Abstract:Pancreatic cancer is highly malignant with a dismal outcome. Current treatment protocols based on cohort studies have limited efficacy in improving its prognosis. This may be caused by the heterogeneity of pancreatic cancer among individuals, which leads to different biological properties and different therapeutic outcomes. The rapid development of precision medicine may bring hope for pancreatic cancer. In recent years, some progress has been made in in areas such as targeted therapy, molecular subtyping and personalized tumor model for pancreatic cancer, which enable the application of precision treatment strategies in pancreatic cancer. The four major driver mutations (KRAS/TP53/CDKN2A/SMAD4) play an important role in the development of pancreatic cancer, but there are no targeted drugs available in clinical practice. A phase II clinical trial demonstrated that AMG510 was effective in solid tumor patients with KRAS G12C mutation, but the KRAS G12C mutation frequency was relatively low in pancreatic cancer. The POLO trial suggested that olaparib can improve progression-free survival in metastatic pancreatic cancer patients with germline BRCA mutations. Based on this result, NCCN guideline recommended olaparib for maintenance treatment of advanced pancreatic cancer with germline BRCA1/2 mutations. In addition, the phase II KEYNOTE-158 study suggested that pancreatic cancer patients who were deficient in DNA mismatch repair (dMMR) and have high microsatellite instability may benefit from anti-programmed death-1 therapy with pembrolizumab. In general, the actionable targets for pancreatic cancer are inadequate. Therefore, researches on drugs that targeting the four high frequency mutations and their related pathways are important for precision treatment of pancreatic cancer. Compared with traditional pathological subtyping, transcriptomic subtyping uses mRNA (transcriptome) profiling to define intrinsic molecular subtypes, which can provide more valuable information for the implementation of precision therapy. The first transcriptome subtyping system for pancreatic cancer was proposed in 2011. After that, several studies have proposed new transcriptome subtyping systems. In general, according to the transcriptome profiling, pancreatic cancer can be defined as two subtypes: the classical and basal-like subtypes. The basal-like subtypes seem more resistant to chemotherapy and have a worse prognosis than the classical subtypes. In the future, advances in epigenetics and proteomics may provide new avenues for the clinical application of molecular subtyping.Personalized tumor model can screen potential effective drugs for cancer patients, which is an important approach for individual treatment. Compared with traditional tumor cell lines, patient-derived tumor xenograft (PDX) and organoid retain the molecular and biological characteristics of pancreatic cancer. Our center's practices on PDX and organoid research have confirmed that these two models have high success rate of cultivation, and organoid model can accurately predict patient response to chemotherapy. However, PDX and organoid have different tumor microenvironment from patients, and there is no standard for modeling methods and drug sensitivity test, which limits their application. Overall, the precision medicine approach for pancreatic cancer is still in the preliminary stage. The future researches should focus on finding new therapeutic targets for pancreatic cancer by means of multi-omics, establishing biobanks to accelerate preclinical researches of new drugs, and conducting prospective clinical trials to promote clinical translation of basic scientific achievements. In the future, the precision medicine will certainly offer more options for the treatment of pancreatic cancer.

Abstract:Infected pancreatic necrosis (IPN), which often leads to severe sepsis, organ failure and even death, is one of the most severe complications of acute pancreatitis. In recent years, with the advancements of treatment concepts and technologies of acute pancreatitis, the overall mortality of IPN has declined. However, the diagnosis, especially the early diagnosis of IPN, is still very difficult, and there still exists some controversies on the timing, methods and strategies for the intervention of IPN. Moreover, as the diagnosis and treatment of IPN often involve multidisciplinary cooperation, it is crucial to unify the understanding and take full advantage of the multidisciplinary team. Through literature review combined with introduction of the practical experience gained in the author's own center, this paper systematically elaborates the advancements in terms of the diagnosis, microbiological changes and treatment of IPN.

Abstract:The treatment concept of infected pancreatic necrosis (IPN) has experienced a historic shift from open necrosectomy (ON) to minimally invasive approach. However, the role and status of ON in IPN are still accepted both in domestic and foreign guidelines. Determining the indications and timing of ON to maximize the clinical benefits in IPN has been a vital problem faced by the multidisciplinary team of severe acute pancreatitis. Here, the authors elaborate the indications and timing of ON under new treatment concept based on recent advances, and discuss the practice of process reengineering for the step-up approach.

Abstract:The global pandemic of coronavirus disease 2019 (COVID-19) is still ongoing, and the literature concerning COVID-19 is growing exponentially. The existing data from case reports, retrospective cohort studies and bioinformatics have suggested the relationship between SARS-CoV-2 and acute pancreatitis (AP). The mechanism of how SARS-CoV-2 attacks pancreas remains unclear. However, the expression of the receptor of SARS-CoV-2 in pancreatic tissue has been confirmed, and the components of SARS-CoV-2 have been isolated in the pancreas from patients with COVID-19. These evidences indicate that there may be a causality between SARS-CoV-2 and AP. The SARS-CoV-2 associated acute pancreatitis (SAAP) is likely to be misdiagnosed in clinical settings. Its diagnosis, severity classification and prognosis have specificities that deserve special attention.

Abstract:Background and Aims The incidence rate of hypertriglyceridemic pancreatitis (HTGP) has been continuously increasing in recent years, and there is no relevant guideline for its treatment available so far. Currently, the main treatment is conservative treatment based on lipid-lowering therapy, but the treatment efficacy is unsatisfactory, and the mortality and incidence rates of complications are still high, so the prognosis is relatively poor. Therefore, simple conservative treatment has some limitations. This study was conducted to evaluate the effectiveness and safety of pancreatic duct stent implantation in the treatment of HTGP, so as to provide a new approach for clinical management of this condition.Methods The clinical data of all patients with HTGP undergoing pancreatic duct stenting from January 2017 to July 2020 were reviewed, and the eligible patients were picked up according to the inclusion and exclusion criteria. In the included patients, the incidence of pancreatic ductal obstruction was observed; the APACHE II score, serum triglyceride (TG) level and blood glucose level were compared between admission and 48 h after treatment; the incidence of complications, mortality, incidence of new organ failure, the lengths of time for fasting and hospitalization as well as the hospitalization expenses were analyzed.Results A total of 33 patients were included, with 15 males and 18 females. Of the patients, the average age was (37.42±9.69) years, and the median serum TG level was 19.83 (11.85-39.18) mmol/L; 16 cases had pancreatic duct protein thrombus, and the incidence rates of pancreatic duct protein thrombus in cases with mild, moderate and severe HTGP were 17%, 56% and 100%, respectively. The severity of illness in patients with pancreatic duct protein thrombus was greater than those without pancreatic duct protein thrombus. Two patients (6%) developed post-ERCP hyperamylasemia, and postoperative complications occurred in 3 patients (9%). All patients were cured after pancreatic duct stenting. The median time of oral feeding was 3 (2-5) d, and the median length of hospital stay was 5 (3-9) d. After 48-h treatment, the APACHE II score decreased by approximately 70% compared with that at admission. In patients who underwent pancreatic duct stenting within 48 h after onset, the fasting time and hospitalization time were shortened by 33% and 38%, and the hospitalization cost was reduced by 33% compared with those undergoing pancreatic duct stenting over 48 h after onset, and all the differences had statistical significance (all P<0.05).Conclusion Early pancreatic duct stenting treatment can quickly alleviate the clinical symptoms of HTGP patients, significantly reduce the length of hospital stay and improve the prognosis. It is a safe and effective new treatment strategy.

Abstract:Background and Aims Severe acute pancreatitis (SAP) with infected pancreatic necrosis (IPN) is a really challenging situation in clinical practice. A step-up, minimally invasive drainage or debridement is a widely accepted treatment approach. However, not all patients can benefit from a rigid implementation of step-up approach. In some patients, using a “skip-up” strategy based on step-up approach to perform a direct open debridement may provide a chance for treatment. Here, the authors summarized the treatment process of five patients with SAP complicated with IPN, so as to provide a reference for the selection of step-up or skip-up approaches.Methods The diagnosis and treatment process of five SAP patients with IPN was retrospectively analyzed, and the relevant literature was reviewed.Results Of the 5 patients, 3 cases were males and 2 cases were females, whose age ranged from 37 to 54 years, with an average age of (45.2±6.06) years. The length of hospital stay ranged from 22 to 108 d, with an average of (68±38.03) d. One patient was successfully cured after treatment by a step-up method, and two patients had a poor response after treatment with a step-up approach and eventually treatment was given up their families. Two patients achieved a better result after treatment using a skip-up strategy based on the step-up procedure.Conclusion Individualized treatment is critical for SAP patients complicated with IPN, striving for “one patient one plan”. A large proportion of patients can benefit from the treatment in a step-up approach. However, the rigid implementation of step-up approach must be avoided in patients presenting with fulminant organ failure, severe infection, and extensive abdominal abscesses, for whom a skip-up approach based on sufficient assessment may be more effective.

Abstract:Background and Aims Pancreatic fistula is the most common complication after distal pancreatectomy (DP), and it is closely related to the patient's prognosis and outcome. Therefore, this study was conducted to investigate the occurrence of postoperative pancreatic fistula after DP and the risk factors, so as to provide a basis for developing the protective measures.Methods The clinical data of 99 patients undergoing DP for pancreatic tumors in the Second Affiliated Hospital of Air Force Medical University from January 2015 to February 2021 were retrospectively analyzed. The incidence rate postoperative pancreatic fistula was calculated, and relevant factors possibly causing postoperative of pancreatic fistula were determined by univariate and multivariate Logistic regression analysis.Results In the 99 patients after DP, the incidence of biochemical leakage was 34.3% (34/99), grade B pancreatic fistula was 18.2% (18/99), and grade C pancreatic fistula was 1.0% (1/99), respectively. The results of univariate analysis showed that age, operative time, pancreatic duct diameter and undergoing combined splenectomy or not were significantly related to postoperative pancreatic fistula (all P<0.05). Multivariate Logistic regression analysis results revealed that age <42 years (OR=0.955, 95% CI=0.914-0.998), operative time ≥ 253 min (OR=1.013, 95% CI=1.005-1.021) and combined splenectomy (OR=4.152, 95% CI=1.043-16.535) were independent risk factors for postoperative pancreatic fistula after DP (all P<0.05).Conclusion There is certain incidence rate of pancreatic fistula after DP. Age, operative time, and synchronous splenectomy are independent risk factors for pancreatic fistula after DP. Assessment of these factors may provide certain basis for predicting the risk of postoperative pancreatic fistula and implementing the prevention measures.

Abstract:Background and Aims Surgical resection is still the preferred treatment for malignant pancreatic diseases at present. However, the use of robotic-assisted distal pancreatectomy (RDP) or laparoscopic distal pancreatectomy (LDP) is still controversial. This study was conducted to evaluate the efficacy and safety of using RDP and LDP in the treatment of patients with malignant pancreatic diseases by Meta-analysis, so as to obtain evidence-based information to provide basis for clinical decision-making.Methods The studies comparing the clinical efficacy of RDP versus LDP for malignant pancreatic diseases were collected by a computer-based search in several national and international databases from their inception to March 2021. After literature screening, data extraction and bias risk evaluation by two reviewers independently, Meta-analysis was performed using RevMan 5.4 software.Results Fifteen studies were finally included, involving 2 940 patients, of whom, 997 cases underwent RDP and 1 943 cases underwent LDP. The results of Meta-analysis showed that in RDP group compared with LDP group, the spleen preservation rate (OR=2.31, 95% CI=1.37-3.90, P=0.002) was increased, the intraoperative conversion rate (OR=0.36, 95% CI=0.24-0.52, P?0.000 01), 90-d reoperation rate (OR=0.46, 95% CI=0.24-0.89, P=0.02), and 30-d mortality (OR=0.18, 95% CI=0.06-0.53, P=0.002）were reduced, the operative time was prolonged (MD=-40.09, 95% CI=-77.64-2.54, P=0.04), and the number of lymph nodes harvested (MD=2.06, 95% CI=0.65-3.47, P=0.004) was increased. However, no significant differences were found in intraoperative blood loss, total complication rate, surgical site infection, pancreatic fistula, length of hospital stay, and 90-d readmission rate (all P>0.05).Conclusion The current evidence indicates that RDP may increase the spleen preservation rate and the number of lymph nodes harvested, and reduce open conversion rate, 90-d reoperation rate, and 30-d mortality compared with LDP. These results indicate that RDP and LDP have similar safety and efficacy in the treatment of malignant pancreatic diseases. Limited by the quality and quantity of the included studies, the above conclusions need to be verified by more multicenter randomized controlled trials with large sample size.

Abstract:Background and Aims The signaling pathways associated with phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and SMAD family member 4 (SMAD4) are closely linked to pancreatic adenocarcinoma (PAAD). However, the relationships of the two genes with the occurrence or prognosis of PAAD are not fully understood. This study was conducted to investigate the expressions PIK3C3 and SMAD in PAAD and their influences on prognosis of patients.Methods The mRNA expressions of PIK3C3 and SMAD4 in PAAD tissue and their corresponding effects on prognosis of PAAD patients were analyzed using UALCAN website. The mRNA expression profiles of PIK3C3 and SMAD4 together with the indicated clinicopathologic data were downloaded from TCGA. The PAAD patients were divided into two clusters based on the combined expression of the PIK3C3 and SMAD4 genes by consensus clustering analysis, the differences in PIK3C3 mRNA or SMAD4 mRNA expression pattern, clinicopathologic variables and overall survival between two clusters were analyzed by Kolmogorov-Smirnov test and Kaplan-Meier method. The protein levels of PIK3C3 and SMAD4 in tissue microarrays containing PAAD and adjacent normal tissue samples were determined by immunohistochemical staining, and the differences of the two proteins in tumor and adjacent normal tissue were evaluated by independent sample t test as well as the area under ROC curve (AUC); the effects of individual PIK3C3 and SMAD4 protein or their combination on the survival of PADD patients were assessed by Kaplan-Meier analysis.Results The results of analysis showed that mRNA expression of PIK3C3 or SMAD4 alone did not change significantly in PAAD and did not significantly affect the prognosis of PAAD patients as well (all P>0.05). There was a high correlation in co-expression between PIK3C3 mRNA and SMAD4 mRNA in PAAD. Between the two clusters of PAAD patients, there were significant differences in mRNA levels of the two genes and age (P<0.05), and the cluster with higher mRNA level of both PIK3C3 and SMAD4 had a better survival probability (P=0.006). The protein levels of both PIK3C3 and SMAD4 were significantly higher in PAAD tissue than those in adjacent normal tissue (both P<0.001), and their AUC were 0.7417 and 0.7991, respectively. PAAD patients with positive expression of PIK3C3 or SMAD4 protein have better survival than those with negative expression of both proteins (P=0.0359).Conclusion This study suggests that PIK3C3 and SMAD4 protein may be the potential biomarkers for diagnosis of PAAD. Combined analysis of PIK3C3 and SMAD4 can be used for predicting the prognosis of PAAD patients.

Abstract:Background and Aims The Gasdermin (GSDM) family consists of 6 important molecules, which are mainly responsible for regulating various biological processes such as pyroptosis. Recent studies have shown that the expression disorder of the GSDM family is involved in the initiation and development of various types of cancer. However, the expression profiles, prognosis value, related function and potential mechanism of GSDM family in gastric cancer remain to be elucidated. This study was conducted to systematically analyze the role of GSDM members in gastric cancer based on bioinformatics approaches.Methods By databases that included ONCOMINE, GEPIA2, UALCAN, Kaplan-Meier Plotter, cBioPortal, TIMER 2.0, and DiseaseMeth, the expression profiles, prognostic value, function enrichment, gene alterations, association with immune cell infiltration, and methylation status of GSDM family were comprehensively analyzed.Result Only DFNA5 in the GSDM family was significantly highly expressed in gastric cancer, and the expression level is 2.479 times higher than that of normal tissues. The expression level of DFNA5 was significantly increased in subtypes of TNM stages 2, 3, and 4, as well as in subtypes of tumor grades 2 and 3. In the GSDM family, only DFNA5 had prognostic value in gastric cancer, and the high expression of DFNA5 indicated poor overall survival. In the GSDM family, the gene alteration frequency was highest in GSDMD (19%), followed by GSDMA, GSDMB, GSDMC (14%), and lowest in DFNA5 (8%) and PJVK (6%). A total of 186 co-expressed genes of GSDM family were further screened in gastric cancer. These molecules may be involved in the tumorgenesis and development process of gastric cancer through signaling pathways related to inflammatory cell apoptosis, chemokine response, and acute inflammatory response. The expression of most GSDM family members was significantly positively correlated with the infiltration of CD4⁺ T cells, CD8⁺ T cells, B cells, neutrophils, macrophages, and dendritic cells, whereas only PJVK is found to have negative association with macrophages and dendrites. The low methylation status of GSDMA and GSDMD in gastric cancer were also detected.Conclusion The expression and function profiles of GSDM family are disordered in gastric cancer. GSDM family members, especially DFNA5, may have the potential to become essential biomarkers for the diagnosis and prognosis of gastric cancer, as well as provide insight for the development of therapeutic targets.

Abstract:Background and Aims The robotic scope holder is a robot-assisted camera holding system, by which, the surgeon can control the scope movement via a joystick, and a precise and stable surgical field of vision can be secured, and meanwhile, one participating surgeon will be spared. So, it is very suitable for meticulous operation in a narrow space such as endoscopic thyroid surgery. Therefore, this study was conducted to investigate the application efficacy of the robotic scope holder in endoscopic transthoracic thyroid surgery.Methods The clinical data of 80 patients with benign thyroid disease undergoing endoscopic transthoracic thyroid surgery from January 2019 to December 2020 in the Department of General Surgery, the Second Affiliated Hospital, Bengbu Medical College were retrospectively analyzed. Of the patients, the scope was held by robotic scope holder in 42 cases (observation group) and was held by the second surgeon in 38 cases (control group). The main clinical variables between the two groups of patients and the subjective perception of the same team of operating surgeons who performed the operations of the two groups were compared.Results There were no significant differences in general data such as age, sex, BMI, tumor diameter, surgical approach and pathology between the two groups of patients (all P>0.05). The operations were successfully completed in all patients, without conversion to open surgery, and conversion from robotic to manual holding. The operative time in observation group was significantly shorter than that in control group (P<0.05). There were no significant differences in the intraoperative blood loss, volume of postoperative drainage, drainage time, length of postoperative hospital stay, hospitalization cost and incidence of complications between the two groups (all P>0.05). No serious postoperative complications were noted in both groups of patients. Questionnaire survey on the subjective perception of the operating surgeons showed that observation group was significantly superior to control group in terms of visual field accuracy and visual field stability, as well as the sense of operation during surgery (all P<0.05), while there was no statistical significance with regard to visual fatigue between the two groups (P>0.05).Conclusion The application of robotic scope holder is safe and feasible in the operation for benign thyroid diseases. Compared with manual holding, the complexity of intraoperative procedures is relatively increased, but the number of participating surgeons is reduced, the operative time is shortened. It can provide a more accurate and stable surgical vision for surgeon and thereby improve the surgical efficiency.

Abstract:Background and Aims With the development of concept of fast-track surgery, perioperative multimodal analgesia has been gradually accepted. Among them, preemptive analgesia is a common method. This study was conducted to determine the efficacy and safety of parecoxib sodium preemptive analgesia in laparoscopic cholecystectomy (LC) through a systematic review and Meta-analysis.Methods The randomized controlled trails or observational studies comparing the preoperative intravenous injection of parecoxib sodium (preemptive analgesia) and without intravenous use of parecoxib sodium (blank control) or intravenous injection of parecoxib sodium at the end of operation (postoperative analgesia group) in LC were collected by searching several Chinese and English databases. The retrieval time from inception to May 2021. After the quality evaluation and data extraction of the included studies, Meta-analysis was performed by using RevMan 5.1 and Stata 12.0 software.Results Thirteen articles in Chinese and English were finally included, involving 974 patients. Results of Meta-analysis showed that the visual analogue score (VAS) at postoperative 2, 4, 6, 8, 12 and 24 h were lower in preemptive analgesia group than those in blank group (all P<0.05) and postoperative analgesia group (partial P<0.05); the number of patients requiring additional painkillers in preemptive analgesia group was less than that in blank group or postoperative analgesia group, and the incidence of postoperative adverse reactions (nausea and vomiting) in the preemptive analgesia group was lower than that in the blank group (all P<0.05). Results of publication bias sensitivity analysis based on the number of cases requiring additional painkillers and the incidence of postoperative adverse events showed that there was no significant publication bias (both P>0.05), and this method would not change the results of the initial overall analysis.Conclusion Preemptive analgesia with intravenous injection of parecoxib sodium in LC has netter analgesic efficacy with low adverse effect. It provides a safe and effective alternative for clinical multimode analgesia.

Abstract:Acute pancreatitis (AP) is an acute chemical inflammation of the pancreas, characterized by pancreatic edema, bleeding and necrosis caused by internal digestion, and it is a relatively common digestive system disease in clinical practice. Studies have found that AP is associated with cardiovascular system injury, and the degree of injury is positively correlated with the severity of AP. At present, the symptomatic supportive treatment is the main therapeutic approach for AP, and the control of pancreatitis itself is the focus of treatment. Here, the authors address the clinical manifestations of AP-induced cardiovascular injury and the research progress of relevant mechanisms, so as to provide new ideas for timely preventing AP-induced cardiovascular injury as well as reducing the mortality rate of AP.

Abstract:Acute pancreatitis (AP) is one of the common digestive system emergencies in clinical practice. Its pathogenesis is complex and has not yet been fully elucidated, and there is also no specific treatment. The finding of creamy ball epidermal growth factor 8 (MFG-E8) has provided a new direction and approach for the diagnosis and treatment of AP. Studies have shown that MFG-E8 is involved in the pathophysiological process of AP and may be the endogenous protection medium of AP. At the same time, the high expression of MFG-E8 in serum of patients with AP may be used as a potential biomarker to evaluate the effectiveness of AP treatment. In recent years, with the deepening of research on the pathophysiological mechanism of AP, calcium-mediated mechanism for acinar cell injury and death has been confirmed, as well as the necessity of eliminating apoptotic and necrotic cells in the AP inflammatory response, and the importance of mitochondrial permeability transition holes and intestinal mucosal barrier in AP. MVG-E8 plays an important role in the occurrence and development of AP. On the one hand, MFG-E8 relieves AP by improving the pancreatic structure, restoring the regeneration function of pancreatic acinar cells and removing the necrotic acinus, and reducing the serum amylase and lipase in AP animal model mice. On the other hand, MFG-E8 promotes macrophage reprogramming through a mediated inflammatory signaling pathway to reduce the production of pro-inflammatory cytokines and thus inhibits AP inflammatory response. At the same time, MFG-E8 can repair the structure and function of mitochondria by improving mitochondrial biogenesis and increasing mitochondrial fusion, thereby reduces oxidative stress response and prevents AP progression. In addition, MFG-E8 also plays an important role in repairing the intestinal mucosal barrier, reducing intestinal bacterial translocation, and improving intestinal ischemia-reperfusion. As a lipophilic anti-inflammatory glycoprotein, MFG-E8 has multiple biological activities against autoimmune and inflammatory diseases, and has multiple biological functions by binding to integrin receptor αvβ3/5 and phosphatidylserine, and is involved in the cellular processes such as maintenance and repair of intestinal epithelial cells, angiogenesis, adhesion and proliferation between tumor cells, and the clearance of apoptotic cells. At present, studies have found that MFG-E8 plays an important role in a variety of diseases, such as infectious diseases, tumors, nervous system diseases, autoimmune diseases. However, the role of MFG-E8 in AP has been recognized only in recent years, and the specific mechanism is still in the preliminary understanding stage and not completely clear. Besides, the current literature reports mostly focus on the inflammatory reaction, mitochondrial function recovery and intestinal mucosal barrier protection, and further research is needed for its role in other pathological mechanisms of AP, such as pancreatic microcirculation. Second, there is no definitive conclusion about the timing, applicable stage and specific dose-effect relationship of MFG-E8 intervention on AP. However, targeting MFG-E8 is a new strategy for the treatment of AP. Therefore, it is important to further study the role of MFG-E8 in the pathogenesis of AP for the diagnosis and treatment of AP. Therefore, in this paper, the structure and function of MFG-E8 and its mechanism of action in AP are reviewed, and the related literature concerning treatment of AP with MFG-E8 as the target is summarized, which will provide a new breakthrough point for the clinical diagnosis and treatment of AP in the future.