The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice.

The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1ß, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow-derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage's response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

Ghrelin promotes angiogenesis by activating the Jagged1/Notch2/VEGF pathway in preeclampsia.

AIM: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has been found to be involved in the regulation of blood pressure; however, its effects in preeclampsia (PE) and the potential underlying mechanism remain poorly understood. In this study, we aimed to investigate the correlation between ghrelin and PE and reveal the possible mechanism underlying any relationship. METHODS: The levels of ghrelin and VEGF in the plasma of 6 early-onset PE (EOPE), 6 late-onset PE (LOPE) and 12 healthy pregnant (HP) women were detected using enzyme-linked immunosorbent assay (ELISA). The recombinant plasmid, pCDH-ghrelin, was designed to overexpress ghrelin in human umbilical vein endothelial cells (HUVECs). We analyzed angiogenesis in vitro and investigated the mechanism using MTT assay, colony formation assay, transwell migration assay, Matrigel-induced tube formation assay and western blotting. RESULTS: Ghrelin was significantly decreased in EOPE patients (P < 0.05) but elevated in LOPE patients compared to HP groups (P > 0.05). There was a significant decrease in plasma level of VEGF in EOPE and LOPE patients compared to the controls (P < 0.05). The proliferation, migration and tube formation ability of HUVECs were enhanced after transfection with pCDH-ghrelin. Ghrelin increased VEGF by activating the Jagged1/Notch2 pathway. CONCLUSION: Our study uncovered that ghrelin has the potential to improve endothelial function by promoting angiogenesis through Jagged1/Notch2/VEGF pathway.

Toll-like receptor 4 protects against irradiation-induced hematopoietic injury by promoting granulopoiesis and alleviating marrow adipogenesis.

Irradiation induces severe damage in the hematopoietic system, which leads to bone marrow hyperplasia, pancytopenia, and aggravated tissue formation in bone marrow. Studies have shown that Toll-like receptor 4 (TLR4) has a protective effect against irradiation, but the underlying mechanism remains unclear. In this study, we used a TLR4 knockout (TLR4-/-) mouse irradiation model and found that the white blood cell and platelet counts in the peripheral blood of TLR4-/- mice recovered slowly after irradiation, with bone marrow hyperplasia and increased mortality. Additionally, we found that the proportion of CD11b+Gr1+ granulocytes in the peripheral blood and bone marrow of TLR4-/- mice was lower than that of wild-type mice after irradiation. Further, we found that the expression of NADPH Oxidases (NOXs) in the bone marrow was down-regulated after irradiation of TLR4-/- mice, and administration of the NOXs inhibitor VAS2870 reduced the proportion of CD11b+Gr1+ cells in the bone marrow and peripheral blood of wild-type mice after irradiation. Irradiation induced severe marrow adipocytes accumulation in TLR4-/- mice, TLR4 ligand lipopolysaccharide promoted proliferation and inhibited adipogenic differentiation of mesenchymal stromal cells. In summary, our data suggest that TLR4 promotes myeloid hyperplasia by up-regulating the expression of NOXs after irradiation, prohibits marrow adipogensis and increases the tolerance of mice to irradiation.

The ED50 and ED95 of oxytocin infusion rate for maintaining uterine tone during elective caesarean delivery: a dose-finding study.

BACKGROUND: The 90% effective dose (ED90) of oxytocin infusion has been previously estimated to be 16.2 IU h- 1. However, bolus administration of oxytocin prior to the infusion may decrease the infusion dose required. The aim of this study was to estimate the ED95 for oxytocin infusion after a bolus at elective caesarean delivery (CD) in nonlaboring parturients. METHODS: We performed a randomized, triple blinded study in 150 healthy termparturients scheduled for elective CD under epidural anaesthesia. After delivery of the infant and i.v. administration of 1 IU oxytocin as a bolus, Participants were randomized to receive oxytocin infusion at a rate of 0, 1, 2, 3, 5, or 8 IU h- 1, to be given for a total of 1 h. Uterine tone assessed by the blinded obstetrician as either adequate or inadequate. Secondary outcomes included estimated blood loss (EBL), requirement for supplemental uterotonic agents, and development of side effects. RESULTS: The 95% effective dose (ED95) of oxytocin infusion was estimated to be 7.72 IU h- 1 (95% confidence interval 5.80-12.67 IU h- 1). With increasing oxytocin infusion rate, the proportion of parturients who needed rescue oxytocin bolus or secondary uterotonic agents decreased. No significant among-group differences in the EBL and oxytocin-related side effects were observed. CONCLUSIONS: In parturients who receive a 1 IU bolus of oxytocin during elective cesarean delivery, an infusion rate of oxytocin at 7.72 IU h- 1 will produce adequate uterine tone in 95% of parturients. These results suggest that the total dose of oxytocin administered in the postpartum period can be decreased when administered as an infusion after oxytocin bolus.

NMR-based serum metabolomics study reveals a innovative diagnostic model for missed abortion.

A missed abortion (MA) is an in-utero death of the embryo or fetus before the 20th week of gestation with retained products of conception. In order to discover novel biomarkers for MA, a 1H NMR spectroscopy-based metabolomics approach was applied to detect human MA serum metabolic profiles. Serum samples were obtained from patients with MA (n = 15) and healthy controls (n = 9) for study. The NOESYPR1D spectrum combined with multi-variate pattern recognition analysis was used to cluster the groups and establish a disease-specific metabolites phenotype. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) models were capable of distinguishing MA patients from healthy subjects. The results revealed that 24 metabolites altered in MA patients compared with the control population. Metabolomic pathway analysis demonstrated that alanine, aspartate and glutamate metabolism, citrate cycle (TCA cycle), taurine and hypotaurine metabolism were significantly altered in MA. The results indicated that serum NMR-based metabolomic profiling method is sensitive and specific enough to distinguish MA and from healthy controls, this method could be developed as a clinically useful diagnostic tool for MA. The finding from the MA serum metabolic profiling shed a new light on further understanding of MA disease mechanisms.

The effect and biological mechanism of granular sludge size on performance of autotrophic nitrogen removal system.

The autotrophic process for nitrogen removal has attracted worldwide attention in the field of wastewater treatment, and the performance of this process is greatly influenced by the size of granular sludge particles present in the system. In this work, the granular sludge was divided into three groups, i.e. large size (> 1.2 mm), medium size (0.6-1.2 mm) and small size (< 0.6 mm). The medium granular sludge was observed to dominate at high volumetric nitrogen loading rates, while offering strong support for good performance. Its indispensable contribution was found to originate from improved settling velocity (0.84 ± 0.10 cm/s), high SOUR-A (specific oxygen uptake rate for ammonia oxidizing bacteria, 25.93 mg O2/g MLVSS/h), low SOUR-N (specific oxygen uptake rate for nitrite oxidizing bacteria, 3.39 mg O2/g MLVSS/h), and a reasonable microbial spatial distribution.

Deciphering the Multisite Interactions of a Protein and Its Ligand at Atomic Resolution by Using Sensitive Paramagnetic Effects.

Quantitative analysis of multisite interactions between a protein and its binding partner at atomic resolution is complicated because locating the binding sites is difficult and differentiating the flexibility of each binding site is even more elusive. Introduction of a paramagnetic metal center close to the binding pocket greatly attenuates the signals in the NMR spectrum upon binding. Herein, the multisite binding of hen egg white lysozyme (HEWL) with lanthanide complexes [Ln(DPA)3 ]3- (DPA=dipicolinic acid) was analyzed with sensitive paramagnetic NMR spectroscopy. Paramagnetic relaxation enhancement (PRE) revealed that HEWL interacts with [Ln(DPA)3 ]3- at four major binding sites in aqueous solution, which is in contrast to a previous X-ray structural analysis. The varied binding affinities for the ligands and different flexibilities at each binding site were in good agreement with atomistic molecular dynamics (MD) simulations. The present work demonstrates that a combination of paramagnetic NMR spectroscopy and MD simulations is a powerful tool to delineate the multisite interactions of a protein with its binding partner at atomic resolution, in terms of both affinity and flexibility.

Plasma metabolomic profile and potential biomarkers for missed abortion.

A missed abortion (MA) is an in utero death of the embryo or fetus before the 20th week of gestation with retained products of conception, and this condition is currently common in China. In order to discover novel biomarkers for MA, ultrahigh performance liquid chromatography was applied to study plasma metabolite profiles for 33 patients with MA and 29 control subjects. Thirty-seven differential plasma metabolites were found to discriminate between the two groups in the initial cohort (15 subjects with MA and 15 healthy controls). The feasibility of using these potential biomarkers to predict MA was further evaluated in the validation cohort (18 subjects with MA and 14 healthy controls) and 15 had an area under the receiver operating characteristic curve of >0.80, making them satisfactory. Tryptophan metabolism and sphingolipid metabolism were identified as important potential target pathways for MA using metabolic pathway impact analysis. Furthermore, three of the 15 satisfactory metabolites (glyceric acid, indole and sphingosine) were combined to establish a predictive model with 100% sensitivity and 100% specificity in the validation cohort. Taken together, these results suggest that MA results in significant disturbance of metabolism and those various novel biomarkers have satisfactory diagnostic and predictive power for MA.

Autocrine and paracrine effects of MDK promote lymph node metastasis of cervical squamous cell carcinoma.

Lymph node metastasis (LNM) is the main metastatic pathway of cervical cancer, which is closely related to 5-year survival rate of cervical squamous cell carcinoma (CSCC), yet the underlying mechanism remains unconfirmed. In this study, we show that midkine (MDK) was highly expressed in CSCC and overexpression of MDK was associated with CSCC LNM. Functional investigations demonstrated that MDK promoted LNM by enhancing proliferation, migration and invasion capacity of cervical cancer cells, facilitating lymphangiogenesis and down-regulating the expression of tight junction proteins of human lymphatic endothelial cells (HLECs). MDK exerted these biological effects by interacting with Syndecan-1 and activating PI3K/AKT and p38 MAPK pathways. A retrospective study showed that s-MDK was related to LNM. s-MDK combined with serum-squamous cell carcinoma antigen(s-SCCA) improved the diagnostic accuracy of CSCC LNM. These findings established a new mechanism of LNM and highlighted MDK as a candidate tumor biomarker and therapeutic target in CSCC.

Machine learning developed a CD8+ exhausted T cells signature for predicting prognosis, immune infiltration and drug sensitivity in ovarian cancer.

CD8+ exhausted T cells (CD8+ Tex) played a vital role in the progression and therapeutic response of cancer. However, few studies have fully clarified the characters of CD8+ Tex related genes in ovarian cancer (OC). The CD8+ Tex related prognostic signature (TRPS) was constructed with integrative machine learning procedure including 10 methods using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 dataset. Several immunotherapy benefits indicators, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore (IPS), TMB score and tumor escape score, were used to explore performance of TRPS in predicting immunotherapy benefits of OC. The TRPS constructed by Enet (alpha = 0.3) method acted as an independent risk factor for OC and showed stable and powerful performance in predicting clinical outcome of patients. The C-index of the TRPS was higher than that of tumor grade, clinical stage, and many developed signatures. Low TRPS score indicated a higher level of CD8+ T cell, B cell, macrophage M1, and NK cells, representing a relative immunoactivated ecosystem in OC. OC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score, suggesting a better immunotherapy response. Moreover, higher TRPS score indicated a higher score of cancer-related hallmarks, including angiogenesis, EMT, hypoxia, glycolysis, and notch signaling. Vitro experiment showed that ARL6IP5 was downregulated in OC tissues and inhibited tumor cell proliferation. The current study constructed a novel TRPS for OC, which could serve as an indicator for predicting the prognosis, immune infiltration and immunotherapy benefits for OC patients.

Global, regional, and national burdens of early onset pancreatic cancer in adolescents and adults aged 15-49 years from 1990 to 2019 based on the Global Burden of Disease Study 2019: a cross-sectional study.

BACKGROUND: Early-onset pancreatic cancer (EOPC) in younger populations (age ≤50 years) is likely to be a more aggressive phenotype characterized by poor differentiation. The emerging analysis of the global burden of EOPC is limited and outdated. AIM: To systematically investigate the burden and trend of EOPC based on global populations. METHODS: In this systematic analysis based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, the authors present the number of cases, age-standardized rates (ASRs) per 100 000 population, and risk factors for 204 countries and territories. The average annual percentage changes (AAPCs) for the incidence, mortality, and disability-adjusted life-years (DALYs) of EOPC were calculated using joinpoint regression analysis. RESULTS: According to the GBD 2019 estimates, there were 36 852 new cases of EOPC and 32 004 related deaths. East Asia had the highest number of cases, with 11 401 incidences and 10 149 deaths. The ASRs were 0.94 per 100 000 individuals for incidence and 0.81 per 100 000 for mortality. From 1990 to 2019, the age-standardized incidence increased by 46.9%, mortality increased by 44.6%, and DALYs increased by 41.9% globally. In trend analysis, the global incidence (AAPC, 1.26), mortality (AAPC, 1.24), and DALYs (AAPC, 1.25) of EOPC showed an increasing pattern. The ASRs of incidence, mortality, and DALYs of EOPC in Africa, America, and Asia exhibited a continuous upward trend, while the trend in Europe was fluctuating. Asian males exhibited the fastest growth in incidence (AAPC, 2.15) and mortality (AAPC, 2.13), whereas males in the Americas experienced the slowest increase in new cases (AAPC, 0.72) and deaths (AAPC, 0.67). A certain proportion of EOPC DALYs were attributable to known risk factors: tobacco smoking (13.3%), high BMI, 5.6%, and high fasting plasma glucose 3.2%. Integrating the socio-demographic index (SDI), ASRs of incidence and mortality initially increased with rising SDI, reaching a peak in central Europe (1.5 per 100 000

Evaluation of Pathological Response and Surgical Safety of Total Neoadjuvant Therapy for Patients with Clinical Stage III Gastric Cancer in a Real-world Setting.

BACKGROUND: Perioperative chemotherapy is the standard treatment for locally advanced gastric cancer. However, the potential benefit of extending therapy before surgery remains largely unknown. In this study, we aimed to evaluate the efficacy and safety of total neoadjuvant chemotherapy, with or without immune checkpoint blockade. METHOD: A cohort of 174 patients with clinical stage III gastric cancer who underwent D2 gastrectomy from October 2021 to March 2024 in the real-world setting were included in this study. Among these patients, 101 were treated with total neoadjuvant therapy (TNT) and 73 were treated with perioperative neoadjuvant therapy (PNT). We compared the pathological complete response (pCR) rate, ypN0 rate, recurrence-free survival (RFS), overall survival (OS), and postoperative complications between the two groups. Multivariate logistic regression analysis was conducted to identify factors associated with pCR or ypN0. RESULTS: Compared to the PNT group, the patients in the TNT group were more frequently treated with intensive chemotherapy with triplets + immunotherapy. Apart from this, there were no significant differences in baseline characteristics. There were no statistically significant differences in pCR (16.8% vs. 12.3%), ypN0 (49.5% vs. 38.4%), RFS, OS, and postoperative complications (27.7% vs. 26.0%) between the TNT and PNT group. Older age, diffuse type, and stable disease/ progressive disease based on clinical efficacy evaluation were independently associated with non-pCR. Stable disease / progressive disease, linitis plastica, and poor differentiation were independently associated with ypN+. Neither the number of neoadjuvant therapy cycles nor the specific regimens were associated with pCR or ypN0. In the subgroup analysis of patients receiving total gastrectomy, there were still no statistically significant differences in pCR (16.7% vs. 2.6%), ypN0 (43.8% vs. 39.5%), and postoperative complications (43.8% vs. 39.5%) between the two groups. CONCLUSION: Although TNT did not increase the postoperative complication rate, it also did not provide anyadditional short-term benefits compared to PNT for clinical stage III gastric cancer.

Preoperative prognostic nutritional index predicts long-term outcomes of patients with ampullary adenocarcinoma after curative pancreatoduodenectomy.

BACKGROUND: The prognostic nutritional index (PNI), a marker of immune-nutrition balance, has predictive value for the survival and prognosis of patients with various cancers. AIM: To explore the clinical significance of the preoperative PNI on the prognosis of ampullary adenocarcinoma (AC) patients who underwent curative pancreaticoduodenectomy. METHODS: The data concerning 233 patients diagnosed with ACs were extracted and analyzed at our institution from January 1998 to December 2020. All patients were categorized into low and high PNI groups based on the cutoff value determined by receiver operating characteristic curve analysis. We compared disease-free survival (DFS) and overall survival (OS) between these groups and assessed prognostic factors through univariate and multivariate analyses. RESULTS: The optimal cutoff value for the PNI was established at 45.3. Patients with a PNI ≥ 45.3 were categorized into the PNI-high group, while those with a PNI < 45.3 were assigned to the PNI-low group. Patients within the PNI-low group tended to be of advanced age and exhibited higher levels of aspartate transaminase and total bilirubin and a lower creatinine level than were those in the PNI-high group. The 5-year OS rates for patients with a PNI ≥ 45.3 and a PNI < 45.3 were 61.8% and 43.4%, respectively, while the 5-year DFS rates were 53.5% and 38.3%, respectively. Patients in the PNI- low group had shorter OS (P = 0.006) and DFS (P = 0.012). In addition, multivariate analysis revealed that the PNI, pathological T stage and pathological N stage were found to be independent prognostic factors for both OS and DFS. CONCLUSION: The PNI is a straightforward and valuable marker for predicting long-term survival after pancreatoduodenectomy. The PNI should be incorporated into the standard assessment of patients with AC.

RACGAP1 knockdown synergizes and enhances the effects of chemotherapeutics on ovarian cancer.

Among the three most prevalent cancers affecting the female reproductive system, ovarian cancer (OV) ranks as the second most frequently diagnosed. It is important to investigate the genomic complexity of OV to develop diagnostic and therapeutic strategies. Through the utilization of bioinformatics analysis, it was determined that RacGTPase Activating Protein 1 (RACGAP1) holds significant significance in the field of OV chemotherapeutics, an aspect that has not been thoroughly explored in prior investigations. In our study, a notable increase in RACGAP1 expression was detected in ovarian cancer, demonstrating a robust association with clinicopathological features and patient prognosis. In vivo and in vitro testing revealed that RACGAP1 acts synergistically with chemotherapeutics to enhance their effects on ovarian cancer. Furthermore, an interaction between RACGAP1 and the subunit G2 of the condensin II complex, known as non-SMC condensin II complex subunit G2 (NCAPG2), has been identified. Our findings may provide new insight for improving therapeutic strategies for OV.

Does Surgical Resection Significantly Prolong the Long-Term Survival of Patients with Oligometastatic Pancreatic Ductal Adenocarcinoma? A Cross-Sectional Study Based on 18 Registries.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a type of lethal gastrointestinal malignancy. It is mainly discovered at, and diagnosed with, an advanced stage of metastasis. As the only potentially curative treatment for PDAC, surgical resection has an uncertain impact on the survival of these patients. As such, we aimed to investigate if patients with metastatic PDAC (mPDAC) benefit from surgery. Methods: Patients with pancreatic cancer in 18 registries of the Surveillance, Epidemiology, and End Results database between 2000 and 2018 were reviewed retrospectively. According to the American Joint Committee on Cancer (AJCC), the eighth edition staging system was utilized. Propensity score matching was applied to strengthen the comparability of the study. The impact of surgery on survival was evaluated by restricted mean survival time (RMST) and Kaplan−Meier analysis. Results: A total of 210 well-matched mPDAC patients were included in the study. The 1 year, 3 year, and 5 year overall survival (OS) of patients undergoing surgery was 34.3%, 15.2%, and 11.0%, respectively. The 1 year, 3 year, and 5 year cancer-specific survival (CSS) of these patients was 36.1%, 19.7%, and 14.2%, respectively. RMST analysis revealed that mPDAC patients with surgery had better OS and CSS than those without (OS: 9.49 months vs. 6.45 months, p < 0.01; CSS: 9.76 months vs. 6.54 months, p < 0.01). Nevertheless, subgroup analysis demonstrated that such statistical significance especially existed in oligometastatic PDAC patients, which refers to those metastases that were limited in number and concentrated to a single organ in this study. Additionally, surgery was identified as a significant predictor for the long-term prognosis of patients (OS: [HR, hazard ratio] = 0.48, 95% CI: 0.36−0.65, p < 0.001; CSS: HR = 0.45, 95% CI: 0.33−0.63, p < 0.001). Lastly, a nomogram was established to predict whether an individual was suitable for surgical treatment in this study. Conclusions: Surgical resection significantly prolonged the long-term prognosis of oligometastatic PDAC patients. Such insights might broaden the management of patients with mPDAC to a large extent. However, a prospective clinical trial should be conducted before a recommendation of surgery in these patients.

Hepatoid adenocarcinoma of the stomach with neuroendocrine differentiation: A case report and review of literature.

BACKGROUND: Both hepatoid adenocarcinoma of the stomach (HAS) and neuroendocrine differentiation (NED) are rare histological subtypes of gastric cancer with unique clinicopathological features and unfavorable outcomes. HAS with NED is even rarer. CASE SUMMARY: Here, we report a 61-year-old man with HAS with NED, as detected by gastric wall thickening by positron emission tomography/computed tomography for a pulmonary nodule. Distal gastrectomy was performed, and pathological examination led to the diagnosis of HAS with NED. However, liver metastases occurred 6 mo later despite adjuvant chemotherapy, and the patient died 27 mo postoperatively. CONCLUSION: We treated a patient with HAS with NED who underwent adjuvant chemotherapy after radical surgery and still developed liver metastases. We first report the detailed processes of the treatment and development of HAS with NED, providing an important reference for the clinical diagnosis and treatment of this condition.

Dissimilar survival and clinicopathological characteristics of mucinous adenocarcinoma located in pancreatic head and body/tail.

BACKGROUND: Growing evidence shows that pancreatic tumors in different anatomical locations have different characteristics, which have a significant impact on prognosis. However, no study has reported the differences between pancreatic mucinous adenocarcinoma (PMAC) in the head vs the body/tail of the pancreas. AIM: To investigate the differences in survival and clinicopathological characteristics between PMAC in the head and body/tail of pancreas. METHODS: A total of 2058 PMAC patients from the Surveillance, Epidemiology, and End Results database diagnosed between 1992 and 2017 were retrospectively reviewed. We divided the patients who met the inclusion criteria into pancreatic head group (PHG) and pancreatic body/tail group (PBTG). The relationship between two groups and risk of invasive factors was identified using logistic regression analysis. Kaplan-Meier analysis and Cox regression analysis were conducted to compare the overall survival (OS) and cancer-specific survival (CSS) of two patient groups. RESULTS: In total, 271 PMAC patients were included in the study. The 1-year, 3-year, and 5-year OS rates of these patients were 51.6%, 23.5%, and 13.6%, respectively. The 1-year, 3-year, and 5-year CSS rates were 53.2%, 26.2%, and 17.4%, respectively. The median OS of PHG patients was longer than that of PBTG patients (18 vs 7.5 mo, P < 0.001). Compared to PHG patients, PBTG patients had a greater risk of metastases [odds ratio (OR) = 2.747, 95% confidence interval (CI): 1.628-4.636, P < 0.001] and higher staging (OR = 3.204, 95% CI: 1.895-5.415, P < 0.001). Survival analysis revealed that age < 65 years, male sex, low grade (G1-G2), low stage, systemic therapy, and PMAC located at the pancreatic head led to longer OS and CSS (all P < 0.05). The location of PMAC was an independent prognostic factor for CSS [hazard ratio (HR) = 0.7, 95%CI: 0.52-0.94, P = 0.017]. Further analysis demonstrated that OS and CSS of PHG were significantly better than PBTG in advanced stage (stage III-IV). CONCLUSION: Compared to the pancreatic body/tail, PMAC located in the pancreatic head has better survival and favorable clinicopathological characteristics.

CD93 serves as a potential biomarker of gastric cancer and correlates with the tumor microenvironment.

BACKGROUND: The tumor microenvironment (TME) plays an important role in the growth and expansion of gastric cancer (GC). Studies have identified that CD93 is involved in abnormal tumor angiogenesis, which may be related to the regulation of the TME. AIM: To determine the role of CD93 in GC. METHODS: Transcriptomic data of GC was investigated in a cohort from The Cancer Genome Atlas. Additionally, RNA-seq data sets from Gene Expression Omnibus (GSE118916, GSE52138, GSE79973, GSE19826, and GSE84433) were applied to validate the results. We performed the immune infiltration analyses using ESTIMATE, CIBERSORT, and ssGSEA. Furthermore, weighted gene co-expression network analysis (WGCNA) was conducted to identify the immune-related genes. RESULTS: Compared to normal tissues, CD93 significantly enriched in tumor tissues (t = 4.669, 95%CI: 0.342-0.863, P < 0.001). Higher expression of CD93 was significantly associated with shorter overall survival (hazard ratio = 1.62, 95%CI: 1.09-2.4, P = 0.017), less proportion of CD8 T and activated natural killer cells in the TME (P < 0.05), and lower tumor mutation burden (t = 4.131, 95%CI: 0.721-0.256, P < 0.001). Genes co-expressed with CD93 were mainly enriched in angiogenesis. Moreover, 11 genes were identified with a strong relationship between CD93 and the immune microenvironment using WGCNA. CONCLUSION: CD93 is a novel prognostic and diagnostic biomarker for GC, that is closely related to the immune infiltration in the TME. Although this retrospective study was a comprehensive analysis, the prospective cohort studies are preferred to further confirm these conclusions.

Exploration of the lymphadenectomy strategy for elderly pancreatic ductal adenocarcinoma patients undergoing curative-intent resection.

There has been a long-standing controversy regarding the number of lymph nodes (LNs) examined intraoperatively for accurate lymphatic staging and significantly better survival of patients with pancreatic ductal adenocarcinoma (PDAC), and no consensus has been reached for the elderly with the age of over 75 years. Given these, the present study aims to investigate the appropriate number of examined lymph nodes (ELNs) for elderly patients mentioned above. In this study, population-based data on 20,125 patients in 2000 to 2019 from the Surveillance, Epidemiology, and End Results database were reviewed retrospectively. The eighth edition staging system of the American Joint Committee on Cancer (AJCC) was applied. Propensity score matching (PSM) was performed to reduce the effects of multiple biases. By using binomial probability law and maximally selected rank statistics, the minimum number of ELN (MNELN) for accurate nodal involvement assessment and optimal ELN number for significantly better survival were calculated, respectively. In addition, Kaplan-Meier curves and Cox proportional hazard regression models were constructed for further survival analysis. As a result, 6623 patients were enrolled in total in the study. Elderly patients had fewer lymph node metastases and a smaller lymph node ratio (LNR) (all P<0.05). However, poorer overall survival (OS) and cancer-specific survival (CSS) of elderly patients were observed in each pN stage (all P<0.05), except for CSS in N2. The proportions of N2 and N0 stages increased and decreased respectively with increasing number of ELN significantly. MNELN for accurate nodal assessment was 19 according to binomial probability law, and the optimal ELN number for significantly better survival was 17. Additionally, the number of ELN (<17 or ≥17) was also considered a strong prognostic predictor for elderly PDAC patients (≥75 years) in the Cox proportional hazard regression model (Overall survival: hazard ratio [HR]=0.74, 95% confidence interval [CI]: 0.65-0.83, P<0.001; Cancer-specific survival: HR=0.75, 95% CI: 0.66-0.85, P<0.001). In conclusion, extended lymphadenectomy is suitable for elderly PDAC patients undergoing curative-intent surgery owing to an accurate assessment of nodal status and improved long-term prognosis. However, a random, prospective clinical trial is warranted before the recommendation of extended lymphadenectomy for the elderly.

At least 16 lymph nodes are recommended to examine during pancreaticoduodenectomy in ampullary adenocarcinoma.

The minimum number of lymph nodes to be examined during pancreaticoduodenectomy (PD) for patients with ampullary adenocarcinoma (AC) is still debatable due to limited clinical data. Therefore, here we explored the relationship between the number of examined lymph node (ELN) and the current N staging (American Joint Committee on Cancer staging system, AJCC, 8 edition) after PD for AC as well as determined the minimum number of examined lymph nodes (MNELN) to ensure the accurate detection of nodal involvement. Patients underwent PD for AC in the National Cancer Center cohort of China (NCC cohort of China) from 1998 to 2020 and in the Surveillance, Epidemiology, and End Results database (SEER database) from 2010 to 2018 were retrospectively reviewed, and a total of 452 eligible patients were included in this study. The MNELN was evaluated by binomial probability law and best survival separation methods. Furthermore, the cut-off value of MNELN was validated in the NCC cohort of China using Least Absolute Shrinkage and Selection Operator (LASSO) regression. Our analysis indicated that the median number of ELN was 14, and the number of ELN was positively correlated with N stage. The MNELN was 16, whereas the best survival separation of ELN was 38 in node-positive patients and 3 in node-negative patients. In the validation cohort, the number of 16 ELNs was identified as a predictive variable for lymph node metastasis with nonzero coefficients in the LASSO-logistic regression model. Together, we concluded that a greater number of ELN was associated with more accurate nodal status assessment in PD for AC patients. A minimum of 16 lymph nodes were required to during PD in AC patients.