Journal of Gastroenterology最新文献

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a formidable health challenge due to its detection at a late stage and a lack of reliable biomarkers for early detection. Although levels of carbohydrate antigen 19-9 are often used in conjunction with imaging-based tests to aid in the diagnosis of PDAC, there is still a need for more sensitive and specific biomarkers for early detection of PDAC.

Methods: We obtained serum samples from 88 subjects (patients with PDAC (n = 58) and controls (n = 30)). We carried out a multi-omics analysis to measure cytokines and related proteins using proximity extension technology and lipidomics and metabolomics using tandem mass spectrometry. Statistical analysis was carried out to find molecular alterations in patients with PDAC and a machine learning model was used to derive a molecular signature of PDAC.

Results: We quantified 1,462 circulatory proteins along with 873 lipids and 1,001 metabolites. A total of 505 proteins, 186 metabolites and 33 lipids including bone marrow stromal antigen 2 (BST2), keratin 18 (KRT18), and cholesteryl ester(20:5) were found to be significantly altered in patients. We identified different levels of sphingosine, sphinganine, urobilinogen and lactose indicating that glycosphingolipid and galactose metabolisms were significantly altered in patients compared to controls. In addition, elevated levels of diacylglycerols and decreased cholesteryl esters were observed in patients. Using a machine learning model, we identified a signature of 38 biomarkers for PDAC, composed of 21 proteins, 4 lipids, and 13 metabolites.

Conclusions: Overall, this study identified several proteins, metabolites and lipids involved in various pathways including cholesterol and lipid metabolism to be changing in patients. In addition, we discovered a multi-analyte signature that could be further tested for detection of PDAC.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Mac2-binding protein glycosylated isomer (M2BPGi), a known biomarker for liver fibrosis, is also elevated in other fibrotic tissues. However, its role in PDAC remains unexplored. This study investigates the potential of M2BPGi as a prognostic biomarker for PDAC and elucidates its role in cancer progression.

Methods: We analyzed serum M2BPGi levels in 83 PDAC patients and 60 healthy controls, examining the relationship with clinical outcomes. Tissue immunostaining and in vitro experiments were conducted to investigate M2BPGi-secreting cells and its role.

Results: Serum M2BPGi levels were significantly higher in PDAC patients than in controls (0.98 vs. 0.59, p < 0.0001). Notably, elevated serum M2BPGi was associated with worse progression-free survival (144 days vs. 260 days, p = 0.017) and overall survival (OS) (245 days vs. 541 days, p < 0.001) following chemotherapy. Multivariable Cox regression analysis further confirmed that a high serum M2BPGi level is an independent risk factor for OS (HR: 2.44, 95% CI 1.26-4.74, p = 0.008). Immunostaining revealed that M2BPGi is secreted by both cancer cells and cancer-associated fibroblasts (CAFs), with high M2BP expression in CAFs correlating with poor prognosis. Furthermore, M2BPGi-secreting CAFs exhibited characteristics of inflammatory CAFs. M2BPGi directly activated mTOR signaling and epithelial-mesenchymal transition in PDAC cells, enhancing their invasive and migratory capabilities.

Conclusions: Our findings identify M2BPGi as a promising prognostic biomarker for PDAC. Moreover, we demonstrate that inflammatory CAFs promote tumor invasion and contribute to poor outcomes by secreting M2BPGi, revealing a novel mechanism of PDAC progression.

Background: Patients with esophageal squamous cell carcinoma (ESCC) frequently develop synchronous head and neck squamous cell carcinoma (HNSCC). With advances in endoscopic technology and widespread screening of synchronous cancers, the detection of synchronous HNSCC and superficial ESCC (SESCC) is increasing. We aimed to evaluate the impact of preceding HNSCC treatment on synchronous SESCC.

Methods: This single-center retrospective study enrolled patients with synchronous HNSCC and SESCC who were treated between January 2010 and December 2023. Tumor size and depth of SESCC before and after HNSCC treatment were evaluated. The factors associated with SESCC progression were investigated.

Results: Of the 299 patients with synchronous HNSCC and SESCC, 134 who underwent preceding HNSCC treatment with follow-up esophagogastroduodenoscopy (EGD) for SESCC were evaluated. Chemoradiotherapy was the most common treatment for HNSCC (56.0%), followed by surgery (17.2%), radiotherapy (14.9%), local resection (7.5%), and chemotherapy (4.5%). The tumor size of SESCC increased after HNSCC treatment in 18 patients (13.4%). Multivariate analysis revealed that an EGD interval of ≥ 120 days was significantly associated with increased tumor size in SESCC (odds ratio, 6.64; 95% confidence interval, 1.91-23.1). Tumor regrowth was observed in 70.6% of SESCCs that shrank with HNSCC treatment, mostly within six months. Tumor depth aggravation was rare (2.2%), but progression to advanced ESCC was observed in two patients.

Conclusions: Timely endoscopic follow-up, preferably within 120 days, is crucial for managing synchronous SESCC after HNSCC treatment to prevent tumor progression. Tumor regrowth should be monitored when SESCC shrinks with HNSCC treatment.

Background: The proto-oncogene WWP1 is overexpressed in various cancers and contributes to tumor growth and poor prognosis. Recently, WWP1 inhibition was reported to suppress tumor development and cell proliferation by activating the PTEN function. However, the expression profiles and clinical significance of WWP1 in pancreatic ductal adenocarcinoma (PDAC) tissues remain undetermined. Therefore, this study aimed to evaluate the WWP1 expression in PDAC and investigate the therapeutic potential of WWP1 inhibition.

Methods: Cellular proliferation assays were performed using a doxycycline-inducible shWWP1 expression system. Transcriptome analyses were conducted to identify the altered pathways in WWP1-depleted cells. PTEN ubiquitination by WWP1 was confirmed using immunoprecipitation assays. In vivo xenograft and drug screening assays were performed to evaluate the clinical significance of WWP1 inhibition.

Results: WWP1 was significantly upregulated in PDAC tissues and associated with poor prognosis. WWP1 depletion significantly reduced the proliferation of PDAC cell lines, correlating with the suppression of the PI3K-AKT pathway. Mechanistically, as reported in other cancer types, PTEN is a target of WWP1 in PDAC cells. PTEN silencing abrogated the growth-inhibitory effects in WWP1-depleted cells, suggesting that the anti-tumor effects of WWP1 inhibition are mediated through PTEN activation. In vivo xenograft studies confirmed that WWP1 depletion substantially inhibited tumor growth. Moreover, drug screening assays revealed that WWP1 depletion had an additive effect with the PI3K-AKT pathway inhibitors on hindering tumor growth.

Conclusion: WWP1 inhibition enhances the anti-tumor effects of PI3K-AKT pathway inhibitors through PTEN activation. Thus, WWP1 could be a potential therapeutic target in PDAC.

Background: The Esophageal Hypervigilance and Anxiety Scale (EHAS) is an English questionnaire created in the USA to assess these factors in all patients with esophageal diseases. The aim of this study was to develop and validate the Japanese version of EHAS and investigate the relationship between EHAS scores and symptoms in untreated disorders of esophagogastric junction (EGJ) outflow.

Methods: This prospective study recruited patients who underwent high-resolution manometry (HRM) at six tertiary centers in Japan. The EHAS was translated to Japanese using standard forward and backward translation methods. Patients completed the following questionnaires: the Japanese EHAS, Eckardt score, Gastroesophageal Reflux Disease Questionnaire, and Hospital Anxiety and Depression Scale for assessment of construct validity. Logistic regression analysis identified factors associated with esophageal symptom severity in untreated disorders of EGJ outflow.

Results: Overall, we analyzed 432 patients. Their main symptoms were dysphagia and reflux. The most common HRM diagnosis was normal (35.9%), followed by achalasia (29.4%). The Japanese EHAS demonstrated excellent reliability, and construct validity, with two subscales similar to the original EHAS. Total EHAS score moderately correlated to Eckardt score (r = 0.545, p < 0.001). In 113 patients with untreated disorders of EGJ outflow, multivariable analysis demonstrated that younger age, type II achalasia, and higher EHAS score were independently associated with higher Eckardt score.

Conclusions: The Japanese EHAS is a reliable and valid questionnaire. Its subscale scores can be used as in the original version with some caution. Future studies are warranted to assess the appropriateness of factor loading.

Background: This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC).

Methods: 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens.

Results: In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group; in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (ρ = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (ρ = -0.4, p < 0.01).

Conclusion: Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.

Background: Behçet's disease (BD) is an autoinflammatory disease that can affect multiple organs, including the gastrointestinal tract. Conventional management comprises anti-inflammatory drugs such as glucocorticoids (GCs) and/or immunomodulators that alleviate symptoms. The introduction of biological agents that target tumor necrosis factor α (TNF-α) has improved disease management. The goal of this work was to analyze the current prevalence and incidence of total BD and gastrointestinal Behçet's disease (GIBD) in Japan, and examine treatment trends, especially regarding the use of TNF-α inhibitors (TNFαi).

Methods: We performed a retrospective descriptive observational study in which BD and GIBD demographic trends, medical treatment patterns, and reported adverse events (AEs) were assessed among patients with data recorded between 2017 and 2021 in the Japan Medical Data Center Claims Database (now JMDC Inc.).

Results: Prevalence of BD and GIBD in Japan during the observation period increased at an annual rate of + 3% and + 4%, respectively, while incidence decreased by - 5% and - 2%, with a more prominent decline in confirmed GIBD cases (- 15%). Although GCs were the most common initial treatment administered, use of TNFαi for BD and GIBD management increased by + 5.6% and + 8.1%, respectively. Severe AEs (mainly pneumonia and GI-associated AEs) were reported in 40% of patients receiving TNFαi; however, a high retention rate (of up to 80%) was observed 3 years after treatment initiation.

Conclusion: The use of TNFαi for GIBD treatment has increased in Japan in recent years. Additional research is necessary to further evaluate TNFαi effectiveness in GIBD and other BD subtypes.

Background: The safety profile of high doses of tumour necrosis factor inhibitors (TNFi) therapy for cancer risk in immune-mediated inflammatory diseases (IMIDs) remains uncertain. We evaluated the risk of cancer development in patients with IMIDs exposed to standard and high doses of TNFi compared with those never exposed to TNFi.

Methods: A cohort study was conducted using the Japanese claims database encompassing over 4.6 million individuals from 2013 to 2021. The study included patients aged 16 years or older with new-onset IMIDs, such as inflammatory bowel disease, rheumatoid arthritis, or psoriasis, who had no cancer history. The subdistribution hazard ratios (SHR) for cancer risk in TNFi standard and high dose groups comparing with TNFi unexposed group were estimated using a Fine and Gray model that accounted for the competing risk of death unrelated to cancer. The high dose of TNFi was defined as either a dose escalation or shortening of the intervals during administrations from the standard dose treatment.

Results: We identified a total of 42,006 patients with new-onset IMIDs (40,573 in TNFi unexposed, 876 in TNFi standard dose, and 557 in TNFi high dose) and 1211 (2.8%) patients developed cancer, yielding an incidence rate of 787.8 (739.9-828.1) per 100,000 person-years. Neither the standard nor high doses of TNFi significantly increased the cancer risk (TNFi standard dose vs. TNFi unexposed, adjusted SHR, 0.65 [0.40-1.08]; TNF high dose vs. TNFi unexposed, adjusted SHR, 1.12 [0.67-1.87]).

Conclusions: There is no association between varying doses of TNFi therapy and cancer risk in IMIDs.