If They'd Said You Should Only Drink Five Units I'd Have Listened: A Mixed Methods Study of Alcohol Consumption Following a Diagnosis of Breast Cancer.

OBJECTIVES: As part of a wider study describing the impact of a breast cancer diagnosis on lifestyle behaviours, this paper describes the impact of a breast cancer diagnosis on alcohol consumption and factors influencing consumption. METHODS: Cross-sectional online survey of 140 people (138 women) and interviews with 21 women diagnosed with breast cancer in the last 10 years. RESULTS: Of the 100 survey participants who drank alcohol 25% were drinking at increasing or higher risk levels and 17% strongly wanted to change their drinking behaviour. The habitual aspects of alcohol consumption were the strongest predictor of current alcohol consumption behaviours. Social norms and perceptions about conflicting information were substantial barriers to change. CONCLUSIONS: Breast cancer survivors need accurate information about the risks of alcohol consumption and guidelines in order to make informed decisions about making changes to their behaviour. Interventions to support breast cancer survivors to reduce alcohol consumption need to focus on the development of healthy habits and may benefit from a focus which includes partners and friends.

Beyond hand-crafted features for pretherapeutic molecular status identification of pediatric low-grade gliomas.

The use of targeted agents in the treatment of pediatric low-grade gliomas (pLGGs) relies on the determination of molecular status. It has been shown that genetic alterations in pLGG can be identified non-invasively using MRI-based radiomic features or convolutional neural networks (CNNs). We aimed to build and assess a combined radiomics and CNN non-invasive pLGG molecular status identification model. This retrospective study used the tumor regions, manually segmented from T2-FLAIR MR images, of 336 patients treated for pLGG between 1999 and 2018. We designed a CNN and Random Forest radiomics model, along with a model relying on a combination of CNN and radiomic features, to predict the genetic status of pLGG. Additionally, we investigated whether CNNs could predict radiomic feature values from MR images. The combined model (mean AUC: 0.824) outperformed the radiomics model (0.802) and CNN (0.764). The differences in model performance were statistically significant (p-values < 0.05). The CNN was able to learn predictive radiomic features such as surface-to-volume ratio (average correlation: 0.864), and difference matrix dependence non-uniformity normalized (0.924) well but was unable to learn others such as run-length matrix variance (- 0.017) and non-uniformity normalized (- 0.042). Our results show that a model relying on both CNN and radiomic-based features performs better than either approach separately in differentiating the genetic status of pLGGs, and that CNNs are unable to express all handcrafted features.

Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma.

Background: Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity. Methods: A retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI. Results: Patients' age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage. Conclusions: Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes.

Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment.

With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.

Understanding diffuse leptomeningeal glioneuronal tumors.

INTODUCTION: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances. METHODS: This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted. RESULTS: DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts. CONCLUSION: Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.

The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings.

PURPOSE: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner. METHODS: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported. RESULTS: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing). CONCLUSION: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

Pediatric-type low-grade gliomas in adolescents and young adults-challenges and emerging paradigms.

Pediatric-type low-grade glioma (PLGG) encompasses a heterogeneous group of WHO grade 1 or 2 tumors and is the most common central nervous system tumor found in children. PLGG extends beyond pediatrics, into adolescents and young adults (AYA, ages 15-40). PLGG represents 25% of all gliomas diagnosed in AYA with differences in tumor location and molecular alterations compared to children, resulting in improved outcome for AYAs. Long-term outcome is excellent, though patients may suffer significant morbidity depending on tumor location. There are differences in treatment practices with radiation used to treat PLGG in AYAs more often than in children. Most PLGG in AYA harbor an alteration in the RAS/MAPK pathway, with limited insight into response to targeted therapy in this age group. This review discusses the epidemiology, current therapeutic approaches, and challenges in the management of PLGG in AYA.

Brain Tumor Imaging in Adolescents and Young Adults: 2021 WHO Updates for Molecular-based Tumor Types.

Published in 2021, the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) introduced new molecular criteria for tumor types that commonly occur in either pediatric or adult age groups. Adolescents and young adults (AYAs) are at the intersection of adult and pediatric care, and both pediatric-type and adult-type CNS tumors occur at that age. Mortality rates for AYAs with CNS tumors have increased by 0.6% per year for males and 1% per year for females from 2007 to 2016. To best serve patients, it is crucial that both pediatric and adult radiologists who interpret neuroimages are familiar with the various pediatric- and adult-type brain tumors and their typical imaging morphologic characteristics. Gliomas account for approximately 80% of all malignant CNS tumors in the AYA age group, with the most common types observed being diffuse astrocytic and glioneuronal tumors. Ependymomas and medulloblastomas also occur in the AYA population but are seen less frequently. Importantly, biologic behavior and progression of distinct molecular subgroups of brain tumors differ across ages. This review discusses newly added or revised gliomas in the fifth edition of the CNS WHO classification, as well as other CNS tumor types common in the AYA population.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Brain Tumors in Adolescents and Young Adults: A Review.

Brain tumors account for the majority of cancer-related deaths in adolescents and young adults (AYAs), defined as individuals aged 15 to 39. AYAs constitute a distinct population in which both pediatric- and adult-type central nervous system (CNS) tumors can be observed. Clinical manifestations vary depending on tumor location and often include headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure. With the publication of the updated World Health Organization CNS tumor classification in 2021, diagnoses have been redefined to emphasize key molecular alterations. Gliomas represent the majority of malignant brain tumors in this age group. Glioneuronal and neuronal tumors are associated with longstanding refractory epilepsy. The classification of ependymomas and medulloblastomas has been refined, enabling better identification of low-risk tumors that could benefit from treatment de-escalation strategies. Owing to their midline location, germ cell tumors often present with oculomotor and visual alterations as well as endocrinopathies. The management of CNS tumors in AYA is often extrapolated from pediatric and adult guidelines, and generally consists of a combination of surgical resection, radiation therapy, and systemic therapy. Ongoing research is investigating multiple agents targeting molecular alterations, including isocitrate dehydrogenase inhibitors, SHH pathway inhibitors, and BRAF inhibitors. AYA patients with CNS tumors should be managed by multidisciplinary teams and counselled regarding fertility preservation, psychosocial comorbidities, and risks of long-term comorbidities. There is a need for further efforts to design clinical trials targeting CNS tumors in the AYA population.

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults.

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.

Shouldn't We Know This Already? UK Women's Views About Communicating the Link Between Alcohol Consumption and Risk of Breast Cancer.

Alcohol is a causal factor in about 10% of breast cancer (BCa) cases, but awareness of this link is low. This study explored how to raise awareness and inform the development of an intervention using the COM-B model (capability, opportunity, motivation, behavior) framework. Eight online focus groups were conducted with 36 participants (6 expert stakeholders,and 30 women aged 40-65). Participants reflected on a package of information about alcohol and BCa and discussed how to impart this information and encourage women to reduce drinking. Thematic analysis of focus group transcripts was undertaken. Three themes were identified: understanding ineffective messaging; transitions and challenges; and message acceptability. Current health information about alcohol was perceived as judgmental and BCa was put down to chance. Mid-life consisted of many challenges that could lead to increased consumption, but menopause transition may be a key moment for alcohol reduction. Barriers and enablers to communicating risk information and encouraging alcohol reduction were mapped onto the COM-B model. Psychological capability (relating to knowledge), social opportunity (in the form of social pressure) and automatic motivation (relating to drinking to cope) were barriers to behavior change.  These will be targeted in an alcohol reduction intervention. It is important to tailor information to women's experiences, taking into account the social benefits of drinking, and encourage the development of healthy coping strategies. Acceptable intervention messages may include personal stories, clear statistics, and suggest healthy alternatives to drinking. It is vital that messaging does not appear judgmental or patronizing.

Adolescent and young adult glioma: systematic review of demographic, disease, and treatment influences on survival.

Background: Prognostic factors in adolescent and young adult (AYA) glioma are not well understood. Though clinical and molecular differences between pediatric and adult glioma have been characterized, their application to AYA populations is less clear. There is a major need to develop more robust evidence-based practices for managing AYA glioma patients. Methods: A systematic review using PRISMA methodology was conducted using multiple databases with the objective of identifying demographic, clinical, molecular and treatment factors influencing AYA glioma outcomes. Results: 40 Studies met inclusion criteria. Overall survival was highly variable across studies depending on glioma grade, anatomic compartment and cohort characteristics. Thirty-five studies suffered from high risk of bias in at least one domain. Several studies included older adults within their cohorts; few captured purely AYA groups. Despite study heterogeneity, identified favorable prognosticators included younger age, higher functional status at diagnosis, low-grade pathology, oligodendroglioma histology and increased extent of surgical resection. Though isocitrate dehydrogenase (IDH) mutant status was associated with favorable prognosis, validity of this finding within AYA was compromised though may studies including older adults. The prognostic influence of chemotherapy and radiotherapy on overall survival varied across studies with conflicting evidence. Conclusion: Existing literature is heterogenous, at high risk of bias, and rarely focused solely on AYA patients. Many included studies did not reflect updated pathological and molecular AYA glioma classification. The optimal role of chemotherapy, radiotherapy, and targeted agents cannot be determined from existing literature and should be the focus of future studies.

Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: a systematic review and survival analysis.

Background: Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT. Methods: A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively. Results: Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. Conclusions: Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline.

The 2021 World Health Organization (WHO) classification of CNS tumors incorporates molecular signatures with histology and has highlighted differences across pediatric vs adult-type CNS tumors. However, adolescent and young adults (AYA; aged 15-39), can suffer from tumors across this spectrum and is a recognized orphan population that requires multidisciplinary, specialized care, and often through a transition phase. To advocate for a uniform testing strategy in AYAs, pediatric and adult specialists from neuro-oncology, radiation oncology, neuropathology, and neurosurgery helped develop this review and testing framework through the Canadian AYA Neuro-Oncology Consortium. We propose a comprehensive approach to molecular testing in this unique population, based on the recent tumor classification and within the clinical framework of the provincial health care systems in Canada. Contributions to the field: While there are guidelines for testing in adult and pediatric CNS tumor populations, there is no consensus testing for AYA patients whose care occur in both pediatric and adult hospitals. Our review of the literature and guideline adopts a resource-effective and clinically-oriented approach to improve diagnosis and prognostication of brain tumors in the AYA population, as part of a nation-wide initiative to improve care for AYA patients.

Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors.

Background: A comprehensive review and description of the clinical features that impact prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is needed. Understanding survival and prognostic features is paramount for clinical advancements and patient care. Methods: PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012 and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumor with at least one measure of survival or progression. Patient-level data were pooled for analyses. This study was prospectively registered in PROSPERO (CRD42021267764) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Twenty-seven studies met the criteria with a total of 135 patients included. Median age at diagnosis was 15.8 years (interquartile range [IQR]: 13.3-22.0) with 90% having localized disease. Co-occurring alterations included ATRX mutation in 93%, TP53 mutation in 88%, and MGMT promoter methylation in 70%. Median time-to-progression was 10.0 months (IQR: 6.0-18.0) and median overall survival was 17.3 months (95% CI: 15.0 to 22.9). The median time from progression to death was 5.0 months (IQR: 3.0-11.7). Factors associated with survival duration were age, as patients ≥18 y/o demonstrated longer survival (hazard ratio [HR] =2.05, 95% CI: 1.16 to 3.62), and degree of upfront resection, as near or gross-total resection demonstrated longer survival compared to those with less than near-total resection (HR = 3.75, 95% CI: 2.11 to 6.62). Conclusion: This systematic review highlights available clinical data for G34-DHG demonstrating poor outcomes and important prognostic features, while serving as a baseline for future research and clinical trials.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

Disseminated craniospinal low-grade glioma in a patient with NF-1 without optic pathway pathology: illustrative case.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is a neurocutaneous autosomal dominant disorder that predisposes patients to develop intracranial low-grade gliomas (LGGs). Most LGGs in patients with NF-1 involve the optic pathway but can arise anywhere throughout the central nervous system. NF-1-related disseminated pediatric LGG (dPLGG) in the absence of a dominant optic pathway glioma has not been described. OBSERVATIONS: The authors discussed a case of a 10-year-old boy who presented with consideration for biopsy with nonoptic pathway PLGG with craniospinal dPLGG in the setting of NF-1. The patient's primary lesion, located in the right medulla, was initially treated with surveillance before induction chemotherapy with carboplatin and vincristine was initiated. However, surveillance imaging demonstrated significant increase in size and enhancement, and subsequent craniospinal imaging demonstrated extensive nodular dissemination in the cervicothoracic spine. A biopsy and molecular testing were subsequently performed to further evaluate the tumor, and the patient was diagnosed with dPLGG with CDKN2A deletion. LESSONS: Thorough craniospinal magnetic resonance imaging evaluation and biopsy in nonoptic pathway-dominant brain lesions in NF-1 are warranted in patients with atypical clinical and radiological findings in whom standard chemotherapeutic therapy fails.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.