Lactobacillus rhamnosus HN001 facilitates the efficacy of dual PI3K/mTOR inhibition prolonging cardiac transplant survival and enhancing antitumor effect.

Solid organ transplantation is a crucial treatment for patients who have reached the end stage of heart, lung, kidney, or liver failure. However, the likelihood of developing cancer post-transplantation increases. Additionally, primary malignant tumors remain a major obstacle to the long-term survival of transplanted organs. Therefore, it is essential to investigate effective therapies that can boost the immune system's ability to combat cancer and prevent allograft rejection. We established a mouse orthotopic liver tumor model and conducted allogeneic heterotopic heart transplantation. Various treatments were administered, and survival curves were generated using the Kaplan-Meier method. We also collected graft samples and measured inflammatory cytokine levels in the serum using an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 to primary liver cancer model mice with cardiac allografts. Consistent with our prior findings, L. rhamnosus HN001 alleviated the intestinal flora imbalance caused by BEZ235. Our previous research confirmed that the combination of BEZ235 and L. rhamnosus HN001 significantly prolonged cardiac transplant survival. IMPORTANCE: We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.

Targeting SIRT1 synergistically improves the antitumor effect of JQ-1 in hepatocellular carcinoma.

Bromodomain and extraterminal domain protein inhibitors have shown therapeutic promise in hepatocellular carcinoma. However, resistance to bromodomain and extraterminal domain protein inhibitors has emerged in preclinical trials, presenting an immense clinical challenge, and the mechanisms are unclear. In this study, we found that overexpression of SIRT1 induced by JQ-1, a bromodomain and extraterminal domain protein inhibitor, may confer resistance to JQ-1 in hepatocellular carcinoma. SIRT1 protein expression was higher in hepatocellular carcinoma tissues than in normal tissues, and this phenotype was correlated with a poor prognosis. Cotreatment with JQ-1 and the SIRT1 inhibitor EX527 synergistically suppressed proliferation and blocked cell cycle progression in hepatocellular carcinoma cells. Combined administration of JQ-1 and EX527 successfully reduced the tumor burden in vivo. In addition, JQ-1 mediated AMPK/p-AMPK axis activation to upregulate SIRT1 protein expression and enhanced autophagy to inhibit cell apoptosis. Activation of AMPK could alleviate the antitumor effect of the combination of JQ-1 and EX527 on hepatocellular carcinoma cells. Furthermore, inhibition of SIRT1 further enhanced the antitumor effect of JQ-1 by blocking protective autophagy in hepatocellular carcinoma. Our study proposes a novel and efficacious therapeutic strategy of a BET inhibitor combined with a SIRT1 inhibitor for hepatocellular carcinoma.

Circulating tumor biomarkers in early-stage breast cancer: characteristics, detection, and clinical developments.

Breast cancer is the most common form of cancer in women, contributing to high rates of morbidity and mortality owing to the ability of these tumors to metastasize via the vascular system even in the early stages of progression. While ultrasonography and mammography have enabled the more reliable detection of early-stage breast cancer, these approaches entail high rates of false positive and false negative results Mammograms also expose patients to radiation, raising clinical concerns. As such, there is substantial interest in the development of more accurate and efficacious approaches to diagnosing breast cancer in its early stages when patients are more likely to benefit from curative treatment efforts. Blood-based biomarkers derived from the tumor microenvironment (TME) have frequently been studied as candidate targets that can enable tumor detection when used for patient screening. Through these efforts, many promising biomarkers including tumor antigens, circulating tumor cell clusters, microRNAs, extracellular vesicles, circulating tumor DNA, metabolites, and lipids have emerged as targets that may enable the detection of breast tumors at various stages of progression. This review provides a systematic overview of the TME characteristics of early breast cancer, together with details on current approaches to detecting blood-based biomarkers in affected patients. The limitations, challenges, and prospects associated with different experimental and clinical platforms employed in this context are also discussed at length.

Cardiomyocytic cyclic GMP-AMP synthase is critical for the induction of experimental cardiac graft rejection.

OBJECTIVE: During cardiac transplantation, cellular injury and DNA damage can result in the accumulation of cytosolic double-stranded DNA (dsDNA), which can activate the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway and thus induce multiple proinflammatory responses. However, the role of the cGAS-STING pathway in cardiac transplantation remains unclear. This study explored the role of cardiomyocytic cGAS in mouse heart transplantation during the ischemia/reperfusion and rejection processes. METHODS AND RESULTS: Cytosolic dsDNA accumulation and cGAS-STING signaling pathway component upregulation were observed in the grafts posttransplantation. The use of cGAS-deficient donor tissues led to significantly prolonged graft survival. The underlying mechanisms involved decreased expression and phosphorylation of downstream proteins, including TANK binding kinase 1 and nuclear factor κB. In parallel, notably diminished expression levels of various proinflammatory cytokines were observed. Accordingly, substantially decreased proportions of macrophages (CD11b+F4/80+) and CD8+ T cells were observed in the spleen. The activation of CD8+ T cells (CD8+CD69+) within the graft and the proportion of effector memory (CD44highCD62Llow) lymphocytes in the spleen were notably decreased. Treatment with the cGAS inhibitor Ru.521 led to significantly prolonged graft survival. CONCLUSIONS: Cardiomyocytic cGAS plays a critical role by sensing cytosolic dsDNA during cardiac transplantation and could serve as a potential therapeutic target to prevent graft rejection.

An efficient combination immunotherapy for antitumor immunity without accelerating cardiac allograft rejection.

Immunotherapy with immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represents a promising systematic treatment for advanced human malignancies. Transplantation remains the ultimate therapy for end-stage organ diseases. However, the efficacy of ICI treatment in solid organ transplant (SOT) recipients remains controversial. We established a transgenic primary liver cancer mouse model and performed allogeneic heterotopic heart transplantation. Different treatments were performed and survival curves were calculated. Graft samples were collected, and immune cells and the cell surface expression of PD-L1 were analysed by flow cytometry. Inflammatory cytokine levels in the serum were measured by an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. A combination immunotherapy comprising a BET protein inhibitor (JQ1) and an immune checkpoint inhibitor (anti-PD-L1 antibody) was administered to primary liver cancer model mice bearing cardiac allografts. Interestingly, the combination immunotherapy effectively suppressed the progression of primary liver cancer but did not accelerate allograft rejection. In accordance with our previous findings, BET protein inhibition enhances the expression of a putative membrane transporter (Rab8A), which upregulates the expression of PD-L1 on the plasma membrane in a transgenic primary liver cancer mouse model. This may be a crucial mechanism of tumour progression arrest. Our data showed that heart transplantation upregulated the expression of the proinflammatory factor IFN-γ and suggested that BET protein inhibition (with JQ1) decreased PD-L1 expression in heart tissues after cardiac transplantation. This phenomenon was accompanied by enhanced infiltration of inflammatory IFN-γ. Our study provides a novel and efficient therapeutic strategy for SOT recipients.

The dynamic cellular landscape of grafts with acute rejection after heart transplantation.

BACKGROUND: Acute cellular rejection (ACR) is a major barrier to the long-term survival of cardiac allografts. Although immune cells are well known to play critical roles in ACR, the dynamic cellular landscape of allografts with ACR remains obscure. METHODS: Single-cell RNA sequencing (scRNA-seq) was carried out for mouse cardiac allografts with ACR. Bioinformatic analysis was performed, and subsequent transplant experiments were conducted to validate the findings. RESULTS: Despite an overall large depletion of cardiac fibroblasts (CFBs), highly expanded cytotoxic T lymphocytes and a CXCL10+Gbp2+ subcluster of CFBs were enriched within grafts at the late stage. CXCL10+Gbp2+ CFBs featured strong interferon responsiveness and high expression of chemokines and major histocompatibility complex molecules, implying their involvement in the recruitment and activation of immune cells. Cell‒cell communication analysis revealed that CXCL9/CXCL10-CXCR3 might contribute to regulating CXCL10+Gbp2+ CFB-induced chemotaxis and immune cell recruitment. In vivo transplant studies revealed the therapeutic potential of CXCR3 antagonism in transplant rejection. CONCLUSIONS: The findings of our study unveiled a novel CFB subcluster that might mediate acute cardiac rejection. Targeting CXCR3 could prolong allograft survival.

BEZ235 Prolongs Murine Cardiac Allograft Survival Through the Autophagy Pathway.

BACKGROUND: BEZ235, a dual PI3K/mTOR inhibitor, has shown a critical impact in the treatment of cancers, with the ability to induce autophagy. However, the effects of BEZ235 in heart transplant have been rarely investigated. The aim of this study was to evaluate the potency of BEZ235 in cardiac allograft survival. METHODS: BEZ235 was administered during the perioperative period of syngeneic or allogeneic heart transplant to assess survival time. Next, the autophagy signaling pathway and the proinflammatory cytokines were analyzed. Furthermore, a cardiomyocytes-specific ATG5 gene-ablated mouse was used to confirm the results. RESULTS: BEZ235 treatment significantly prolonged the survival of the cardiac graft and reduced the infiltration of inflammatory cells. The expression levels of autophagy proteins were increased in the BEZ235 treatment group compared to the control group, but the therapeutic effect of BEZ235 was weakened in the cardiomyocytes-specific ATG5 gene-ablated mice. Moreover, BEZ235 significantly downregulated the expression of IL-1ß, IL-2, and TNF-α. CONCLUSIONS: It seems BEZ235 could induce autophagy and prolonged murine cardiac allograft survival in a mechanism that involved the autophagy pathway and changed multiple inflammatory factors. This study has proposed a theoretical foundation for the strong connection between mTOR-induced autophagy and heart transplant.

Lactobacillus rhamnosus HN001 Ameliorates BEZ235-Induced Intestinal Dysbiosis and Prolongs Cardiac Transplant Survival.

Cardiac allograft rejection remains a major factor limiting long-term engraftment after transplantation. A novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, prolonged cardiac allograft survival by effectively suppressing activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. However, long-term usage of pharmacological immunosuppressant drugs can cause intestinal microbiota dysbiosis. We established mouse models of allogeneic heterotopic heart transplantation with different treatments. Fecal samples were collected and subjected to 16S rRNA sequencing and targeted fecal metabolomic analysis. Graft samples were taken for immune cell detection by flow cytometry. Inflammatory cytokines in serum were quantified by enzyme-linked immunosorbent assay (ELISA). Compared to single-target approaches (IC-87114 and rapamycin), BEZ235 more efficiently prolongs cardiac transplant survival. Interestingly, BEZ235 reduces the diversity and abundance of the intestinal microbiota community. We demonstrated that Lactobacillus rhamnosus HN001 rescues the intestinal microbiota imbalance induced by BEZ235. IMPORTANCE Our data confirmed that the combination of BEZ235 and Lactobacillus rhamnosus HN001 significantly prolongs cardiac transplant survival. A main metabolic product of Lactobacillus rhamnosus HN001, propionic acid (PA), enriches regulatory T (Treg) cells and serves as a potent immunomodulatory supplement to BEZ235. Our study provides a novel and efficient therapeutic strategy for transplant recipients.

Comparison of Different Mandibular Jawlines Classifications on Transoral Endoscopic Thyroidectomy for Papillary Thyroid Carcinoma: Experiences of 690 Cases.

BACKGROUND: The influences of patients' different mandibular jawlines on transoral endoscopic thyroidectomy via vestibular approach (TOETVA) have not been described before. The objective of this study was to introduce a new classification to assess different mandibular jawlines, and to evaluate the effects on TOETVA in terms of safety, feasibility, and postoperative feelings in the treatment of papillary thyroid carcinoma (PTC). METHODS: The crossing angle of esthetic plane and mandibular plane was defined as Wang Angle, used to assess patients' different mandibular jawlines. Mandibular classifications of A (angle: 80° ~ 110°), B (angle > 110°), and C (angle < 80°) types were compared to evaluate the surgical outcomes of TOETVA by a retrospective study. 690 patients of PTC who received TOETVA were included in this study, which were divided into three groups according to mandibular classifications. RESULTS: Clinicopathological characteristics of the patients including age, gender, body mass index, tumor size, Hashimoto thyroiditis were similar in the three groups. Patients' length of jay in group C was significantly longer than group A and group B (P < 0.01). The ratios of using suspension system in group C were significantly higher than group A and group B (P < 0.01). The scores of postoperative visual analogue scale (VAS) and ratios of mandibular swell in group C were significantly higher than group A and group B (P < 0.01). There was no significant difference in the three groups regarding surgical outcomes, including postoperative vocal cord paralysis, hypocalcemia, serum white blood cells and C-reactive protein levels. CONCLUSIONS: The Wang angle and mandibular jawline classifications were firstly introduced in TOETVA. All the patients of class A, B, and C mandibular jawline can achieve safe and effective surgical outcomes in the treatment of PTC with TOETVA. Patients of class C need more assistance of suspension system, would experience higher scores of VAS, and higher ratios of mandibular swell compared with class A and B.

Effects of Intraoperative Neural Tunnel in Protecting Recurrent Laryngeal Nerve: Experiences in Open, Trans Breast, and Transoral Endoscopic Thyroidectomy.

Background: Energy-based devices (EBDs) increase the risks of thermal nerve injuries. This study aimed to introduce a surgical strategy of intraoperative neural tunnel protecting (INTP) for evaluating the effect in reducing the incidence of recurrent laryngeal nerve (RLN) damage in open, trans breast, and transoral endoscopic thyroidectomy. Methods: INTP strategy was introduced: a tunnel was established and protected by endoscopic gauze along the direction of the nerve. A total of 165, 94, and 200 patients with papillary thyroid carcinoma (PTC) were to use INTP in respectively open, trans breast, and transoral endoscopic thyroidectomy as the INTP group. Additionally, 150, 95, and 225 patients who received the same methods without INTP were enrolled in the control group. Ipsilateral thyroidectomy or total thyroidectomy, and central compartment dissection were performed on the enrolled patients. Results: Clinicopathologic characteristics, surgical outcomes, and surgical complications were similar between the INTP group and the control group in open, trans breast, and transoral endoscopic thyroidectomy. The incidences of electromyography (EMG) changes in the INTP group were lower as compared to the control group in trans breast endoscopic thyroidectomy (p < 0.05). The incidence of postoperative hoarse in the INTP group was lower as compared to the control group in open and transoral endoscopic thyroidectomy (p < 0.05). Postoperative calcium levels (p < 0.01) were significantly higher, and the white blood cells (p < 0.05) and C-reactive protein levels (p < 0.01) were significantly decreased in the INTP group compared with the control group in transoral endoscopic thyroidectomy. Conclusions: This was the first instance of the INTP strategy being introduced and was found to be an effective method for protecting the RLN in open, trans breast, and transoral endoscopic thyroidectomy. Additionally, INTP helped protect other important tissues such as the parathyroid glands in transoral endoscopic thyroidectomy as well as in reducing postoperative inflammatory responses.

The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) still ranks among the top cancers worldwide with high incidence and mortality. Due to abnormal activation of the PI3K/AKT/mTOR signalling pathway in HCC, targeting this pathway represents a potential therapeutic strategy. NVP-BEZ235 is a novel dual-targeted ATP-competitive PI3K/mTOR inhibitor that has shown effective antitumor effects. In this study, we found that interleukin-6 (IL-6) was significantly increased after exposure to NVP-BEZ235, and we proposed a treatment in which an anti-IL-6 antibody was combined with NVP-BEZ235 for HCC. In vitro results revealed that targeted inhibition of IL-6 potentiated the antitumor effects of NVP-BEZ235 in HCC cells. The mechanism might be attributed to their synergistic inhibitory activity on the PI3K/AKT/mTOR signalling pathway. Furthermore, an in vivo study demonstrated that combined administration of NVP-BEZ235 and anti-IL-6 Ab reduced HCC tumour load more effectively than either NVP-BEZ235 or anti-IL-6 Ab treatment alone. These findings add guidance value to the analysis of HCC and provide a reference for clinical treatment.

BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

Tadalafil enhances the therapeutic efficacy of BET inhibitors in hepatocellular carcinoma through activating Hippo pathway.

Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.

Characteristics of mouse intestinal microbiota during acute liver injury and repair following 50% partial hepatectomy.

Dysbiosis of the gut microbiota has important roles in various diseases and pathological states of the host. However, the changes of the gut microbiota during partial hepatectomy (PH)-induced acute liver injury have so far remained elusive. The present study investigated the gut microbiome and its related pathways following PH-induced acute liver injury. A total of 50 male C57/BL6 mice were divided into a normal control (NC), sham-operation and liver resection (LR) group (50% PH). Samples were collected at 3 and 14 days post-operation to obtain specimens for the Sham3, Sham14, LR3 and LR14 groups (10 mice/group). Specimens of NC group (n=10) were obtained at the same time as those of Sham3 group. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined using an automatic chemical analyzer and the gut microbiota was assessed by 16S ribosomal RNA gene sequencing of small intestinal contents. The serum levels of ALT and AST in the LR3 group were significantly increased, while those in the LR14 group were decreased again to near-normal levels. In the LR3 group, the operational taxonomic units, species richness (Chao1) and species diversity (Shannon and Simpson indices) were decreased, although without any significant difference. Furthermore, in the LR3 group, significant Cyanobacteria enrichment and Fusobacteria depletion compared with the NC and Sham3 groups was observed, while in the LR14 group, a significant depletion of the abundance of Verrucomicrobia, Chloroflexi and Deferribacteres compared to the LR3 group was obtained. The abundance of Firmicutes was increased in the LR3 group and decreased again in the LR14 group. However, the abundance of Bacteroidetes and Actinobacteria decreased in the LR3 group and increased again in the LR14 group. The alterations of the gut microbiota at the genus level were also revealed, as significant increases in Chloroplast, Curvibacter, Pelomonas, Ruminococcaceae UCG-005 and Blautia and a sharp decrease in Akkermansia and Eubacterium coprostanoligenes were caused by acute liver injury. Furthermore, functional metagenome prediction was performed by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States based on the Greengenes database, revealing alterations in signal transduction, transcription and cell motility, as well as metabolism of amino acids, lipids, glucose, cofactors and terpenoids, and xenobiotics pathways. An improved understanding of the structural and functional changes of the gut microbiota following 50% PH-induced acute liver injury and repair may provide novel strategies for the recovery of hosts undergoing hepatectomy.

Number of Positive Lymph Nodes Is Superior to LNR and LODDS for Predicting the Prognosis of Pancreatic Neuroendocrine Neoplasms.

Background: The American Joint Committee on Cancer (AJCC) staging for pancreatic neuroendocrine neoplasms (PanNENs) based on the number of positive lymph nodes (PLNs) is the most widely accepted nodal staging system. New nodal staging schemes that take both the number of PLNs and the number of examined lymph nodes into consideration have emerged as useful prognostic tools. The aim of the current study was to determine the most effective nodal staging system, among the 8th edition AJCC N staging (or PLN staging), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS), for predicting the cause-specific survival of patients with PanNENs. Methods: The clinicopathological and prognostic data of 2,295 patients from the Surveillance, Epidemiology, and End Results (SEER) database, diagnosed with PanNENs between 1988 and 2015, were reviewed retrospectively. Results: A multivariate analysis identified PLN and LNR staging as independent prognostic factors, but not LODDS. The PLN staging exhibited higher C-index and area under the curve values than those of the LNR and LODDS, indicating better predictive discriminatory capacity. No significant difference in the survival of patients was observed within the same PLN staging subgroup according to the number (high or low) of examined lymph nodes. In contrast, intra-group heterogeneity was seen with use of LNR and LODDS staging, due to overestimation of the risk of insufficient examined lymph nodes, and LODDS failed to stratify patients without lymph nodes metastasis into different risk groups. Conclusions: The PLN staging is more reliable than LNR and LODDS staging for predicting the cause-specific survival of PanNENs.

The prognostic value of external vs internal pancreatic duct stents after pancreaticoduodenectomy in patients with FRS ≥ 4: a retrospective cohort study.

BACKGROUND: The prognostic value of external vs internal pancreatic duct stents after pancreaticoduodenectomy remains controversial. This study aimed to evaluate the benefits of external and internal stents using the Fistula Risk Score system with regard to the incidence of clinically relevant postoperative pancreatic fistula. METHODS: A total of 382 patients who underwent pancreaticoduodenectomy with duct to mucosa pancreaticojejunostomy were retrospectively enrolled from January 2015 to October 2019. The receiver operating characteristic curve was performed for subgroup analysis of the patients at different levels of risk for pancreatic fistula. RESULTS: There were no significant differences in terms of pancreatic fistula or other postoperative complications. According to the receiver operating characteristic curve threshold of 3.5, 172 patients with a Fistula Risk Score ≥ 4 and 210 patients with a Fistula Risk Score < 4 were divided into separate groups. The number of valid cases was insufficient to support the subsequent research in patients with a Fistula Risk Score < 4. In patients with a Fistula Risk Score ≥ 4, the use of an external pancreatic duct stent was significantly more effective than the use of an internal stent, especially with regard to the risk for pancreatic fistula (Grade C) (P = 0.039), at ameliorating the incidence of clinically relevant postoperative pancreatic fistula (P = 0.019). Additionally, the incidence of lymphatic leakage was significantly higher in the external stent group compared with the internal stent group (P = 0.040). CONCLUSIONS: Compared with internal stents, the use of an external stent could reduce the incidence of clinically relevant postoperative pancreatic fistula in patients with a Fistula Risk Score ≥ 4. More large-scale prospective clinical trials are warranted to further clarify our results.

Feasibility of mesentericoportal vein reconstruction by autologous falciform ligament during pancreaticoduodenectomy-cohort study.

BACKGROUND: Mesentericoportal vein (MPV) resection in pancreatic ductal adenocarcinoma (PDAC) surgery has become a common procedure. A few studies had described the use of falciform ligament (FL) for MPV reconstruction and received encouraging preliminary effects. AIMS: This study was designed to explore the feasibility and efficacy of this technique compared with others. METHODS: Patients who underwent pancreaticoduodenectomy (PD) with MPV resection for PDAC from 2009 to 2018 were enrolled. Medical records were retrospectively reviewed, MPV reconstructions using FL were distinguished and compared with other techniques. RESULTS: 146 patients underwent MPV reconstruction, and 13 received FL venoplasty. Other reconstruction techniques included primary end-to-end anastomosis (primary, n = 30), lateral venorrhaphy (LV, n = 19), polytetrafluoroethylene conduit interposition (PTFE, n = 24), iliac artery (IA) allografts interposition (n = 47), and portal vein (PV) allografts interposition (n = 13). FL group holds the advantages of shortest operation time (p = 0.023), lowest blood loss (p = 0.109), and shortest postoperative hospital stay (p = 0.125). The grouped patency rates of FL, primary, LV, PTFE, IA, and PV were 100%, 90%, 68%, 54%, 68%, and 85% respectively. Comparison displayed that FL had the highest patency rate (p = 0.008) and lowest antiplatelet/anticoagulation proportion (p = 0.000). Complications and long-term survival were similar among different techniques. The median survival time of patent group (24.0 months, 95% CI: 22.0-26.0) was much longer than that of the thrombosed (17.0 months, 95% CI: 13.7-20.3), though without significant difference (P = 0.148). CONCLUSIONS: PD with MPV resection and reconstruction by FL is safe, feasible, and efficacious, it might provide a potential benefit for patients.

A self-designed liver circle for on-demand Pringle's manoeuver in laparoscopic liver resection.

BACKGROUND: Laparoscopic liver resection (LLR) allows minimal incisions and relatively quicker post-operative recovery, while intraoperative massive haemorrhage led to conversion to laparotomy. This study aimed to introduce a new, safe and convenient device to serve as Pringle's manoeuver according to the demand in LLR. METHODS: A liver circle consisting of a hole and a round stem with an obtuse small head was made by medical silica gel. It was applied in LLR to perform on-demand Pringle's manoeuver and developed its function in inferior vena cava (IVC) occlusion. The time of performing Pringle's manoeuver by liver circle, extracorporeal tourniquet and endo intestinal clip under laparoscopic simulator and LLR was compared. RESULTS: The liver circle was successfully applied to perform Pringle's manoeuver, IVC exposure and occlusion. It took less time in the occluding step of Pringle's manoeuver than the extracorporeal tourniquet (4.15 ± 0.35 s vs. 9.90 ± 1.15 s, P < 0.05) and the endo intestinal clip (4.15 ± 0.35 s vs. 47.91 ± 3.98 s, P < 0.05) under LLR. The total manipulating time for Pringle's manoeuver with liver circle remained the shortest, and the advantages were more obvious with increased frequencies of intermittent Pringle's manoeuver. CONCLUSION: The new-designed liver circle is more convenient compared to other techniques in performing Pringle's manoeuver, especially the intermittent Pringle's manoeuver in LLR. It can be used to perform on-demand hepatic blood inflow occlusion in every LLR by pre-circling the hepatoduodenal ligament to control bleeding during surgery. It can also be applied to expose the surgical field of vision and perform IVC occlusion to reduce intraoperative blood loss.

The Prognostic Value of External vs Internal Pancreatic Duct Stents in CR-POPF after Pancreaticoduodenectomy: A Systematic Review and Meta-analysis.

BACKGROUND: There is no specific evidence regarding the benefits of external and internal pancreatic duct stents after pancreaticoduodenectomy since pancreatic fistula (grade A) have been redefined with no clinical treatment effect. We aimed to reevaluate the prognostic value of external and internal stents in clinically relevant postoperative pancreatic fistula over pancreaticoduodenectomy. METHODS: PubMed, Web of Science, EMBASE and the Cochrane Database were specifically searched for pertinent and original articles published before May 2019. The project has been registered in PROSPERO (Registration number: CRD42019137579). RESULTS: Four randomized controlled trials and six nonrandomized controlled trials with a total of 2101 patients were enrolled in this meta-analysis. The use of an external stent resulted in better performance than the use of an internal stent in terms of pancreatic fistula (grade C) (OR 0.58, P = 0.03) but did not reduce the rate of pancreatic fistula (grade B) (OR 0.99, P = 0.94) in all studies. The meta-analysis of randomized controlled trials found that the use of an external stent approached a level of significance for an increased rate of clinically relevant postoperative pancreatic fistula compared to the use of an internal stent (OR 1.40, P = 0.10) but had no significant effect on pancreatic fistula (grade B) (OR 1.34, P = 0.26) or pancreatic fistula (grade C) (OR 1.68, P = 0.62). CONCLUSION: Compared with internal stents, the use of external stent might be associated with a lower rate of pancreatic fistula (grade C). More randomized clinical trials are warranted to further explore safety and efficacy of pancreatic duct external stents.

Anti-cytokine therapy and small molecule agents for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, with multifactorial etiologies has led to a global health-associated burden in many countries. Substantial efforts are devoted to understand the pathogenesis, behavioral and environmental triggers, which may be specifically valuable for the treatment of IBD. The specific pathogenesis underlying IBD is as yet incompletely understood. The use of anti-cytokine therapy and small molecule agents targeting the immune system is thought to restore the body's intestinal barrier function and relieve inflammation with manageable adverse effects. In this review, we report recent advances in anti-cytokine therapy and treatment with small molecule agents for the management of IBD.