Fluorescence and immune-cell infiltration of nonneoplastic, postbrachytherapy brain tissue in 5-ALA-guided resection of recurrent anaplastic meningioma: illustrative case.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is a well-established technique for resecting high-grade gliomas. However, its application in meningiomas, especially those previously treated with radiation therapy, remains under investigation. OBSERVATIONS: A 48-year-old female with recurrent anaplastic meningioma, World Health Organization grade 3, underwent a right-sided craniotomy using off-label 5-ALA as a surgical adjunct. The patient had previously undergone brachytherapy seed implantation (20 × cesium 131) for tumor management. During the surgery, a large fluorescent tumor mass adjacent to the brachytherapy-treated area was resected, and the prior brachytherapy seeds were removed. Interestingly, the surrounding brain tissue in the irradiated area showed robust 5-ALA fluorescence. Pathological examination confirmed that the fluorescent brain tissue was nonneoplastic and associated with lymphocyte and macrophage infiltration. LESSONS: This case report presents unique 5-ALA fluorescence in nonneoplastic tissue following brachytherapy, which was found during the resection of recurrent anaplastic meningioma. This phenomenon may reflect an intricate interplay among radiation therapy, immune cells, the tumor microenvironment, and 5-ALA metabolism. Given that false-positive findings in fluorescence-guided surgery can lead to unnecessary tissue resection and increased surgical morbidity, further research is warranted to elucidate the mechanisms underlying this phenomenon and its implications for meningioma surgery.

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study.

OBJECTIVE: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles. METHODS: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated. RESULTS: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047). CONCLUSIONS: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas.

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway  in neoplasia.

Dental anomalies in cleft lip and/or palate children at age 10 - a retrospective review across three cleft centres: Part 1.

Introduction Children with oral clefts often present with dental anomalies which can impact function, aesthetics and complicate the patient's dental treatment and needs. An understanding of potential anomalies, along with early recognition and planning, is thus essential for effective care.Aim This paper is the first in a two-part three-centre series. This paper will assess the dental anomalies identified in 10-year-old patients attending three cleft centres in the UK.Method Retrospective review was undertaken of the clinical notes of 10-year-old patients attending South Wales (SW), Cleft NET East (CNE) and West Midlands (WM) cleft units, for their ten-year audit record appointment in 2016/2017.Results In total, 144 patients were reviewed (SW = 42; CNE = 52; WM = 50). Dental anomalies were recorded for 80.6% of patients (n = 116).Discussion The review gives insight into the dental complexities of UK oral cleft patients. These patients require specialist paediatric dental input and intensive preventive regimes.Conclusion Shared care between cleft team specialists and general dental practitioners is important when providing holistic care for cleft patients.

Associated medical conditions among 10-year-old children with oral clefts - a retrospective review across three cleft centres: Part 2.

Introduction In many cases, children with oral clefts present with accompanying medical conditions. These associated conditions can add complexity to the patient's dental management, both in terms of their treatment need and risk. Recognition and careful consideration of associated medical conditions is therefore crucial in providing safe and effective care for these patients.Aim This paper is the second in a two-part three-centre series. It investigates the prevalence of medical conditions affecting cleft lip and/or palate patients attending three cleft units within the UK.Method Retrospective review was undertaken within three cleft units: South Wales (SW), Cleft NET East (CNE) and West Midlands (WM). This was completed via assessment of the 10-year audit record appointment clinical notes for the year 2016/2017.Results In total, 144 cases were reviewed (SW = 42; CNE = 52; WM = 50). Of these, 38.9% of patients (n = 56) had associated medical conditions recorded.Discussion The review highlights the variety and impact of medical conditions affecting UK cleft patients providing insight into the consequent complexity of their dental care.Conclusion An awareness of cleft lip and/or palate patients' associated medical conditions is important for all health care professionals involved in their care. Indeed, understanding of the patient's medical needs by multidisciplinary cleft teams is essential for effective planning and completion of holistic care. Involvement of specialists in paediatric dentistry sharing care with general dental practitioners is vital in providing appropriate oral health care and preventive support.

Virtual Surgical Planning of Superior Orbital Rim Fractures in Calvarial and Maxillofacial Trauma.

BACKGROUND: Superior orbital rim fractures are challenging fractures as they often concomitantly occur with additional calvaria fractures. Virtual surgical planning (VSP) has been underutilized in this area of craniomaxillofacial trauma for reconstruction. PURPOSE: The purpose of this study is to qualitatively describe the use of VSP and anatomically perfected stereolithic models in treatment of superior orbital rim fractures in combined neurosurgery/oral and maxillofacial surgery cases. STUDY DESIGN, SETTING, SAMPLE: This study is a retrospective case series of subjects who were treated at the Massachusetts General Hospital (July 2022 to November 2022). Inclusion criteria include subjects who had both calvaria and maxillofacial injuries requiring concurrent operative intervention on their superior orbital rim fractures and the use of VSP. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: Not applicable. MAIN OUTCOME VARIABLE: The outcome variable of interest is the difference in the planned position of the orbital rim repair compared to the actual position achieved. COVARIATES: None. ANALYSES: Heat map analysis was used to compare the difference in the planned position versus the actual position achieved. RESULTS: There were six orbits (five subjects, mean age 33.8 ± 21.49 years) that met the criteria. The mean difference in planned versus actual orbital volume achieved was 2.52 ± 2.48 cm3. The superimposition of the postoperative scan to the planned simulation revealed 84% ± 3.27% of the voxel surface was within +2 and -2 millimeters of its planned position. CONCLUSION AND RELEVANCE: This study has demonstrated the use of VSP in combined neurosurgery and oral and maxillofacial surgery procedures in the fixation of superior orbital rim fractures. This case series highlights that the postoperative position achieved in the six orbits was within 84% of the planned position.

Genetic variation associated with condensate dysregulation in disease.

A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. Although proof-of-concept studies have identified specific mutations that cause condensate dysregulation, the full scope of the pathological genetic variation that affects condensates is not yet known. Here, we comprehensively map pathogenic mutations to condensate-promoting protein features in putative condensate-forming proteins and find over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers. This resource captures mutations presently known to dysregulate condensates, and experimental tests confirm that additional pathological mutations do indeed affect condensate properties in cells. These findings suggest that condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases, provide a strategy to identify proteins and mutations involved in pathologically altered condensates, and serve as a foundation for mechanistic insights into disease and therapeutic hypotheses.

New physical insights: Formamide discharge decomposition and the role of fragments in the formation of large biomolecules.

In this work we present a time-resolved FTIR spectroscopic study on kinetics of atomic and molecular species, specifically CO, CN radical, N2, HCN and CO2 generated in a glow discharge of formamide-nitrogen-water mixture in a helium buffer gas. Radicals such as NH, CH and OH have been proven to be fundamental stones of subsequent chemical reactions having a crucial role in a prebiotic synthesis of large organic molecules. This work contains three main goals. Firstly, we present our time-resolved spectra of formamide decomposition products and discuss the mechanism of collisional excitations between specific species. Secondly, according to our time resolution, we demonstrate and explain the band shape of CO's first overtone and the energy transfer between excited nitrogen and CO, present in our spectra. Lastly, we present theoretical results for the non-LTE modelling of the spectra using bi-temperature approach and a 1D harmonic Franck-Condon approach for the multi-molecule spectra of the formamide decomposition process in the 1800-5600 cm-1 spectral range.

Traumatic and non-traumatic dental presentations to the paediatric emergency departments of two UK children's hospitals: A multi-centre evaluation.

BACKGROUND: Dental attendances to paediatric emergency departments (PEDs) represent suboptimal use of resources of an unknown scale. AIM: To evaluate dental attendances at two PEDs in the UK and compare traumatic dental injury (TDI) and non-traumatic dental conditions (NTDCs). DESIGN: Retrospective data were collected for a 12-month period including demographics, attendance pattern, assessment, and management. Maxillofacial conditions were excluded, and attendances were grouped as TDI and NTDC. RESULTS: Of 667 attendances, 35.1% (n = 234) were TDI and 64.9% (n = 433) NTDC. Nineteen children reattended. Proportionately, more TDI attenders were male, White British, of lower mean age, and resided in less deprived areas than NTDCs. Over half (52.3%, n = 339) of attendees resided in the 10% most deprived UK areas. Saturday and Monday were modal attendance days; attendance peaked in summer. Over half (56.4%, n = 376) attended out of hours. A majority (74.8%, n = 499) self-referred and half accessed no other service prior to PED attendance. No PED dental input was received for 38.7% (n = 258), and dental treatment was received for 12.4% (n = 83). Antibiotics were provided for 42.1% (n = 281), and 15.4% (n = 103) were admitted. CONCLUSION: Dental abscesses and toothache accounted for half of attendances, many of these children may be managed in primary care. Improved signposting to alternative dental services for non-urgent conditions may better allocate resources to those with urgent need.

Theoretical rovibronic spectroscopy of the calcium monohydroxide radical (CaOH).

The rovibronic (rotation-vibration-electronic) spectrum of the calcium monohydroxide radical (CaOH) is of interest to studies of exoplanet atmospheres and ultracold molecules. Here, we theoretically investigate the Ã2Π-X̃2Σ+ band system of CaOH using high-level ab initio theory and variational nuclear motion calculations. New potential energy surfaces (PESs) are constructed for the X̃2Σ+ and Ã2Π electronic states along with Ã-X̃ transition dipole moment surfaces (DMSs). For the ground X̃2Σ+ state, a published high-level ab initio PES is empirically refined to all available experimental rovibrational energy levels up to J = 15.5, reproducing the observed term values with a root-mean-square error of 0.06 cm-1. Large-scale multireference configuration interaction calculations using quintuple-zeta quality basis sets are employed to generate the Ã2Π state PESs and Ã-X̃ DMSs. Variational calculations consider both Renner-Teller and spin-orbit coupling effects, which are essential for a correct description of the spectrum of CaOH. Computed rovibronic energy levels of the Ã2Π state, line list calculations up to J = 125.5, and an analysis of Renner-Teller splittings in the ν2 bending mode of CaOH are discussed.

Modelling the non-local thermodynamic equilibrium spectra of silylene (SiH2).

This paper sets out a robust methodology for modelling spectra of polyatomic molecules produced in reactive or dissociative environments, with vibrational populations outside local thermal equilibrium (LTE). The methodology is based on accurate, extensive ro-vibrational line lists containing transitions with high vibrational excitations and relies on the detailed ro-vibrational assignments. The developed methodology is applied to model non-LTE IR and visible spectra of silylene (SiH2) produced in a decomposition of disilane (Si2H6), a reaction of technological importance. Two approaches for non-LTE vibrational populations of the product SiH2 are introduced: a simplistic 1D approach based on the Harmonic approximation and a full 3D model incorporating accurate vibrational wavefunctions of SiH2 computed variationally with the TROVE (Theoretical ROVibrational Energy) program. We show how their non-LTE spectral signatures can be used to trace different reaction channels of molecular dissociations.

Clinical practice guidelines: Oral health care for children and adults living with epidermolysis bullosa.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a genetic disorder characterized by skin fragility and unique oral features. AIMS: To provide (a) a complete review of the oral manifestations in those living with each type of inherited EB, (b) the current best practices for managing oral health care of people living with EB, (c) the current best practices on dental implant-based oral rehabilitation for patients with recessive dystrophic EB (RDEB), and (d) the current best practice for managing local anesthesia, principles of sedation, and general anesthesia for children and adults with EB undergoing dental treatment. METHODS: Systematic literature search, panel discussion including clinical experts and patient representatives from different centers around the world, external review, and guideline piloting. RESULTS: This article has been divided into five chapters: (i) general information on EB for the oral health care professional, (ii) systematic literature review on the oral manifestations of EB, (iii) oral health care and dental treatment for children and adults living with EB-clinical practice guidelines, (iv) dental implants in patients with RDEB-clinical practice guidelines, and (v) sedation and anesthesia for adults and children with EB undergoing dental treatment-clinical practice guidelines. Each chapter provides recommendations on the management of the different clinical procedures within dental practice, highlighting the importance of patient-clinician partnership, impact on quality of life, and the importance of follow-up appointments. Guidance on the use on nonadhesive wound care products and emollients to reduce friction during patient care is provided. CONCLUSIONS: Oral soft and hard tissue manifestations of inherited EB have unique patterns of involvement associated with each subtype of the condition. Understanding each subtype individually will help the professionals plan long-term treatment approaches.

Partitioning of cancer therapeutics in nuclear condensates.

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas.

OBJECTIVE: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts. METHODS: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features. RESULTS: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation. CONCLUSIONS: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.

Extent of Resection Versus Molecular Classification: What Matters When?

For malignant gliomas, the survival benefit of new combination therapies after surgical resection is measured in weeks to months. In contrast, optimizing treatment for low-grade gliomas can potentially provide additional years of life. The relatively indolent but not benign clinical course provides the opportunity for clinicians and scientists to focus not only on the duration of survival, but also to maximize quality of life. Ideal management of low-grade gliomas among the most important yet paradoxically most neglected subjects in neuro-oncology. This article examines the molecular underpinnings of these tumors and evaluates the role of extensive surgery in maximizing outcomes.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

This corrects the article DOI: 10.1038/ncomms14433.

Longitudinal analysis of treatment-induced genomic alterations in gliomas.

BACKGROUND: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. METHODS: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case. RESULTS: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency. CONCLUSIONS: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.