Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

The CD44s Isoform is a Potential Biomarker for Predicting Craniopharyngioma Recurrence in Children.

Adamantinomatous craniopharyngioma (ACP) is an intracranial tumor considered partly malignant due to its ability to infiltrate surrounding structures and tendency to relapse despite radical resection. CD44 is a known stem cell marker in ACP and is upregulated in cell clusters of invasive ACP protrusions; however, the functions of its alternative splicing isoform variants, CD44s and CD44v1-10, have not yet been studied in terms of ACP recurrence, despite their confirmed roles in cancer development and progression. In this study, we first confirmed the difference in total CD44 expression between samples from patients who experienced relapse and those from patients who did not. Moreover, our findings showed that, in recurrent samples, the predominant isoform expressed was CD44s, which might indicate its significance in predicting ACP recurrence. The association between increased CD44 expression and recurrence may lead to the development of prognostic markers of ACP aggressiveness and relapse potential; however, further studies are needed to clarify the exact mechanism of CD44 expression.

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization.

Although adamantinomatous craniopharyngioma (ACP) is a tumour with low histological malignancy, there are very few therapeutic options other than surgery. ACP has high histological complexity, and the unique features of the immunological microenvironment within ACP remain elusive. Further elucidation of the tumour microenvironment is particularly important to expand our knowledge of potential therapeutic targets. Here, we performed integrative analysis of 58,081 nuclei through single-nucleus RNA sequencing and spatial transcriptomics on ACP specimens to characterize the features and intercellular network within the microenvironment. The ACP environment is highly immunosuppressive with low levels of T-cell infiltration/cytotoxicity. Moreover, tumour-associated macrophages (TAMs), which originate from distinct sources, highly infiltrate the microenvironment. Using spatial transcriptomic data, we observed one kind of non-microglial derived TAM that highly expressed GPNMB close to the terminally differentiated epithelial cell characterized by RHCG, and this colocalization was verified by asmFISH. We also found the positive correlation of infiltration between these two cell types in datasets with larger cohort. According to intercellular communication analysis, we report a regulatory network that could facilitate the keratinization of RHCG+ epithelial cells, eventually causing tumour progression. Our findings provide a comprehensive analysis of the ACP immune microenvironment and reveal a potential therapeutic strategy base on interfering with these two types of cells.

Exploration of the shared pathways and common biomarker in adamantinomatous craniopharyngioma and type 2 diabetes using integrated bioinformatics analysis.

Craniopharyngiomas are rare tumors of the central nervous system that typically present with symptoms such as headache and visual impairment, and those reflecting endocrine abnormalities, which seriously affect the quality of life of patients. Patients with craniopharyngiomas are at higher cardiometabolic risk, defined as conditions favoring the development of type 2 diabetes and cardiovascular disease. However, the underlying common pathogenic mechanisms of craniopharyngiomas and type 2 diabetes are not clear. Especially due to the difficulty of conducting in vitro or in vivo experiments on craniopharyngioma, we thought the common pathway analysis between craniopharyngioma and type 2 diabetes based on bioinformatics is a powerful and feasible method. In the present study, using public datasets (GSE94349, GSE68015, GSE38642 and GSE41762) obtained from the GEO database, the gene expression associated with adamantinomatous craniopharyngioma, a subtype of craniopharyngioma, and type 2 diabetes were analyzed using a bioinformatic approach. We found 11 hub genes using a protein-protein interaction network analysis. Of these, seven (DKK1, MMP12, KRT14, PLAU, WNT5B, IKBKB, and FGF19) were also identified by least absolute shrinkage and selection operator analysis. Finally, single-gene validation and receptor operating characteristic analysis revealed that four of these genes (MMP12, PLAU, KRT14, and DKK1) may be involved in the common pathogenetic mechanism of adamantinomatous craniopharyngioma and type 2 diabetes. In addition, we have characterized the differences in immune cell infiltration that characterize these two diseases, providing a reference for further research.

Identification of core genes of craniopharyngioma angiogenesis based on single-cell nuclear transcriptome sequencing.

This study aimed to explore the core genes of craniopharyngioma angiogenesis for targeted vascular therapy based on single-cell nuclear transcriptome sequencing. For single-cell nuclear transcriptome sequencing, we collected six samples from the tumor center and adjacent hypothalamic tumor tissues from three patients with craniopharyngioma, as well as four normal brain tissues based on Gene Expression Omnibus. We screened genes with differential up-regulation between vascular endothelial cells of craniopharyngioma and those of normal brain tissues, performed GO and KEGG analysis, constructed the protein-protein interaction network, and selected key genes verified using immunofluorescence. After data cleaning and quality control, 623 craniopharyngioma endothelial cells and 439 healthy brain endothelial cells were obtained. Compared with normal brain endothelial cells, craniopharyngioma endothelial cells were screened for 394 differentially up-expressed genes (DEGs). GO and KEGG results showed that DEGs probably modulated endothelial cells, adherens junction, focal adhesion, migration, actin cytoskeleton, and invasion via the PI3K-AKT, Rap1, Ras, Wnt, and Hippo pathways. The core genes screened were CTNNB1, PTK2, ITGB1, STAT3, FYN, HIF1A, VCL, SMAD3, PECAM1, FOS, and CDH5. This study obtained possible anti-angiogenic genes in craniopharyngioma. Our results shed novel insights into molecular mechanisms and craniopharyngioma treatment.

Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Integrating Systemic Therapies into the Multimodality Therapy of Patients with Craniopharyngioma.

OPINION STATEMENT: The integration of targeted therapy into the multimodal management of craniopharyngiomas represents a significant advancement in the field of neuro-oncology. Historically, the management of these tumors has been challenging due to their proximity to vital brain structures, necessitating a delicate balance between tumor control and the preservation of neurological function. Traditional treatment modalities, such as surgical resection and radiation, while effective, carry their own set of risks, including potential damage to surrounding healthy tissues and the potential for long-term side effects. Recent insights into the molecular biology of craniopharyngiomas, particularly the discovery of the BRAF V600E mutation in nearly all papillary craniopharyngiomas, have paved the way for a targeted systemic treatment approach. However, advances have been limited for adamantinomatous craniopharyngiomas. The success of BRAF/MEK inhibitors in clinical trials underscores the potential of these targeted therapies not only to control tumor growth but also to reduce the need for more invasive treatments, potentially minimizing treatment-related complications. However, the introduction of these novel therapies also brings forth new challenges, such as determining the optimal timing, sequencing, and duration of targeted treatments. Furthermore, there are open questions regarding which specific BRAF/MEK inhibitors to use, the potential need for combination therapy, and the strategies for managing intolerable adverse events. Finally, ensuring equitable access to these therapies, especially in healthcare systems with limited resources, is crucial to prevent widening healthcare disparities. In conclusion, targeted therapy with BRAF/MEK inhibitors holds great promise for improving outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. However, additional research is needed to address the questions that remain about its optimal use and integration into comprehensive treatment plans.

Genomic drivers in craniopharyngiomas: Analysis of the AACR project GENIE database.

PURPOSE: Craniopharyngiomas are rare tumors originating in the sellar region, with limited information on their somatic mutational landscape. In this study, we utilized a publicly available genomic database to profile the somatic mutational landscape of craniopharyngioma patients and interrogate differences based on histologic subtype. METHODS: We utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE)® database accessed from cBioPortal (v13.1-public) to query all patients with craniopharyngiomas. RESULTS: Of the 336 patients with sellar tumors, 51 (15.2%) had craniopharyngiomas. Of these 51 patients, 42 (82.4%) were adamantinomatous subtype and 9 (17.6%) were papillary subtype. In this cohort, 32 (62.7%) patients were pediatric, while 19 (37.3%) were adult. The top mutations in the cohort were: CTNNB1 (n = 37; 73%), BRAF (n = 7; 14%), ARID1B (n = 5; 10%), KMT2D (n = 4; 8%), FANCA (n = 4; 8%), ATM (n = 4; 8%), and TERT (n = 3; 8%). Of the 37 patients with CTNNB1 mutations, 8 (21.6%) had S33X, 9 (24.3%) had S37X, 7 (18.9%) had T41X, and 5 (13.5%) had D32X. In this cohort, CTNNB1 mutations tended to co-occur with ATM (n = 4; 10.8%), KMT2C (n = 4; 10.8%), TERT (n = 3; 8.1%), BLM (n = 3; 8.1%), and ERBB2/3 (n = 3; 8.1%), suggesting CTNNB1 mutations tended to co-occur with mutations in genes important in cell growth and survival, chromatin accessibility, and DNA damage response pathways. CONCLUSIONS: CTNNB1 mutations account for a large proportion of somatic mutations in craniopharyngiomas. Identification of specific point mutations and secondary drivers may advance development of novel craniopharyngioma preclinical models for targeted therapy testing.

Unraveling the complexity of the senescence-associated secretory phenotype in adamantinomatous craniopharyngioma using multimodal machine learning analysis.

BACKGROUND: Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a senesecence-associated secretory phenotype. However, a detailed analysis of these characteristics has yet to be completed. METHODS: We analyzed primary tissue samples from ACP patients using single-cell, single-nuclei, and spatial RNA sequencing. We performed various analyses, including gene expression clustering, inferred senescence cells from gene expression, and conducted cytokine signaling inference. We utilized LASSO to select essential gene expression pathways associated with senescence. Finally, we validated our findings through immunostaining. RESULTS: We observed significant diversity in gene expression and tissue structure. Key factors such as NFKB, RELA, and SP1 are essential in regulating gene expression, while senescence markers are present throughout the tissue. SPP1 is the most significant cytokine signaling network among ACP cells, while the Wnt signaling pathway predominantly occurs between epithelial and glial cells. Our research has identified links between senescence-associated features and pathways, such as PI3K/Akt/mTOR, MYC, FZD, and Hedgehog, with increased P53 expression associated with senescence in these cells. CONCLUSIONS: A complex interplay between cellular senescence, cytokine signaling, and gene expression pathways underlies ACP development. Further research is crucial to understand how these elements interact to create novel therapeutic approaches for patients with ACP.

Advancing Craniopharyngioma Management: A Systematic Review of Current Targeted Therapies and Future Perspectives.

Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients.

Epigenetic Control of Adamantinomatous Craniopharyngiomas.

INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. METHODS: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. RESULTS: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/ß-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). CONCLUSIONS: ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

Implications of cellular senescence in paediatric pituitary tumours.

The long-standing view of senescent cells as passive and dysfunctional biological remnants has recently shifted into a new paradigm where they are main players in the development of many diseases, including cancer. The senescence programme represents a first line of defence that prevents tumour cell growth but also leads to the secretion of multiple pro-inflammatory and pro-tumourigenic factors that fuel tumour initiation, growth, and progression. Here, we review the main molecular features and biological functions of senescent cells in cancer, including the outcomes of inducing or targeting senescence. We discuss evidence on the role of cellular senescence in pituitary tumours, with an emphasis on adamantinomatous craniopharyngioma (ACP) and pituitary adenomas. Although senescence has been proposed to be a tumour-preventing mechanism in pituitary adenomas, research in ACP has shown that senescent cells are tumour-promoting in both murine models and human tumours. Future studies characterizing the impact of targeting senescent cells may result in novel therapies against pituitary tumours.

Case Report: Successful Use of BRAF/MEK Inhibitors in Aggressive BRAF-mutant Craniopharyngioma.

BACKGROUND: Although a benign intracranial tumor, craniopharyngioma treatment has always been considered a challenging clinical problem. Recently, BRAF V600E mutation in the pathogenesis of papillary craniopharyngioma (PCP) has been further revealed. Thus, BRAF inhibitors (BRAFi) serve as an applicable treatment for patients with PCP. METHODS: Two patients with recurrent PCP were treated with combined BRAFi dabrafenib (150 mg, orally twice daily) and MEK inhibitors (MEKi) trametinib (2 mg, orally twice daily). A follow-up exceeding 2 years was conducted. We meticulously scrutinized the treatment's safety and efficacy profiles by delving into existing literature. RESULTS: One patient harboring a solid tumor achieved a complete tumor response devoid of any adverse events and encountered no recurrence over 2 years subsequent to discontinuation. Moreover, within a mere month of commencing targeted therapy, the tumor demonstrated observable shrinkage. This finding substantiates the considerable potential inherent in targeted therapy for PCP cases marked by the somatic BRAF V600E mutation. CONCLUSIONS: Under specific conditions, individuals diagnosed with PCP can attain a complete tumor response following combined treatment with BRAFi/MEKi.

Transcription Factor GLI1 Induces IL-6-Mediated Inflammatory Response and Facilitates the Progression of Adamantinomatous Craniopharyngioma.

Adamantinomatous craniopharyngioma (ACP) is a neuroendocrine tumor whose pathogenesis remains unclear. This study investigated the role of glioma-associated oncogene family zinc finger 1 (GLI1), a transcription factor in the sonic hedgehog (SHH) signaling pathway, in ACP. We discovered that GLI1 regulates the expression of IL-6, thereby triggering inflammatory responses in ACP and influencing the tumor's progression. Analyzing the Gene Expression Omnibus (GEO) database chip GSE68015, we found that GLI1 is overexpressed in ACP, correlating positively with the spite of ACP and inflammation markers. Knockdown of GLI1 significantly inhibited the levels of tumor necrosis factor α, interleukin-6 (IL-6), and IL-1ß in ACP cells, as well as cell proliferation and migration. We further identified a binding site between GLI1 and the promoter region of IL-6, demonstrating that GLI1 can enhance the expression of IL-6. These findings were verified in vivo, where activation of the SHH pathway significantly promoted GLI1 and IL-6 expressions in nude mice, inducing inflammation and tumor growth. Conversely, GLI1 knockdown markedly suppressed these processes. Our study uncovers a potential molecular mechanism for the occurrence of inflammatory responses and tumor progression in ACP.

[Craniopharyngiomas: The Dawn of a New Era with the Elucidation of Driver Genes].

Craniopharyngiomas(CPs)are primary brain tumors that emerge from the remnants of Rathke's pouch. Despite their histologically non-malignant nature, the proximity to major blood vessels and hypothalamus, as well as the infiltrative growth, make total resection challenging. CPs are classified into two pathological subtypes: adamantinomatous(ACP)and papillary(PCP). CTNNB1 mutations were detected in ACPs, and the BRAF V600E mutation was detected in PCPs. Although both subtypes are epithelial tumors, they have different genetic profiles, clinical presentations, imaging findings, and histopathology. They are mentioned as independent chapters in the World Health Organization Classification of Tumors of the Central Nervous System, 5th edition. In 2023, a prospective clinical trial investigating a BRAF/MEK inhibitor for craniopharyngioma with BRAF mutations demonstrated marked tumor shrinkage. Currently, attempts are being made to elucidate the predictors of BRAF mutations to facilitate the use of neoadjuvant chemotherapy for craniopharyngioma. Additionally, the management of craniopharyngiomas requires the development of a surgical strategy that considers radiation and molecular-targeted therapies.

Craniopharyngioma in Pediatrics and Adults.

Craniopharyngiomas are rare malignancies of dysembryogenic origin, involving the sellar and parasellar areas. These low-grade, epithelial tumors account for two main histological patterns (adamantinomatous craniopharyngioma and papillary craniopharyngioma), which differ in epidemiology, pathogenesis, and histomorphological appearance. Adamantinomatous craniopharyngiomas typically show a bimodal age distribution (5-15 years and 45-60 years), while papillary craniopharyngiomas are limited to adult patients, especially in the fifth and sixth decades of life. Recently, craniopharyngioma histological subtypes have been demonstrated to harbor distinct biomolecular signatures. Somatic mutations in CTNNB1 gene encoding ß-catenin have been exclusively detected in adamantinomatous craniopharyngiomas, which predominantly manifest as cystic lesions, while papillary craniopharyngiomas are driven by BRAF V600E mutations in up to 95% of cases and are typically solid masses. Despite the benign histological nature (grade I according to the World Health Organization classification), craniopharyngiomas may heavily affect long-term survival and quality of life, due to their growth pattern in a critical region for the presence of eloquent neurovascular structures and possible neurological sequelae following their treatment. Clinical manifestations are mostly related to the involvement of hypothalamic-pituitary axis, optic pathways, ventricular system, and major blood vessels of the circle of Willis. Symptoms and signs referable to intracranial hypertension, visual disturbance, and endocrine deficiencies should promptly raise the clinical suspicion for sellar and suprasellar pathologies, advocating further neuroimaging investigations, especially brain MRI. The optimal therapeutic management of craniopharyngiomas is still a matter of debate. Over the last decades, the surgical strategy for craniopharyngiomas, especially in younger patients, has shifted from the aggressive attempt of radical resection to a more conservative and individualized approach via a planned subtotal resection followed by adjuvant radiotherapy, aimed at preserving functional outcomes and minimizing surgery-related morbidity. Whenever gross total removal is not safely feasible, adjuvant radiotherapy (RT) and stereotactic radiosurgery (SRS) have gained an increasingly important role to manage tumor residual or recurrence. The role of intracavitary therapies, including antineoplastic drugs or sealed radioactive sources, is predominantly limited to monocystic craniopharyngiomas as secondary therapeutic option. Novel findings in genetic profiling of craniopharyngiomas have unfold new scenarios in the development of targeted therapies based on brand-new biomolecular markers, advancing the hypothesis of introducing neoadjuvant chemotherapy regimens in order to reduce tumor burden prior to resection. Indeed, the rarity of these neoplasms requires a multispecialty approach involving an expert team of endocrinologists, neurosurgeons, neuro-ophthalmologists, neuroradiologists, radiotherapists, and neuro-oncologists, in order to pursue a significant impact on postoperative outcomes and long-term prognosis.

BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas.

BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).