Methylation profiling in the contemporary management of meningioma.

BACKGROUND: The last decade has seen major international research efforts focus on better understanding disease heterogeneity in meningioma. Multiple molecular platforms have generated significant biological and clinical utility, and there is a need to translate these findings into routine clinical practice. Here we review the role of DNA methylation profiling in meningioma and advocate for its widespread adoption. METHODS: We review modern DNA methylation-based classification and outcome prediction tools in meningioma. Biological classifiers, which were constructed agnostic to outcome using unsupervised approaches, outcome predictors, and liquid biopsy models are discussed in detail. RESULTS: DNA methylation has been used for biological classification and outcome in meningioma with considerable success. Several groups have proposed novel molecular classification systems which share similar features with one another and outperform WHO grade in their ability to predict outcome and explain subgroup-specific biological processes. In addition, recent studies have suggested a role for methylation-based liquid-biopsy in meningioma, which represents an exciting avenue for further exploration. CONCLUSIONS: DNA methylation profiling has been revolutionary in meningioma. There is a need for widespread adoption of these approaches to personalize care and inform clinical trial design.

Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma.

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.

Meningioma: International Consortium on Meningiomas consensus review on scientific advances and treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Intergroup conflict as contest and disease.

Intergroup conflict has been conceptualized as a strategic interaction (conflict-as-contest) and separately as a pathological condition (conflict-as-disease). We highlight how insights and tools from the former perspective can potentially inform the latter. Harnessing the science of strategic decision-making can facilitate the development of novel approaches for mitigating intergroup conflict.

OXPHOS capacity is diminished and the phosphorylation system inhibited during diapause in an extremophile, embryos of Artemia franciscana.

Diapause exhibited by embryos of Artemia franciscana is accompanied by severe arrest of respiration. A large fraction of this depression is attributable to downregulation of trehalose catabolism that ultimately restricts fuel to mitochondria. This study now extends knowledge on the mechanism by revealing metabolic depression is heightened by inhibitions within mitochondria. Compared with that in embryo lysates during post-diapause, oxidative phosphorylation (OXPHOS) capacity P is depressed during diapause when either NADH-linked substrates (pyruvate and malate) for electron transfer (electron transfer capacity, E) through respiratory Complex I or the Complex II substrate succinate are used. When pyruvate, malate and succinate were combined, respiratory inhibition by the phosphorylation system in diapause lysates was discovered as judged by P/E flux control ratios (two-way ANOVA; F1,24=38.78; P<0.0001). Inhibition was eliminated as the diapause extract was diluted (significant interaction term; F2,24=9.866; P=0.0007), consistent with the presence of a diffusible inhibitor. One candidate is long-chain acyl-CoA esters known to inhibit the adenine nucleotide translocator. Addition of oleoyl-CoA to post-diapause lysates markedly decreased the P/E ratio to 0.40±0.07 (mean±s.d.; P=0.002) compared with 0.79±0.11 without oleoyl-CoA. Oleoyl-CoA inhibits the phosphorylation system and may be responsible for the depressed P/E in lysates from diapause embryos. With isolated mitochondria, depression of P/E by oleoyl-CoA was fully reversed by addition of l-carnitine (control versus recovery with l-carnitine, P=0.338), which facilitates oleoyl-CoA transport into the matrix and elimination by ß-oxidation. In conclusion, severe metabolic arrest during diapause promoted by restricting glycolytic carbon to mitochondria is reinforced by depression of OXPHOS capacity and the phosphorylation system.

Intergroup psychological interventions: The motivational challenge.

Social scientists have increasingly applied insights from descriptive research to develop psychological interventions aimed at improving intergroup relations. These interventions have achieved marked success-reducing prejudicial attitudes, fostering support for conciliatory social policies, and promoting peacebuilding behaviors. At the same time, intergroup conflict continues to rage in part because individuals often lack motivation to engage with these promising interventions. We take a step toward addressing this issue by developing a framework of approaches for delivering interventions to an unmotivated target audience. Along with (a) directly motivating targets by increasing their values and expectancies for addressing intergroup conflict, researchers can deliver interventions by (b) satisfying other psychological motivations of the target audience, (c) providing an instrumental benefit for engaging with the intervention, (d) embedding the intervention in a hedonically captivating medium, or (e) bypassing motivational barriers entirely by delivering the intervention outside of targets' conscious awareness. We define each approach and use illustrative examples to organize them into a conceptual framework before concluding with implications and future directions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Outcomes and predictors of response to fractionated radiotherapy as primary treatment for intracranial meningiomas.

Background: Surgery is the primary treatment for most meningiomas. However, primary fractionated radiotherapy (fRT) remains an option for patients with larger meningiomas in challenging anatomic locations or patients at prohibitively high surgical risk. Outcome prediction for these patients is uncertain and cannot be guided by histopathology without available tumor tissue from surgery. Therefore, we aimed to assess the clinical factors that contribute to treatment failure in a large cohort of meningiomas consecutively treated with fRT as primary therapy, with the goal of identifying predictors of response. Methods: Patients treated with primary fRT for intracranial meningiomas from 1998 to 2017 were reviewed. Those who received primary surgical resection, radiosurgery, previous fRT, or had <6 months of clinical follow-up were excluded. We applied logistic regression and Cox regression modeling to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events (AE) following fRT. Results: Our cohort included 137 meningiomas, 21 of which progressed after fRT (median PFS 3.45 years). Progressive meningiomas had a larger median gross tumor volume (GTV) compared to those that remained stable (19.1 cm3 vs 9.6 cm3, p = 2.86 × 10-2). GTV > 11.27 cm3 was independently predictive of progression and larger GTV was associated with higher risk of significant (grades 3/4) AE following fRT. Cavernous sinus and optic nerve sheath meningiomas had overall excellent outcomes post-fRT. Conclusions: We present a large cohort of meningiomas treated with primary fRT and find GTV and anatomic location to be key predictors of outcome, adding to the complex treatment considerations for this heterogeneous disease.

The multiomic landscape of meningiomas: a review and update.

PURPOSE: Meningiomas are the most common primary brain tumor in adults. Traditionally they have been understudied compared to other central nervous system (CNS) tumors. However over the last decade, there has been renewed interest in uncovering the molecular topography of these tumors, with landmark studies identifying key driver alterations contributing to meningioma development and progression. Recent work from several independent research groups have integrated different genomic and epigenomic platforms to develop a molecular-based classification scheme for meningiomas that could supersede histopathological grading in terms of diagnostic accuracy, biological relevance, and outcome prediction, keeping pace with contemporary grading schemes for other CNS tumors including gliomas and medulloblastomas. METHODS: Here we summarize the studies that have uncovered key alterations in meningiomas which builds towards the discovery of consensus molecular groups in meningiomas by integrating these findings. These groups supersede WHO grade and other clinical factors in being able to accurately predict tumor biology and clinical outcomes following surgery. RESULTS: Despite differences in the nomenclature of recently uncovered molecular groups across different studies, the biological similarities between these groups enables us to likely reconciliate these groups into four consensus molecular groups: two benign groups largely dichotomized by NF2-status, and two clinically aggressive groups defined by their hypermetabolic transcriptome, and by their preponderance of proliferative, cell-cycling pathways respectively. CONCLUSION: Future work, including by our group and others are underway to validate these molecular groups and harmonize the nomenclature for routine clinical use.

Multiplatform molecular analysis of vestibular schwannoma reveals two robust subgroups with distinct microenvironment.

BACKGROUND: Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle and poses a significant morbidity for patients. While many exhibit benign behaviour, others have a more aggressive nature and pattern of growth. Predicting who will fall into which category consistently remains uncertain. There is a need for a better understanding of the molecular landscape, and important subgroups therein, of this disease. METHODS: We select all vestibular schwannomas from our tumour bank with both methylation and RNA profiling available. Unsupervised clustering methods were used to define two distinct molecular subgroups of VS which were explored using computational techniques including bulk deconvolution analysis, gene pathway enrichment analysis, and drug repurposing analysis. Methylation data from two other cohorts were used to validate our findings, given a paucity of external samples with available multi-omic data. RESULTS: A total of 75 tumours were analyzed. Consensus clustering and similarity network fusion defined two subgroups ("immunogenic" and "proliferative") with significant differences in immune, stroma, and tumour cell abundance (p < 0.05). Gene network analysis and computational drug repurposing found critical differences in targets of immune checkpoint inhibition PD-1 and CTLA-4, the MEK pathway, and the epithelial to mesenchymal transition program, suggesting a need for subgroup-specific targeted treatment/trial design in the future. CONCLUSIONS: We leverage computational tools with multi-omic molecular data to define two robust subgroups of vestibular schwannoma with differences in microenvironment and therapeutic vulnerabilities.

BAP1-deficient meningioma presenting with trabecular architecture and cytokeratin expression: a report of two cases and review of the literature.

AIMS: BRCA (BReast CAncer gene)-associated protein 1 (BAP1), encoded by the BAP1 gene, a tumour suppressor that is lost in several cancers. Importantly, such mutations have been shown to be susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in preclinical studies, offering hope for targeted therapy. While rare, BAP1 loss has been observed in a subset of rhabdoid and papillary meningioma and is associated with earlier recurrence. We seek to add to the literature on this rare disease and advocate for more routine BAP1 testing. METHODS: We present a report of two cases of BAP1-deficient meningioma and review the available literature on this rare entity. RESULTS: Both cases present with a distinct trabecular architecture without rhabdoid or papillary features. Interestingly, both also presented with radiographic and histopathological findings unusual for meningioma. While immunohistochemistry and genetic sequencing confirmed BAP1 loss, DNA methylation analysis was required to confirm the final diagnosis. CONCLUSIONS: We suggest that BAP1-deficient meningioma should be considered in the differential diagnosis of extra-axial central nervous system (CNS) tumours with atypical imaging or histopathological features and that BAP1 loss may constitute a clinically important meningioma subtype with opportunities for targeted therapy.

Dehumanization and mass violence: A study of mental state language in Nazi propaganda (1927-1945).

Dehumanization is frequently cited as a precursor to mass violence, but quantitative support for this notion is scarce. The present work provides such support by examining the dehumanization of Jews in Nazi propaganda. Our linguistic analysis suggests that Jews were progressively denied the capacity for fundamentally human mental experiences leading up to the Holocaust. Given that the recognition of another's mental experience promotes moral concern, these results are consistent with the theory that dehumanization facilitates violence by disengaging moral concern. However, after the onset of the Holocaust, our results suggest that Jews were attributed a greater capacity for agentic mental states. We speculate this may reflect a process of demonization in which Nazi propagandists portrayed the Jews as highly capable of planning and intentionality while nonetheless possessing a subhuman moral character. These suggestive results paint a nuanced portrait of the temporal dynamics of dehumanization during the Holocaust and provide impetus for further empirical scrutiny of dehumanization in ecologically valid contexts.

Calcium pyrophosphate dihydrate crystal deposition disease and retro-odontoid pseudotumor rupture managed via posterior occipital cervical instrumented fusion: illustrative case.

BACKGROUND: Craniocervical junction and subaxial cervical spinal manifestations of calcium pyrophosphate deposition disease are rarely encountered. The authors presented a severe case of retro-odontoid pseudotumor rupture causing rapid quadriparesis and an acute comatose state with subsequent radiographic and clinical improvement after posterior occipital cervical fusion. OBSERVATIONS: The authors surveyed the literature and outlined multiple described operative management strategies for compressive cervical and craniocervical junction calcium pyrophosphate deposition disease manifestations ranging from neck pain to paresthesia, weakness, myelopathy, quadriparesis, and cranial neuropathies. In this report, radiographic features of cervical and craniocervical junction calcium pyrophosphate deposition disease were explored. Several previously described surgical strategies were compiled, including patient characteristics and outcomes. LESSONS: With this case report, the authors presented for the first time an isolated posterior occipital cervical fusion for treatment of a compressive retro-odontoid pseudotumor with rupture into the brainstem. They demonstrated rapid clinical and radiographic resolution after stabilization of cranial cervical junction only 12 weeks postsurgery.

Multiplicity does not significantly affect outcomes in brain metastasis patients treated with surgery.

Background: Brain metastasis quantity may be a negative prognostic factor for patients requiring resection of at least one lesion. Methods: We retrospectively reviewed patients who underwent surgical resection of brain metastases from July 2018 to June 2019 at our institution, and examined outcomes including overall survival (OS), progression free survival (PFS), and rates of local failure (LF). Patients were grouped according to the number of metastases at the time of surgery (single vs multiple). Results: We identified 130 patients who underwent surgical resection as the initial treatment modality. At the time of surgery, 87 patients had only one lesion (control) and 43 had multiple (>1). Two-year OS for the entire cohort was 46%, with equal rates in both the multiple metastases group and the control group (P = .335). 2-year PFS was 27%; 21% in the multiple metastases group and 31% in the control group (P = .766). The rate of LF at 2 years was 32%, with equal rates in both the multiple lesion group and control group (P = .889). On univariate analysis, multiplicity was not significantly correlated to OS (HR = 0.80, 95% CI: 0.51-1.26, P = .336), PFS (HR = 1.06, 95% CI: 0.71-1.59, P = .766) or LF (HR = 1.06, 95% CI: 0.57-1.97, P = .840). Multivariate analysis revealed preoperative tumor volume of the resected lesion to be the single correlate for OS (P = .0032) and PFS (P = .0081). Conclusions: Having more than one metastasis does not negatively impact outcomes in patients treated with surgery. In carefully selected patients, especially those with large tumors, surgery should be considered regardless of the total number of lesions.

Dehumanization: trends, insights, and challenges.

Despite our many differences, one superordinate category we all belong to is 'humans'. To strip away or overlook others' humanity, then, is to mark them as 'other' and, typically, 'less than'. We review growing evidence revealing how and why we subtly disregard the humanity of those around us. We then highlight new research suggesting that we continue to blatantly dehumanize certain groups, overtly likening them to animals, with important implications for intergroup hostility. We discuss advances in understanding the experience of being dehumanized and novel interventions to mitigate dehumanization, address the conceptual boundaries of dehumanization, and consider recent accounts challenging the importance of dehumanization and its role in intergroup violence. Finally, we present an agenda of outstanding questions to propel dehumanization research forward.

Postoperative CT scans after resection of brain metastases: neurosurgical routine or added value?

BACKGROUND: Metastasis is the most common brain tumor in adults. It is the standard of care at most North American centers to obtain an early postoperative imaging after their resection. However, the necessity of this practice in the absence of a new postoperative deficit remains unclear. METHODS: We retrospectively reviewed our surgical cohort of patients who underwent resection of brain metastases from July 2018 to June 2019. We collected demographic data and reviewed results of routine postoperative CT scans and neurological morbidities to examine the diagnostic and therapeutic yield of an early postoperative scan. In addition, we performed a systematic review of the topic. RESULTS: Our review included 130 patients, all of whom underwent gross total resection of one or more brain metastases. On postoperative CT, none had unexpected findings such as cavity hematoma or new ischemia; no changes in management resulted from postoperative imaging. One patient required a higher dose of dexamethasone on postoperative day 4 for delayed hemiparesis and aphasia due to cerebral edema. Three additional patients underwent a wound washout for delayed infection during a subsequent admission. Our systematic review identified three additional studies; in a combined cohort of 450 patients (including our own), no patients had clinically actionable findings on routine postoperative CT. CONCLUSIONS: Following resection of brain metastases, a routine postoperative CT scan has low diagnostic yield and did not change patient management in any cases examined in this work.

Filthy Animals: Integrating the Behavioral Immune System and Disgust into a Model of Prophylactic Dehumanization.

The behavioral immune system (BIS) is an evolved psychological mechanism that motivates prophylactic avoidance of disease vectors by eliciting disgust. When felt toward social groups, disgust can dampen empathy and promote dehumanization. Therefore, we investigated whether the BIS facilitates the dehumanization of groups associated with disease by inspiring disgust toward them. An initial content analysis found that Nazi propaganda predominantly dehumanized Jews by portraying them as disease vectors or contaminants. This inspired three correlational studies supporting a Prophylactic Dehumanization Model in which the BIS predicted disgust toward disease-relevant outgroups, and this disgust in turn accounted for the dehumanization of these groups. In a final study, we found this process of prophylactic dehumanization had a downstream effect on increasing anti-immigrant attitudes during the COVID-19 pandemic. However, consistent with the evolutionary logic of a functionally flexible BIS, this effect only occurred when the threat of COVID-19 was salient. The implications of these results for the study of dehumanization and evolutionary theories of xenophobia are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s40806-021-00296-8.

Outcomes in vestibular schwannoma treated with primary microsurgery: Clinical landscape.

BACKGROUND: Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle. Owing to complex anatomy and high rates of morbidity, surgical management of large tumours is challenging. We seek to explore the clinical landscape of VS to identify predictors of outcome and help guide surgical decision making. METHODS: We retrospectively reviewed charts of patients who underwent primary surgery for VS between 2005 and 2020 at a quaternary referral center in Toronto, Canada. Mined data includes patient demographics, clinical presentation, radiological features, and treatment details. Regression modelling was used to identify predictors of tumour control, postoperative morbidity, and correlates of progression free survival (PFS). RESULTS: Two hundred and five tumours with sufficient data were included in our study. Syndromic NF2, large tumours (>3cm), subtotal resection (vs gross total resection), presence of edema on preoperative MRI, and preoperative trigeminal symptoms were all predictors of postoperative progression/need for further treatment; the latter four were also associated with shorter progression free survival. Extent of resection (EOR), tumour size, and Koos grade were independently predictive of postoperative progression/secondary intervention in multivariate models; however, only EOR was independently predictive of progression-free survival. EOR, tumour size, and patient age are each independently predictive of facial nerve outcome. CONCLUSIONS: We comprehensively explore the clinical landscape of surgically treated vestibular schwannoma and highlight important outcome predictors and disease subgroups. This may have important implications in risk stratifying these challenging cases.

Integrated computational analyses reveal novel insights into the stromal microenvironment of SHH-subtype medulloblastoma.

Medulloblastoma is the most common malignant brain tumour of childhood. While our understanding of this disease has progressed substantially in recent years, the role of tumour microenvironment remains unclear. Given the increasing role of microenvironment-targeted therapeutics in other cancers, this study was aimed at further exploring its role in medulloblastoma. Multiple computational techniques were used to analyze open-source bulk and single cell RNA seq data from primary samples derived from all subgroups of medulloblastoma. Gene expression is used to infer stromal subpopulations, and network-based approaches are used to identify potential therapeutic targets. Bulk data was obtained from 763 medulloblastoma samples and single cell data from an additional 7241 cells from 23 tumours. Independent bulk (285 tumours) and single cell (32,868 cells from 29 tumours) validation cohorts were used to verify results. The SHH subgroup was found to be enriched in stromal activity, including the epithelial-to-mesenchymal transition, while group 3 is comparatively stroma-suppressed. Several receptor and ligand candidates underlying this difference are identified which we find to correlate with metastatic potential of SHH medulloblastoma. Additionally, a biologically active gradient is detected within SHH medulloblastoma, from "stroma-active" to "stroma-suppressed" cells which may have relevance to targeted therapy. This study serves to further elucidate the role of the stromal microenvironment in SHH-subgroup medulloblastoma and identify novel treatment possibilities for this challenging disease.