The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma.

We aimed to evaluate the relationship between imaging features, therapeutic responses (comparative cross-product and volumetric measurements), and overall survival (OS) in pediatric diffuse intrinsic pontine glioma (DIPG). A total of 134 patients (≤ 18 years) diagnosed with DIPG were included. Univariate and multivariate analyses were performed to evaluate correlations of clinical and imaging features and therapeutic responses with OS. The correlation between cross-product (CP) and volume thresholds in partial response (PR) was evaluated by linear regression. The log-rank test was used to compare OS patients with discordant therapeutic response classifications and those with concordant classifications. In univariate analysis, characteristics related to worse OS included lower Karnofsky, larger extrapontine extension, ring-enhancement, necrosis, non-PR, and increased ring enhancement post-radiotherapy. In the multivariate analysis, Karnofsky, necrosis, extrapontine extension, and therapeutic response can predict OS. A 25% CP reduction (PR) correlated with a 32% volume reduction (R2 = 0.888). Eight patients had discordant therapeutic response classifications according to CP (25%) and volume (32%). This eight patients' median survival time was 13.0 months, significantly higher than that in the non-PR group (8.9 months), in which responses were consistently classified as non-PR based on CP (25%) and volume (32%). We identified correlations between imaging features, therapeutic responses, and OS; this information is crucial for future clinical trials. Tumor volume may represent the DIPG growth pattern more accurately than CP measurement and can be used to evaluate therapeutic response.

Clinical characteristics and prognostic factors of adult brainstem gliomas: A retrospective analysis of histologically-proven 40 cases.

To illustrate the clinical characteristics and prognostic factors of adult patients pathologically confirmed with brainstem gliomas (BSGs). Clinical data of 40 adult patients pathologically diagnosed with BSGs admitted to Beijing Shijitan Hospital from 2009 to 2022 were recorded and retrospectively analyzed. The primary parameters included relevant symptoms, duration of symptoms, Karnofsky performance status (KPS), tumor location, type of surgical resection, diagnosis, treatment, and survival. Univariate and multivariate analyses were evaluated by Cox regression models. The gliomas were located in the midbrain of 9 patients, in the pons of 14 cases, in the medulla of 5 cases, in the midbrain and pons of 6 cases and invading the medulla and pons of 6 cases, respectively. The proportion of patients with low-grade BSGs was 42.5%. Relevant symptoms consisted of visual disturbance, facial paralysis, dizziness, extremity weakness, ataxia, paresthesia, headache, bucking, dysphagia, dysacousia, nausea, dysphasia, dysosmia, hypomnesia and nystagmus. 23 (57.5%) patients accepted stereotactic biopsy, 17 (42.5%) patients underwent surgical resection. 39 patients received radiotherapy and 34 cases were treated with temozolomide. The median overall survival (OS) of all patients was 26.2 months and 21.5 months for the median progression-free survival (PFS). Both duration of symptoms (P = .007) and tumor grading (P = .002) were the influencing factors for OS, and tumor grading was significantly associated with PFS (P = .001). Duration of symptoms for more than 2 months and low-grade are favorable prognostic factors for adult patients with BSGs.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Laminin-associated integrins mediate Diffuse Intrinsic Pontine Glioma infiltration and therapy response within a neural assembloid model.

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.

Management of patients with diffuse intrinsic pontine glioma in Australia and New Zealand: Australian and New Zealand Children's Haematology/Oncology Group position statement.

INTRODUCTION: The main mission of the Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG) is to develop and facilitate local access to the world's leading evidence-based clinical trials for all paediatric cancers, including brain tumours, as soon as practically possible. Diffuse intrinsic pontine gliomas (DIPGs) - a subset of a larger group of tumours now termed diffuse midline glioma, H3K27-altered (DMG) - are paediatric brain cancers with less than 10% survival at two years. In the absence of any proven curative therapies, significant recent advancements have been made in pre-clinical and clinical research, leading many to seek integration of novel therapies early into standard practice. Despite these innovative therapeutic approaches, DIPG remains an incurable disease for which novel surgical, imaging, diagnostic, radiation and systemic therapy approaches are needed. MAIN RECOMMENDATIONS: All patients with DIPG should be discussed in multidisciplinary neuro-oncology meetings (including pathologists, neuroradiologists, radiation oncologists, neurosurgeons, medical oncologists) at diagnosis and at relapse or progression. Radiation therapy to the involved field remains the local and international standard of care treatment. Proton therapy does not yield a superior survival outcome compared with photon therapy and patients should undergo radiation therapy with the available modality (photon or proton) at their treatment centre. Patients may receive concurrent chemotherapy or radiation-sensitising agents as part of a clinical trial. Biopsy should be offered to facilitate consideration of experimental therapies and eligibility for clinical trial participation. After radiation therapy, each patient should be managed individually with either observation or considered for enrolment on a clinical trial, if eligible, after full discussion with the family. Re-irradiation can be considered for progressive disease. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Every child diagnosed with DIPG should be offered enrolment on a clinical trial where available. Access to investigational drugs without biological rationale outside the clinical trial setting is not supported. In case of potentially actionable target identification with molecular profiling and absence of a suitable clinical trial, rational targeted therapies can be considered through compassionate access programs.

Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Bibliometric analysis of emerging trends and research foci in brainstem tumor field over 30 years (1992-2023).

PURPOSE: Over the past several decades, numerous articles have been published on brainstem tumors. However, there has been limited bibliometric analysis in this field. Therefore, we conducted a bibliometric analysis to elucidate the evolution and current status of brainstem tumor research. METHODS: We retrieved 5525 studies published in English between 1992 and 2023 from the Web of Science Core Collection database. We employed bibliometric tools and VOSviewer to conduct the analysis. RESULTS: We included a total of 5525 publications for further analysis. The annual publications have exhibited steady growth over time. The United States accounted for the highest number of publications and total citations. Among individual researchers, Liwei Zhang had the highest number of publications, while Cynthia Hawkins and Chris Jones shared the most citations, closely followed by Eric Bouffet in this field. The study titled "Diffuse brainstem glioma in children: critical review of clinical trials" stood out as the most cited work in this field. Keyword analysis revealed that immune therapy and epigenetic research are the focal points of this field. CONCLUSIONS: Our bibliometric analysis underscores the enduring significance of brainstem tumors in the realm of neuro-oncology research. The field's hotspots have transitioned from surgery and radiochemotherapy to investigating epigenetic mechanisms and immune therapy.

Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies.

Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.

[Primary tumors of the brain stem. State of the problem]. / Pervichnye opukholi stvola golovnogo mozga. Sostoyanie problemy.

Primary brainstem gliomas are still poorly studied in neurooncology. This concept includes tumors with different histological and genetic features, as well as variable clinical course and outcomes. Nevertheless, treatment implies radiotherapy without a clear idea of morphological substrate of disease in 80% of cases. Small number of studies and insufficient data on histological and genetic nature of brainstem tumors complicate clear diagnostic and treatment algorithms. This review provides current information regarding primary glial brainstem tumors. Appropriate problems and objectives are highlighted. The purpose of the review is to provide a comprehensive and updated understanding of the current state of brainstem glial tumors and to identify areas requiring further study for improvement of diagnosis and treatment of these diseases. Brainstem tumors are an understudied problem with small amount of data that complicates optimal treatment strategies. Further researches and histological verification are required to develop new methods of therapy, especially for diffuse forms of neoplasms.

Just a spoonful of metformin helps the medicine go down.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.

Influence of socioeconomic status on clinical outcomes of diffuse midline glioma and diffuse intrinsic pontine glioma.

OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.

Decoding the puzzle: A multidisciplinary systematic review of adult brainstem glioma.

Adult brainstem gliomas (BSGs) are a group of rare central nervous system tumors with varying prognoses and controversial standard treatment strategies. To provide an overview of current trends, a systematic review using the PRISMA guidelines, Class of evidence (CE) and strength of recommendation (SR), was conducted. The review identified 27 studies. Surgery was found to have a positive impact on survival, particularly for focal lesions with CE II SR C. Stereotactic image-guided biopsy was recommended when resective surgery was not feasible with CE II and SR B. The role of systemic treatments remains unclear. Eight studies provided molecular biology data. This review gathers crucial literature on diagnosis and management of adult BSGs. It provides evidence-based guidance with updated recommendations for diagnosing and treating, taking into account recent molecular and genetic advancements. The importance of brain biopsy is emphasized to optimize treatment using emerging genetic-molecular findings and explore potential targeted therapies.

Brain stem tumors in children less than 3 months: Clinical and radiologic findings of a rare disease.

PURPOSE: Brain stem tumors in children < 3 months at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS: This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers, including patients with a brainstem tumor diagnosed between 2009 and 2020 and aged < 3 months at diagnosis. Clinical data were collected, and imaging characteristics were analyzed blindly and independently by two neuroradiologists. RESULTS: Five cases were identified. No patient received any therapy. The epicenter of two tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in three. For patients with tumor in equal parts in the medulla oblongata and the pons (n = 3), the extension at diagnosis involved the spinal cord; for the two patients with the tumor epicenter in the medulla oblongata alone (n = 2), the extension at diagnosis included the pons (n = 2) and the spinal cord (n = 1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died. In one patient, autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n = 2) or stable disease (n = 1). Survivors were followed up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS: No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy may provide useful information regarding the patient management.

TIM-3 blockade: immune and targeted therapy in DIPG.

Diffuse intrinsic pontine glioma (DIPG) remains intractable to conventional treatments. While targeted therapy and immuno-oncology advances offer hope, few strategies show promising results. In a recent article in Cancer Cell, Ausejo-Mauleon et al. introduce TIM-3 blockade as a potential breakthrough for DIPG treatment by targeting cancer cells and regulating the immune microenvironment simultaneously.

H3 K27M-altered glioma and diffuse intrinsic pontine glioma: Semi-systematic review of treatment landscape and future directions.

H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.

The Role of Advanced MRI Sequences in the Diagnosis and Follow-Up of Adult Brainstem Gliomas: A Neuroradiological Review.

The 2021 WHO (World Health Organization) classification of brain tumors incorporated the rapid advances in the molecular, genetic, and pathogenesis understanding of brain tumor pathogenesis, behavior, and treatment response. It revolutionized brain tumor classification by placing great emphasis on molecular types and completely splitting adult-type and pediatric-type diffuse gliomas. Brainstem gliomas (BSGs) are the leading primary tumors of the brainstem, although they are quite uncommon in adults compared with the pediatric population, representing less than 2% of adult gliomas. Surgery is not always the treatment of choice since resection is rarely feasible and does not improve overall survival, and biopsies are not generally performed since the location is treacherous. Therefore, MRI (Magnetic Resonance Imaging) without and with gadolinium administration represents the optimal noninvasive radiological technique to suggest brainstem gliomas diagnosis, plan a multidisciplinary treatment and for follow-up evaluations. The MRI protocol encompasses morphological sequences as well as functional and advanced sequences, such as DWI/ADC (Diffusion-Weighted Imaging/Apparent Diffusion Coefficient), DTI (Diffusion Tensor Imaging), PWI (Perfusion-Weighted Imaging), and MRS (Magnetic Resonance Spectroscopy), which improve the accuracy of the diagnosis of BSGs by adding substantial information regarding the cellularity, the infiltrative behavior toward the v fiber tracts, the vascularity, and the molecular changes. Brainstem gliomas have been divided into four categories on the basis of their MRI radiological appearance, including diffuse intrinsic low-grade gliomas, enhancing malignant gliomas, localized tectal gliomas, and other forms. The aim of our review is to provide insight into the role of advanced MRI sequences in the diagnosis and follow-up of adult brainstem gliomas.

Fifty years of DIPG: looking at the future with hope.

Diffuse intrinsic pontine glioma (DIPG) is a primary brainstem tumor of childhood that carries a dismal prognosis, with median survival of less than 1 year. Because of the brain stem location and pattern of growth within the pons, Dr. Harvey Cushing, the father of modern neurosurgery, urged surgical abandonment. Such a dismal prognosis remained unchanged for decades, coupled with a lack of understanding of tumor biology and an unchanging therapeutic panorama. Beyond palliative external beam radiation therapy, no therapeutic approach has been widely accepted. In the last one to two decades, however, increased tissue availability, an improving understanding of biology, genetics, and epigenetics have led to the development of novel therapeutic targets. In parallel with this biological revolution, new methods intended to enhance drug delivery into the brain stem are contributing to a surge of exciting experimental therapeutic strategies.

Oncolytic virotherapy for the treatment of pediatric brainstem gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.

Inducing primary brainstem gliomas in genetically engineered mice using RCAS/TVA retroviruses and Cre/loxP recombination.

Genetically engineered mice are commonly used to model brainstem gliomas in pre-clinical research. One technique for inducing primary tumors in these genetically engineered mice involves delivering viral vectors containing the code for gene-editing proteins. We present a protocol for generating primary brainstem gliomas using the RCAS-TVA retroviral delivery system and the Cre/loxP gene editing system. We describe steps for transfecting and harvesting chicken fibroblast cells, intracranially injecting cells into mice, imaging primary tumors, and treating primary tumors with focal, image-guided brain irradiation. For complete details on the use and execution of this protocol, please refer to Deland et al. (2021).1.