Tyrosine kinase inhibitors (TKIs) have markedly improved the prognosis of chronic myeloid leukemia (CML). In Japan, in addition to the four established first-line TKIs, asciminib is now approved as an initial therapy, expanding the treatment options. Nevertheless, more than 10% of patients treated with asciminib over 48 weeks, and approximately 20-30% of those receiving other TKIs over five years, require second-line therapy because of resistance or intolerance. As first-line choices diversify, selecting the optimal second-line regimen has become increasingly complex. For intolerance, switching should be guided by the adverse-event profile with attention to potential cross-intolerance. For resistance, assessment of BCR::ABL1 mutations is essential, and second-line agents should be chosen according to the initial TKI and mutation sensitivity. This article summarizes the criteria and timing for switching to second-line therapy and key considerations for selecting and managing second-line TKIs, and briefly reviews the evidence for asciminib and ponatinib in second-line and later settings.

Diffuse intrinsic pontine glioma (DIPG) remains one of the most devastating pediatric central nervous system tumors, with a median survival of approximately 11 months despite decades of research. The identification of histone H3 K27M mutations marked a pivotal moment, leading to major advancements in understanding the molecular and epigenetic characteristics of these tumors. This discovery enabled molecular classification and provided a basis for the development of novel therapeutic strategies. In recent years, clinical trials have investigated molecular targeted agents and epigenetic modulators. Immunotherapeutic approaches, such as CAR-T cell therapy, have shown promising early results, whereas innovative drug delivery techniques, including convection-enhanced delivery and focused ultrasound, aim to overcome the challenges of the blood-brain barrier. Two major international registries, the International DIPG/DMG Registry (IDIPGR) and the European Society for Paediatric Oncology (SIOPE) DIPG/DMG Registry, play crucial roles in collecting comprehensive clinical data across multiple countries. The DIPG-2023 registry study was launched in Japan to collect prospective clinical, radiological, and molecular data systematically and to provide a high-quality external control cohort for future intervention trials. These collaborative efforts highlight a new era of DIPG/DMG research, offering cautious optimism for therapeutic progress in this historically refractory disease.

Recent advances in molecular profiling have transformed pediatric brain tumors management. The use of targeted agents is guided by actionable alterations including the BRAF V600E mutation, NTRK fusions, NF1 pathway activation, and H3 K27M mutation. Dabrafenib plus trametinib has shown superiority over chemotherapy in pediatric low-grade gliomas and activity against high-grade diseases. Larotrectinib and entrectinib provide tumor-agnostic options for NTRK-fusion-positive tumors with central nervous system penetration. Selumetinib offers clinical benefits in NF1-associated plexiform neurofibromas and shows promise for treating NF1-related low-grade gliomas. Tovorafenib, a type II RAF inhibitor active in BRAF-altered tumors (including BRAFKIAA1549 fusion), achieved robust responses, thereby leading to FDA approval. ONC201 (dordaviprone) has received accelerated approval for the treatment of H3 K27M-mutant diffuse midline gliomas, with Japanese trials and patient-initiated programs expanding access. Abemaciclib, a CDK4/6 inhibitor, is under phase II evaluation for pediatric high-grade glioma and diffuse midline glioma, including sites in Japan. Neurosurgeons play a pivotal role in securing high-quality biopsies, thus enabling comprehensive molecular diagnostics and facilitating enrollment in international trials. This review summarizes current targeted therapies and ongoing studies and outlines practical considerations for integrating precision oncology into pediatric neuro-oncology in Japan.

Precision medicine in pediatric brain tumors aims to transcend traditional organ-based therapy by customizing treatment according to each patient's tumor molecular and genomic profiles. By leveraging comprehensive genomic profiling and expert panel reviews, actionable mutations may direct the use of targeted therapies or immunotherapies. In July 2025, three oncology societies in Japan released a joint briefing report outlining 12 reform proposals to optimize the cancer gene panel testing system. Included among these are timing restrictions on testing, loosening the expert panel criteria. These reforms are designed to enhance test utility, improve patient access, and ultimately improve survival outcomes of pediatric patients with brain tumors.

Medulloblastoma is the most common malignant brain tumor in children. Advances in sequencing technologies have allowed the identification of four major molecular subgroups, each defined by distinct genetic alterations, biological features, and clinical courses. Recent studies have shown that medulloblastomas arise following disruptions in normal neurodevelopment, in which genetic abnormalities impair differentiation and lead to the persistence and malignant transformation of normally eliminated progenitor cells. Subgroup-specific cell of origin have since been identified. In Group 3 and Group 4, which were previously poorly understood, genetic alterations were shown to impair neuronal differentiation, revealing their pathogenesis. In SHH medulloblastomas, mutations in genes associated with RNA biology, including ELP1 and U1 snRNA, highlight alternative mechanisms of tumor development. Each subgroup can be further divided into subtypes that enable finer distinctions between clinical outcomes, support treatment intensification in high-risk patients, and de-escalation strategies in favorable groups. Although medulloblastoma is one of the best-studied pediatric brain tumors, its complexity continues to present challenges, and a deeper understanding of its molecular heterogeneity is essential to advance risk-adapted and targeted therapies.

Clinicians commonly encounter cases of childhood brain tumors that are difficult to diagnose pathologically in a clinical setting. In such situations, molecular genetic analysis is essential for the diagnosis and clinical management of pediatric brain tumors. This analysis supports pathological diagnosis, identifies potential targets for molecular therapy, and predicts patient prognosis. According to the updated World Health Organization classification of central nervous system (CNS) tumors, molecular genetic analysis is essential for diagnosing several brain tumors, including High-Grade Astrocytoma with Piloid Features (HGAP) and diffuse glioneuronal tumors with oligodendroglioma-like features and nuclear clusters (DGONC). Comprehensive Genomic Profiling (CGP) was first made available for molecular analysis in our country in 2019. Herein, we describe the clinical importance of detecting molecular alterations in pediatric brain tumors. This article also provides a comprehensive review of molecular classification using DNA methylation analysis, which has recently emerged as a diagnostic tool for CNS tumors.

Over the past decade, molecular biology techniques have identified numerous key genetic mutations in brain tumors. This has improved understanding of disease pathogenesis, and facilitated prognostic prediction, and the development of effective targeted molecular therapies. In 2021, the World Health Organization published the fifth edition of its classification of CNS tumors(WHO 5th), recommending a reporting format based on an integrated diagnosis combining histopathological and molecular genetic information. The classification of pediatric brain tumors has also advanced significantly, clarifying the disease backgrounds specific to childhood and differences in prevalence. The WHO 5th classification represents a significant advancement in selecting optimal treatments and recognizing patient groups that share similar clinical characteristics. However, some challenges remain for its implementation in routine clinical practice, including establishing access to molecular genetic testing. Herein, we reviewed the tumor types listed in the WHO 5th edition that predominantly affect children and adolescents, referring to recently published reports and concepts.

The cytokine interleukin 6 (IL-6) has redundant biological activities in regulating the proliferation, differentiation, and function of various cell types. IL-6 regulates inflammation, immune responses, and hematopoiesis, as well as homeostasis of the nervous, renal, hormonal, and bone systems. IL-6 is also involved in tumorigenesis, including myeloma cell growth. The janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is one of the key IL-6 signals both in normal and pathological conditions. In particular, STAT3 plays essential roles in mediating IL-6 signals, and its dysregulation can induce cancer and/or autoimmune diseases. In addition to biological and molecular mechanisms of IL-6-mediated signals, we have identified STAT3-interacting proteins, which regulate STAT3-mediated signals at various steps and mediate crosstalk between STAT3 and other intracellular signaling pathways. This review focuses on tyrosine kinase 2 (TYK2) and signal-transducing adapter protein-2 (STAP-2), followed by their potential as therapeutic targets in the development of novel treatments.

Prostaglandins (PGs) are oxygenated derivatives of arachidonic acid, synthesized through sequential catalysis involving cyclooxygenase (COX) and PG terminal synthases. Of the two COX enzymes, COX-2 is induced by inflammatory and pro-carcinogenic stimuli and it not only promotes inflammatory reactions but it also plays a role in the development of various tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs), which suppress inflammatory responses by inhibiting COX, have also been reported to suppress carcinogenesis in the colon. However, long-term use of NSAIDs for the prevention of cancer causes several side-effects; therefore, an alternative COX target is required. In this review, the role of PG synthases that are produced downstream of COX in carcinogenesis will be explained and novel drug targets to inhibit carcinogenesis will be discussed. Microsomal PGE synthase (mPGES)-1 and prostacyclin synthase (PGIS), which are coupled with COX-2 to generate PGE2 and PGI2, respectively, promote inflammation. In mPGES-1 knock-out mice, carcinogenesis in the colon, skin, and bladder were suppressed. As mPGES-1 deficiency does not result in abnormalities, mPGES-1 inhibitors are expected to be promising alternatives to NSAIDs for the suppression of cancer. On the other hand, it has been reported that PGIS suppresses colon cancer, suggesting that it has an opposite role to mPGES-1 in carcinogenesis in the colon. However, PGIS not affect carcinogenesis in the skin. These results suggest that PGIS has differential effects on carcinogenesis in different tissues.

While acute myeloid leukemia (AML) treatment has significantly advanced in recent years, many promising novel agents remain unapproved in Japan. This review focuses on menin inhibitors and covers IDH inhibitors, oral azacitidine, antibody-drug conjugates, bispecific antibodies, radioisotope therapies, and CAR-T cell therapies for AML. Menin inhibitors, which are particularly effective against AML with KMT2A rearrangements or NPM1 mutations, have shown promising results in clinical trials. These novel agents may expand treatment options and improve outcomes for AML patients.

Acute myeloid leukemia (AML) is common in elderly adults and is a genetically heterogeneous disease. Many factors such as adverse chromosomal and/or genetic abnormalities contribute to disease risk, along with defining features related to antecedent hematologic disorders and a history of exposure to radiation or cytotoxic agents in the case of secondary AML. The "7+3" regimen combining cytarabine and anthracycline, along with its reduced-dose variant, was once the only first-line treatment option for AML in Japan. However, treatment options have expanded in recent years to include azacitidine with or without venetoclax, as well as CPX-351 and quizartinib combination chemotherapy. Nevertheless, there are still many high-risk conditions with a low chance of cure even with these new drugs or allogeneic transplantation, and many other issues remain to be addressed. This article outlines the current best treatment options and future prospects for high-risk disease types.

Acute myeloid leukemia (AML) is associated with various genetic abnormalities in its development and progression, which also affect treatment response and prognosis. The advent of gene panel testing is expected to clarify the involvement of these genetic mutations, which will provide useful information for treatment decision-making and prediction of prognosis in clinical practice. Some therapies have already been developed for actionable mutations: quizartinib for FLT3-ITD mutations is available for newly diagnosed AML, and ivosidenib for IDH1 mutations is awaiting approval. Knowledge of baseline genetic characteristics also allows for diagnosis according to the ICC 2022 and 5th edition of the WHO Classification, as well as risk stratification by the ELN2022 risk classification for patients receiving intensive chemotherapy and ELN2024 risk classification for patients receiving reduced-intensity chemotherapy. CPX-351, a liposomal formulation of cytarabine and daunorubicin, has also shown efficacy in patients with MDS-related gene mutations. Decisions on allogeneic transplantation and accessibility of investigational drugs are also expected. Detailed diagnosis and prognosis prediction based on the profile of genetic abnormalities should enable precision medicine.

The Ser/Thr-specific kinase, polo-like kinase 1 (Plk1), is a crucial eukaryotic cell cycle regulatory protein. Overexpression of this kinase is observed in many cancer cells and where it can be related to their aggressiveness. Dysfunction of Plk1 in cancer cells causes mitotic arrest and subsequent apoptosis. Accordingly, Plk1 is considered as a target for the development of anti-cancer agents. Plk1 has two domains, a catalytic kinase domain (KD) and a polo-box domain (PBD). PBD intramolecularly interacts with its KD and regulates Plk1 activity and localization. Therefore, in addition to the KD, the PBD is considered to be a potential drug target. We have been developing peptidic low-nanomolar-affinity PBD-binding inhibitors. However, these peptides do not show significant cytotoxicity, due to their low cell membrane permeability. To obtain cell-active Plk1 inhibitors, I applied a bivalent approach designed to simultaneously engage both KD and PBD regions of Plk1 for enhancing the potency, selectivity and lipophilicity. Here, I developed bivalent Plk1 inhibitors, in which the PBD-binding peptides are conjugated with the known KD-binding inhibitors BI2536 or wortmannin using PEG linkers. These bivalent inhibitors exhibit up to 100-fold enhanced Plk1 affinity relative to the best monovalent PBD-binding ligands, higher selectivity for tested kinases compared to BI2536, and significant cytotoxicity against HeLa cells.

Venetoclax, a BCL-2 inhibitor, has transformed the treatment of elderly patients with acute myeloid leukemia (AML), but resistance remains a major clinical challenge. Approximately 30% of patients exhibit primary resistance, and many relapse despite achieving remission. Resistance mechanisms are multifaceted. AML stem cells rely on oxidative phosphorylation (OXPHOS) for survival, and venetoclax disrupts this energy metabolism by inducing mitochondrial dysfunction. However, resistant cells activate compensatory pathways such as fatty acid oxidation, amino acid metabolism, and the MEK-ERK signaling axis. Expression of anti-apoptotic proteins such as MCL-1 and BCL-XL also increases, circumventing BCL-2 inhibition. Furthermore, rare BCL2 mutations can directly impair drug binding. Sensitivity or resistance to venetoclax correlates strongly with specific molecular abnormalities. TP53 mutations predict poor response and survival, while RAS and FLT3 mutations confer moderate resistance. In contrast, IDH1/2 and NPM1 mutations are associated with high treatment sensitivity. Moving forward, personalized treatment strategies based on genetic profiles, along with combination therapies targeting metabolism or anti-apoptotic escape pathways, hold promise in overcoming resistance and improving outcomes in AML.

Treatment for acute myeloid leukemia (AML) in older adults has traditionally focused on adjusting treatment intensity and expanding the indications for the 3+7 regimen and allogeneic stem cell transplantation. However, recent advances, particularly the introduction of venetoclax plus azacitidine, have significantly improved outcomes. New agents such as quizartinib, CPX-351, venetoclax plus low-dose cytarabine, gemtuzumab ozogamicin, and ivosidenib have also emerged. Low-intensity treatment options, especially regimens incorporating molecularly targeted agents, offer potential survival benefits for older patients. Consequently, selecting and combining these therapies with conventional treatments has become a significant challenge in clinical practice. In treatment decision-making, it is essential to utilize a comprehensive geriatric assessment, which evaluates not only disease factors but also physical and cognitive function, nutritional status, and social background. It is particularly important to identify the molecular prognostic risk signature based on genetic mutation data and apply stratification models to carefully assess disease factors. This comprehensive approach ensures a tailored treatment strategy. This article provides an overview of AML in older adults and current treatment options in Japan, as well as discusses future drug developments and necessary approaches to make informed treatment decisions.

Acute lymphoblastic leukemia (ALL) is a hematologic neoplastic disease characterized by monoclonal proliferation of lymphoid progenitor cells that have ceased to differentiate, primarily in the bone marrow. Although outcomes of adult ALL remain poorer than those of pediatric ALL, they have dramatically improved in the past decade with better understanding of prognostic factors and the advent of novel therapies. In particular, BCR-ABL1 tyrosine kinase inhibitors and targeted agents against cell surface antigens (CD19, CD20, and CD22) have revolutionized the treatment of ALL. Clinical adoption of genomic screening and sensitive MRD assays should also inform appropriate treatment selection based on recurrence risk. This article outlines the current classification approach for ALL stratification and discusses future prospects for ALL treatment strategies.

RNA processing, including splicing, polyadenylation, and capping, plays a central role in post-transcriptional gene regulation. Recent genomic studies have revealed frequent mutations in RNA processing factors, particularly splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, in hematologic malignancies. These mutations result in aberrant splicing, contributing to tumorigenesis and disease progression. In this review, we summarize the molecular consequences of these mutations and their pathophysiological impact. We discuss shared downstream mechanisms such as R-loop accumulation, impaired transcriptional elongation, and the generation of immunogenic neoantigens derived from abnormal splicing. We also review recent advances in therapeutic strategies targeting splicing dysregulation, including small molecule splicing modulators and antisense oligonucleotides. These approaches offer the potential for selective targeting of cancer cells with aberrant RNA processing. Novel strategies to exploit splicing abnormalities for cancer treatment are emerging as understanding of RNA processing biology progresses and precision RNA-based therapeutics are developed.

Treatment strategies for chronic myeloid leukemia (CML) have changed significantly with the development of new tyrosine kinase inhibitors (TKIs). Due to its extreme rarity, pediatric CML has historically been managed based on evidence in adult patients. However, as the unique biological and clinical characteristics of pediatric CML have become increasingly apparent, the need for pediatric-specific treatment guidelines is now widely recognized. This review outlines the treatment of pediatric CML as of 2025, with a focus on clinical trial results from Japan and the latest consensus guidelines issued by the International Pediatric CML Working Group.

The advent of novel anti-multiple myeloma (MM) agents has led to dramatic improvement in patient survival. Nevertheless, the majority of patients with MM have bone lesions, and destructive bone lesions significantly reduce quality of life. Progressive destructive bone lesions develop when osteoblast differentiation from bone marrow stromal cells is inhibited and osteoclasts are activated in the bone marrow microenvironment in patients with MM. Recent research has also shed light on the functions and roles of osteocytes, which account for the majority of bone cells. Since MM cells mainly invade the red marrow, bone lesions are often found in the skull, spine, and ilium, which contain red marrow. Imaging is essential for the diagnosis of MM bone lesions, and whole-body low-dose CT, whole-body MRI, and FDG-PET/CT have demonstrated utility. Furthermore, recent advances in anti-MM drugs have improved the prognosis of MM significantly, highlighting the importance of treating and managing MM bone lesions. This review will explain the molecular pathology and management of MM bone lesions.

Follicular lymphoma (FL) has a wide spectrum of clinical manifestations, ranging from cases that require little or no treatment to cases that are refractory to any treatment. In recent years, advances in DNA and RNA profiling, as well as analysis of the tumor microenvironment, have progressively increased understanding of the underlying molecular pathogenesis of FL. Early progression of disease following immunochemotherapy includes histologic transformation to a more aggressive phenotype, which is associated with poor survival outcomes. Recent advances beyond conventional immunochemotherapy, including small molecular compounds, bispecific antibodies, and CAR-T cell therapy, have expanded therapeutic options and improved prognosis for FL patients. Research suggests that factors associated with treatment efficacy and prognosis may not be consistent across therapeutic agents. A deeper understanding of the molecular biology of FL should pave the way for optimized, individualized treatment sequences.