scholarly journals High Grade Meningiomas: Current Therapy Based on Tumor Biology

2021 ◽  
Author(s):  
Juan Esteban Garcia-Robledo ◽  
Camila Ordóñez-Reyes ◽  
Alejandro Ruiz-Patiño ◽  
Álvaro Muñoz ◽  
Oscar Arrieta ◽  
...  
Keyword(s):  
Drug Targets ◽  
Treatment Options ◽  
Tumor Biology ◽  
Molecular Therapy ◽  
Current Therapy ◽  
High Recurrence Rate ◽  
High Grade ◽  
Who Grade ◽  
Emerging Treatments ◽  
Molecular Sequencing

Atypical (WHO grade II) and malignant meningiomas (WHO Grade III) are a rare subset of primary intracranial tumors. Due to the high recurrence rate after surgical resection and radiotherapy, there has been a recent interest in exploring other systemic treatment options for these refractory tumors. Recent advances in molecular sequencing of tumors have elucidated new pathways and drug targets currently being studied. This article provides a thorough overview of novel investigational therapeutics, including targeted therapy, immunotherapy, and new technological modalities for atypical and malignant meningiomas. There is encouraging preclinical evidence regarding the efficacy of the emerging treatments discussed in this chapter. Several clinical trials are currently recruiting patients to translate targeted molecular therapy for recurrent and high-grade meningiomas.

Effect of temozolomide chronotherapy in patients with high-grade glioma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14525-e14525 ◽  
Author(s):  
Himachandana Atluri ◽  
Jian Li Campian ◽  
Grayson Talcott ◽  
Melissa Meyer ◽  
Emily Slat ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Biological Rhythms ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Well Being ◽  
Current Therapy ◽  
High Grade ◽  
Who Grade ◽  
Significant Difference ◽  
Morning Administration

e14525 Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.

scholarly journals Successful Treatment of a Spinal Clear Cell Meningiomas Patient With Anti-PD-1 Plus Anti- Angiogenesis

2021 ◽  
Author(s):  
Yong Wang ◽  
Baoyan Liu ◽  
Rongjie Tao ◽  
Yingxue Qi ◽  
Ningning Luo ◽  
...  
Keyword(s):  
Clear Cell ◽  
Treatment Options ◽  
Reference Value ◽  
Treatment Method ◽  
Disease Recurrence ◽  
World Health ◽  
High Recurrence Rate ◽  
Who Grade ◽  
Primary Tumors ◽  
Health Organization

Abstract Clear cell meningioma (CCM), an unusual subtype of World Health Organization (WHO) grade II meningioma, represents only 0.2– 0.8% of meningiomas. Spinal CCMs are even rarer with unique clinical features: more common in younger patients; more likely to appear in lumbar spine; high recurrence rate. Although surgery and radiotherapy are the most common treatment for primary tumors and disease recurrence, there are lack of treatment options for recurrent or metastasis disease. It is urgent need to explore new effective treatment method. In our case, we firstly reported a rare spinal CCM patient with PD-L1 positive and multiple metastases benefiting from PD-1 inhibitor plus anti- angiogenesis therapy. This treatment program is effective, safe, and has a strong therapeutic reference value, which provides promising treatment options and the direction of future clinical trials for spinal CCMs.

scholarly journals MNGI-11. HIGH-GRADE AND LOW-GRADE MENINGIOMAS HARBOR DIFFERING METABOLOMIC PROFILES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi141-vi142
Author(s):  
Garrett Fitzpatrick ◽  
Maryam Rahman ◽  
Timothy Garrett ◽  
Jesse Kresak
Keyword(s):  
Brain Tumor ◽  
Treatment Options ◽  
Disease Free Survival ◽  
Metastatic Potential ◽  
Primary Brain Tumor ◽  
Sphingolipid Metabolism ◽  
Low Grade ◽  
Tumor Type ◽  
High Grade ◽  
Who Grade

Abstract BACKGROUND Meningiomas are the most common primary brain tumor in adults. While the majority of meningiomas are low-grade and effectively treated by resection alone, there is a subset of tumors that have a high incidence of recurrence, metastatic potential, and morbidity. Radiation has been employed with variable success for high-grade meningiomas. No chemotherapeutic approaches have proven effective against these tumors to date. There is a need for a better understanding of this tumor type in order to provide our patients with better treatment options. OBJECTIVE The purpose of this study is to investigate the metabolomic profile of meningiomas with a focus on comparing low- and high-grade tumors and identifying biologically significant metabolites which could correlate with overall and disease-free survival. METHODS Ten tumor samples of each meningioma grade (WHO grades I-III) were collected from the Florida Center for Brain Tumor Research. Global metabolomic profiling by liquid chromatography mass spectrometry was performed on the frozen tumor samples. Statistical analyses were performed using the Southeast Center for Integrated Metabolomics Galaxy interface. Select metabolites which significantly differed between low-grade (WHO Grade I) and high-grade (WHO grade II-III) were identified using the Human Metabolome Database. RESULTS Differing metabolomic profiles between low-grade and high-grade meningiomas were confirmed by multivariate analysis and demonstrated by unsupervised hierarchical clustering. Notably, lysophospholipid and sphingolipid metabolism was increased in the high-grade tumors, while FAPy-adenine, an oxidized nucleoside which may serve as a tumor marker, was decreased. Guanine was found to be consistently decreased in patients with negative outcomes. CONCLUSIONS High-grade and low-grade meningiomas harbor different metabolomic profiles. The significance of these specific differences requires further investigation.

Predictors of treatment response in colorectal high-grade neuroendocrine carcinomas (HGNEC): A single institution experience.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 690-690
Author(s):  
Virginia Corbett ◽  
Nitya Prabhakar Raj ◽  
Virginia Kelly ◽  
Diane Lauren Reidy
Keyword(s):  
Treatment Options ◽  
Locally Advanced ◽  
Molecular Data ◽  
Molecular Characteristics ◽  
High Grade ◽  
Molecular Alterations ◽  
Predictors Of Response ◽  
Significant Difference ◽  
Molecular Sequencing ◽  
Neuroendocrine Carcinomas

690 Background: Colorectal high-grade neuroendocrine carcinomas (HGNEC) are aggressive tumors; treatment options consist of cis/carboplatin and 5FU-based chemotherapy. To date, choice of systemic therapy and sequencing of these drugs remains poorly understood. We examined clinical and molecular characteristics of colorectal HGNEC to better define predictors of response to cis/carboplatin and 5FU-based treatment. Methods: Patients (pts) with colorectal HGNEC treated at MSKCC from 1990-2018 were identified. MANEC (mixed adeno-neuroendocrine carcinoma) were excluded. Demographics, response to first- and second-line chemotherapy (by radiology report), outcomes, and molecular data (next-generation sequencing of tumor tissue), were collected. Results: 65 pts (mean age 58, 52% male) were identified, 13 (20%) with small cell carcinomas. 52 (79%) metastatic, 13 (20%) locally advanced. 27 (42%) received surgery and 11 (17%) received radiation. 56 pts received cis/carboplatin-based therapy, partial response (PR) in 18 (32%), stable disease (SD) in 4 (7%), and progressive disease (PD) in 31 (55%); 3 (5%) did not tolerate therapy. 28 pts received 5FU-based therapy, 13 PR in (46%), SD in 6 (21%), and PD in 7 (25%); 2 (7%) did not tolerate therapy. Median overall survival was 11.4 months. 21/65 (32%) pts underwent molecular sequencing of tumor; the most common alterations were KRAS 11 (52%), TP53 13 (62%), BRAF 7 (33%), APC 8 (38%), RB1 7 (33%). Most tumors (13/21, 62%) harbored alterations in genes traditionally altered in colorectal adenocarcinoma (KRAS/BRAF/APC) and in HGNEC (TP53/RB1). There was no significant difference in response to cis/carboplatin or 5FU-based chemotherapy based on location of the primary tumor (right vs. left) (p = 0.69/0.85), histologic features of the disease (p = 0.71/0.87), and for response to cis/carboplatin by molecular alterations in KRAS (p = 0.94), BRAF (p = 0.24), APC (p = 0.28), TP53 (p = 0.58), or RB1 (p = 0.28). Conclusions: Colorectal HGNEC are highly aggressive and more effective therapies are desperately needed. In this series, OS was poor. Clinical and molecular characteristics failed to predict response to cis/carboplatin and 5FU-based chemotherapy.

Pediatric Gliomas: Current Concepts on Diagnosis, Biology, and Clinical Management

2017 ◽  
Vol 35 (21) ◽  
pp. 2370-2377 ◽  
Author(s):  
Dominik Sturm ◽  
Stefan M. Pfister ◽  
David T.W. Jones
Keyword(s):  
Large Scale ◽  
Treatment Options ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Cns Tumors ◽  
Low Grade ◽  
Who Grade ◽  
Short Period ◽  
Life Threatening

Gliomas are the most common CNS tumors in children and adolescents, and they show an extremely broad range of clinical behavior. The majority of pediatric gliomas present as benign, slow-growing lesions classified as grade I or II by the WHO classification of CNS tumors. These pediatric low-grade gliomas (LGGs) are fundamentally different from IDH-mutant LGGs occurring in adults, because they rarely undergo malignant transformation and show excellent overall survival under current treatment strategies. However, a significant fraction of gliomas develop over a short period of time and progress rapidly and are therefore classified as WHO grade III or IV high-grade gliomas (HGGs). Despite all therapeutic efforts, they remain largely incurable, with the most aggressive forms being lethal within months. Thus, the intentions of neurosurgeons, pediatric oncologists, and radiotherapists to improve care for pediatric patients with glioma range from increasing quality of life and preventing long-term sequelae in what is often a chronic, but rarely life-threatening disease (LGG), to uncovering effective treatment options to prolong patient survival in an almost universally fatal setting (HGG). The last decade has seen unprecedented progress in understanding the molecular biology underlying pediatric gliomas, fueling hopes to achieve both goals. Large-scale collaborative studies around the globe have cataloged genomic and epigenomic alterations in gliomas across ages, grades, and histologies. These studies have revealed biologic subgroups characterized by distinct molecular, pathologic, and clinical features, with clear relevance for patient management. In this review, we summarize hallmark discoveries that have expanded our knowledge in pediatric LGGs and HGGs, explain their role in tumor biology, and convey our current concepts on how these findings may be translated into novel therapeutic approaches.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
Macarena De La Fuente ◽  
Tulay Koru-Sengul ◽  
Deborah Heros ◽  
Feng Miao ◽  
Alain Fernandez Marrero ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rna Sequencing ◽  
Tumor Antigens ◽  
High Grade Glioma ◽  
Treatment Discontinuation ◽  
Sequencing Analysis ◽  
High Grade ◽  
Who Grade ◽  
Cytokine Levels ◽  
Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

scholarly journals CBIO-16. SUPPRESSION OF HISTONE H3.3 MITOTIC PHOSPHORYLATION DRIVES DEVELOPMENT OF H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii18-ii19
Author(s):  
Charles Day ◽  
Alyssa Langfald ◽  
Florina Grigore ◽  
Leslie Sepaniac ◽  
Jason Stumpff ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Treatment Options ◽  
Chromosome Instability ◽  
Pericentromeric Heterochromatin ◽  
Low Grade ◽  
High Grade ◽  
Chromosome Missegregation ◽  
Mitotic Phosphorylation ◽  
Chk1 Kinase

Abstract Pediatric midline gliomas – including DIPG – are lethal brain tumors in children, with poor prognosis and limited treatment options that provide only short-term benefits. The majority have a lysine-to-methionine substitution at residue 27 (H3K27M) in genes expressing histone H3 – predominantly in the H3.3 variant. This causes a global reduction in H3 Lys27 tri-methylation (H3K27Me3), comprehensive epigenetic reprogramming, and is a key driver in gliomagenesis. We show that the H3.3K27M mutation also induces chromosome segregation defects, which in high-grade tumors, results in extensive copy number alterations (CNAs). Ser31 is one of five amino acid substitutions differentiating H3.3 from canonical H3.1. Mitotic phosphorylation of H3.3 Ser31 by Chk1 kinase is restricted to pericentromeric heterochromatin, where it plays a role in chromosome segregation. We show that the K27M mutation affects neighboring Ser31 phosphorylation and pericentromeric heterochromatin organization. We demonstrate that (i) H3.3 K27M protein is defective for Ser31 phosphorylation by Chk1 kinase in vitro; (ii) DIPG cell lines have significantly decreased mitotic Ser31 phosphorylation, and are chromosomally unstable; and (iii) CRISPR-reversion of H3.3K27M to Lys27 restores phospho-Ser31 (and Lys27 tri-methylation) and significantly decreases chromosome instability. Expression of H3.3K27M or non-phosphorylatable H3.3S31A mutants in WT cells results in chromosome missegregation; this is suppressed by co-expression of phospho-mimetic H3.3K27M/S31E. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. Finally, in a novel mouse model of glioma, mean survival of mice with tumors induced with H3.3K27M and H3.3S31A was 81 and 68 days: 100% of H3.3S31A mice developed high-grade tumors. H3.3 WT controls developed only low-grade tumors and all survived 100 days. H3.3S31A is WT for Lys27 tri-methylation and thus, loss of Ser31 phosphorylation alone is oncogenic.

scholarly journals The Role of Conventional and Stereotactic Microwave Ablation for Intrahepatic Cholangiocarcinoma

2021 ◽  
Vol 10 (13) ◽  
pp. 2963
Author(s):  
Corina Kim-Fuchs ◽  
Daniel Candinas ◽  
Anja Lachenmayer
Keyword(s):  
Literature Review ◽  
Intrahepatic Cholangiocarcinoma ◽  
Microwave Ablation ◽  
Treatment Options ◽  
Tumor Biology ◽  
Tumor Ablation ◽  
Curative Treatment ◽  
Complication Rates ◽  
Curative Therapy ◽  
Incidence And Mortality

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of palliative chemotherapy and radiotherapy is relatively small. In contrast to hepatocellular carcinoma, minimal-invasive thermal tumor ablation, and in particular stereotactic tumor ablation for small primary cancers or metastases, is not established and data are scarce. Methods: We conducted a literature review in the field of ICCA ablation and retrospective analysis of 10 patients treated by stereotactic microwave ablation (SMWA) for either primary ICCA or liver metastases of ICCA. Results: While current guidelines have no consensus for ablation of primary ICCA, some state that it might be an option in inoperable patients or those with recurrent disease. The literature review revealed 11 studies on microwave ablation for ICCA reporting that MWA for ICCA ≤ 5 cm might be safe and could be a treatment option for patients who are not candidates for surgery. No data has been published on stereotactic microwave ablation (SMWA) for ICCA. The analyses of our own data of 10 patients treated by SMWA for primary ICCA (n = 5) or recurrent ICCA (n = 5) show that the treatment is safe and efficient with short hospital stays and low complication rates. Conclusion: Although thermal ablation, and in particular SMWA, might be a minimally invasive and tissue-sparing curative treatment alternative for small ICCA in the diseased liver and ICCA metastases, the oncologic benefit still needs to be shown in larger studies with longer follow-up.

scholarly journals Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)

2021 ◽  
Vol 11 (3) ◽  
pp. 386
Author(s):  
Alice Giotta Lucifero ◽  
Sabino Luzzi
Keyword(s):  
Monoclonal Antibodies ◽  
Natural Killer ◽  
Immune Escape ◽  
Meta Analysis ◽  
Treatment Options ◽  
High Grade Glioma ◽  
High Grade ◽  
Future Challenges ◽  
Genetic Landscape ◽  
High Grade Gliomas

The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed.

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