Analysis of Methylation of Tumor-suppressive miRNAs and Mutations in Pancreatic Juice.

Background/aim: We previously reported the usefulness of detecting aberrant methylation in tumor suppressive microRNAs (miRNAs) in bile and plasma to discriminate pancreaticobiliary cancers from benign pancreaticobiliary diseases. This study analyzed the methylation of miRNAs in pancreatic juice to identify those specific to pancreatic cancer (PC).

Patients And Methods: Pancreatic juice was collected from 20 patients with PC, including eight with intraductal papillary mucinous carcinoma (IPMC), two with low grade-pancreatic intraepithelial neoplasia (LG-PanIN), 32 with LG-intraductal papillary mucinous neoplasm (IPMN), and seven with benign pancreatic lesions.

Comprehensive genomic profiling for advanced hepatocellular carcinoma in clinical practice.

Aim: Although several therapeutic agents show efficacy in advanced hepatocellular carcinoma (HCC), biomarkers such as comprehensive genomic profiling (CGP) for the selection of second-line treatments after immunotherapy have not been established. We evaluated the value of CGP for the treatment decision in patients with HCC.

Methods: We retrospectively studied 52 patients with advanced HCC who received CGP tests at three tertiary hospitals between February 2022 and November 2023.

Pembrolizumab efficacy in a tumor mutation burden-high glioblastoma patient: A case study and implications for precision oncology.

A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management.

Comprehensive antitumor immune response boosted by dual inhibition of SUMOylation and MEK in MYC-expressing KRAS-mutant cancers.

Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition.

A Supramolecular Biosensor for Rapid and High-Throughput Quantification of a Disease-Associated Niacin Metabolite.

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide -methyltransferase (NNMT).

Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage.

Background: KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation.

Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations.

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations.

Case report: Navigating treatment pathways for cardiac intimal sarcoma with N666K mutation.

In the realm of rare cardiac tumors, intimal sarcoma presents a formidable challenge, often requiring innovative treatment approaches. This case report presents a unique instance of primary intimal sarcoma in the left atrium, underscoring the critical role of genomic profiling in guiding treatment. Initial genomic testing unveiled a somatic, active mutation in ( N666K), accompanied by and amplifications.

Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAF-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.

Background: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAF-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAF-mutant mCRC.

Materials And Methods: The EAP was an open-label, single-arm study including Japanese patients with BRAF-mutant mCRC whose disease progressed after 1 to 2 prior regimens.

Successful second-line treatment with cabozantinib for hepatocellular carcinoma harboring cytoplasmic mesenchymal-epithelial transition factor amplification.

A 72-year-old man with metastatic hepatocellular carcinoma previously received first-line systemic therapy with atezolizumab plus bevacizumab. His disease was judged to be progressing 5 months after treatment initiation. Comprehensive genomic profiling revealed cytoplasmic mesenchymal-epithelial transition factor amplification.

Ultrafast single-molecule imaging reveals focal adhesion nano-architecture and molecular dynamics.

Using our newly developed ultrafast camera described in the companion paper, we reduced the data acquisition periods required for photoactivation/photoconversion localization microscopy (PALM, using mEos3.2) and direct stochastic reconstruction microscopy (dSTORM, using HMSiR) by a factor of ≈30 compared with standard methods, for much greater view-fields, with localization precisions of 29 and 19 nm, respectively, thus opening up previously inaccessible spatiotemporal scales to cell biology research. Simultaneous two-color PALM-dSTORM and PALM-ultrafast (10 kHz) single fluorescent-molecule imaging-tracking has been realized.

Development of ultrafast camera-based single fluorescent-molecule imaging for cell biology.

The spatial resolution of fluorescence microscopy has recently been greatly enhanced. However, improvements in temporal resolution have been limited, despite their importance for examining living cells. Here, we developed an ultrafast camera system that enables the highest time resolutions in single fluorescent-molecule imaging to date, which were photon-limited by fluorophore photophysics: 33 and 100 µs with single-molecule localization precisions of 34 and 20 nm, respectively, for Cy3, the optimal fluorophore we identified.

MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements.

Background: Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs.

Methylation of Tumor Suppressive miRNAs in Plasma from Patients With Pancreaticobiliary Diseases.

Background/aim: We previously reported the usefulness of aberrant methylation of tumor suppressive miRNAs in bile to discriminate pancreaticobiliary cancers (PBCs) from benign pancreaticobiliary diseases (BD). Here we performed a methylation analysis of plasma miRNAs to identify miRNAs specific for PBCs.

Patients And Methods: Plasma was collected from 80 patients with pancreatic cancer (PC); 18 with biliary tract cancer (BTC) and 28 with BD.

STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis.

Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition.

A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer.

Objectives: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials.

Severe Skin Toxicity Caused by Sequential Anti-PD-1 Antibody and Alectinib in Non-small-cell Lung Cancer: A Report of Two Cases and a Literature Review.

Immune checkpoint inhibitors (ICIs) have demonstrated marked efficacy in some cancer patients, but they may cause various severe immune-related adverse events. Alectinib is a second-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) approved for ALK-rearranged non-small-cell lung cancer (NSCLC). Alectinib is said to be safer than other TKIs.

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab.

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage.

Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy.