Craniopharyngiomas are among the most challenging intracranial tumors for neurosurgeons. Their management is complicated due to growth patterns such as infiltration into the pituitary stalk, chiasma, and hypothalamus. Therefore, patients may present with various conditions such as endocrine disorders, visual disturbances, or hypothalamic dysfunction in the first medical examination. Moreover, surgical management is challenging because of the high risk of recurrence. Two well-known histological subtypes include adamantinomatous and papillary craniopharyngiomas, and recent advances in genetic analysis have provided significant findings about these subtypes. The adamantinomatous subtype can be distinguished by mutations in CTNNB1, whereas the V600E mutation of the BRAF gene characterizes the papillary subtype. This review describes the etiology, genetic features, and clinical presentations of craniopharyngiomas.

As the molecular pathology of pituitary cell development and the process of tumorigenesis in this organ continues to advance, it is recommended that pituitary neuroendocrine tumors(PitNETs)be classified based on three lineage-specific transcription factors(PIT1, Tpit, and SF1). In the hyperaging society of Japan, the number of cases traditionally classified as nonfunctioning PitNETs is increasing, and it is possible that some of these tumors may be associated with tumors that are known to exhibit aggressive behavior. The molecular pathological background of PitNET development is highly variable, and its pathogenesis in many cases remains unclear. As genomic analysis of PitNETs progresses, it is becoming increasingly clear that abnormalities in germline and somatic cell genomes contribute to our understanding of their etiology but do not explain most of them. Epigenetic modifications, such as deoxyribonucleic acid methylation and histone modifications(methylation and acetylation), are thought to be intricately related to tumorigenesis.

Pituitary tumors or tumors of the sella turcica include pituitary neuroendocrine tumors, Rathke's cleft cysts, craniopharyngiomas, tuberculum sellae, planum sphenoidale meningiomas, germ cell tumors, and hypophysitis. In addition, some rare tumors, such as pituicytomas, granular cell tumors, spindle cell oncocytomas, and chordomas or chondrosarcomas, arise from the parasellar regions. The treatment strategy is completely different for each lesion; therefore, accurate diagnosis is essential.

Acute myeloid leukemia (AML) is one of the most common hematologic malignancies derived from self-renewing and highly propagating leukemic stem cells (LSCs). We have previously identified T-cell immunoglobulin mucin-3 (TIM-3) as an AML LSC-specific surface molecule by comparing the gene expression profiles of LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminates LSCs from HSCs within the CD34+CD38- stem cell fraction. Furthermore, AML cells secrete galectin-9 (Gal-9, a TIM-3 ligand) in an autocrine manner, resulting in constitutive TIM-3 signaling, which maintains LSC self-renewal capacity through β-catenin accumulation. In this study, we investigated the LSC-specific mechanisms of TIM-3 signaling. We found that TIM-3 signaling drove the canonical Wnt pathway, which was independent of Wnt ligands, to maintain cancer stemness in LSCs. Gal-9 ligation activated the cytoplasmic Src homology 2 (SH2) binding domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase that is highly expressed in LSCs. HCK phosphorylated p120-catenin to promote the formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis was employed principally in immature LSCs compared to TIM-3-expressing exhausted T-cells.

Development of tumor agnostic treatment based on specific biomarkers has been quite active in recent years. In Japan, pembrolizumab for microsatellite instability high(MSI-high), entrectinib and larotrectinib for NTRK fusion gene and pembrolizumab for tumor mutation burden high(TMB-high)have been approved. In addition to these approvals, dostarlimab for mismatch repair deficiency(dMMR), dabrafenib and trametinib for BRAF V600E, and selpercatinib for RET fusion gene have been approved in the United States as tumor agnostic biomarkers and their treatment. Development of tumor agnostic treatment requires efficient implementation of clinical trials to target rare subtypes. Various efforts are underway to conduct such clinical trials, including the use of appropriate registries and the implementation of decentralized clinical trial. Another approach is to evaluate a number of combination regimens in parallel, as in the trials of KRAS G12C inhibitor, with the aim of improvement of efficacy or overcoming assumed resistant.

The clinical application of chimeric antigen receptor T-cell therapy (CAR-T therapy) has significantly altered the therapeutic strategy for B-cell tumors and is now being used to treat myeloid and solid tumors. Nonetheless, the efficacy of CAR-T cell therapy for myeloid and solid tumors has been limited, and several studies are being conducted to understand and overcome the underlying mechanisms. Recent research achievements have revealed that the properties of CAR-T cells, particularly their memory function, which can be continuously amplified in the body without exhaustion after administration, are closely related to CAR-T cell clinical efficacy. Furthermore, because the characteristics of CAR-T cells are greatly influenced by the quality of peripheral blood mononuclear cells, the raw material of CAR-T cells, and the T-cell used during the manufacturing process, attention has been drawn to the development of high-quality CAR-T cell manufacturing methods and combination therapies that maintain CAR-T cell memory function and suppress immune exhaustion. This article provides an overview of the current state of CAR-T cell development and clinical application to cancer, particularly emphasizing the development of manufacturing processes and efforts to improve CAR-T cell efficacy in combination therapy with molecular-targeting drugs.

Multiple myeloma (MM) is characterized by genomic instability, which causes multiple genetic and chromosomal alterations and leads to disease progression and therapeutic resistance. Overlapping mechanisms, including defective genome repair machinery such as the loss of TP53 activity, as well as chromosomal segregation error represented by the abnormality of mitotic checkpoint kinases such as BUB1, cell cycle dysregulation, and tumor environment, cause structural and numerical chromosomal abnormalities. Cytogenetic abnormalities are important prognostic factors, and they are also linked to the use of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and the BCL2 inhibitor venetoclax. We developed new diagnostic modalities for chromosomal analysis to improve the sensitivity and convenience of chromosomal diagnosis. The immunophenotyped-suspension-multiplex (ISM)-fluorescence in situ hybridization (FISH) can use imaging flow to examine three IGH-related chromosomal translocations at the same time. We also created a new FISH method called amplified FISH (amFISH) to detect microdeletion involving narrow chromosomal regions (approximately<100 kb), such as the microdeletions of 1p32 (CDKN2C) or of 14q32 (TRAF3), by using a fluorescent antibody to amplify the signals of small probes. Even in the era of clinical sequencing, these convenient modalities may hasten the cytogenetics-oriented therapeutic approach for MM.

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the Philadelphia (Ph) chromosome, which is formed by a t (9;22)(q34;q11) translocation. The aberrant activation of the ABL1 tyrosine kinase is caused by the BCR::ABL1 fusion gene on the Ph chromosome, leading to significant leukemic cell proliferation. CML is typically diagnosed in the chronic phase with few clinical symptoms and progresses to a blast crisis within years. CML acquires additional genetic abnormalities on top of BCR::ABL1 fusion during clonal evolution. ASXL1 mutations are found in the chronic phase, with a frequency of approximately 20%, whereas other mutations are rare. Most blast crisis cases have additional genetic abnormalities, including frequent ASXL1 and RUNX1 mutations. Recent studies have revealed that a subset of these genetic mutations affects the sensitivity of tyrosine kinase inhibitors to leukemic cells as well as patient prognosis, indicating applications for patient stratification and individualized treatment.

Acute myeloid leukemia (AML) is a heterogeneous disease, and the accumulation of various chromosomal and genetic abnormalities is considerably involved in its pathogenesis and prognosis. Recently, the disease classification based on molecular abnormalities and novel molecular-targeting therapies has been developed. In Europe and the United States, several agents have been approved for AML and incorporated into guidelines as the standard treatment depending on comorbid genetic mutations combined with conventional chemotherapy or monotherapy since 2017. The combination therapy of FLT3 inhibitor midostaurin and intensive chemotherapy has improved the prognosis of patients with FLT3-ITD-positive AML, which has been considered a poor prognosis for a long period. In addition to small-molecule compounds, various novel therapies for AML are under clinical investigation, including antibody therapies targeting CD47 and TIM-3, bispecific antibodies, and CAR-T-cell therapies. Considering the treatment strategies with diverse therapeutic modalities, the pathogenesis and clonal selection process of refractory AML, including the surrounding environment of residual leukemia cells, should be clarified. The combination of new therapies and chemotherapies is highly expected to improve the prognosis of patients with AML in the near future.

Rearranged during transfection(RET)is one of the driver genes in thyroid cancer, which encodes a receptor tyrosine kinase. There are 2 types of genomic alterations of RET seen in thyroid cancer. Fusions of the RET tyrosine kinase domain region with partner genes are observed in papillary thyroid cancer, whereas RET mutations are observed in hereditary and sporadic medullary thyroid cancers. These alterations constantly activate downstream signaling pathways, leading to oncogenesis. Recently, selective RET inhibitors have been developed and approved overseas and in Japan for the treatment of RET-altered thyroid and lung cancers, and it will be important to detect genomic alterations in the RET gene using methods including companion diagnostics in the future.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal and predominantly inherited disorder. A 43 year-old woman was admitted to our hospital for right spontaneous pneumothorax and the thoracoscopic pulumonary wedge resection was performed. A chest computed tomography (CT) scan before surgery showed multiple bilatetal thin walled pulmonary cysts predominant to the lower mediastinum side of the lung field. Since her brother had history of pneumothorax with BHD syndrome. Diagnosed by deoxyribonucleic acid (DNA) sequence analysis of his BHD gene, she was diagnosed as BHD syndrome.

On March 28th, 2022, asciminib hydrochloride (Scemblix® Tablets 20 ‍mg/40 ‍mg), the world's first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40 ‍mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200 ‍mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.

Olaparib, a PARP inhibitor, was approved in 2018 for BRCA1/2 gene mutation and HER2-negative inoperable or recurrent breast cancer with previous chemotherapy. Olaparib is an important drug with minor adverse events compared to chemotherapeutic drugs. In addition, it is expected to exert a high therapeutic effect on breast cancer with BRCA mutations due to its characteristics. We report a case of BRCA2-mutated breast cancer in a patient in whom olaparib was initiated. The patient complained of strong nausea; however, the treatment could be continued by reducing the dose of olaparib to 400 mg and using multiple drugs such as antiemetics and anxiolytics in advance.

The World Health Organization Classification of the Tumours, 5th Edition Central Nervous System Tumours(WHO CNS5), has undergone ground-breaking changes in collaboration with cIMPACT-NOW(the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). Tumors are now classified and named according to the tumor type alone, and the tumor grading is defined within each tumor type. CNS WHO grading is based on either histological or molecular criteria. WHO CNS5 promotes the molecular finding-based classification system and diagnostic criteria, including DNA methylation-based molecular classification. In particular, the classification and CNS WHO grades have extensively been restructured for gliomas. Adult gliomas are now classified into three tumor types according to the IDH and 1p/19q status. Diffuse gliomas with morphological features of glioblastoma and IDH mutation are no longer classified as glioblastoma, IDH-mutant, but as astrocytoma, IDH-mutant, CNS WHO grade 4. Diffuse gliomas without IDH mutation but with molecular features of glioblastoma are classified as glioblastoma, IDH-wildtype. Pediatric-type gliomas are classified separately from adult-type gliomas. Although the shift toward the molecular classification is inevitable, the current WHO classification system has limitations. WHO CNS5 should be regarded as an intermediate stage toward further refined, better structured classification systems in the future.

A tyrosine kinase inhibitor (TKI) was used to treat the patient, a 35-year-old woman who was diagnosed with chronic myeloid leukemia at the age of 22 years. Since a four-year deep molecular response (DMR) was obtained, spontaneous pregnancy was planned under TKI withdrawal. Even though her disease had advanced to MR2.0 at the time of pregnancy confirmation, 2 months from TKI cessation, interferon α therapy was initiated in light of the patient's history. Later, the patient reached MR3.0, gave birth to a healthy baby, and maintained MR3.0-4.0. TKI was resumed after about 6 months of breastfeeding. Treatment-free remission (TFR) is required for natural conception despite the teratogenicity and miscarriage risks associated with BCR::ABL1 TKIs. When planning a pregnancy, it is also necessary to take the patients' backgrounds, disease states, and medical history into account.

An 85-year-old woman was admitted to our hospital because of leukocytosis. Abnormal lymphocytic leukocytosis, including few plasmacytes, anemia, and thrombocytopenia, were observed. A diagnosis of primary macroglobulinemia was made based on immunoglobulin M-kappa monoclonal gammopathy, FACS of abnormal lymphocytes, and confirmed MYD88 L265P somatic mutation. Abnormal lymphocytes were markedly increased temporarily after the administration of tirabrutinib. However, the patient continued treatment after abdominal computed tomography showed that splenomegaly and lymphadenopathy had improved, and the patient recovered from leukocytosis. There are no reports that leukocytosis is a side effect of tirabrutinib; therefore, this case can be considered unique.