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BackgroundMicrosatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers.MethodsWe examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS).ResultsOf 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%, P = 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy.ConclusionsLoss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.

Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.

Background Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC. Methods A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen. Results Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD. Conclusions Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole‐transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin‐18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD‐L1). Concurrently, WTS was employed as part of the analyses in MONSTAR‐SCREEN‐2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD‐L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC‐positive patients treated with anti‐HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression‐free survival ( ERBB2 ‐high vs. ‐low: median 9.0 vs. 5.6 months, log‐rank p  = 0.046). IHC‐based molecular profiling revealed significantly high expression of CLDN18 in RTK‐negative patients, with 78.4% positive for either CLDN18 or PD‐L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC‐negative but WTS‐positive status may benefit from specific biomarker‐targeted therapies.

Background: The effect of claudin 18.2 (CLDN18.2) expression on the outcomes of a first-line immune checkpoint inhibitor (ICI)-containing chemotherapy (ICI-chemo) in patients with human epidermal growth factor receptor 2 (HER2)-negative, proficient mismatch repair (pMMR), and programmed death-ligand 1 (PD-L1)-expressing metastatic or recurrent gastric or gastroesophageal junction cancers (mGC/GEJC) remains unclear. Objectives: We assessed the effects of CLDN18.2 expression on the outcomes of first-line ICI-containing chemotherapy in patients with HER2-negative, pMMR, and PD-L1-expressing mGC/GEJC. Patients and methods: Medical records of patients with HER2-negative, pMMR, and PD-L1 combined positive score (CPS) ⩾1 unresectable/metastatic or recurrent GC/GEJC who received first-line ICI-chemo or chemotherapy alone (chemo-alone) between January 2016 and August 2024 were retrospectively analyzed. The impact of CLDN18.2 status on the clinical outcomes was evaluated in patients receiving ICI-chemo and chemo-alone to assess the prognostic significance of CLDN18.2 in the absence of ICI. Results: A total of 150 patients were treated with ICI-chemo, whereas 313 patients received chemo-alone. CLDN18.2 positivity (⩾2+ in ⩾75% tumor cells) was identified in 42 patients (28.0%) in the ICI-chemo group and 94 patients (30.0%) in the chemo-alone group. There were no significant differences in the objective response rate (ORR; 68.3% vs 70.3%, p = 0.842), disease control rate (DCR; 92.7% vs 94.1%, p = 0.718), progression-free survival (PFS; hazard ratio (HR) 1.01, p = 0.955), or overall survival (OS; HR 1.12, p = 0.615) between CLDN18.2-positive and CLDN18.2-negative patients in the ICI-chemo group. Similarly, the DCR, ORR, PFS, and OS outcomes were comparable between the CLDN18.2-positive and -negative patients in the chemo-alone group. Conclusion: CLDN18.2 expression exerted no impact on outcomes of first-line ICI-chemo and chemo-alone in patients with HER2-negative, pMMR, and PD-L1 CPS ⩾1 mGC/GEJC.

Background Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). Methods This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. Discussion If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. Trial registration This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

IntroductionIn locally recurrent rectal cancer (LRRC), surgery is a standard treatment for resectable disease. However, short-term and long-term outcomes are unsatisfactory due to the invasive nature of surgical procedures and the high proportion of local recurrence. Consequently, the identification of reliable prognostic and predictive biomarkers to guide treatment decisions may improve outcomes. The presence of circulating tumour DNA (ctDNA) in plasma after surgery may signify the presence of minimal residual disease (MRD) in various cancers. Therefore, we have launched a multi-institutional prospective observational study of ctDNA for MRD detection in conjunction with JCOG1801, a randomised, controlled phase III trial evaluating the efficacy of preoperative chemoradiotherapy (pre-CRT) compared with up-front surgery for LRRC (jRCTs031190076, NCT04288999).Methods and analysisJCOG1801A1 is the first correlative study that assesses ctDNA in LRRC patients enrolled in JCOG1801. Patients randomised to up-front surgery will provide whole blood samples at three time points (prior to surgery, after surgery and after postoperative chemotherapy); those to pre-CRT will provide at five time points (prior to pre-CRT, after pre-CRT, prior to surgery, after surgery and after postoperative chemotherapy). Cell-free DNA will be extracted from plasma and analysed by Guardant Reveal, a tumour tissue–agnostic assay that assesses both genomic alterations and methylation patterns to determine the presence or absence of ctDNA. We will compare the prognosis and treatment response of patients according to their ctDNA status after surgery and at other time points.Ethics and disseminationThe study protocol received approval from the Institutional Review Board of National Cancer Center Hospital East on behalf of the participating institutions in February 2023. The study is conducted in accordance with the precepts established in the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects. Written informed consent will be obtained from all eligible patients prior to registration.

Primary malignant melanoma of the esophagus (PMME) has been reported to be a rare and highly malignant disease, and to date a standard treatment strategy has not been established due to limited evidence. The aim of the present study was to investigate the clinicopathological characteristics of this extremely rare disease. A total of 6 out of 2,093 patients with PMME treated in our institution between 1995 and 2016 were retrospectively analyzed and their clinicopathological parameters including treatment course and long-term survival were investigated. The major clinicopathological characteristics of patients were that they were >70 years of age, male sex, dysphagia at first diagnosis, and macroscopic black protruding tumors located in the lower third of the thoracic esophagus. Four of the five patients receiving pretherapeutic endoscopic biopsy were correctly diagnosed with PMME, and two patients received preoperative treatment with ineffective histopathological responses. There were two unresectable cases, one was treated with an immune-checkpoint inhibitor and the other received palliative care. Three of the four patients receiving curative surgery developed hematogenous recurrence within two years of surgery and only one patient with pT1aN0M0 achieved long-term survival. The median overall survival of all six patients was 19.6 (6.4-40.5) months. Patients with stage I disease exhibited significantly more favorable prognoses than those with stage II-IV (P=0.025) and surgically-treated patients had significantly better prognoses than those who did not receive surgery (P=0.018). In conclusion, PMME was associated with highly malignant features and tended to develop hematogenous metastases even after radical resection. Early diagnosis appears to be important to cure this refractory disease.

Introduction We aimed to analyze the clinical and histological effects of chemotherapy in superficial esophageal squamous cell carcinoma (SESCC). Methods We analyzed tumor samples from five patients with cT1bN1M0 who underwent subtotal esophagectomy following two courses of a new triplet chemotherapy regimen including docetaxel, cisplatin, and 5-fluorouracil (DCF). To assess the histological effects of chemotherapy, resected specimens were analyzed by macroscopic examination, hematoxylin & eosin (HE) staining, immunohistochemical (IHC) staining (p53, Ki-67 and cytokeratin) and periodic acid-Schiff (PAS) staining. Results All five patients had a pathological T stage of T0/1a-LPM/1a-MM/1b (1/2/1/1) and histological grade of grade1a/1b/2/3 (1/1/2/1). Endoscopic examination revealed substantial shrinkage of lugol-voiding lesions (LVLs) in all cases. One case showed complete LVL disappearance, and resected specimen examination confirmed pathological complete response (pCR). IHC and PAS staining revealed that most initial LVLs were PAS-negative. Obvious viable cells were confirmed in two cases. The other three cases exhibited nuclear atypia and strong expression of p53 and Ki-67 in the basal layer of mucosa or lamina propria mucosae, even though the superficial layer of mucosa showed no obvious LVLs with PAS-positive. p53-positive lesions were also observed in Ki-67-positive. This indicated discordance between the endoscopic findings and histopathological evaluation. Conclusion DCF chemotherapy alone had a substantial therapeutic effect on SESCC in all cases. However, despite the normal appearance of the mucosal surface, viable cancer cells remained below the basal layer of mucosa. Careful attention should be paid when diagnosing clinical CR, or securing a resection margin of SESCC after DCF chemotherapy.

Chromodomain helicase DNA-binding 5 (CHD5), which is a member of the CHD family, has been identified as a tumor suppressor gene in a variety of malignancies. The aim of the current study was to clarify the clinical significance of CHD5 expression in gastric cancer. CHD5 expression was evaluated using immunohistochemistry (IHC) in 154 specimens resected from patients with gastric cancer from January 2011 to December 2013, and assessed its relationships with clinicopathological characteristics and survival. In vitro cell proliferation, invasion, and migration assays and western blotting analysis were performed to clarify the role of CHD5 in human gastric cancer cell lines. Of a total of 154 patients, 57 (37.0%) exhibited low CHD5 expression, which was significantly associated with positive lymphatic invasion (P=0.032), advanced pT status (P=0.011), and advanced pStage (P=0.014). Overall survival (OS) in patients with low CHD5 expression was significantly worse compared with patients with high CHD5 expression (hazard ratio, 1.96; 95% confidence interval, 1.09-3.45; log-rank P=0.023). Cox multivariate analysis for OS revealed that CHD5 expression was an independent prognostic factor with age and pN status. In vitro, the upregulation of CHD5 in gastric cancer cells with low CHD5 expression significantly decreased cell proliferation, migration and invasion. CHD5 was associated with the regulation of multiple cancer-related targets, including p53 and enhancer of zeste homolog 2 (EZH2) in western blotting analysis. In conclusion, since CHD5 regulated multiple cancer-related targets, its expression may be a useful prognostic biomarker in patients with gastric cancer.