was instantly upgraded to Hero of the Horn. Given that Guy Roberts is a self-professed fan who first read the series in the ‘90s it gave me a lot of joy to see him get to inhabit the role of Uno with such obvious scene-stealing relish and to know that he's living the actor's dream of bringing to life a character that he loves Artur Hawkwing (Adrian Bouchet) delivers some lines to Mat that he originally delivered to Rand in the book I suppose it's all part of the new path the showrunners have put Mat on The destination is getting a little clearer but I'm still wondering if he's going to keep his knifey-stick or if it's going to get upgraded at one point—after all fully separating him from the dagger and its influence is a major deal in the first few books We have our first on-screen utterance of Mat's "it's time to toss the dice" in the Old Tongue he's finally given something good—and it's so good The Sounding of the Horn leaves book readers with more questions about Mat than answers—but my guess is these are questions that will be tackled in the front half of the next season leading the charge of the Heroes of the Horn is a wonderful bow to tie around his two-season journey through crap if I have a complaint about Mat's sounding of the Horn it's that budget and cost of production necessarily limits what should be a Helms Deep-scale routing of the bad guys by a horde of legendary warriors whose deeds have elevated them to immortal demigod status Egwene's capture and torment by the Seanchan is transformational for her in the books as in the show—it massively increases her strength and aptitude with the One Power and it gives her a deep hatred of the Seanchan and everything about them That hatred occasionally gets a little dark And despite continuing to resist her sul'dam earlier in the battle while still being used as a damane she quite willingly takes a shot at her former Whitecloak captor Eamon Valda when she spots him from the ramparts The White Tower women have all followed their book arcs to this point a bit more closely than our Two Rivers boys even!) streak in Egwene could distinguish her a bit from book-Egwene If Nynaeve gets some of the best and most substantial plotlines early in the season she and Elayne continue to feel underutilized in these last couple episodes; Nynaeve is still having trouble channeling and despite their work with the a'dam collars neither of them get anywhere near close enough to Egwene or any of the other captive Aes Sedai to free any of them because in the show it sure seems like the only surefire way to get the collar off is to die while you're wearing it Definitely agree with Elayne being underutilized—though as you say healing Rand was a nice way to facilitate an introduction The only problem is that Elayne is crap at healing Don't expect her patch job to hold very long or very well Moiraine will likely have harsh words for her later so—I greatly enjoyed almost everything about this episode but there were two major book events we didn't get The first was the blademaster fight with High Lord Turak which in the books is used to shove Rand further along the path of getting used to channeling and embracing the One Power given the Raiders of the Lost Ark fashion in which Rand sidesteps the fight But the other thing we're missing is much harder to overlook: the oft-teased proclamation of the Dragon in the sky above Falme this is a giant epic flaming sword fight between Ishamael and Rand projected like a Pink Floyd laser light show onto the clouds above Falme Moiraine does a Final Fantasy VII-style summoning and calls up a large fiery dragon which curls around the tower and makes some dragon noises and disappears There is also a lot of hand-waviness going on here with respect to how strong Moiraine is since she can't take on Lanfear directly but can single-handedly sink an entire Seanchan fleet and have enough leftover to make a big fire dragon besides The show downplaying Rand's sword skills and amping up his channeling skill is the same kind of early power-up that Mat is getting (to borrow your phrasing) You get all the way to book four or five before you see Rand doing anything that resembles enthusiastic or competent channeling but show Rand is already casually raining fire bullets down on his enemies The only one of our three boys who is still kind of muddling through with respect to his new Chosen One Abilities is Perrin who gets very mad when his wolf friend goes down in battle but still hasn't manifested much by way of superpowers and speaking of people to keep an eye on—book readers know this but non-readers may not: shortly before Mat sounds the Horn during the little reunion on the streets of Falme between our main characters Perrin makes it a point to give a quick hug to the other Shienaran present—a gentleman he calls Masema (Arnas Fedaravicius) He was introduced at the end of season one and this will not be the last time we see him there are eight remaining Forsaken that have yet to appear or be mentioned in the show If "the boys" can be taken to mean that all the remaining unnamed Forsaken are male we can drop the two remaining Forsaken who are female That leaves us with six candidates for our last three spots: Aginor We can dump Aginor and Balthamel immediately as they were killed in the book version of The Eye of the World and didn't appear in the show given what he's doing in the books and how it works out—I think the show is going to nix his entire plot And that neatly leaves us with three dudes left and my picks for the remaining Forsaken: Rahvin in a manner similar to how he shows up in the books since his activities also impact Elayne pretty directly I agree Aginor and Balthamel can be discounted They are part of a group of three or four Nothing Forsaken who exist mostly as canon fodder And it does seem like Demandred is pretty far away from the action the show is focusing on though this read does assume that the show will stick with the books' version of events and the show has been hard to predict on that score I'd tend to include Be'lal among the Nothing Forsaken since "ruler of [redacted city] who gets smoked by Rand at their first encounter" doesn't leave the show much personality to work with Maybe cannon fodder is what the show needs especially if we're still doing the Callandor storyline next year We know the book answers to these questions, but folks, we are heading into uncharted territory with our Two Rivers TV show crew and their rapidly expanding list of friends. Unexpected things no doubt await us in season three. Volume 12 - 2022 | https://doi.org/10.3389/fonc.2022.1016343 This article is part of the Research TopicWomen in Pediatric Oncology Vol II: 2022View all 16 articles Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults These highly heterogeneous malignancies arise in different sites of the Central Nervous System (CNS) carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity) deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity) Despite the recent advances made in the field the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity This is one of the most advanced technologies of the “-omics” era that using antibodies conjugated to heavy metals allows the simultaneous measurement of more than 40 markers at single-cell level we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups directly conjugated to metals or specifically customized to detect important histone variants significant differences were highlighted in the expression of the considered antigens The single-cell multiparametric approach realized has deepened our understanding of PDHGG confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups a powerful tool that allows to simultaneously study the expression of multiple proteins (over than 40 targets) at single-cell level by means of antibodies linked to rare heavy metal isotopes this technology does not restrict the investigation at one level but enables to define multiple cellular features such as protein expression level as well as post-translational modifications within the same experiment providing a high-throughput marker quantification with single-cell resolution We take advantage of single-cell mass cytometry to profile a panel of eight patient-derived cell lines from different locational and molecular PDHGG subgroups to dissect their cellular heterogeneity at the protein level The antibody panel adopted for the analysis included 15 markers specifically set to recognize antigens expressed on the surface and in the intracellular compartments of brain and PDHGG tumor cells through the use of antibodies directly conjugated to metals or specifically customized to detect the unique histone variants Our data revealed great phenotypic heterogeneity among the analyzed PDHGG cell lines and highlighted that the degree of plasticity as well as the clusters of cells populating each cell line it also allowed to identify key antigens specifically associated with particular PDHGG subgroups that were further investigated through RNA-seq and immunohistochemistry on a more extended panel of tumor samples DNA extraction and sanger sequencing was performed as previously described (28) cells were seeded onto laminin (10 μg/mL the medium was removed and PDHGG adherent cells were washed with 1X PBS and fixed with 4% paraformaldehyde (PFA) for 10 minutes at RT permeabilized with 0.5% Triton X-100 in 1X PBS for 10 minutes at RT and non-specific bindings were blocked with 10% Normal Goat Serum (NGS) in 1X PBS for 1 hour at RT Incubation was performed by diluting metal-tagged primary antibodies in a solution containing 1% Bovine Serum Albumin (BSA) and 2% NGS in 1X PBS (IFF) RRID : AB_2860570 metal conjugated antibody 1:100) incubation was performed for 1 hour RT while H3.3G34R-170Er (RevMab RRID : AB_2716433 metal conjugated antibody 1:100) incubation was performed for 20 minutes at 37°C Cells were then washed twice and incubated with Goat anti-Rabbit secondary antibody (Alexa Fluor 488 ThermoFisher) diluted in IFF for 1 hour at RT Nuclei were counterstained with 1 mg/ml Hoechst33342 (Invitrogen) for 5 min at RT Samples were acquired using LEICA fluorescence microscopy (DMi8) For single-cell mass cytometry experiments Once removed medium and washed twice with 1X PBS w/o Calcium and Magnesium (Euroclone) adherent cells were incubated with Accutase (Carlo Erba) for 5 minutes Detached cells were resuspended in TSM+ and centrifuged at 1300 rpm for 5 minutes Viability staining was performed by incubating cell suspensions in Rh-103 (Fluidigm) diluted 1:500 in TSM+ for 15 minutes at 37°C Reaction was inactivated with TSM+ and cells were centrifuged for 5 minutes at 1300 rpm at RT To minimize inter-sample antibody staining variation a palladium-based barcoding approach on fixed cells was applied Cells were fixed with 1 mL of Fix I Buffer (Fluidigm) and incubated for 10 minutes at RT The fixation was quenched by adding the Barcode Perm Buffer (Fluidigm) and the different samples were centrifuged at 800 g for 10 minutes Samples were individually barcoded by incubating cell pellets with the appropriate combination of Palladium isotopes from the Cell-ID™ 20-Plex Pd Barcoding Plate (Fluidigm) in Barcode Perm Buffer for 30 minutes at RT The staining was quenched with MaxPar Cell Staining Buffer (Fluidigm) and cells were centrifuged at 800 g for 10 minutes cells were washed twice with MaxPar Cell Staining Buffer and incubated overnight at 4°C in the intercalator Iridium (191Ir-193Ir) (Fluidigm) according to manufacturer’s instructions Table 1 Summary of the 15 antibodies used for the mass cytometry analysis cell suspension was washed once with MaxPar Cell Staining Buffer and twice with MaxPar Water and filtered through 30 μm filter-cap FACS tube Cells were then resuspended at 2.5 x 105 cells/mL in MaxPar Water containing 10% of EQ™ Four Element Calibration Beads (Fluidigm) and acquired on a CyTOF1 mass cytometer system (Fluidigm) RNAseq dataset are from Mackay et al., 2017, Mackay et al., 2018, Carvalho et al., 2020 and Izquierdo et al., 2021 (6, 10, 29, 30) Data was aligned with STAR to ensembl hg37 counted using HTSeq and normalized with rlog transformation in DESEq2 Data for cell cultures were from a total of 68 individual patients (H3.1K27M n=7; H3.3G34RV n=5; H3.3K27M n=33 and WT n=23) while data for tumors were from 133 individual patients (H3.1K27M n=5; H3.3G34R n=10; H3.3K27M n=52; WT n=66) The mean intensity feature evaluated for each image was normalized over the number of manually counted nuclei for each image After the acquisition, raw data was bead-normalized using CyTOF software and cells were assigned back to their initial samples (debarcoded) by using the commercially available debarcoder software (Fluidigm). Normalized data were then uploaded onto the Cytobank (RRID : SCR_014043) environment to perform initial gating strategies (Figure 1) cells were manually gated from debris on the basis of DNA content monitored by the incorporation of the Iridium (Ir) intercalator Doublets were then excluded according to the event length parameter and single live cells were finally manually gated by using the Rhodium (Rh103) intercalator signal Figure 1 Experimental workflow adopted for single-cell mass cytometry analysis Eight PDHGG primary cell lines were established upon dissociation from tumor patients After short expansion in stem-cell culture conditions cells were detached for mass cytometry analysis The different cell suspensions were barcoded with unique combinations of heavy metal tags and pooled together prior to staining with the selected metal-tag antibodies The cells were nebulized into a spray of single-cell droplets as they were introduced into the mass cytometer and atomized and ionized by the plasma (ICP) The resulting ion cloud was selected by the quadrupole for heavier reporter masses (>100 Da) which were profiled and quantified on their Time-Of-Flight (TOF) Data were converted to.fcs file and further debarcoded and analyzed in the Cytobank environment Figure 2 CyTOF single-cell analysis of surface antigens in PDHGG patient-derived cell lines t-SNE maps showing the expression of 10 surface markers (CD31 CD56 and CD61) in each of the eight different PDHGG patient-derived cell lines analyzed through mass cytometry technique The color gradient refers to the intensity of the expression of the considered marker in a blue to red scale indicating low and high intensity respectively Figure 3 CyTOF single-cell analysis of intracellular antigen in PDHGG patient-derived cell lines t-SNE maps showing the expression of 5 intracellular markers (GFAP H3.3G34R and H3K27M) in each of the eight different PDHGG patient-derived cell lines analyzed through the mass cytometry technique Figure 4 Marker expression analyzed through CyTOF technique in PDHGG patient-derived cell lines (A) Heatmap summarizing the expression of the analyzed cell markers in the eight PDHGG cell lines (B) Scatter dot plots showing the normalized expression of the indicated surface (B) and intracellular (C) markers in hemispheric and pontine PDHGG patient-derived cell lines Each shape of the scatter dot plot indicates a different tumor location (round for hemispheric square for pontine) while the color coding refers to the cell line mutational subgroups (see the key legend) Figure 5 Comparison of marker expression in different molecular PDHGG patient-derived cell lines (A) Bar plots showing the comparison between the H3WT vs H3.3G34R and H3K27M vs H3.3G34R PDHGG molecular subgroups relative to the expression of the indicated marker The data on the top refer to the marker normalized expression obtained from mass cytometry data analysis while the plots on the bottom were obtained from RNA seq analysis on both patient-derived cell cultures (n=68) and tumor tissues (n=133) (B) Bar plots relative to the expression of GFAP marker in the H3.3K27M vs H3.1K27M PDHGG molecular subgroups obtained from CyTOF and RNA seq analysis Representative images of GFAP immunohistochemistry on H3.3K27M and H3.1K27M PDHGG FFPE tissue slides together with the relative quantification of GFAP signal intensity normalized on the number of nuclei (n=5 for H3.1K27M; n=6 for H3.3 K27M) *p < 0.05; **p < 0.01; ***p < 0.001 Figure 6 Hemispheric and pons patient-derived cell line separation (A) UMAP projections and (B) Multidimensional Scaling plot (MDS) of PDHGG patient-derived cell lines obtained by including (left) or not (right) H3.3G34R and H3K27M histone variants in the relative analysis performed on single-cell mass cytometry data The color refers to the locational subgroup to which the PDHGG patient-derived cell lines belong (hemispheric or pons (A) UMAP plots of the hemispheric and pons cell lines colored according to the identified clusters (B) UMAP plots for each of the analyzed cell lines colored according to the identified cluster (C) Bar plots representing the abundance of each of the clusters identified in each cell lines (D) Heatmap summarizing the antigenic profile of each of the identified cluster Table 2 List of the cell antigens used together with the molecular function and reported expression To gain insight into PDHGG tumor heterogeneity through a single-cell mass cytometry approach, eight patient-derived cell lines, were established from fresh tumor tissue specimens collected through biopsy and resection procedures (Table 3) and grown adherent on laminin The cell lines were derived from hemispheric and pontine tumors and included the main molecular subgroups: two PDHGG-WT of which there were two H3.3K27M and two H3.1K27M Table 3 Summary of the clinico-pathological data for the eight PDHGG primary patient-derived cell lines used for the study This result confirms the notion of the existence of intra-tumor heterogeneity for surface marker expression within PDHGG patient-derived cell lines This was particularly observed in the case of wild-type cell lines for which a non-specific expression of the H3.3G34R antigen was observed the expression level of the astroglial differentiation marker GFAP was clearly higher in the H3.1K27M histone mutant PDHGG patient-derived cell lines the IHC staining performed on FFPE patient tissue sections showing a higher expression of GFAP at protein level in H3.1K27M tumors compared to H3.3K27M Although the anti-H3.3G34R antibody functionality was suboptimal when we performed the UMAP and MDS analysis the eight patient-derived cell lines that were tested in our mass cytometry experiments clearly separated in two subgroups when histone variants antibodies were not included in the analysis and This observation suggests the hypothesis that patient-derived cell line antigenic profiles may be largely imprinted by their molecular alterations In order to circumvent any alteration that could affect cell clustering due to the non-specific binding of the H3.3G34R antibody to cells we decided to remove both histone variant antibodies from the downstream analysis UMAP analysis shows that the hemispheric H3G34R and the pontine H3.1 patient-derived cell lines were more homogenous than the hemispheric WT and pontine H3.3 lines in terms of cell cluster subcomposition The hemispheric H3G34R were mainly populated by cluster 4 (CD56+ Nestinint) while the pontine H3.1 were mainly distinguished by cluster 6 (CD56+ Our mass cytometry analysis on PDHGG primary patient-derived cell lines has pointed out toward potential biomarkers given by the association of specific antigens to distinct tumor subgroups Although cell cultures are only partially recapitulating the complexity and the heterogeneity of PDHGG patient tumors we have shown that our mass cytometry data can be validated by IHC analysis on patient tissue sample as exemplified for GFAP staining Additional work on further validation on patient tissue sample may demonstrate the utility of the antigenic profiles we have identified on the primary cell lines by mass cytometry analysis Although our study is limited by a relatively small number of antibodies and also a small number of primary patient-derived cell lines it is the first CyTOF study of this kind across the heterogeneous repertoire of the diffuse pediatric-type high-grade glioma family and highlighted the opportunity to apply the mass cytometry technology to this complex biological context with its relevant potential and limitations the use of a larger panel of metal-tagged antibodies will further highlight the multidimensional potential of mass cytometry for PDHGG This will require though a more extensive work for the ad-hoc customization of specific antigens of interest for which there still is a lack of commercially available metal-conjugated antibodies for PDHGG it will be useful to generate focused antibody panels for pathology driven biomarkers or to study specific cellular processes such as invasion/migration and/or to focus on specific pathways in relation to potential therapeutic treatments We believe that the mass cytometry technology and its multidimensional analysis capability may contribute to further advance the field of PDHGG It can be used to comprehensively characterize patient-derived models to determine how certain antigenic profiles are retained in different culture conditions (2D vs 3D and organoid cultures) the use of focused metal-tagged antibody panels may be employed to study how primary patient-derived cells respond to therapeutic approaches of interest highlighting the identification of biomarkers allowing to follow the dynamic modulation of multiple markers and their functional states pre and posttreatment) and identifying unique cell populations responsive and/or resistant to treatment the effort to generate a custom-conjugated antibody panel for the PDHGG and the brain tumor-immune microenvironment will offer a more expanded vision on the complexity of these tumors with more advanced CyTOF based imaging mass cytometry technology for studying patient tissue samples in situ at single-cell level mass cytometry analysis has shown that PDHGG patient-derived cell lines are comprised by cells having different antigenic profile at both intra- and inter-tumor level Our study opens to the possibility of employing tumor cell antigens identified through mass cytometry analysis as predictive biomarkers for molecular/locational PDHGG subgroup and for patient stratification The raw data supporting the conclusions of this article will be made available by the authors The studies involving human participants were reviewed and approved by Institutional Ethical Committee of the Bambino Gesù Children’s Hospital Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin and YG; 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Locatelli F and Vinci M (2022) Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry Received: 11 August 2022; Accepted: 16 November 2022;Published: 08 December 2022 Copyright © 2022 Petrilli, Fuoco, Palma, Pasquini, Pericoli, Grabovska, Mackay, Rossi, Carcaboso, Carai, Mastronuzzi, Jones, Cesareni, Locatelli and Vinci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Maria Vinci, bWFyaWEudmluY2lAb3BiZy5uZXQ= Volume 10 - 2019 | https://doi.org/10.3389/fgene.2019.00391 Astroblastoma is a rare tumor of the central nervous system (CNS) with uncertain clinical behavior DNA methylation profiling has been shown to provide a highly robust and reproducible approach for the classification of all CNS tumors across different age groups a subset of CNS high-grade tumors with astroblastoma-like morphology characterized by the meningioma 1 gene (MN1) rearrangements has been identified; they were termed “CNS high-grade neuroepithelial tumors with MN1 alteration” (CNS-HGNET-MN1) we describe a case of CNS-HGNET-MN1 diagnosed by DNA methylation profiling using Illumina Infinium HumanMethylationEPIC BeadChip (EPIC) that offers the opportunity to conduct a brief literature review The patient presented with an episode of partial seizures involving the right hemisoma No other treatment was proposed in light of the histological and molecular findings the patient is disease-free in good clinical conditions we recommend DNA-methylation profiling as an important tool for diagnosis and more effective patient stratification and management Modern molecular approaches are allowing a deeper characterization of AB. Approximately one-third of these tumors harbor the V600E substitution in BRAF, like other primarily cortically based, circumscribed gliomas (Lehman et al., 2017). Mutations in isocitrate dehydrogenase (IDH) are absent, and no other recurrent mutations have been reported (Fu et al., 2013; Bale et al., 2016; Hirose et al., 2018) In recent years, DNA methylation profiling has been shown to be a highly robust and reproducible approach for the classification of CNS tumors across age groups (Capper et al., 2018). This technique exploits the notion that the cancer methylome is a combination of both somatically acquired DNA methylation changes and characteristics that reflect both cell of origin and events contributing to transformation (Capper et al., 2018) By using DNA methylation profiling, Sturm et al. (2016) identified a subset of CNS high-grade tumors with an AB-like pattern characterized by the meningioma 1 gene (MN1) rearrangements, described as “CNS high-grade neuroepithelial tumors with MN1 alteration” (CNS-HGNET-MN1). In parallel, MN1 rearrangements, together with alterations of the X chromosome, have been reported to be a feature of AB (Hirose et al., 2018) Notwithstanding these insights, AB histology is not specific for any entity, including CNS-HGNET-MN1, and additional genetic characterization is required for a more accurate AB classification. Of note, recent studies have documented methylation profiles and genetic mutations indicating a heterogeneous landscape, which is likely to explain the clinical unpredictability of AB (Wood et al., 2018) we report a case of parietal tumor with characteristic histological features of AB confirmed and further classified by DNA-methylation profiling (A) T2W image shows a heterogeneous mass in the left parietal lobe with characteristic multicystic bubbly appearance (B,C) There are mild peritumoral edema on FLAIR image and diffusion restriction on ADC (D) No sign of hyperperfusion on dynamic susceptibility-weighted MRI (E) The T1W post-contrast image shows strong contrast-enhancement of the lesion (F) Post-contrast-enhanced cerebral MRI performed 20 months after surgery shows no evidence of recurrent/residual disease Gross total resection was performed. Histologically (Figure 2) the tumor showed non-infiltrative borders and consisted of elongated tapering cells Astroblastic pseudorosettes were observed throughout; sclerosing vessels with foamy perivascular histiocytes were present ribbon-like or fusiform patterns were observed Few high-cellular areas with moderate cellular pleomorphism were noticed Immunohistochemistry revealed strong positivity for glial fibrillary acidic protein (GFAP) and OLIG2 mild dot-like and superficial positivity for epithelial membrane antigen (EMA) and negativity for synaptophysin (SYP) and cytokeratin Proliferation index resulted about 3%; in more dense cellular areas High-grade ABs were characterized by multiple foci of high cellularity increased mitotic activity (>5 mitoses per HPF) elevated proliferative index (>10%) Histology – The tumor was composed of elongated cells with abundant eosinophilic cytoplasm and tapered processes radiating from the vessels and forming characteristic astroblastic rosettes throughout (A: HE 10x Sclerosing vessels with scattered foamy histiocytes were present (C: HE 20x) ribbon-like (D: HE 40x) or fusiform patterns were observed (E: HE 40x) A few highly cellular areas with moderate cellular pleomorphism were noticed (F: HE 20x) MDS (multidimensional scaling) analysis performed on the 1000 most variable probes of the whole genome DNA methylation data shows a close similarity between our case (OPBG) and CNS-HGNET-MN1 while it clearly separates from other CNS-HGNET Color legend of the MDS plot as follows: Astroblastoma case (black); CNS-NB-FOXR2 (blue); EFT-CIC (violet); HGNET-MN1 (pink); HGNET-BCOR (light green) Copy number variation profile – Depiction of chromosome 1 to 22 and X Gains/amplifications represent positive (green) losses negative (red) deviations from the baseline 29 brain tumor relevant genomic regions are highlighted The presented case showed losses of chromosome X and multiple deletions near the MN1 locus on 22q12.1 In light of the histological and molecular findings no adjuvant treatment was proposed to the patient Clinical onset with signs of raised intracranial pressure is typical for AB, as most cases reported in the literature are characterized by large mass lesions, but non-specific signs and symptoms, including headaches, focal neurological deficits, seizures, nausea, vomiting, diplopia, dizziness and confusion (Navarro et al., 2005) since ependymoma generally does not express it diffuse astroblastic pseudorosettes were present but hyalinization of the vascular network occurred only focally immunohistochemistry profile was consistent with AB Our case was considered to be in the low-grade group, as it showed an orderly growth pattern with only mild cellular atypia, focal higher proliferation rate, and lack of necrosis or vascular proliferation. A prolonged overall survival has been described for MN1 altered tumors, even in presence of multiple local tumor recurrence (Sturm et al., 2016; Wood et al., 2018) ABs do not share mutation signatures with low-grade (WHO grade II) diffuse astrocytoma (IDH1/2 and TP53) or ependymomas (IDH1 Next-generation sequencing (NGS) of three cases identified mutations in a few genes known to be altered in low-grade gliomas, (e.g., BCOR, BCORL1, ERBB3, MYB, and ATM), but no recurrent mutations were seen (Bale et al., 2016) In our case, copy number variation (CNV) showed losses of chromosome X and multiple deletions near the MN1 locus on 22q12.1, which is a common event in these tumors (Capper et al., 2018) This finding, together with those reported in other available genetic and molecular studies (Hirose et al., 2018; Wood et al., 2018) suggests that “astroblastoma” is a morphological model that can be observed through a spectrum of molecular entities Very recently, Wood et al. (2018) further characterized the genetic alterations underlying AB by performing targeted NGS of 500 cancer-associated genes in a series of eight cases and correlating these results with break-apart fluorescence in situ hybridization (FISH) analysis of MN1 locus and DNA methylation profiling They were able to reclassify most cases into more specific molecular entities: (1) four tumors with MN1 alteration with good prognosis and mostly classifying as CNS-HGNET-MN1 by DNA methylation profile (3 out of 4); (2) two cases of high-grade astrocytoma originally diagnosed as AB CDKN2A/B deletion and TERT promoter mutation classifying as pleomorphic xantoastrocytoma by DNA methylation; the second characterized by TP53 mutation and numerous chromosome losses and no specific grouping by DNA methylation profile; (3) two cases of unclassifiable tumors both with intact MN1 FISH good prognosis and no clear DNA methylation profile Since ABs are rare and tumor description in the literature concerns only individual cases or small collections of cases, optimal treatment protocols have not been established. Whenever feasible, total resection is the best treatment. It provides excellent tumor-control rates. Chemotherapy and radiotherapy could play an adjuvant role. Merfled et al. analysis (Merfeld et al., 2018) identified 63 patients diagnosed with AB between 2004 and 2012 Assigned histopathological grade was known for 38 (60%) patients All but one patients were treated with surgical resection A total of 20 (31%) patients received chemotherapy A total of 26 (43%) patients received radiotherapy Among patients with high-grade and low-grade tumors That study failed to identify an association between tumor grade and survival but the authors emphasized that there is no benefit from chemotherapy even among patients with high-grade tumors patients who did not receive radiotherapy had poor survival Mallick et al. (2017) proposed a treatment algorithm for AB They recommended gross total resection for all these tumors whenever possible a central review should be done to reconfirm the diagnosis As lower-grade tumors behave more indolently regular follow-up should be preferentially considered for lower-grade AB after gross total resection Patients with a sub-total excision and those with a high-grade tumor should be offered adjuvant radiation along with concurrent temozolomide we decided not to propose further treatments Patients’ stratification by using DNA-methylation profiling will certainly be a useful tool for guiding the clinical management Astroblastoma is an extremely rare CNS tumor as the typical astroblastic rosettes may be present also in other CNS tumors AB can be considered as a morphologic pattern which can be associated with a spectrum of molecular entities Total resection is the best treatment; the precise role of chemotherapy and radiotherapy is still debated We believe that DNA-methylation profiles represents an important instrument for confirming diagnosis predicting prognosis and better defining the molecular characteristics of AB This study was carried out in accordance with the recommendations of the Internal Review Board of the Bambino Gesù Ospedale Pediatrico with written informed consent from all subjects All subjects gave written informed consent in accordance with the Declaration of Helsinki The protocol was approved by the Internal Review Board of the Bambino Gesù Ospedale Pediatrico ACa contributed to patient management and revision ACar contributed to neurosurgery and revision MT supervised the study and critically revised the manuscript for intellectual content and approved the final version of the manuscript to be published This work was supported by Ministry of Health Ricerca Corrente to EM and AIRC (IG 21614) to MT We thank the association HEAL for the support and end results (SEER)-based patterns of care analysis CrossRef Full Text | Google Scholar Classification of the Tumors of the Glioma Group on a Histogenetic Basis With a Correlated Study of Prognosis Google Scholar Genomic characterization of recurrent high-grade astroblastoma Astroblastomas: a pathological study of 23 tumors with a postoperative follow-up in 13 patients CrossRef Full Text | Google Scholar Astroblastoma: clinicopathologic features and chromosomal abnormalities defined by comparative genomic hybridization DNA methylation-based classification of central nervous system tumours Neuroradiologic characteristics of astroblastoma and systematic review of the literature: 2 new cases and 125 cases reported in 59 publications normalization and integration of the Illumina human methylation EPIC array with minfi Cerebral astroblastoma in an adult: an immunohistochemical Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement Astroblastoma: report of two cases with unexpected clinical behavior and review of the literature “Low-grade” astroblastoma with rapid recurrence: a case report Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation Morphological and molecular features of astroblastoma suggest an ontological relationship to other cortical-based gliomas of children and young adults WHO Classification of Tumours of the Central Nervous System Lyon: International Agency For Research On Cancer Google Scholar Patterns of care and survival outcomes in patients with astroblastoma: an individual patient data analysis of 152 cases Patterns of care and treatment outcomes of patients with astroblastoma: a national cancer database analysis Astroblastoma in childhood: Pathological and clinical analysis Brainstem astroblastoma with MN1 translocation New brain tumor entities emerge from molecular classification of CNS-PNETs Astroblastoma: does histology predict biologic behavior CrossRef Full Text | Google Scholar Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities Mastronuzzi A and Miele E (2019) Role of DNA Methylation Profile in Diagnosing Astroblastoma: A Case Report and Literature Review Copyright © 2019 Petruzzellis, Alessi, Colafati, Diomedi-Camassei, Ciolfi, Pedace, Cacchione, Carai, Tartaglia, Mastronuzzi and Miele. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Evelina Miele, ZXZlbGluYS5taWVsZUBvcGJnLm5ldA== Volume 12 - 2021 | https://doi.org/10.3389/fimmu.2021.634031 This article is part of the Research TopicT Cell Therapy for CNS TumorsView all 6 articles Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation currently none of these approaches have received approval from the regulatory agencies are tumors characterized by highly immunosuppressive tumor microenvironment limiting the possibility of effectively eliciting an immune response the peculiar anatomic location of these tumors poses relevant challenges in terms of safety since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation Despite some sporadic complete remissions achieved in clinical trials the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor Based on the lessons learned from these unsatisfactory experiences novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors although resting T cells do not cross the BBB they traffic from meningeal blood vessels into the CSF where cells can enter the brain parenchyma via the pia mater or choroid plexus activated T cells are able to traverse the BBB trough the capillary tight junctions immunotherapy approaches associated with in vivo or ex vivo activation of T cells may potentially provide a potent tool to facilitate the penetration of the immune system toward the BBB Moreover, the development of an effective immunotherapy approach should take into consideration that normal brain parenchyma has evolved to protect itself against an immunologic attack (8), characterized by the paucity of professional antigen-presenting cells (APC) (9) and by the downregulated expression of the major histocompatibility complex (MHC), both features limiting antigen presentation (10) New evidence shows that the tumor microenvironment (TME) plays a key role in negative modulation of immunotherapeutic approaches These evidences led to the clinical exploration of the use of monoclonal antagonist antibodies directed towards PD1 and PD-L1, with clinical trials enrolling patients with recurrent GBM (24) (Table 1) Table 1 Summary of recruiting or completed clinical trials covering brain tumor immuno-therapeutic approaches Finally, encouraging results were observed in CNS neoplasia treated with Adoptive Cell Transfer (ACT), of both un-modified or gene-modified immune cells, as well as tumor associated vaccines and oncolytic virus (Figure 1) Figure 1 Potential strategies for the treatment of brain tumors The cartoon summarizes the main immunotherapeutic approaches currently used in clinical trials subdivided in four major categories: 1) Cancer Vaccine based on Dendritic Cells (DC) pulsed with neoantigens or electropored/infected to transfer neo-antigen genes; 2) Checkpoint Inhibitors based on the use of antibody blocking relevant exhaustion pathway in T cells; 3) Adoptive Cell Therapy based on genetic modification of effector cells with expression vector for TCR or CAR; 4) Oncolytic Virus Therapy based on tumor cell infection and the consequent activation of adaptive immunity we analyze several aspects that limit efficacy of adoptive cell therapy in patients with CNS tumors and present strategies to overcome these hurdles Several groups proved that CNS tumors can be targeted by conventional α/β T although their activity is significantly modulated by the TME resulting in no significant (Grade 3 or 4) complications the best response being represented by partial response in three out of six patients Although these studies provided evidence that non-engineered immune cells may traffic to CNS and exert measurable antitumor activity mainly associated to difficulties to isolate and expand TILs from tiny fractions of primary brain tumors have hampered the wide clinical application for this approach in CNS tumors it should also be mentioned that macromoleculs such cytokines but systemically delivered cytokines have limited access to the CNS RNA-modified T cells have been considered in order to deliver cytokines directly into brain tumors to bypass the hurdles to access the CNS. In a GBM murine model, T cells modified with GM-CSF RNA delivered this cytokine into brain tumors, significantly prolonging overall survival of the animals (18). In particular, GM-CSF recruited DCs in to the tumors, induced their differentiation and maturation, leading to activation of TILs (58) whereas their expression in healthy tissues is restricted to germ cells that lacking the major histocompatibility complex (MHC) T cells genetically modified with CAR emerged in recent years as a promising immunotherapeutic approach, which could mediate a non-MHC-restricted anti-tumor response (84) CARs are artificial receptors composed of a region targeting a specific antigen linked to the T-cell activation domain CD3zeta chain (first-generation CAR) The target specific region can comprise a single-chain variable fragment (scFv) obtained from a specific monoclonal antibody as well as a receptor domain binding a specific ligand expressed on tumor cells Different approaches with CAR T-cells have been evaluated for the treatment of patients with GBM and/or MB, also in phase I/II clinical trials, by targeting one or more of the following targets (Table 2): Table 2 Summary of recruiting or completed clinical trials related to the use of CAR-T cells in the treatment of brain tumors Confirmation papers are highly desirable to assess whether the same gene editing could potentially optimize the activity of CAR T lymphocytes characterized by antigenic specificity other than IL-13Rα2 a Phase I study testing locoregional infusion of CAR.EGFR806-CAR T-cells has been opened to enrol paediatric patients with EGFR-positive recurrent/refractory CNS tumors (NCT03638167) Choi et al. (111) proposed a CAR.EGFRvIII T-cells secreting EGFR-bispecific T-cell engager (BiTE) to circumvent antigen escape. In mouse models of GBM, they showed that CART.BiTE cells were able to secrete BiTEs locally in the brain tumor, redirecting non-specific bystander T cells against tumors which eliminated efficacy heterogeneous tumors more efficiently, compared to the use of a conventional CAR T cell approach (111) This group elegantly combined two therapeutic tools (CAR and BiTE) which are typically considered competitive technologies which instead could be applied in a synergic manner Lastly, Zhang et al., in a preclinical model targeting HER2, proposed a different platform to treat GBM patients, based on NK-92 cell line transduced with CAR.HER2.CD28.ζ construct. In the in vitro and in vivo models, they show a potent and specific lytic activity of the CAR NK-92 cell line toward GBM (118) These encouraging studies have fastened the clinical translation of CAR.GD2 T cells in patients with brain tumors (NCT04099797 Many pediatric CNS tumors express B7-H3; in particular, high B7-H3 expression has been found in the following tumors: atypical teratoid/rhabdoid tumors (ATRT), ependymomas (all grades), MB, CNS embryonal tumors, choroid plexus tumors (CPTs), meningioma and craniopharyngiomas (136, 137) In MB, WNT subtype expresses the highest B7-H3, while SHH subtype show the lowest one (136). However, low-grade gliomas and germ cell tumors show a negligible difference of B7-H3 expression respect to normal brain (136) The Seattle Children’s Hospital has started a clinical trial in 2019 based on CAR.B7-H3 T Cell based locoregional infusion in DIPG/DMG patients and recurrent/refractory paediatric CNS tumors (NCT04185038) Clinical studies need to be conducted to study the safety and real therapeutic activity of the proposed innovative CAR approaches Approaches to optimize endogenous T-cell immune responses, including Immune Checkpoint Inibitors (ICIs) (157, 158), oncolytic viruses (159), and tumor neoantigen vaccines (160) have shown evidence of bioactivity against brain tumors, also in clinical trials (Figure 1 and Table 1) It could also be plausible that the clinical response to ICI may be associated to the newly recruitment of T cells to the tumor site that are induced by the signal generated from activated APCs Further investigations to study the clinical efficacy of combinatory therapy between CARs and ICI are ongoing including a clinical trial in GBM patients (NCT03726515) that will evaluate the combination of CAR.EGFRvIII T cells in association with pembrolizumab (PD-1 inhibitor) HSPPC-96, a vaccine based on heat-shock tumor peptides, has been applied to recurrent GBM in a phase II trial, showing 6-month survival rate of 90% (196). A different vaccination approach has been developed for AFTV, which is based on formalin-fixed tumor sample fragments, infused intradermal in GBM patients. This approach allows to reach a 3-year survival rate in 38% of the treated patients (197) Data coming from this trial will clarify the impact of DC vaccination on patient outcome Pivotal clinical trials need to be designed and carried out to corroborate the safety and efficacy of the described combinatory approach coupled with the essential insights in the understanding of neuro-immunology are creating innovative opportunities to treat CNS cancer it is likely that combinatorial regimens will be required and based on 1) increase of CNS delivery; 2) “multi-valent” tumor targeting; 3) targeting both tumor cells and the CNS TME The road to identify an effective cure for brain tumors still appears long and filled with pitfalls but the deep knowledge of these tumors and their microenvironment will lead in the near future to increasingly personalized treatment possibly changing the natural history of these diseases BDA coordinated the coauthor’s contribution and rearranged the final version All authors contributed to the article and approved the submitted version We would like to thank all agencies supporting our work on immunotherapy in particular the Italian Health Ministry [for GR-2013-02359212 CAR T RCR-2019-23669115]; AIRC; Ricerca Corrente (CQ BDA); All the charities that support our research and clinical translation including “Raffaele Passarelli” Onlus “Il laboratorio di Chiara,” “Fondazione Heal,” “IRENE” Onlus “Oscar’s Angels Italia,” and “Martina e la sua luna.” to which we are indebted for the critical revision of the manuscript and his helpful suggestions Childhood Brain Tumors: Current Management J Neurosurg Pediatr (2019) 23:261–73 Receptor-Targeted Glial Brain Tumor Therapies CrossRef Full Text | Google Scholar Part I: Strategies for Utilizing Oncolytic Herpes Simplex Virus-1 in Children Engineering Challenges for Brain Tumor Immunotherapy Adv Drug Delivery Rev (2017) 114:19–32 CrossRef Full Text | Google Scholar Development of the Choroid Plexus and 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Immunovirotherapy and Immune Checkpoint Blockade Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma Mastronuzzi A and De Angelis B (2021) Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We Received: 26 November 2020; Accepted: 30 April 2021;Published: 07 June 2021 Copyright © 2021 Quintarelli, Camera, Ciccone, Alessi, Del Bufalo, Carai, Del Baldo, Mastronuzzi and De Angelis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Concetta Quintarelli, Y29uY2V0dGEucXVpbnRhcmVsbGlAb3BiZy5uZXQ= Europe works to improve cancer management through the use of artificialintelligence (AI), and there is a need to accelerate the development of AI applications for childhood cancer. However, the current strategies used for algorithm development in childhood cancer may have bias and limited generalizability. This study reviewed existing publications on AI tools for pediatric brain tumors, Europe's most common type of childhood solid tumor, to examine the data sources for developing AI tools. We performed a bibliometric analysis of the publications on AI tools for pediatric brain tumors, and we examined the type of data used, data sources, and geographic location of cohorts to evaluate the generalizability of the algorithms. We screened 10503 publications, and we selected 45. A total of 34/45 publications developing AI tools focused on glial tumors, while 35/45 used MRI as a source of information to predict the classification and prognosis. The median number of patients for algorithm development was 89 for single-center studies and 120 for multicenter studies. A total of 17/45 publications used pediatric datasets from the UK. Volume 13 - 2023 | https://doi.org/10.3389/fonc.2023.1285775 This article is part of the Research TopicArtificial Intelligence and Machine Learning in PediatricsView all 4 articles Introduction: Europe works to improve cancer management through the use of artificialintelligence (AI) and there is a need to accelerate the development of AI applications for childhood cancer the current strategies used for algorithm development in childhood cancer may have bias and limited generalizability This study reviewed existing publications on AI tools for pediatric brain tumors Europe's most common type of childhood solid tumor to examine the data sources for developing AI tools Methods: We performed a bibliometric analysis of the publications on AI tools for pediatric brain tumors and geographic location of cohorts to evaluate the generalizability of the algorithms A total of 34/45 publications developing AI tools focused on glial tumors while 35/45 used MRI as a source of information to predict the classification and prognosis The median number of patients for algorithm development was 89 for single-center studies and 120 for multicenter studies A total of 17/45 publications used pediatric datasets from the UK Discussion: Since the development of AI tools for pediatric brain tumors is still in its infancy there is a need to support data exchange and collaboration between centers to increase the number of patients used for algorithm training and improve their generalizability there is a need for increased data exchange and collaboration between centers and to explore the applicability of decentralized privacy-preserving technologies consistent with the General Data Protection Regulation (GDPR) This is particularly important in light of using the European Health Data Space and international collaborations a notable concern arises: how the current AI tools customized for clinical use in Europe are trained with datasets representing diverse populations Central nervous system (CNS) tumors constitute nearly 20% of childhood cancers, making them the predominant solid neoplasms in this age group (11). Despite significant progress that has improved the outlook for pediatric CNS tumor patients, challenges persist in fully implementing precision medicine, enabling less invasive interventions, predicting treatment responses, and identifying new therapeutic approaches (10–12) Childhood CNS tumors significantly differ from their adult counterparts by incidence, histology, molecular biology, treatment strategies, outcomes, and long-term outcomes. Consequently, extrapolating data from adults to children is not appropriate (13) the rarity of brain tumors in pediatric patients poses a challenge in amassing a substantial volume of observations to appropriately train algorithms in this disease group we undertook a systematic review of the current literature related to AI tools specifically developed for tackling pediatric brain tumors in the European context Our objective was to describe the characteristics of the data utilized in their development and the potential associated bias Our inquiry centered on delineating the sources of data ascertaining the presence of external validation and scrutinizing the geographic representation of the cohorts employed in refining the algorithms we discuss potential strategies to accelerate the development and integration of AI tools for pediatric brain tumors into clinical practice in Europe We performed a systematic review of the current literature by employing a search query based on the terms recommended by the Cochrane collaboration for pediatric tumors (18), including terms specific to pediatric brain cancer. Furthermore, we developed a distinct search query tailored to encompass AI techniques, subsequently merging it with the prior query (Supplemental materials - S1) Our search spanned the databases of MEDLINE, EMBASE, Web of Science, and Scopus, limiting the inquiry to papers published in English within the period spanning January 2010 to May 31, 2022. The outcomes of this search were imported into the Rayyan software (19) and subjected to a duplicate screening process we manually reviewed the remaining records to ascertain their eligibility against a set of predefined criteria encompassing: 1) original articles; 2) papers detailing the development of AI tools tailored for pediatric brain tumor diagnosis or therapeutic decision support; 3) at least one author affiliated with a European institution; 4) publications in English we excluded articles: 1) not presenting original data or reviews; 2) published in languages other than English; 3) authored by individuals not affiliated with European institutions; 4) describing studies conducted on animals or simulated environments We have included authors from institutions based in the UK as they continue to be eligible for collaborative projects within established European networks following Brexit The selected articles were categorized into two distinct groups: 1) those exclusively comprising observations from patients under 18 years of age for algorithm training; 2) those encompassing both pediatric and adult populations Bibliometric details were extracted in a format compatible with bibliometric analytical tools while three independent reviewers manually extracted specific details from each publication including: a) the specific brain tumor type under examination; b) the scope of the AI tool; c) the nature of data utilized; d) the data repository employed; e) the count of patients contributing data for algorithm development; e) the use of data standards for interoperability; f) the use of external validation of the algorithms; g) the performance of the AI tool; h) the geographic representation of the cohorts used for developing the algorithm The resulting information was subjected to descriptive analysis, with bibliometric data analyzed through the Biblioshiny software (20). Additionally, we evaluated the FAIR Guiding Principles score (21) for each dataset included in the reviewed articles using the SATIFYD online tool (https://satifyd.dans.knaw.nl/). Other statistical analyses were performed utilizing the R software (22) Our search strategy yielded a total of 10503 scientific publications. The selection process adhered to PRISMA standards and is visually represented in Figure 1 Upon eliminating duplicates across diverse databases Subsequent review of titles and abstracts narrowed down the selection to 572 records we excluded 246 articles solely centered on adult populations 24 that didn’t involve AI methodologies and 29 that didn’t meet the eligibility criteria for various reasons Figure 1 Review process of selected publications according to PRISMA Of these 273 studies, 228 failed to report the age of the patients and were consequently excluded. Ultimately, we selected 45 articles that incorporated pediatric data for the AI algorithm development. Among these, 25 articles exclusively focused on children, while 20 articles used data from both pediatric and adult cohorts (Supplemental materials - S2) Our review encompassed publications dating back to 2012 27 out of the 45 articles (60.0%) included in this study were published from 2020 onward eight studies were published before 2016 and were characterized by relatively modest patient numbers during algorithm training The array of AI methods utilized for analysis was diverse although the preponderance of papers analyzed data within a Python environment the selected publications garnered 57.8 citations each the predominant thrust of the selected papers (24 out of 45 accounting for 53.3%) was directed towards algorithmic development for tumor classification Table 1 Diagnoses included in the selected publications by type of population Table 2 Scopes of the articles included in the review The majority of publications employed the same dataset for both testing and validating their algorithms with only 3 out of 45 utilizing external datasets for validation the external validation performance of the algorithm was lower than that reported for internal validation Table 3 shows the data sources utilized across the reviewed publications. The majority of AI studies examined diagnostic images as primary data sources, specifically employing multiple conventional MRI sequences for classification and prognosis of CNS tumors. However, some studies delved into spectroscopy, a more specialized MRI sequence often utilized at the point of diagnosis (23) computer tomography and histopathology images made appearances as data sources and clinical features were used less frequently than images only 6 out of 45 publications (13.3%) integrated data from multiple sources Table 3 Data sources used in the selected publications by type of population Table 4 shows the repositories gathering data from multiple sites used for the development of algorithms and accessible on the web as reported in the articles included in the review Table 4 Data repositories gathering data from multiple sites used in articles included in this review 29 articles (64.4%) drew from single centers while 16 (35.6%) were the result of multicenter collaborations Two studies used synthetic data to inform their algorithms’ development and no instances of federated learning were noted no selected publication provided insights into the interoperability of their datasets the median value for the datasets used in the articles in this review stood at 23 (IQR: 15-32) This relatively modest score stemmed from the frequent absence of accessible metadata and from the limited accessibility of datasets used for algorithm development The number of patients included in the datasets for the development of AI algorithms was quite variable and essentially limited for most data sources The median observation count used for single-center studies was 89 whereas publications emerging from multicenter collaborations exhibited a median observation count of 120 7 out of the 45 reviewed articles tapped into public repositories for data An additional 14 articles incorporated data from beyond the EU In terms of pediatric datasets within the EU 17 publications (37.8%) harnessed cohorts from the UK while individual datasets emerged from Belgium Delving into the collaborative landscape, Figure 2 illustrates the interconnected network of institutions represented across the selected publications the UK stood out as a frequent contributor but also due to its extensive collaborations with both European and non-European entities the network reveals consistent partnerships between EU countries and the USA Figure 2 Country collaboration network The thickness of lines reflects the frequency of collaborations Our review unveiled a scarcity of publications regarding AI applied to CNS tumors in children in Europe Most of the studies emerged from individual centers indicating a pressing need for improving research in this field This holds particular significance for the less prevalent tumor types often overshadowed in the development of AI tools our review underscored that several European institutions are engaged in crafting AI tools for identical categories of pediatric brain tumors with only 16 publications reflecting multicenter data contributions we did not find any information about data standards for interoperability that can support collaborative research in this field illustrating a fertile ground for reinforcing and expanding such partnerships We also observed that most publications reported AI tools trained with a low number of observations from selected populations few publications reported an external validation of their algorithms research on AI on pediatric CNS tumors suffers from fragmented data and studies performed on small sample sizes Although the performance of the published algorithm in this domain is fair according to reported results for internal validation the potential for bias is high and their generalizability may be limited Identifying the trade-off between privacy preservation and the full development of AI solutions will represent one of the most important topics for discussion at the data governance level While compliance with regulations for data sharing is important for scientific research in the field of AI (26), technologies such as federated and swarm learning (27–29) and synthetic data (30) may be prioritized to accelerate the development of AI tools none of the publications reviewed in our study used federated or swarm learning and only two studies explored the use of synthetic data The datasets examined in the review seldom adhered to all FAIR principles reinforcing the observation of a limited commitment to reusing and integrating data across different contexts Moreover, interoperability and data harmonization (31) are critical for addressing the fragmentation of data. The Observational Health Data Sciences and Informatics (OHDSI) community conducts research to promote the use of standards such as OMOP and standardized vocabularies (32, 33). Another standard that supports interoperability is HL7 FHIR (34) our review did not find any information on the interoperability of the datasets used for the development of AI tools AI tools can further improve classification if algorithms are trained with generalizable data The majority of AI tools used in the publications reviewed utilized diagnostic images as their data source. Neuroimaging, a well-developed area for AI in oncology, offers detailed analysis of brain microstructures and pathophysiology specific to children (35) AI also has the potential for integrating multiple types of data which could be beneficial for investigating complex patterns and increasing algorithm accuracy Our review found that only a small number of publications utilized this approach which is an area that should be given more attention The development of AI tools outside medicine typically aggregates massive datasets from multiple sources which correlate with accurate predictions (36) Open repositories for developing AI tools represent an attempt to concentrate large amounts of diagnostic images and overcome the existing barriers to data access 7 have used a data repository for the development of their algorithm which represents the main area of application of AI in neuro-oncology the success of AI tools depends heavily on the quality and representativeness of the data used for training many AI models for pediatric brain tumors are trained on small there is a need for collaboration among research groups working on the same diseases sharing data to enhance the robustness of AI models AI models developed in isolation may lack the necessary accuracy for clinical decision-making The absence of such collaboration leaves AI models vulnerable to overfitting performing well on training data but poorly on external validation from different settings we focused on data-driven bias only and we did not evaluate potential algorithmic bias in the studies included in this review Data access remains the biggest challenge in training and developing AI tools and requires significant research effort and investment to enable the development of AI tools for pediatric brain tumors The original contributions presented in the study are included in the article/Supplementary Material Further inquiries can be directed to the corresponding author a project funded by the European Union’s Call for Pilot Projects and Preparatory Actions (PPPA) under Grant Agreements No 101052609 This work was supported also by the Italian Ministry of Health with Current Research funds The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1285775/full#supplementary-material Artificial intelligence in medicine: today and tomorrow CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Clinical applications of artificial intelligence and machine learning in cancer diagnosis: looking into the future Addressing bias in artificial intelligence in health care PubMed Abstract | CrossRef Full Text | Google Scholar Artificial intelligence in cancer research and precision medicine Google Scholar The European Union general data protection regulation: what it is and what it means Inf Commun Technol Law (2019) 28:65–98 CrossRef Full Text | Google Scholar 8. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Alberto Eugenio Tozzi, YWxiZXJ0b2V1Z2VuaW8udG96emlAb3BiZy5uZXQ= Volume 16 - 2023 | https://doi.org/10.3389/fnmol.2023.1228389 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 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 Here we report the first pediatric case of PHTS with both a germline and somatic variant in PTEN and in CHEK2 who presented a significantly early onset of MB SHH (15 months) in addition to a remarkably early picture of hamartomatous intestinal polyposis The patient and his legal guardians conferred informed consent for the study A centralized review of histological characterization was performed Molecular genetics studies were performed on genomic DNA extracted from peripheral blood using a next-generation sequencing (NGS) panel including medulloblastoma and cancer predisposition genes (APC according to the manufacturer’s protocol (Twist Bioscience The presence of deletions and duplications in PTCH1 and SUFU genes on peripheral blood was also excluded by multiplex ligation-dependent probe amplification (MLPA) according to the manufacturer’s protocol (MRC Holland referred to the Bambino Gesù Children’s Hospital at 15 months of age after the removal of a cerebellar mass histologically compatible with MB at another center He is the firstborn child to unrelated parents His family history is free of neurocognitive developmental alterations his paternal grandfather and uncle died of intestinal cancer; his paternal grandmother died of pancreatic cancer He was born at 39 weeks of gestational age after an uneventful pregnancy while his head circumference was above normal (38 cm he presented with macrocephaly (+3.0 SD) and psychomotor delay with major weaknesses related to language skills as detected by Griffiths Developmental Scales The surgical removal was fraught with difficulty, despite neuroimaging suggested a superficial, almost extra-axial lesion. The tumor was in fact very hard and bled profusely, to the point of reminding more of a hemangioblastoma, with a complex pattern of intratumoral vessels, than of an MB, which was moreover completely isodense at the pre-operative computed tomography (CT) scan. Complete resection was confirmed by postoperative magnetic resonance imaging (MRI) (Figure 1) Cerebrospinal fluid was free of neoplastic cells B) and SWI (susceptibility weighted imaging sagittal CISS (three-dimensional constructive interference in steady state C) Gd T1w (D) and MIP (maximum intensity projection There is a well-circumscribed lesion in the posterior fossa (A which is centered on the cisterna magna and pushing the vermis cranially with growth into the fourth ventricle and extension through the foramen of Magendie onto the posterior aspect of the upper cervical cord (D The tumor is isointense to the cerebellar cortex on T2 (A) and shows restriction of diffusivity (B) due to high cell density along with high nuclear-to-cytoplasmic ratio (B) There is significant contrast-enhancement (D) and intralesional vessels (E,F Cystic components are appreciable and appear larger in the cranial portions of the lesion (arrow The histological examination revealed an embryonic neoplasm characterized by the presence of nodular and internodular areas The nodular areas showed elongated aspects and consisted of neurocytic-type cells immersed in a fibrillar stroma the cells were markedly hyperchromic with frequent mitosis The immunohistochemical investigation showed a pattern coherent with MB SHH The cells were positive for synaptophysin in the nodular areas; positivity was observed for GAB1 The proliferation index evaluated with Ki67 was high in the internodular areas (about 30%) This single-base substitution affects the last nucleotide position of the exon 1 and could be a splicing variant further RNA studies are needed to test this hypothesis but are not feasible at present due to sample unavailability This variant can be classified as pathogenic according to the ACMG criteria (PP3 Segregation analysis performed on the parents confirmed the de novo nature of the variant The variant in CHEK2 was also found in the tumor sample with an allele burden of 46% the child is currently in remission from MB Capsular picture (B): middle ileum micro-polyp We present the first known case of a child carrying a germline and somatic pathogenic variant of PTEN associated with a germline and somatic variant of CHEK2 with a phenotype characterized by macrocephaly and very early onset of MB SHH and intestinal polyps Known pediatric cases of MB with germline variants of PTEN Known cases of affected by PHTS with bowel polyps’ onset before age of 12 years sequencing analysis on tumor revealed the well-characterized loss of function somatic variant of PTEN p.Arg130Gly that together with the germline missense change p.Tyr27Asn likely determines the complete loss of phosphatase activities of the protein providing a strong evidence that the MB in our patient is associated with PHTS we did not observe a loss of heterozygosity or the presence of a second deleterious somatic variant in CHEK2 suggesting this gene could have a marginal role in the tumorigenesis in our patient Our 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progression after Apc mutation Evolving of therapeutic strategies for CNS-PNET Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes When overgrowth bumps into cancer: the PTEN-Opathies PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol CrossRef Full Text | Google Scholar Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations The genetic landscape of the childhood cancer medulloblastoma Novel mutations target distinct subgroups of medulloblastoma Deletion of PTEN and BMPR1A on chromosome 10q23 is not always associated with juvenile polyposis of infancy The hamartomatous polyposis syndromes: a clinical and molecular review CrossRef Full Text | Google Scholar MBCL-18.CHEK2 mutation in high-risk MEDULLOBLASTOMA CrossRef Full Text | Google Scholar Conformational dynamics and allosteric regulation landscapes of germline PTEN mutations associated with autism compared to those associated with cancer A novel germline mutation of PTEN associated with brain tumours of multiple lineages Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands The risk of gastric cancer in carriers of CHEK2 mutations and a pathogenic germline PTEN variant: cause or coincidence Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome doi: 10.1002/(SICI)1098-2264(199802)21:2<113::AID-GCC6>3.0.CO;2-3 Childhood cerebellar tumours mirror conserved fetal transcriptional programs Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort PTEN Signaling in the postnatal perivascular progenitor niche drives medulloblastoma formation Keywords: cancer predisposition syndrome (CPS) Cinalli G and Mastronuzzi A (2023) SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome Received: 24 May 2023; Accepted: 07 August 2023; Published: 24 August 2023 Copyright © 2023 Caroleo, Rotulo, Agolini, Macchiaiolo, Boccuto, Antonelli, Colafati, Cacchione, Megaro, Carai, De Ioris, Lodi, Tornesello, Simone, Torroni, Cinalli and Mastronuzzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Angela Mastronuzzi, YW5nZWxhLm1hc3Ryb251enppQG9wYmcubmV0; Assistant District Attorney Shauna Barnett later described the hearing as "one of the most profound sentencings I have ever been a part of." "From the moment the first person got up to speak," she said it was nothing but an emotional journey in that courtroom." Multiple witnesses delivered impact statements on behalf of victims Alexa Jeanne Hannig even Circuit Judge Dennis O'Dell had tears in his eyes as witnesses spoke The packed courtroom was filled with the sounds of sobbing and sniffling throughout the hearing Emotions ran particularly high as Britney Morris told the court that she had chosen to forgive Cortez "I forgive him for doing something selfish and stupid that took someone I love," she said adding that she was forgiving him because it's what her brother would have done Cortez was traveling west in the eastbound lanes of I-565 when his vehicle collided head-on with the SUV driven by Johnson while Hannig and Johnson were taking Martella to Huntsville Hospital because the boy had a fever "What is going to stay with me forever is seeing Hayden still strapped in his car seat," said Barnett said the case was one of the more emotionally difficult cases he'd had in his career teenagers (about making good decisions) this is the case I'm going to talk about." He said his client did not have a history of criminal behavior and had been remorseful since the crash "He's never shown anything but heartache about what he did," said Morgan his mom took him to his very first teeball practice talked about playing trains and Paw Patrol with him remembered how he loved to gather eggs on her farm "There are no words that can properly convey the magnitude of this loss," said Kioutas She described her daughter as "sassy from the moment she was born" and a young woman who loved celebrating every holiday talked about how Hannig "lit up a room," with her smile how she loved eating at Roise's and Taco Mama Hannig was an employee of Hyde Homes and a 2011 graduate of Grissom High School she was launching a part-time cupcake baking business called Petite Cakes by Alexa "I hope some day their memories fill me with joy and warmth," Shellie Kioutas said but that for now she was filled with sorrow when thinking about the lives her daughter and grandson could have lived Johnson's sister Britney called him "sunshine on a cloudy day." "He loved being silly and making others around him laugh," she said "It was almost impossible not to like him "(Johnson and Hannig) were together and ready to take on the world." saying the weight of his grief and remorse over what he had done was "suffocating "I wish I could take away all of that pain and put your babies back in your arms," he told the victims' family members "My actions took your angels from this world and not a day goes by I don't (regret it) I don't deserve to be forgiven for what I did." talented young many who was working to better himself through his education," said his mother "There needs to be consequences for his actions," but "a lengthy prison sentence will only serve to take another beautiful life." Most of the victims' family members had requested a sentence of life in prison O'Dell talked about his faith and gave Bible verses as he talked to the court about how he had come to his decision Cortez was sentenced to 30 years in prison with parole Barnett said she thought it was a just sentence "This will stay with me and everyone in that courtroom adding that she wished she could bottle the feeling inside the courtroom and give it to anyone considering driving while intoxicated Use of and/or registration on any portion of this site constitutes acceptance of our User Agreement, (updated 8/1/2024) and acknowledgement of our Privacy Policy, and Your Privacy Choices and Rights (updated 1/1/2025) © 2025 Advance Local Media LLC. All rights reserved (About Us) The material on this site may not be reproduced except with the prior written permission of Advance Local Community Rules apply to all content you upload or otherwise submit to this site YouTube's privacy policy is available here and YouTube's terms of service is available here Ad Choices \n m_gallery = \"new_gallery_name_287\";\n m_gallery_id = \"20392747\";\n m_gallery_title = \"Victims of head-on collision on I-565 in Huntsville mourned by family friends 5.20.16\";\n m_gallery_blog_id = \"4558\";\n m_gallery_creation_date = \"Friday 9:36 AM\";\n m_gallery_permalink = \"http://photos.al.com/4558/gallery/new_gallery_name_287/index.html\";\n m_gallery_json = \"https://blog.al.com/photogallery/4558/20392747.json\";\n m_gallery_pagetype = \"embed\";\n m_gallery_type = \"photo\";\n <\/script>\n Gallery: Victims of head-on collision on I-565 in Huntsville mourned by family, friends 5.20.16 Volume 8 - 2020 | https://doi.org/10.3389/fped.2020.00091 This article is part of the Research TopicPediatric Central Nervous System Tumors: State-of-the-Art and Debated AspectsView all 10 articles Editorial on the Research Topic Pediatric Central Nervous System Tumors: State-of-the-Art and Debated Aspects Central nervous system tumors are the second most frequent malignancy in children and young adults they remain rare conditions and management standardization continues to be challenging despite international networking efforts The Research Topic on “pediatric central nervous system tumors: state-of-the-art and debated aspects” we included innovative and original contributions on multiple aspects of pediatric neuro-oncology In reference to the neuroimaging, the work of Colafati et al. presents preliminary data suggesting direct involvement of the V cranial nerve at diagnosis as a negative prognostic marker in DIPG 13.8% of the children presented cranial nerve V involvement at diagnosis This finding was associated with a poor prognosis (median overall survival: 7 vs concluding that cranial nerve V should be routinely evaluated with diagnostic scans Even if these findings need to be confirmed with a larger series accurate interpretation of traditional MR sequences can still contribute in advancing clinical knowledge In the paper by Yalon et al. an elevated neutrophil to lymphocyte ratio which is a relatively simple blood-derived biomarker is suggested to be a hallmark of malignant brain tumors The biological justification for this observation would be both a reduction in lymphocytes This paper highlights two promising fields of pediatric neuro-oncology: the potential role of immunity modulation for treatment and the opportunity offered by the development of biomarkers to assist in the treatment of patients The contribution by Foster et al. offers a wide overview on the advancement of neuro-oncology surgery Sophisticated techniques allow more accurate surgical planning better visualization and orientation during surgery Advancing the possibilities in tumor resection while preserving neurological functions will certainly overall contribute to better treatment results specifically for patients with low-grade lesions that still suffer significant surgical morbidity the authors investigated Vemurafenib's safety and efficacy as a single agent in pediatric patients with BRAFv600E positive LGG Petruzzellis et al. further demonstrated the efficacy and safety of this target therapy in the setting of Pleomorphic Xanthoastrocytoma (PXA) associated with Down syndrome PXA is a rare WHO grade II tumor that can harbor the BRAF mutation p.V600E This case report describes the first occurrence of a PXA reported in a child with Down syndrome (DS) as well as the first use of Vemurafenib in DS and the efficacy was seen by a partial response and a stabilization of the disease not yet standardized for pediatric patients affected by brain tumors and DS we have shown the feasibility of this therapeutic approach In addition to the molecular characterization of tumors several significant discoveries have contributed to shedding light on the role of epigenetic modification and cellular microenvironment in tumor growth and progression which is one of the major epigenetic modification can be differentiated in polycomb repressive complexes (PRCs): PRC1 and PRC2 The trimethylation of lysine on Histone H3 is an epigenetic modification induced by enhancer of zeste homolog 2 (EZH2) leading to the silencing of many tumor suppressor genes is associated with a poor outcome and progression in a large number of cancer cases a crucial transcription factor involved in promoting and regulating tumor development In their review, Papale et al. analyzed the activity and influence of EZH2 and HIF in pediatric cancer progression the correlation between them and the possible future role of specific inhibitors Medulloblastoma is among the most common malignant childhood brain tumors (WHO grade IV) Genomic studies have defined four consensus molecular subgroups (WNT each are characterized by distinct clinical outcomes Aberrant expression of long non-coding RNAs, which are normally expressed in the human brain, have been linked to neuro-oncological disorders. In their paper, Laneve et al. tried to explain the function of long non-coding RNAs in the medulloblastoma biology and development Moreover, Abballe et al. investigated the role of Numb in medulloblastoma's cancer cells which is expressed in medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) the medulloblastoma samples analyzed in this study showed low levels of Numb p66 and overexpression of Numb p72 compared to normal tissue These results show different roles for the two major Numb isoforms evaluated in medulloblastoma which highlighted a central role for Numb p66 in regulating stem-like cells and NCS maintenance Pediatric neuro-oncology remains a challenging arena for researchers with different expertise We believe that the coordinated work on the study of different types of tumor will be vital in the contribution to advancing the knowledge of these tumors will be key to the improvement clinical results AC and AM have jointly contributed intellectually and materially to the work We sincerely would like to thank Evelina Miele and Elisabetta Ferretti and all the authors for their contribution to this Research Topic and Megan Eckley for the revision of the language Citation: Carai A and Mastronuzzi A (2020) Editorial: Pediatric Central Nervous System Tumors: State-of-the-Art and Debated Aspects Received: 21 September 2019; Accepted: 21 February 2020; Published: 10 March 2020 Edited and reviewed by: Paul A. Northcott Copyright © 2020 Carai and Mastronuzzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) Mpox (monkeypox) Campaigns Events Multimedia Newsletters Spotlights The European Health Report 2024 Ukraine emergency Second European Programme of Work Carai, Susanne, Kuttumuratova, Aigul & Weber, Martin. (‎2018)‎. Review of Integrated Management of Childhood Illness (‎IMCI)‎ in Europe. World Health Organization. Regional Office for Europe. Volume 13 - 2023 | https://doi.org/10.3389/fonc.2023.1346803 Editorial on the Research TopicPediatric diencephalic tumors: a constellation of entities and management modalities This Frontiers Research Topic encompasses a collection of five papers and is focused on pediatric diencephalic neoplasms exploring their manifold aspects and their multi-modality management approaches The diencephalon, situated in the central part of the brain as a deep-seated midline region, comprises crucial structures and many different tumors can originate in this area (Figure 1), such as optic pathway/hypothalamic gliomas, craniopharyngiomas, low and high-grade gliomas, germ cell tumors, Langerhans cell histiocytosis, and pituitary adenomas (1) Each of these tumors exhibits significant differences in terms of biological behavior symptoms (secondary to the anatomical structures involved) Figure 1 Diencephalon and anatomical areas The comprehensive review of Pinto et al. aims to offer a comprehensive overview of diencephalic tumors in the context of the 2021 WHO classification of central nervous system neoplasms (2) providing insights into their epidemiology along with an exploration of the current strategies employed in their management These diencephalic tumors can be broadly categorized into four groups: ● Tumors of the neurohypophysis: germ cell tumors pituicytomas and neurocytomas can be found in this zone ● Thalamic neoplasms: low and high-grade gliomas ● Tumors of the pineal region: germ cell tumors pineal parenchymal tumor of intermediate differentiation (PPTID) Del Baldo et al. reported a single-center experience of 17 pediatric patients affected by intracranial germ cell tumors (iGCTs) treated with upfront proton therapy (PT) Given the high treatment success rates, the primary goal now must be focused on enhancing the quality of life by mitigating the long-term complications (7) Cockle et al. in their review have updated the constellation of histopathological entities making up pediatric diencephalic tumors, with a focus on their therapeutic approaches to ensure function preserving management (9, 10) They highlighted the evolving knowledge of the molecular aberrations underpinning the different type of neoplasms which offer potential targets for novel therapeutic toxicity-sparing drugs: ● Low-grade gliomas (LGG): typically exhibit nearly universal upregulation of the RAS-MAPK pathway providing an opportunity for employing targeted therapies ● High-grade glioma (HGG): one of the future challenges -also considering their heterogeneity- will be employing a precision medicine approach strategy allowing patients’ stratification into treatment regimens based on genetic alterations detected within each different type of HGG ● Germ cell tumors: they present an area with an unmet need for innovative therapies. However, the KIT/RAS signaling pathway has been identified as mutated in over 50% of iGCTs (14) ● Langerhans cell histiocytosis (LCH): the identification of the BRAF V600E mutation in LCH has opened avenues for the utilization of BRAF/MEK inhibitors in the treatment diencephalic tumors are intricate midline tumors and pediatric patients with these tumors typically present with symptoms resulting from mass effect on the hypothalamic–pituitary axis and optic nerve Molecular analyses allow for the identification of potential targets within specific tumor entities which may play an important role in disease control While radiation therapy carries several side effects in the pediatric population different techniques as proton beam therapy (the main choice for many of these neoplasms) have contributed to higher treatment response rates with reduced morbidity ACar: Writing – review & editing We thank authors of the papers published in this Research Topic for their valuable contributions and the referees for their rigorous review Nolte’s the Human Brain an Introduction to its Functional Anatomy Google Scholar The 2021 who classification of tumors of the central nervous system: a summary Implications of new understandings of gliomas in children and adults with Nf1: report of a consensus conference Recent updates on radiation therapy for pediatric optic pathway glioma Brain Tumor Res Treat (2022) 10(2):94–100 PubMed Abstract | CrossRef Full Text | Google Scholar 5. Children s Cancer and Leukaemia Group (CCLG). Craniopharyngioma: Guideline for the management of children and young people (CYP) aged <19 years. UK: CCLG (2021). Available at: https://www.cclg.org.uk/guidelines Google Scholar and emerging adults with craniopharyngioma from proton therapy through five years of follow–up and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence—results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK) Strahlenther Onkol (2021) 197(8):700–10 Endocrine disorders in children with brain tumors: at diagnosis Disease control after reduced volume conformal and intensity modulated radiation therapy for childhood craniopharyngioma Int J Radiat Oncol Biol Phys (2023) 85(4):187–92 Small–molecule inhibitors targeting the canonical WNT signaling pathway for the treatment of cancer Expression of interleukin–6 in human craniopharyngiomas: a possible inducer of tumor–associated inflammation Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target Acta Neuropathol (2018) 135(5):757–77 Molecular pathology and targeted therapies for personalized management of central nervous system germinoma Mastronuzzi A and Vennarini S (2023) Editorial: Pediatric diencephalic tumors: a constellation of entities and management modalities Received: 29 November 2023; Accepted: 05 December 2023;Published: 14 December 2023 Copyright © 2023 Cacchione, Carai, Biassoni, Mastronuzzi and Vennarini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Antonella Cacchione, YW50b25lbGxhLmNhY2NoaW9uZUBvcGJnLm5ldA== This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page .st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a}By Ashley Remkus | aremkus@al.comThe Huntsville man accused of driving under the influence of alcohol in an Interstate 565 crash that killed 3 people is expected to plead guilty Monday Carai Cortez is charged with three counts of reckless murder in the May 19 her 3-year-old son Hayden Martella and her boyfriend The 24-year-old from Huntsville was scheduled to appear in Madison County Circuit Court for a status conference this morning the hearing was canceled after his defense attorney filed a motion stating Cortez intends to plead guilty The case is on Monday's court docket for arraignment Defense Attorney Chad Morgan told AL.com Cortez plans to make a "blind plea." A blind plea is different from a plea bargain in that the defense hasn't reached a prearranged deal with prosecutors about sentencing or pleading guilty to a lesser charge The final sentence always is up to the judge but typically in a plea bargain the judge will sentence a defendant in accordance with the prearranged deal The maximum sentence for reckless murder is life in prison with the possibility of parole Cortez is accused of being drunk when he was driving west in the eastbound lanes of I-565 and collided head on with the victims' SUV The crash happened near the Bob Wallace Avenue exit The eastbound side of the interstate was shut down when the crash happened around 1:30 a.m a 2011 graduate of Grissom High School and an employee at Hyde Homes Cortez is held without bail in the Madison County Jail. Cortez had been released on bail in August 2016. But a judge ordered in December 2016 that he be held without bail for violating conditions of bond, records show. Cortez was accused of leaving the state without permission to attend a football game in Louisiana consuming alcohol and failing to register for color code drug and alcohol screenings Carai Cortez to plead guilty in reckless murder cases` by Ashley Remkus on Scribd Gallery: Victims of head-on collision on I-565 in Huntsville mourned by family The company is moving forward with the acquisition after completion of due diligence Enova Mining has announced plans to proceed with an option agreement it entered into with B Geologia E Mineração Mineração Paranaí Ltda and Rafael Viola Mottin on 18 December 2023 Enova was granted an option to acquire a 100% interest in the Carai Salinas East and Santo Antônio permits in the state of Minas Gerais Enova noted that it will proceed with the acquisition of the Poços de Caldas Rare Earth and Brazil Lithium Valley Tenements after confirming that due diligence has de-risked the project opportunity It added that the due diligence was carried out by a team led by Dr Klaus Petersen and geologist Leonardo Souza Due diligence identified considerable outcrops of saprolite clay within Enova’s Poços rare earth elements project areas in Brazil’s prolific Poços de Caldas/Caldera Alkaline Complex the team discovered numerous pegmatite outcrops in the tenement regions of Resplendor which are indicative of potential lithium mineralisation Don’t let policy changes catch you off guard Stay proactive with real-time data and expert analysis These resources offer a solid foundation for growing the corporation’s operations in a favourable mining business climate Completion of the transaction is subject to Enova shareholder approval and will allow the company to transfer assets to a Brazilian-registered Enova-held company Enova Mining said in a statement: “The Board intends to promptly commence exploration firstly focusing on identifying drill targets with rare earth potential at Poços de Caldas we will commence general exploration (multi-spectral survey mapping and geochemical sampling) in the other tenement areas Tenements at Carai are considered priority “Enova welcome the Option Agreement vendors as future stakeholders Their experience and advice in establishing our business in Brazil will be invaluable and allow us to focus on the core business of exploration.” Enova added that it is committed to developing the Charley Creek rare earth project with ongoing activities proceeding without disruption It will also continue to review projects and business opportunities as they arise Give your business an edge with our leading industry insights View all newsletters from across the GlobalData Media network .st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a}By Crystal BonvillianResearch Park Boulevard and Interstate 565 interchange.jpg Pictured is the Research Park Boulevard and Interstate 565 interchange not far from where three people were killed May 19 in a wrong-way driving crash on I-565 in front of the U.S A study released this past fall shows that drunk or impaired driving play a significant role in wrong-way driving crashes on Alabama's interstate system A Huntsville woman, her 3-year-old son and her boyfriend were killed last week when a wrong-way driver plowed into their SUV on Interstate 565 in front of the U.S is charged with three counts of reckless murder for the deaths of 22-year-old Alexa Jeanne Hannig her son Hayden Christopher Martella and 21-year-old Benjamin Daniel Johnson Cortez is also charged with driving under the influence of alcohol and driving on the wrong side of the highway He is set for a felon examination hearing at 1 p.m He was booked into the Madison County Jail the day after the crash after being treated for minor injuries at Huntsville Hospital Cortez is accused of hitting the victims head-on as he drove westbound in the eastbound lanes of the interstate. Lt. Stacy Bates, a Huntsville police spokesman, told AL.com Thursday that it remained unclear where Cortez entered the controlled-access interstate going the wrong way Results are still pending on his blood alcohol concentration at the time of the crash The circumstances of the crash that killed Hannig, Johnson and little Hayden on May 19 are mirrored in the November 2015 study which was funded by the Alabama Department of Transportation and conducted by experts at Auburn University culled from data from a 10-year period ending in 2013 show that nearly half of the drivers responsible for wrong-way driving accidents on Alabama interstates are driving under the influence Less than 4 percent of drivers in non-wrong-way driving crashes are impaired "Previous studies have found extensive correlation between alcohol consumption and impaired driving that causes difficulties for drivers in perceiving roadway information," the study reads Scroll to the bottom of this story to read the entire study The evening and nighttime hours also account for about 80 percent of wrong-way driving interstate crashes Crashes in the evening hours are nearly three times more likely to be caused by drivers going the wrong way while similar crashes are about five and a half times more likely in the "nighttime" hours The crash that killed the Huntsville victims occurred around 1:30 a.m. That data and the fact that drivers over 65 years old are more than nine times more likely to get involved in a wrong-way driving accident indicate that difficultly seeing or reading road markings and signage - whether through the confusion caused by intoxication or through aging - play a big part in these crashes The study also found that the majority of the drivers in the crashes studied had those accidents within 25 miles of their homes About 60 percent of those drivers close to home were drunk Only about 40 percent of drivers were drunk in this type of crash when it occurred more than 25 miles from home "It can be inferred that drivers who had the crash at locations farther than miles from their dwelling place are less probable to get involved in WWD crashes suggesting that distraction (due to factors like intoxication) might play a considerable role in these kinds of crashes," the study reads Cortez was less than 10 miles from his home on Camrose Lane when the wreck occurred Last week's crash also fell into another category affecting wrong-way driving incidents The study found that crashes in the months of March May and November are three times more likely to be caused by wrong-way driving The researchers were unable to determine a reason for that phenomenon Volume 6 - 2018 | https://doi.org/10.3389/fped.2018.00108 Extraventricular neurocytoma (EVN) is an extremely rare tumor of neuroglial origin with a tendency toward ganglionic or glial differentiation In the 2016 World Health Organization Classification EVN was classified as a grade II tumor and described as a neoplasm with good outcome the presence of cellular atypia is an important unfavorable prognostic factor we describe the first case of a patient with a congenital EVN localized in the brainstem his disease rapidly progressed despite several chemotherapies we report an atypical case of EVN presenting an extremely aggressive behavior The brainstem origin and the age of the patient may have represented two important prognostic factors for our patient We report the first case of congenital EVN localized in the brainstem of a 3-month-old patient The patient presented a dismal outcome despite multimodal therapy and absence of cellular atypia A 3-month-old male was referred to our hospital for the management of a congenital intracranial mass and infective endocarditis in the bicuspid aortic valve At birth, the child presented lower limb weakness, left seventh nerve palsy and left neck swelling, due to his cardiac problem, associated with a head turning difficulty. A magnetic resonance imaging of the brain showed a left pontine-bulbar lesion extended upward into the cerebellum. The fourth ventricle and the cerebellar vermis was dislocated (Figure 1) he presented fever associated to Staphylococcus aureus bacteremia An echocardiogram showed a vegetative endocarditis in the bicuspid aortic valve with an ejection fraction of 45% The patient received antibiotic therapy for this infection Axial T2w (a,b) ADC map (c) and Gd T1w (d) images Extensive hyperintense mass in the left cerebellopontine angle extended upward into the cerebellum with lower peripheral ADC values and subtle peripheral linear irregular enhancement after gadolinium injection medulla oblongata and the cerebellum are dislocated and compressed he underwent aortic valve replacement via Ross Procedure with no complications He presented a neurological deterioration with a left sided hemiparesis he underwent suboccipital craniotomy in the prone position with intraoperative neuronavigation and neurophysiologic monitoring The surgery was interrupted during resection of the infiltrating bulbar component because of sustained bradycardia and arterial hypertension and only a sub-total resection (STR) was performed He presented a stable neurological status after surgery but received a tracheostomy for a mild pulmonary insufficiency (A) Hematoxylin&Eosin staining shows a diffused round cell proliferation with various degrees of ganglioid differentiation (B) Strong positivity for synaptophysin immunostain Considering the young age of the patient and the sub-total resection After two cycles with high-dose carboplatin and etoposide Magnetic Resonance Imaging (MRI) showed a local disease progression as single agent was started but no tumor response was observed Despite further treatments with irinotecan temozolomide and then the BRAFV600E inhibitor Vemurafenib the MRI showed a gradual increase of tumor size associated with hydrocephalus The patient underwent a ventriculo-peritoneal shunt The number and duration of desaturation episodes increased due to the involvement of the medullary respiratory center Intermittent mechanical ventilation and total parenteral nutrition were necessary The child died of a cardiorespiratory arrest thirteen months after diagnosis Previously reported extra-ventricular neurocytoma in children two cycles of high dose of carboplatin and cisplatin and the use of targeted therapies including topoisomerase the disease progressed and the young patient died 13 months after diagnosis this is the first report of a congenital EVN presented an aggressive behavior and progressed rapidly leading to death despite the absence of unfavorable histology with the exception of a focal high proliferation index The impossibility to achieve a GTR and the critical localization of the tumor are two potentially significant factors for the prognosis of patients who develop an EVN This study was carried out in accordance with the recommendations of the Internal Review Board of the Bambino Gesù Ospedale Pediatrico with written informed consent from all subjects The protocol was approved by the Internal Review Board of the Bambino Gesù Ospedale Pediatrico The authors declare that written informed consent was obtained from the patient's parents for publication of this case report final approval to be published; 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Accepted: 03 April 2018; Published: 11 May 2018 Copyright © 2018 Piras, Miele, Di Giannatale, Colafati, Diomedi-Camassei, Vinci, de Billy, Mastronuzzi and Carai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited *Correspondence: Andrea Carai, YW5kcmVhLmNhcmFpQG9wYmcubmV0 .st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a}By Ashley Remkus | aremkus@al.comCarai Cortez (Madison County Jail photo) A 23-year-old Huntsville man today pleaded guilty to multiple counts of murder in the Interstate 565 DUI crash deaths of three people Carai Cortez pleaded guilty in the 2016 crash deaths of Alexa Jeanne Hannig Cortez was driving west in the eastbound lanes of I-565 when his vehicle collided head-on with the SUV Johnson was driving while Hannig and Johnson were taking Martella to Huntsville Hospital because of a fever Assistant District Attorney Shauna Barnett said Cortez was scheduled for trial today on three counts of reckless murder and one count of DUI. But, as reported this past week by AL.com Cortez chose to enter a "blind plea" and avoid a trial in a "blind plea," the defendant hasn't reached a prearranged deal with prosecutors about sentencing or pleading guilty to a lesser charge Defense attorney Chad Morgan said Cortez felt like a guilty plea was the "best option." "This is tragic on both sides," Morgan said "He's been broken up the entire time Madison County Circuit Judge Dennis O'Dell said he will schedule a sentencing date after a pre-sentence report is completed The report will include information about Cortez' background Cortez faces a maximum of life in prison for each murder charge no agreements or anything," Barnett said "The only thing we're doing is there was a fourth count Barnett said she appreciates Cortez taking responsibility for his actions but she hasn't decided whether she'll ask for the maximum sentence "I'll speak with the family," she said "You do get credit in this world for taking responsibility for the bad things that you do I do appreciate him taking responsibility for what he did." the victims' family members will be allowed to ask the judge for whatever sentence they see fit They can write letters or speak at the sentencing Cortez also can have witnesses speak on his behalf Both families cried during this morning's emotional plea "Until people are held accountable for things like this and given sentences that make them and the people that they talk to and live with and associate with think twice about taking those few drinks or those few shots or those pills or whatever their drug of choice is and getting behind the wheel of a car it's going to be an uphill battle," Barnett said of preventing DUI crash deaths until somebody gets killed -- until we have a tragedy like this and everybody on the comments after the story is (saying) 'put them under the jail' and 'no excuse for this.' It's like it's OK if this doesn't happen It's not OK because this could be any of us at any time." Johnson and Martella were dead at the scene of the May 19 died after being taken to Huntsville Hospital Cortez is being held in the Madison County Jail pending sentencing. He has been jailed since last December when he was rearrested for violating bond conditions. Cortez was accused of leaving the state without permission to attend a football game in Louisiana This weekend from 3pm, Saturday June 21st, you are warmly invited to a full 10 hours of live music performances, over no less than 9 stages in the beautiful village of San Carlos Organised by local promoters ‘Ai Carai!' the gloriously free event provides a platform for the richly diverse live music scene which flourishes here on the island hippy spirit of Ibiza to unfold magnificently before your eyes with not just hundreds of talented musicians taking part but vibrant performances an artisan market and many other surprises in store The occasion is the annual summer solstice and the location of San Carlos is delightfully appropriate Nico and Mick Jagger in those heady days of Ibiza hippy heaven What's more, the festival coincides with the International Day of Music. Last year there were events in over 108 countries and 726 cities around the world celebrating the international language of music It all sounds like a fantastic day out for the whole family a chance to experience a precious glimpse of that Bohemian Ibiza that many of us can only imagine wistfully Not only that, but the beautiful village of San Carlos is a sight in itself, ancient, charming and oozing with history. You can either get there on the bus from Santa Eulalia or drive - there is plenty of parking around the village Before you leave, we highly recommend you check out Bar Anita A legendary bar with an illustrious history of feeding impoverished artists who in return would gift their paintings we recommend you proceed immediately to San Carlos this Saturday PHOTOGRAPHY | Kindly provided by Ai Carai with permission Catch up with all the week's news and updates: Copyright © 1999 - 2025 Ibiza Spotlight S.L We are a member of the PIMEEF - the small and medium business association of Ibiza and Formentera All prices published on the site include VAT 'Carai roipota co yvype reyujhu mborayjhu jha poa' affection and love'." With this Paraguayan tune belonging to the Salesian Youth Movement (SYM) moved everyone present at the meeting with the Rector Major was welcomed to the rhythm of music and then made himself available for an open dialogue the 10th Successor of Don Bosco celebrated Mass in the Church of Mary Help of Christians and welcomed the Religious Profession of Salesian Brother Sergio Paredes hundreds of young people had the opportunity to speak with Fr Á.F ask him their questions and express their dreams and concerns "Do not be afraid to find out what God wants from you because when you do good you find the way of your happiness," said the Rector Major Before the many young people who feel confused and disappointed because they walk in life without being able to recognize the presence of God in their lives Artime was able to break through to the hearts of the children so much so that one commented: "I met the Rector Major in person: he is truly a faithful mirror-image of Don Bosco." the Rector Major met with Fr Néstor Ledesma Then he joined the Salesian Agro-Pastoral Institute "Carlos Pfannl" of Coronel Oviedo a Salesian center bearing the name of one of its benefactors which also houses a vast parish dedicated to Mary Help of Christians ANS - “Agenzia iNfo Salesiana” is a on-line almost daily publication the communication agency of the Salesian Congregation enrolled in the Press Register of the Tibunal of Rome as n 153/2007 This site also uses third-party cookies to improve user experience and for statistical purposes By scrolling through this page or by clicking on any of its elements Alderan Resources (ASX:AL8) has begun a stream sediment sampling program over its Itambacuri Project as part of the recently acquired Minas Gerais lithium tenement package in Brazil. The samples have been collected at 1km intervals along major drainages and at stream junctions to ensure that the entire project area is covered. Samples will be analysed at the ALS laboratory in Belo Horizontale including lithium and key lithium indicators. This program is expected to be completed in Q1 2024 and once assay results are returned the work program will focus on narrowing down to prospect areas for drilling. a soil and rock chip sampling program will be carried out as well as geological mapping over anomalous areas within the Minas Gerais projects. The company notes if lithium-rich pegmatites are uncovered it may be possible to fast-track drilling on the project areas Alderan Resources Managing Director Scott Caithness says the stream sediment sampling is aimed to uncover lithium anomalies which are expected to extend into Q1 2024 with the company’s Carai “Projects have been prioritised for sampling based on the occurrence of pegmatites and potential lithium indicator minerals identified during the due diligence field visit in October 2024. an 8m wide pegmatite dyke was identified with coarse feldspar and quartz plus tourmaline and red garnets.” The Minas Gerais projects comprise 24 granted exploration licences covering 472km-square within 7 projects. and Governador Valadares projects and all lie in the eastern lithium belt of Eastern Brazil. Alderan Resources is a critical metals and precious metals explorer focused on its portfolio of assets in Brazil and the US. the company had $1.529 million cash and cash equivalents at hand Write to Aaliyah Rogan at Mining.com.au Unico Silver makes ‘multiple new discoveries’ at Cerro Leon Unico Silver (ASX:USL) says the final results from phase-two diamond drilling at.. Dateline Resources pursues OTCQB listing in US North Bay advances gold production optimisation Gilded market: Has jewellery demand lost lustre? ASX ends winning streak as energy sector... Critica readies to drill satellite rare earths... Metro on track to hit 2025 bauxite... ASX shifts down a gear Stay Informed on up-to-the-minute mining news Get the best articles straight to your inbox ASX ends winning streak as energy sector tumbles05 May Military Metals discusses antimony exploration in Slovakia05 May Unico Silver makes ‘multiple new discoveries’ at Cerro Leon05 May Critica readies to drill satellite rare earths targets 05 May Javascript Menu by Deluxe-Menu.com This article was posted in its entirety as received by SKNVibes.com This media house does not correct any spelling or grammatical error within press releases and commentaries The views expressed therein are not necessarily those of SKNVibes.com Enova Mining (ASX:ENV) will be proceeding with an option agreement following confirmation that due diligence has de-risked the Poços which has a market capitalisation of $13.45 million entered into a binding option agreement with vendors B Geologia E Mineração LTDA (RTB) and Rafael Viola Mottin to acquire these Brazilian tenements. Enova has made a $30,000 cash payment and will also make a $120,000 cash payment to RTB. The company will also issue 190 million shares and 100 million unlisted options at $0.012 with a 5-year expiry date to RTB within 5 days after shareholder approval. Enova will be finalising and distributing a notice of general meeting to shareholders as soon as possible. Enova can complete the transaction and transfer of assets to a Brazilian registered Enova-held company. The company says that on completing due diligence the land package is considered prospective and of ‘exceptional’ exploration value. the assets provide a sound basis to expand on Enova’s operations in a ‘positive’ mining business environment like Minas Gerais The majority of the tenements strategically sit in Brazil’s prolific Poços de Caldas / Caldeira Rare Earth Complex and Lithium Valley in Minas Gerais. Enova Mining is a minerals explorer focused on its critical minerals and rare earths assets Write to Aaliyah Rogan at Mining.com.au