Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study.

BACKGROUND & AIMS: Glucose-lowering drug is associated with various cancers, but the causality with gastrointestinal cancer risk is rarely reported. We aimed to explore the causality between them in this Mendelian randomization (MR) study. METHODS: Two-sample MR, summary-data-based (SMR), mediation MR, and colocalization analyses was employed. Ten glucose-lowering drug targets (PPARG, DPP4, GLP1R, INSR, SLC5A2, ABCC8, KCNJ11, ETFDH, GPD2, PRKAB1) and seven types of gastrointestinal cancer (anal carcinoma, cardia cancer, gastric cancer, hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), pancreatic cancer, rectum cancer) were included. Patients with gastrointestinal cancers from six different large GWAS databases, including the UK Biobank and Finnish cohorts were incorporated, for discovery and external validation. Meta-analysis was employed to integrate the results from both discovery and validation cohorts, thereby ensuring the reliability of findings. RESULTS: ABCC8/KCNJ11 were associated with pancreatic cancer risk in both two-sample MR (odds ratio (OR): 15.058, per standard deviation unit (SD) change of glucose-lowering durg target perturbation equivalent to 1 SD unit of HbA1c lowering; 95% confidence interval (95% CI): 3.824-59.295; P-value = 0.0001) and SMR (OR: 1.142; 95% CI: 1.013-1.287; P-value = 0.030) analyses. The mediation effect of body mass index (OR: 0.938; 95% CI: 0.884-0.995; proportion of mediation effect: 3.001%; P-value = 0.033) on ABCC8/KCNJ11 and pancreatic cancer was uncovered. Strong connections of DPP4 with anal carcinoma (OR: 0.123; 95% CI: 0.020-0.745; P-value = 0.023) and ICC (OR: 7.733; 95% CI: 1.743-34.310; P-value = 0.007) were detected. PPARG was associated with anal carcinoma (OR: 12.909; 95% CI: 3.217-51.795; P-value = 0.0003), HCC (OR: 36.507; 95% CI: 8.929-149.259; P-value < 0.0001), and pancreatic cancer (OR: 0.110; 95% CI: 0.071-0.172; P-value < 0.0001). SLC5A2 was connected with pancreatic cancer (OR: 8.096; 95% CI: 3.476-18.857; P-value < 0.0001). Weak evidence indicated the connections of GLP1R, GPD2, and PRKAB1 with anal carcinoma, cardia cancer, ICC, and rectum cancer. In addition, the corresponding results were consistently validated in both the validation cohorts and the integrated outcomes. CONCLUSIONS: Some glucose-lowering drugs were associated with gastrointestinal cancer risk, which might provide new ideas for gastrointestinal cancer treatment.

Prognostic value of diffuse reduction of spleen density on postoperative survival of pancreatic ductal adenocarcinoma: A retrospective study.

PURPOSE: It is difficult to predict the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) before radical operation. The purpose of this study was to explore the connection between the diffuse reduction of spleen density on computed tomography (DROSD) and the postoperative prognosis of patients with PDAC. PATIENTS AND METHODS: A total of 160 patients with PDAC who underwent radical surgery in the First Affiliated Hospital of Wenzhou Medical University were enrolled. Cox regression analysis was used to cast the overall survival (OS) and evaluate the prognostic factors. Nomogram was used to forecast the possibility of 1-year, 3-year, and 5-year OS. The prediction accuracy and clinical net benefit are performed by concordance index (C-index), calibration curve, time-dependent receiver operating characteristics (tdROC), and decision curve analysis. RESULTS: In multivariable Cox analysis, DROSD is independently related to OS. Advanced age, TNM stage, neutrophil/lymphocyte ratio, and severe complications were also independent prognostic factors. The calibration curves of nomogram showed optimal agreement between prediction and observation. The C-index of nomogram is 0.662 (95%CI, 0.606-0.754). The area under tdROC curve for a 3-year OS of nomogram is 0.770. CONCLUSION: DROSD is an independent risk factor for an OS of PDAC. We developed a nomogram that combined imaging features, clinicopathological factors, and systemic inflammatory response to provide a personalized risk assessment for patients with PDAC.

Gut microbiome as a biomarker for predicting early recurrence of HBV-related hepatocellular carcinoma.

To investigate the potential of the gut microbiome as a biomarker for predicting the early recurrence of HBV-related hepatocellular carcinoma (HCC), we enrolled 124 patients diagnosed with HBV-associated HCC and 82 HBV-related hepatitis, and 86 healthy volunteers in our study, collecting 292 stool samples for 16S rRNA sequencing and 35 tumor tissue samples for targeted metabolomics. We performed an integrated bioinformatics analysis of gut microbiome and tissue metabolome data to explore the gut microbial-liver metabolite axis associated with the early recurrence of HCC. We constructed a predictive model based on the gut microbiota and validated its efficacy in the temporal validation cohort. Dialister, Veillonella, the Eubacterium coprostanoligenes group, and Lactobacillus genera, as well as the Streptococcus pneumoniae and Bifidobacterium faecale species, were associated with an early recurrence of HCC. We also found that 23 metabolites, including acetic acid, glutamate, and arachidonic acid, were associated with the early recurrence of HCC. A comprehensive analysis of the gut microbiome and tissue metabolome revealed that the entry of gut microbe-derived acetic acid into the liver to supply energy for tumor growth and proliferation may be a potential mechanism for the recurrence of HCC mediated by gut microbe. We constructed a nomogram to predict early recurrence by combining differential microbial species and clinical indicators, achieving an AUC of 78.0%. Our study suggested that gut microbes may serve as effective biomarkers for predicting early recurrence of HCC, and the gut microbial-tumor metabolite axis may explain the potential mechanism by which gut microbes promote the early recurrence of HCC.

Development of sarcopenia-based nomograms predicting postoperative complications of benign liver diseases undergoing hepatectomy: A multicenter cohort study.

Background: Sarcopenia has a remarkable negative impact on patients with liver diseases. We aimed to evaluate the impact of preoperative sarcopenia on the short-term outcomes after hepatectomy in patients with benign liver diseases. Methods: A total of 558 patients with benign liver diseases undergoing hepatectomy were prospectively reviewed. Both the muscle mass and strength were measured to define sarcopenia. Postoperative outcomes including complications, major complications and comprehensive complication index (CCI) were compared among four subgroups classified by muscle mass and strength. Predictors of complications, major complications and high CCI were identified by univariate and multivariate logistic regression analysis. Nomograms based on predictors were constructed and calibration cures were performed to verify the performance. Results: 120 patients were involved for analysis after exclusion. 33 patients were men (27.5%) and the median age was 54.0 years. The median grip strength was 26.5 kg and the median skeletal muscle index (SMI) was 44.4 cm2/m2. Forty-six patients (38.3%) had complications, 19 patients (15.8%) had major complications and 27 patients (22.5%) had a CCI ≥ 26.2. Age (p = 0.005), SMI (p = 0.005), grip strength (p = 0.018), surgical approach (p = 0.036), and operation time (p = 0.049) were predictors of overall complications. Child-Pugh score (p = 0.037), grip strength (p = 0.004) and surgical approach (p = 0.006) were predictors of major complications. SMI (p = 0.047), grip strength (p < 0.001) and surgical approach (p = 0.014) were predictors of high CCI. Among the four subgroups, patients with reduced muscle mass and strength showed the worst short-term outcomes. The nomograms for complications and major complications were validated by calibration curves and showed satisfactory performance. Conclusion: Sarcopenia has an adverse impact on the short-term outcomes after hepatectomy in patients with benign liver diseases and valuable sarcopenia-based nomograms were constructed to predict postoperative complications and major complications.

Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study.

BACKGROUND AND AIMS: Observational epidemiology studies suggested a relationship between the gut microbiome and primary liver cancer. However, the causal relationship remains unclear because of confounding factors and reverse causality. We aimed to explore the causal role of the gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWAS) of the gut microbiome and liver cancer, and sequencing data from a case-control study validated the findings. A 5-cohort GWAS study in Germany (N = 8956) served as exposure, whilst the UK biobank GWAS study (N = 456 348) served as an outcome. The case-control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from December 2018 to October 2020 and included 184 HCC patients, 63 ICC patients and 40 healthy controls. RESULTS: A total of 57 features were available for MR analysis, and protective causal associations were identified for Family_Ruminococcaceae (OR = 0.46 [95% CI, 0.26-0.82]; p = .009) and Genus_Porphyromonadaceae (OR = 0.59 [95% CI, 0.42-0.83]; p = .003) with HCC, and for Family_Porphyromonadaceae (OR = 0.36 [95% CI, 0.14-0.94]; p = .036) and Genus_Bacteroidetes (OR = 0.55 [95% CI, 0.34-0.90]; p = .017) with ICC respectively. The case-control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (p = .00033), Family_Porphyromonadaceae (p = .0055) and Genus_Bacteroidetes (p = .021) than the liver cancer patients. CONCLUSIONS: This study demonstrates that Ruminococcaceae, Porphyromonadaceae and Bacteroidetes are related to a reduced risk of liver cancer (HCC or ICC), suggesting potential significance for the prevention and control of liver cancer.

Nomogram based on intramuscular adipose tissue content for predicting the prognosis of patients with gallbladder cancer after radical resection.

Background: To investigate the predictive value of intramuscular adipose tissue content (IMAC) on the outcome of gallbladder cancer (GBC) patients after resection, by then develop and evaluate a nomogram to predict the prognosis of GBC patients. Methods: This research incorporated 123 patients with a pathological diagnosis of GBC. Evaluating the prognosis by the Kaplan-Meier method. Independent predictors of overall survival (OS) were screened using multifactorial Cox regression analysis, and a nomogram was constructed from these. Consistency index and calibration curve were used to identify and calibrate the nomogram. The accuracy of the nomogram was assessed by receiver operating characteristic (ROC) curve and decision curve analysis (DCA) was used to assess the net benefit. Results: Patients with high IMAC showed a worse prognosis. A nomogram was constructed to predict OS based on IMAC. The C-index for the nomogram was 0.804. The calibration curve showed well performance of the nomogram. The area under the ROC curve (AUC) for the nomogram at three and five years was 0.839 and 0.785, respectively. A high net benefit was demonstrated by DCA. Conclusions: IMAC was a valid predictor for GBC patients. A nomogram with good performance is constructed to predict the prognosis of GBC patients.

Impact of sarcopenia on outcomes of patients undergoing liver resection for hepatocellular carcinoma.

BACKGROUND: Previous studies have indicated that sarcopenia is associated with poor post-operative outcomes in liver cancer patients, but the studies are limited by confounding from mixed diseases, retrospective data, and non-standardized measurement methods. At present, there is no research with both muscle mass and strength as predictors for hepatocellular carcinoma (HCC) outcomes. We studied the impact of sarcopenia on post-operative outcomes in HCC patients in a cohort study designed according to the European Working Group on Sarcopenia in Older People standards. METHODS: A total of 781 consecutive patients admitted to our centre were registered from May 2020 to August 2021. All participants submitted questionnaires and underwent handgrip strength, chair stand test, physical performance, and computed tomographic evaluation. Then, they were divided into three groups according to muscle mass and strength: Group A (reduced muscle mass and strength), Group B (reduced muscle strength or reduced muscle mass), and Group C (normal muscle mass and strength). The baseline data and post-operative outcomes were compared and analysed. The primary outcome variable in this study was the presence of a major post-operative complication, and the secondary outcome was the 90-day re-admission rate. RESULTS: A total of 155 patients [median age, 60.00 (IQR, 51.00-66.00) years; 20 females (12.90%)] were included after strict exclusion. The mean (SD) BMI was 23.37 ± 0.23 kg/m2 . The mean (SD) SMI of all participants was 47.05 ± 0.79 cm2 /m2 , and the mean (SD) handgrip strength was 32.84 ± 0.69 kg. Among them, 77 (49.68%) patients underwent laparoscopic hepatectomy, and 73 (47.10%) patients received major hepatectomy. Regarding the post-operative results, Group A had a higher rate of major complications [40.91% (9 of 22) vs. 11.94% (8 of 67) in Group B and 6.06 (4 of 66) in Group C; P = 0.001], higher rate of blood transfusion (77.27% vs. 46.27% in Group B and 42.42% in Group C; P = 0.015), higher hospitalization expenses (P = 0.001), and longer hospital stay (P < 0.001). There was no difference in 90-day re-admission rates among the three groups. Sarcopenia (hazard ratio, 10.735; 95% CI, 2.547-45.244; P = 0.001) and open surgery (hazard ratio, 4.528; 95% CI, 1.425-14.387; P = 0.010) were independent risk factors associated with major complications. CONCLUSIONS: Sarcopenia is associated with adverse outcomes after liver resection for HCC. It should be evaluated upon admission to classify high-risk patients and reduce the risk of major complications.

A Novel Clinical-Radiomics Model Based on Sarcopenia and Radiomics for Predicting the Prognosis of Intrahepatic Cholangiocarcinoma After Radical Hepatectomy.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant tumor with a poor prognosis. This study aimed to establish a novel clinical-radiomics model for predicting the prognosis of ICC after radical hepatectomy. METHODS: A clinical-radiomics model was established for 82 cases of ICC treated with radical hepatectomy in our hospital from May 2011 to December 2020. Radiomics features were extracted from venous-phase and arterial-phase images of computed tomography. Kaplan-Meier survival analysis was generated to compare overall survival (OS) between different groups. The independent factors were identified by univariate and multivariate Cox regression analyses. Nomogram performance was evaluated regarding discrimination, calibration, and clinical utility. C-index and area under the curve (AUC) were utilized to compare the predictive performance between the clinical-radiomics model and conventional staging systems. RESULTS: The radiomics model included five features. The AUC of the radiomics model was 0.817 in the training cohort, and 0.684 in the validation cohort. The clinical-radiomics model included psoas muscle index, radiomics score, hepatolithiasis, carcinoembryonic antigen, and neutrophil/lymphocyte ratio. The reliable C-index of the model was 0.768, which was higher than that of other models. The AUC of the model for predicting OS at 1, and 3 years was 0.809 and 0.886, which was significantly higher than that of the American Joint Committee on Cancer 8th staging system (0.594 and 0.619), radiomics model (0.743 and 0.770), and tumor differentiation (0.645 and 0.628). After stratification according to the constructed model, the median OS was 59.8 months for low-risk ICC patients and 10.1 months for high-risk patients (p < 0.0001). CONCLUSION: The clinical-radiomics model integrating sarcopenia, clinical features, and radiomics score was accurate for prognostic prediction for mass-forming ICC patients. It provided an individualized prognostic evaluation in patients with mass-forming ICC and could helped surgeons with clinical decision-making.

Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma.

PURPOSE: Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD. METHODS: The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan-Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network. RESULTS: A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints-PD-L1, CD47, CD276, and PVR-was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis. CONCLUSION: We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.

Diffuse reduction of spleen density is a novel prognostic marker for intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Diffuse reduction of spleen density (DROSD) is related to cancer prognosis; however, its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. AIM: To assess the predictive value of DROSD in the prognosis of ICC after curative resection. METHODS: In this multicenter retrospective cohort study, we enrolled patients with ICC who underwent curative hepatectomy between 2012 and 2019. Preoperative spleen density was measured using computed tomography. Overall survival (OS) and recurrence-free survival (RFS) rates were calculated and compared utilizing the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were applied to identify independent factors for OS and RFS. A nomogram was created with independent risk factors to predict prognosis of patients with ICC. RESULTS: One hundred and sixty-seven ICC patients were enrolled. Based on the diagnostic cut-off values (spleen density ≤ 45.5 Hounsfield units), 55 (32.9%) patients had DROSD. Kaplan-Meier analysis indicated that patients with DROSD had worse OS and RFS than those without DROSD (P < 0.05). Cox regression analysis revealed that DROSD, carcinoembryonic antigen level, carbohydrate antigen 19-9 level, length of hospital stay, lymph node metastasis, and postoperative complications were independent predictors for OS (P < 0.05). The nomogram created with these factors was able to predict the prognosis of patients with ICC with good reliability (OS C-index = 0.733). The area under the curve for OS was 0.79. CONCLUSION: ICC patients with DROSD have worse OS and RFS. The nomogram is a simple and practical method to identify high-risk ICC patients with poor prognosis.