Advances in cancer research最新文献

Choroid Plexus Tumors (CPT) are rare (2-4% of all pediatric CNS tumors), predominantly early childhood brain neoplasms. Due to their rarity and the lack of prospective clinical trials, evidence-based treatment guidelines remain limited. This review provides a comprehensive summary of the current knowledge.nnCPTs span a spectrum from mature Choroid Plexus Papillomas (CPP) to malignant Choroid Plexus Carcinomas (CPC), with Atypical Choroid Plexus Papillomas (aCPP) in between. A significant proportion of CPCs are driven by either somatic or germline TP53 mutations (Li-Fraumeni syndrome); however, other molecular drivers of CPT tumorigenesis remain poorly understood. CPTs exhibit distinct DNA methylation profiles, allowing for classification into clinically relevant subgroups. These tumors also display a chromosomal instability phenotype, characterized by multiple copy number alterations. nnAdvances in molecular profiling have revealed that TP53-mutated CPCs have significantly worse outcomes. Both retrospective and limited prospective data have shown 5-year event-free survival rates of 0-25% for TP53-mutant CPCs versus 70-80% for TP53-wild-type cases. The extent of surgical resection remains another established prognostic factor, while data on the roles of radiation therapy (RT) and myeloablative chemotherapy with stem cell rescue are still evolving. Preliminary evidence suggests that TP53-mutant patients may be getting less benefit from RT, but greater benefit from myeloablative chemotherapy approach with avoidance of RT.nn The emerging insights into CPC biology and long-term outcomes can direct the design of future clinical trials. A new international prospective study led by the Pediatric Neuro-Oncology Consortium is in development, with the goal to stratify patients by molecular subtype to receive different therapy based on individual molecular profiles and patient age.

Some of the earliest anticancer drugs were alkylating agents, capable of covalently modifying critical cellular nucleophiles in proteins and nucleic acids. For many years, adapting another type of covalent reaction, Michael addition reactions, which involve the nucleophilic attack of a carbon nucleophile on an α,β-unsaturated carbonyl compound, have been explored in designing covalent inhibitors that selectively target cancer-related biomolecules. Numerous natural products demonstrate Michael addition properties, contributing to their bioactivity in antioxidant, anti-inflammatory and anticancer mechanisms. These compounds often interact with cellular nucleophiles, modulating redox signaling, enzyme catalysis, and stress response pathways. In the context of cancer treatments, several FDA-approved drugs, including proteostatic, EGFR and Ras inhibitors, employ Michael addition chemistry to achieve irreversible inhibition of cancer-related targets. The review emphasizes the challenges associated with these drugs, including off-target effects, toxicity, and drug resistance, but highlights some advances in medicinal chemistry that have improved selectivity and therapeutic efficacy. There are emerging covalent inhibitors that leverage Michael addition to enhance cancer treatment, underscoring the ongoing efforts to refine these compounds for clinical translation. Overall, this review examines the mechanisms, applications, and therapeutic potentials of Michael addition drugs in oncology, alongside relevant literature, and clinical findings.

The incidence and prevalence of CNS metastases of systemic cancer is only increasing worldwide, especially as our available systemic therapies have improved, resulting in longer survival and more time to allow for CNS progression. Fortunately, we have made substantial therapeutic advances in drug development in the last decade, with newer agents demonstrating significant penetration into the nervous system and notable efficacy. Treatments specifically targeted for certain mutations in the cancer pathway have been especially successful in aborting the onward trajectory and growth of cancer cells in the nervous system. In this review, we provide an overview and update of the drugs that have demonstrated benefit in achieving intracranial control (at times including leptomeningeal disease), many of which have already received or are pending regulatory approval. We also provide a brief look into the landscape of ongoing clinical research including challenges in the field.

Gliomas are a common form of intracranial malignancy in adults with poor overall survival and limited treatment strategies. There is significant genetic heterogeneity in this tumor group with a complex network of signaling that leads to rapid infiltrative growth as well as chemo- and radio-resistance. This chapter will delve into the complex processes and molecular alterations that feed into the formation and growth of these primary brain tumors.

Acute myeloid leukemia is a poor prognostic blood cancer with dismal survival rates. Major challenges in improving AML survivorship include its heterogeneity and ability to evade immunosurveillance. To facilitate subtyping and therapeutic decision-making, AML is risk stratified according to the genetic landscape, however, less is known about phenotypic differences and immune receptor signatures. Immune profiling of cancer cells is complex and a key determinant of tumor progression. In addition to influencing disease management, an understanding of cell surface immune receptor profiles provides key information on how different AML subgroups evade surveillance. Several robust studies aimed at characterizing the immune profile of cancer cells and gaining a deeper understanding of their function as cellular markers, have provided key information within the field. This review aims to compile information on the immune profiles of AML, understand their role in immune evasion, therapy responses, recurrence, and outcomes.

Five-year survival rates exceed 70 % for the 10-20 % children with central nervous system (CNS) tumors in high-income countries (HICs) but are less than 30 % for the 80 % children in lower-middle-income countries (LMICs). The management of CNS tumors is complex and multidisciplinary. It requires a minimum of infrastructure and interactive collaboration between the different actors involved in the care of these patients. This chapter addresses the main challenges associated with the management of pediatric CNS tumors in LMIC, and describes examples of successful development, particularly in the context of twinning programs between institutions in HIC and institutions in LMIC.

Advancements in imaging techniques and analyses have evolved in parallel with advancements in precision oncology and the transformative changes in glioma diagnosis and management. This chapter explores the pivotal roles of modern qualitative and quantitative imaging in characterizing gliomas, particularly low-grade gliomas (LGGs). Key topics include the integration of standard imaging biomarkers (e.g., T2-FLAIR mismatch sign) and advanced imaging modalities (e.g., 2-hydroxyglutarate [2HG] spectroscopy, diffusion and perfusion imaging) into routine clinical practice. These approaches enhance diagnostic accuracy, facilitate treatment planning, and enable longitudinal monitoring of disease progression. Practical challenges, such as the logistical demands to implement tumor segmentation, variability in imaging acquisition and interpretation, and integration of imaging into decision-making discussions between physicians and patients, are also discussed. Additionally, the role of radiomics and artificial intelligence (AI) in refining tumor characterization and predicting treatment response is explored. The inclusion of emerging therapeutic strategies, including IDH inhibitors and AI-driven imaging tools, underscores this chapter's emphasis on precision-driven innovations. By synthesizing current research and clinical practices, this chapter provides a comprehensive framework for leveraging advanced imaging in glioma care. Improved imaging methodologies not only allow for earlier detection of disease progression but also offer insight into treatment response and resistance mechanisms. As imaging continues to evolve, its integration with molecular and computational tools will further refine personalized approaches in glioma management, ultimately contributing to better patient outcomes.

In recent years, supramaximal resection has emerged as a critical surgical principle in the management of primary brain tumors, particularly gliomas. This approach goes beyond traditional gross total resection, typically limited to contrast-enhancing tumor margins on T1-weighted MRI in IDH-wildtype glioblastoma and the T2/FLAIR region in IDH-mutant glioma, while aiming to preserve neurological function. Growing evidence suggests that this more extensive resection, if performed safely, may confer survival benefits without compromising quality of life. In this chapter, we review the historical development, conceptual underpinnings, and clinical data supporting supramaximal resection. We also describe modern techniques-including intraoperative mapping and functional preservation strategies-that enable safe and effective implementation of this approach.

Atypical teratoid rhabdoid tumors (ATRT) are rare, often lethal embryonal tumors of the central nervous system (CNS) that primarily affect very young children. Intensive multimodal approaches have resulted in improvements in survival albeit with significant associated toxicity. Recent molecular studies have led to the discovery of SMARCB1 inactivation and resultant BAF47/INI1 loss as the near-universal key genetic event that leads to widespread epigenetic dysregulation. Rarely, SMARCA4 encoding BRG1 is impacted. SMARCB1 and SMARCA4 are core subunits of the SWI/SNF chromatin remodeling complex, which is a fundamental epigenetic regulator of gene transcription. Up to a third of patients diagnosed with ATRT have Rhabdoid Tumor Predisposition Syndrome (RTPS) characterized by germline SMARCB1 (or SMARCA4) alterations. Patients with RTPS are at increased risk of developing synchronous or metachronous rhabdoid tumors outside the CNS. At least three molecular subgroups of ATRT (ATRT-TYR, ATRT-SHH, ATRT-MYC) have been identified through large-scale DNA methylation and transcriptomic studies, with each subgroup having distinct transcriptional, epigenomic and clinicopathologic features. In this book chapter, we will summarize key epidemiological and clinical features of ATRT, review current conventional multimodal regimens, summarize key findings from conducted prospective trials and recently concluded (2020 to present) meta-analyses, as well as discuss emerging targeted treatment approaches that exploit potential therapeutic vulnerabilities of this epigenetically influenced tumor.