Publications by authors named "Koushiro Ohtsubo"
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.
Background: While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.
Methods: We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients.
Article Synopsis
- A glioblastoma patient with high tumor mutation burden and mismatch repair deficiency showed a strong positive response to pembrolizumab, an immune checkpoint inhibitor, despite previous treatment with temozolomide which usually leads to resistance.
- Despite rapid disease progression, indicated by high Ki67 levels, the patient's condition improved significantly with pembrolizumab.
- This case highlights the potential of precision oncology in treating GBM and emphasizes the need for thorough genomic profiling to inform treatment strategies.
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.
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- - Comprehensive genomic profiling using circulating tumor DNA (ctDNA) has potential in capturing tumor diversity and improving therapy choices, but it's not fully utilized in clinical settings, especially for advanced solid tumors.
- - The GOZILA study found that ctDNA profiling led to a 24% match rate for targeted therapies, significantly improving patient outcomes, with those receiving matched treatments experiencing better overall survival rates compared to those who were unmatched.
- - Key ctDNA characteristics, like biomarker clonality and plasma copy number, serve as indicators of treatment effectiveness, suggesting that ctDNA can enhance precision in oncology and should be more widely used to optimize patient survival in advanced solid tumors.
Article Synopsis
- Immune checkpoint inhibitors (ICIs) can improve cancer treatment but may cause serious side effects, including myocarditis.
- The report discusses two cases of myocarditis that did not respond to corticosteroids, indicating a severe reaction to ICIs.
- Additional treatments like intravenous immunoglobulin and tacrolimus were effective in resolving the myocarditis, suggesting that early use of alternative immunosuppressive therapies should be considered when corticosteroids fail.
Article Synopsis
- The study focuses on using circulating tumor DNA (ctDNA) analysis to identify homologous recombination deficiency (HRD) and BRCA1/2 and ATM mutations in patients with advanced pancreatic cancer (APC).
- Out of 702 APC patients analyzed, 4.8% had BRCA1/2 mutations and 4.4% had ATM mutations, with those having BRCA mutations showing significantly better response rates to platinum-based chemotherapy compared to those without.
- ctDNA profiling is suggested as a valuable, non-invasive method for assessing mutation status and selecting appropriate treatments in advanced pancreatic cancer, offering a practical approach to HRD screening.
Article Synopsis
- - The case involves a 59-year-old man with poorly differentiated lung carcinoma and a rare K601E mutation who showed limited response to the targeted drugs dabrafenib and trametinib after failing chemotherapy and immunotherapy.
- - Although the patient had a significant initial response to the treatment, the tumor's regression lasted only 52 days before progressing, indicating a rapid development of resistance.
- - A follow-up liquid biopsy revealed additional genetic changes associated with resistance, highlighting the complexities of treating K601E-mutant lung carcinoma and the need for improved molecular diagnostics and personalized therapy strategies.
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.
View Article and Find Full Text PDFIn 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.
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- Nivolumab is an effective treatment for advanced gastric cancer, but identifying reliable biomarkers like TP53 mutations could help predict patient response.
- A study involving 913 patients found that those with TP53 wild type (wt) had a higher response rate to nivolumab (24.6%) compared to TP53 mutant patients (14.8%).
- For TP53 mutants, those with the frameshift type had a slightly better response rate and progression-free survival compared to other mutation types, suggesting some variants may still benefit from treatment.
Article Synopsis
- Circulating tumor DNA (ctDNA) genotyping using next-generation sequencing (NGS) may aid in targeted therapy for metastatic colorectal cancer (mCRC), but its effectiveness in assessing the V600E mutation and guiding therapies needs further validation.
- A study compared NGS-based ctDNA testing to traditional tissue testing in 212 mCRC patients, showing high concordance, sensitivity, and specificity rates for detecting V600E mutations, particularly when ctDNA levels were ≥1.0%.
- The results indicate that ctDNA genotyping is a reliable method for identifying V600E mutations and can inform treatment decisions for anti-EGFR and BRAF therapies, highlighting its potential role in improving patient outcomes.
Article Synopsis
- The SCRUM-Japan GI-SCREEN program uses next-generation sequencing (NGS) to profile genomic data for patients with advanced gastrointestinal cancers, aiming to facilitate enrollment in targeted clinical trials and enhance real-world data collection.
- The study involved 5,743 patients, revealing that those enrolled in matched trials after starting their first-line treatment experienced longer overall survival compared to those who enrolled before treatment, indicating possible immortal time bias.
- Results showed significant improvements in survival rates for colorectal cancer patients receiving targeted therapies based on genomic alterations, highlighting the importance of genetic profiling in clinical trial participation.
Article Synopsis
- Liquid biopsy is a promising method for tumor genotyping in pancreatic ductal adenocarcinoma (PDAC), which often sheds low levels of circulating-tumor DNA (ctDNA).
- A study of 512 PDAC patients found that 57% had KRAS mutations, with higher detection rates in those with liver metastasis (78%) compared to other sites.
- The research suggests that ctDNA analysis can be particularly useful for assessing PDAC cases with liver metastases due to higher mutation prevalence and variant allele frequency.
Article Synopsis
- Out of 885 patients analyzed, 74 with high amplification of CN who received trastuzumab-combined chemotherapy were evaluated, leading to findings that CN did not significantly affect tumor response.
- It concluded that while high CN served as a positive predictor for progression-free survival, coexisting gene amplifications in the HER2 pathway indicated poorer outcomes, suggesting a need for alternative treatments for patients with high variant allele frequencies (VAFs).
Article Synopsis
- The study investigates the role of NOTCH gene alterations in metastatic colorectal cancer (CRC) and aims to understand their clinical significance in a large patient cohort.
- Researchers analyzed tumor tissues from 1154 CRC patients, finding notable frequencies of NOTCH1, NOTCH2, and NOTCH3 variants, predominantly missense mutations of uncertain impact.
- NOTCH3 variants were linked to significantly better overall survival rates, suggesting it as a potential favorable prognostic marker, while traditional driver mutations were not identified in the NOTCH genes.
Purpose: Low concordance between plasma-based and tissue-based tests for determining the mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology.
Materials And Methods: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315).
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.
Background/aim: Primary mediastinal non-seminomatous germ cell tumors (PMNSGCTs) are occasionally complicated by a hematologic malignancy, as with somatic-type malignant tumors called germ cell tumors with somatic-type malignancy (GCTSTM) and are known to have a poor prognosis.
Patients And Methods: Data obtained between September 1997 and February 2020 for patients with mediastinal germ cell tumor at our institution were retrospectively analyzed. Key outcome measures included survival rates and the clinical features of non-seminoma cases.
Article Synopsis
- TRK inhibitors are effective for patients with NTRK gene fusions, but resistance can develop, particularly with mutations like NTRK1-G595R.
- The study found that M3B tumor cells, which had the NTRK1-G595R mutation, were resistant to repotrectinib due to ERK reactivation linked to EGFR activation.
- Combining repotrectinib with an EGFR inhibitor and a MEK inhibitor showed promise in overcoming this resistance both in lab tests and a brain metastasis model.
Purpose: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard.
Patients And Methods: The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing-based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction-based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study.
Background: Gemcitabine plus nab-paclitaxel (GnP) therapy is used for unresectable pancreatic ductal adenocarcinoma, but may cause interstitial lung disease (ILD) as a serious side effect. However, the risk factors for ILD in patients receiving GnP therapy are not well established. Here, we retrospectively investigated the incidence of GnP-induced ILD in pancreatic ductal adenocarcinoma patients, and the risk factors.
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- Circulating tumor DNA (ctDNA) is being studied for its ability to detect amplification and resistance mechanisms in advanced gastric cancer, which is often linked with poor outcomes.
- In a nationwide screening, ctDNA identified amplification in 7.7% of patients compared to just 2.6%-4.4% through tissue analysis, revealing cases that might have been missed by standard tests.
- Findings suggest that patients with ctDNA-detected amplification can respond to FGFR inhibitors, indicating that ctDNA sequencing could be a valuable tool for improving treatment strategies in this patient population.
The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis.
View Article and Find Full Text PDFBackground: Potential disparities between cancer patients with and without disabilities remained to be validate in Japan.
Methods: We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015.