First-line hepatic arterial infusion chemotherapy plus lenvatinib and PD-(L)1 inhibitors versus systemic chemotherapy alone or with PD-(L)1 inhibitors in unresectable intrahepatic cholangiocarcinoma.

PURPOSE: Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC. METHODS: Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups. RESULTS: The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others. CONCLUSION: In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.

Endoscopic ultrasonography-related diagnostic accuracy and clinical significance on small rectal neuroendocrine neoplasms.

This research aimed to examine the diagnostic accuracy and clinical significance of endoscopic ultrasonography (EUS) in the context of small rectal neuroendocrine neoplasms (NENs). A total of 108 patients with rectal subepithelial lesions (SELs) with a diameter of < 20 mm were included in the analysis. The diagnosis and depth assessment of EUS was compared to the histology findings. The prevalence of NENs in rectal SELs was 78.7% (85/108). The sensitivity of EUS in detecting rectal NENs was 98.9% (84/85), while the specificity was 52.2% (12/23). Overall, the diagnostic accuracy of EUS in identifying rectal NENs was 88.9% (96/108). The overall accuracy rate for EUS in assessing the depth of invasion in rectal NENs was 92.9% (78/84). Therefore, EUS demonstrates reasonable diagnostic accuracy in detecting small rectal NENs, with good sensitivity but inferior specificity. EUS may also assist physicians in assessing the depth of invasion in small rectal NENs before endoscopic excision.

A novel prognostic prediction model of cuprotosis-related genes signature in hepatocellular carcinoma.

Background: Cuprotosis is a recently discovered copper-dependent cell death mechanism that relies on mitochondrial respiration. However, the role of cuprotosis-related genes (CRGs) in hepatocellular carcinoma (HCC) and their prognostic significances remain unknown. Methods: Based on the recently published CRGs, the LASSO Cox regression analysis was applied to construct a CRGs risk model using the gene expression data from the International Cancer Genome Consortium as a training set, followed by validation with datasets from The Cancer Genome Atlas and the Gene Expression Omnibus (GSE14520). Functional enrichment analysis of the CRGs was performed by single-sample gene set enrichment analysis. Results: Five of the 13 previously published CRGs were identified to be associated with prognosis in HCC. Kaplan-Meier analysis suggested that patients with high-risk scores have a shorter overall survival time than patients with low-risk scores. ROC curves indicated that the average AUC was more than 0.7, even at 4 years, and at least 0.5 at 5 years. Moreover, addition of this CRG risk score can significantly improve the efficiency of predicting overall survival compared to using traditional factors alone. Functional analysis demonstrated increased presence of Treg cells in patients with high-risk scores, suggesting a suppressed immune state in these patients. Finally, we point to the possibility that novel immunotherapies such as inhibitors of PDCD1, TIGIT, IDO1, CD274, CTLA4, and LAG3 may have potential benefits in high-risk patients. Conclusion: We constructed a better prognostic model for liver cancer by using CRGs. The CRG risk score established in this study can serve as a potentially valuable tool for predicting clinical outcome of patients with HCC.

Comprehensive analysis of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2): A potential novel pan-cancer immune checkpoint.

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Gastric lymphangioma: a case report and review of literature.

BACKGROUND: Gastric lymphangioma is one of the highly rare benign tumors characterized by multilocular or unilocular lymphatic spaces. Herein, we report a case of lymphangioma in the gastric antrum. CASE PRESENTATION: A 77-year-old male patient who had been experiencing epigastric discomfort for a year was presented to our hospital. A gastric subepithelial lesion was diagnosed by upper endoscopy and was entirely excised via diatal subtotal gastrectomy. Endoscopic ultrasonography revealed an echoless homogenous echo pattern in the third wall layer. A lymphangioma was diagnosed by pathologic investigation of the resected specimen. The PubMed, Embase and Web of Science databases were reviewed for literature in English while using the keywords of "gastric lymphangioma" or "lymphangioma of stomach" or "gastric lymphatic cyst" or "lymphatic cyst of stomach" and the results were discussed. CONCLUSION: Gastric lymphangioma is a rarely occurring submucosal tumor that should be considered when diagnosing subepithelial lesions in the stomach.

Mechanism of Abnormal Coagulation Induced by Tigecycline in Cancer Patients.

Tigecycline is a broad-spectrum active intravenous antibiotic that is active against methicillin-resistant staphylococcus aureus. In Phase 3 and 4 clinical trials, increased all-cause mortality was observed in patients treated with tigecycline compared to patients in the control group. The reason for the increase is unclear. In this study, we found that tigecycline cause abnormal coagulation in tumor patients, especially in patients with hematological malignancies. The main manifestations were decreased fibrinogen and prolonged activated prothrombin time (APTT), thrombin time (TT), and D-dimer. In addition, through functional studies, we found that tigecycline inhibit platelet adhesion and aggregation, and the coagulation function of patients gradually recover after discontinuation. Gene sequencing results suggested that tigecycline significantly regulate the expression of genes related to platelet function pathways and increase the incidence of single nucleotide polymorphisms and the number of alternative splices in the Chinese hamster ovary (CHO) cells treated with tigecycline. An abnormal function and low numbers of platelets are common in patients with hematological malignancies. Our study can explain the mechanism of abnormal coagulation caused by tigecycline. Additionally, doctors who apply tigecycline to cure infections in tumor patients should be warned.

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.

Oral maintenance therapy using apatinib combined with S-1/capecitabine for esophageal squamous cell carcinoma with residual disease after definitive chemoradiotherapy.

BACKGROUND: A substantial number of patients with esophageal squamous cell carcinoma (ESCC) do not achieve complete remission after definitive concurrent chemoradiotherapy (dCRT). We performed this retrospective study to evaluate the efficacy and safety of apatinib combined with S-1/capecitabine as the oral maintenance therapy for these patients. METHODS: Thirty-nine ESCC patients with residual disease after dCRT were included. Patients were treated with apatinib combined with S-1 /capecitabine after dCRT. Efficacy, toxicity, and survival were analyzed. RESULTS: Of the 39 patients, 5 (12.8%) achieved a partial response and 29 (74.4%) achieved stable disease, yielding a disease control rate of 87.2%. The median progression-free survival (PFS) and overall survival (OS) were 27.5 (95%CI: 14.9 - 40.1) and 38.1 (95%CI: 31.3 - 44.8) months. Most frequent adverse events were of grade 1 to 2. Multivariate analysis revealed the occurrence of any adverse events (HR = 0.274, 95%[CI] = 0.119 - 0.630) correlated to better PFS and occurrence of proteinuria (HR = 0.108, 95%[CI] = 0.025 - 0.456) predicted better OS. CONCLUSION: The oral combination therapy consisting of apatinib and S-1/capecitabine showed a tolerable toxicity profile and achieved satisfactory disease control in ESCC patients with residual disease after dCRT.

High incidence of esophageal fistula on patients with clinical T4b esophageal squamous cell carcinoma who received chemoradiotherapy: A retrospective analysis.

BACKGROUND AND PURPOSE: Despite definitive chemoradiotherapy (CRT) being a recommended therapeutic method for patients with T4b esophageal squamous cell carcinoma (ESCC), treatment response and complications remain unclear. Esophageal fistula is a severe CRT-related complication when treating locally advanced ESCC, but data on risk factors that lead to esophageal fistula formation are limited. The aim of this analysis is to characterize the outcomes of T4b ESCC treated by CRT and investigate the risk factors of esophageal fistula. MATERIALS AND METHODS: We retrospectively analyzed 136 patients with clinically unresectable T4b ESCC who were treated with CRT. Response, survival, and complication rates, particularly the rate of esophageal fistula and its associated risk factors were analyzed. RESULTS: The median progression-free survival and overall survival (OS) of all patients were 7.9 (95% confidence interval [CI]: 6.1-9.7) and 12.2 months (95% [CI]: 8.9-15.4), respectively. The Kaplan-Meier curves showed that the 3- and 5-year OS rates were 29.9% and 20.2%, respectively. The incidence rate of esophageal fistulas was 30.1%. The median OS for patients with esophageal fistula was only 6.9 (95%[CI] = 6.0-7.8) months. The risk for developing esophageal fistulas was significantly high for ulcerative-type tumors (odds ratio [OR] = 3.202; 95%[CI] = 1.036-7.850, P = 0.011) and for those invading the bronchus/trachea (OR = 3.378; 95%[CI] = 1.223-9.332, P = 0.048). CONCLUSION: We demonstrated that CRT for T4b ESCC patients has a curative potential, despite a high incidence of esophageal fistula, which was the main cause of treatment failure. The higher risk for fistula formation were tumors with ulceration or bronchus/trachea invasion.

Blood Pressure is Associated with Rapid Kidney Function Decline in a Very Elderly Hypertensive Chinese Population.

PURPOSE: In prior analyses, blood pressure (BP) was related to rapid kidney function decline (RKFD). However, studies of this relationship in populations of advanced age are lacking. In the present study, we therefore examined the relationship between BP and RKFD in a population of 284 hypertensive Chinese individuals over the age of 80. PATIENTS AND METHODS: All study participants were diagnosed with hypertension (systolic BP [SBP] 160-200 mmHg; diastolic BP [DBP] <110 mmHg). RKFD was defined based upon a decline in estimated glomerular filtration rate (eGFR) >5mL/min per 1.73 m2 per year during follow-up. The Cox regression models (competing risk models) were used for calculating hazard ratios (HRs) to examine the relationship between SBP, DBP, pulse pressure (PP) and RKFD. RESULTS: Over a 3.3-year median follow-up period, 68 study participants (23.9%) were diagnosed with RKFD, while 35 (12.3%) died. After adjusting for confounding variables, we determined that each 10 mmHg rise in SBP and PP was associated with a 34% and 110% increase, respectively, in RKFD risk (adjusted HR: 1.34, 95% confidence interval [CI]: 1.05-1.71 for SBP, p=0.02; HR: 2.10, 95% CI: 0.87-5.08 for PP, p=0.10). In addition, we determined that each 10 mmHg increase in DBP was linked to a 10% reduction in RKFD risk (adjusted HR: 0.90, 95% CI: 0.70-1.14, p=0.37). CONCLUSION: Our results indicate that SBP, but not DBP or PP, is positively correlated with RKFD risk in a very elderly hypertensive Chinese population.

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index.

Cancer stem cells (CSCs) are characterized by self-renewal and -differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell-related genes in LIHC. We found that mRNA expression-based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co-expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA-binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

Mir-124 Attenuates STAT3-Mediated TH17 Differentiation in Colitis-Driven Colon Cancer.

BACKGROUND: Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the miR-124 acts as a safeguard to inhibit the pro-inflammatory production and reparative regeneration. METHODS: The expression levels of miR-124 and IL-17, IFN-γ were detected by qRT-PCR. TH17 or TH1 cells were detected by flow cytometer, respectively. The binding of STAT3 to the promoter region of IL-17 gene was analyzed by Chip assay. miR-124 binding to the 3'UTR of STAT3 gene was detected by reported plasmid construction and luciferase assay. Furthermore, DSS-induced colitis mice model and T cell transfer model were used to confirm the function of miR-124 in vivo. The related gene expression was analyzed by ELISA and western blot experiments. RESULTS: The results indicated that miR-124 decrease promotes colon tumorigenesis after Citrobacter rodentium infection and AOM/DSS induced colon cancer murine model. In molecular mechanism, miR-124 targets STAT3 to inhibit TH17 cell polarization and keep TH17 polarization in colonic microenvironment. CONCLUSIONS: Our study strengthened the important role of miR-124 in the regulation of adaptive immune responses and blocking the development of colitis-related cancer.

Electrocardiographic left ventricular hypertrophy and mortality in an oldest-old hypertensive Chinese population.

PURPOSE: Previous studies have identified that electrocardiographic pattern of left ventricular hypertrophy (ECG LVH) is associated with mortality, but studies of its correlation in the oldest-old hypertensive population is extremely limited. We investigated the correlation between ECG LVH and mortality in a hypertensive Chinese population aged 80 years and older. PATIENTS AND METHODS: In this study, we included 284 Chinese participants older than 80 years. All included participants with hypertension (sitting systolic blood pressure [BP] 160 to 200 mmHg; sitting diastolic BP <110 mmHg) were ascertained at the baseline. ECG LVH was defined as a Sokolow-Lyon voltage calculated as the amplitude of SV1+ (max RV5 or RV6) greater than 3.5 mV. We categorized participants into two groups by the status of baseline ECG LVH. We used Cox regression models to calculate hazard ratio (HRs) for mortality due to ECG LVH, including cardiovascular mortality and all-cause mortality. RESULTS: In this study, with a 28-month median follow-up, a total of 35 (12.3%) patients died; 21 of those died due to cardiovascular causes. Compared with participants without ECG LVH, there was an increased risk of cardiovascular mortality in participants with ECG LVH (adjusted HR 4.25 [95% confidence interval [CI], 1.50-12.06]) but ECG LVH did not predict all-cause mortality (adjusted HR 2.31 [95% CI, 0.93-5.72]). CONCLUSION: Our study shows that ECG LVH predicts the risk of cardiovascular mortality in an oldest-old hypertensive Chinese population.

Executive summary for the 2015 Annual Data Report of the China Kidney Disease Network (CK-NET).

Chronic kidney disease (CKD) has received increased attention as a leading public health problem worldwide. Globally surveillance systems for kidney disease are still lacking, especially in developing countries like China, which constitutes an obstacle to develop effective preventive strategies. China Kidney Disease Network (CK-NET) was initiated in 2014 and further developed in accordance with the national strategy of prompting Big Data application in China. One major output of CK-NET is to generate an Annual Data Report (ADR) providing resourceful information regarding kidney disease in China. Entering the second cycle of ADR, we have expanded the scope and depth of our research based on the previous ADR. There are 2 sections in the current ADR, generated from data from 2015 from various sources. Section I is based on a dataset of national hospitalized patients and describes the characteristics regarding hospitalized patients with CKD. Section II focuses on patients receiving renal replacement therapy based on 2 nationwide claims databases. There is also a chapter that focuses on patients on the waiting list for renal transplantation based on the China Organ Transplant Response System. Certain findings, including the effect of metabolic disease on the spectrum of CKD, the underdiagnoses of CKD and acute kidney injury among hospitalized patients, and the less-optimal treatment of complications among dialysis patients, will inspire the following research as well as changes in health policy. By integrating and mining national patient-level administrative or claim databases, we are able to provide a comprehensive description of the burden of CKD and end stage kidney disease in China, which could be used by multiple stakeholders with interests in kidney disease.

Cognitive function and 3-year mortality in the very elderly Chinese population with chronic kidney disease.

BACKGROUND: Cognitive function has been suggested to be correlated with mortality, while studies regarding the association among the very elderly population with chronic kidney disease (CKD) are extremely limited. AIM: To explore the association between cognitive function and mortality among the very elderly Chinese population with CKD. METHODS: This prospective study included 163 Chinese participants aged 80 years or older with CKD. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Cognitive function was evaluated using the mini-mental state examination (MMSE) at baseline. Participants were divided into three groups based on the MMSE score. Cox proportional hazard models were used to assess the contribution of cognitive function to mortality. RESULTS: During a median follow-up of 28 months, 24 (14.7%) participants died, and 14 of the events were cardiovascular death. After making adjustment for potential confounders, every 1-point increase of MMSE score was associated with 29% decreased risk of all-cause mortality (adjusted hazards ratio [HR], 0.71; 95% CI, 0.58-0.87) and 39% decreased risk of cardiovascular mortality (adjusted HR, 0.61; 95% CI, 0.44-0.83). Compared with participants with top category of MMSE score, the adjusted HRs for all-cause mortality and cardiovascular mortality among those with bottom category of MMSE score were 8.18 (95% CI, 2.05-32.54) and 14.72 (95% CI, 1.65-131.16). CONCLUSION: Cognitive function was associated with all-cause mortality and cardiovascular mortality among the very elderly population with CKD.

Kidney function and cognitive decline in an oldest-old Chinese population.

BACKGROUND: Early-stage chronic kidney disease has been suggested to be correlated with cognitive decline, but the association has rarely been explored in the oldest old. SUBJECTS AND METHODS: This prospective study included 284 Chinese participants aged 80 years or older with serum creatinine levels <150 µmol/L. The median follow-up time was 3.3 years, and 247 (87.0%) participants provided valid data at their last visit. Kidney function was evaluated by measuring the estimated glomerular filtration rate (eGFR) at baseline, and cognitive function was evaluated using the Mini-Mental State Examination (MMSE) at both baseline and annual visits. A reliable decrease in the MMSE score over the follow-up period was observed based on a Reliable Change Index of 1.645 (equivalent to a 90% confidence interval [CI]), which was used to define cognitive decline. Poisson regression models were built to analyze the association between baseline kidney function and cognitive decline. RESULTS: A total of 18 (7.3%) cases of incident cognitive decline were observed during the follow-up period. After adjusting for potential confounders, the relative risk of developing cognitive decline was 4.03 (95% CI 1.09-13.81) among participants with an eGFR of 30-59 mL/min/1.73 m2 compared to participants with an eGFR of ≥60 mL/min/1.73 m2. CONCLUSION: Early-stage chronic kidney disease was correlated with cognitive decline in an oldest-old Chinese population.