Risk Factors and Clinical Impacts of Post-Pancreatectomy Acute Pancreatitis After Pancreaticoduodenectomy: A Single-Center Retrospective Analysis of 298 Patients Based on the ISGPS Definition and Grading System.

Background: The definition and grading system of post-pancreatectomy acute pancreatitis (PPAP) has recently been proposed by ISGPS. This study aimed to put this definition and classification into practice and investigate the potential risk factors and clinical impacts of PPAP. Methods: Demographic and perioperative data of consecutive patients who underwent pancreaticoduodenectomy (PD) from January 2019 to July 2021 were collected and analyzed retrospectively. The diagnostic criteria of PPAP published by ISGPS, consisting of biochemical, radiologic, and clinical parameters, were adopted. The risk factors were analyzed by univariate and multivariate analyses. Results: A total of 298 patients were enrolled in this study, and the total incidence of PPAP was 52.4% (150 patients). Stratified by clinical impacts of PPAP, the incidences of grades B and C PPAP were 48.9% and 3.5%, respectively. PPAP after PD was significantly associated with pancreatic fistula and other unfavorable complications. Soft pancreatic texture (OR 3.0) and CRP ≥ 180 mg/L (OR 3.6) were the independent predictors of PPAP, AUC 0.613. Stratified by the grade of PPAP, soft pancreatic texture (OR 2.7) and CRP ≥ 180 mg/L (OR 3.4) were the independent predictors of grade B PPAP, and soft pancreatic texture (OR 19.3), operation duration >360 min (OR 13.8), and the pancreatic anastomosis by using conventional duct to mucosa methods (OR 10.4) were the independent predictors of grade C PPAP. PPAP complicated with pancreatic fistula significantly increased the severe complications and mortality compared to only PPAP occurrence. Conclusion: PPAP was not an uncommon complication after PD and was associated with unfavorable clinical outcomes, especially since it was complicated with pancreatic fistula. Soft pancreatic texture and CRP ≥ 180 mg/L were the independent predictors of PPAP. Higher-volume multicenter and prospective studies are strongly needed.

Necrolytic migratory erythema is an important visual cutaneous clue of glucagonoma.

Glucagonoma is an extremely rare neuroendocrine tumor that arises from pancreatic islet alpha cells. Although glucagonoma is usually accompanied by a variety of characteristic clinical symptoms, early diagnosis is still difficult due to the scarcity of the disease. In this study, we present the cumulative experiences, clinical characteristics and treatments of seven patients diagnosed with glucagonoma during the past 10 years at the First Affiliated Hospital of Xi'an Jiaotong University. The seven patients in our cohort consisted of six females and one male with an average diagnosis age of 40.1 years (range 23-51). The average time from onset of symptoms to diagnosis of glucagonoma was 14 months (range 2-36 months). All the patients visited dermatology first for necrolytic migratory erythema (NME) 7/7 (100%), and other presenting symptoms included diabetes mellitus (DM) 4/7 (57%), stomatitis 2/7 (28%), weight loss 4/7 (57%), anemia 4/7 (57%), diarrhea 1/7 (14%), and DVT1/7 (14%). Plasma glucagon levels were increased in all patients (range 216.92-3155 pg/mL) and declined after surgery. Imaging studies revealed that four of seven patients had liver metastasis. Six of seven patients received surgical resection, and all of them received somatostatin analog therapy. Symptoms improved significantly in 6 out of 7 patients. Three of seven patients died of this disease by the time of follow-up. Our data suggest that if persistent NME is associated with DM and high glucagon levels, timely abdominal imaging should be performed to confirm glucagonoma. Once diagnosed, surgery and somatostatin analogs are effective for symptom relief and tumor control.

LINC00963/miR-4458 regulates the effect of oxaliplatin in gastric cancer by mediating autophagic flux through targeting of ATG16L1.

Oxaliplatin resistance is the greatest obstacle to the management of local recurrence in gastric cancer patients after surgery. Accumulating evidence has suggested that inhibiting autophagy may be a novel approach for reversing resistance to oxaliplatin treatment. In this manuscript, we aimed to investigate the role of LINC00963 in regulating autophagy and oxaliplatin resistance. qRT-PCR, immunochemistry staining, and western blotting were used to detect gene expression. Plasmids were used to up- and downregulate the expression of LINC00963 and miR-4458. A caspase 3/7 activity kit and flow cytometry were used to detect the apoptosis rate. CCK8 and Transwell assays were used to test cell proliferation and migration, respectively. Transmission electron microscopy and a dual fluorescent lentivirus autophagy system were used to evaluate autophagic flux. Dual luciferase reporter gene assays and RNA pulldown assays were used to evaluate the potential crosstalk. LINC00963 was highly expressed in gastric cancer patients and cell lines. In addition, high LINC00963 expression was found to be associated with poor prognosis and local recurrence in gastric cancer patients, indicating that LINC00963 might be involved in oxaliplatin resistance. Moreover, we found that LINC00963 was aberrantly highly expressed in oxaliplatin-resistant SGC-7901 (SGC-7901-R) cells and promoted proliferation and migration and reduced the apoptosis rate in SGC-7901-R cells. Furthermore, among all potential target microRNAs, miR-4458 was found to be negatively regulated by LINC00963 both in vivo and in vitro. In addition, miR-4458 overexpression led to impaired proliferation and migration and enhanced cell apoptosis and G1 arrest in SGC-7901-R cells. Further RNA pulldown and dual luciferase reporter gene assays indicated the interaction between LINC00963 and miR-4458. Moreover, we found enhanced autophagic flux in SGC-7901-R cells compared with SGC-7901 cells; in addition, an inhibitor of autophagy induced apoptosis in SGC-7901-R cells. Then, we found that downregulation of LINC00963 expression and upregulation of miR-4458 expression significantly suppressed autophagic flux in SGC-7901-R cells. Based on starBase V3.0 and dual luciferase reporter gene assays, we predicted and confirmed that ATG16L1 might be the target of miR-4458 to regulate autophagy. In conclusion, LINC00963 and miR-4458 are potential biomarkers for predicting the overall survival of gastric cancer patients. Moreover, targeting LINC00963 to inhibit autophagic flux sensitizes gastric cancer cells to oxaliplatin treatment, suggesting that it is a potential novel therapeutic target for improving oxaliplatin sensitivity.

Linc01559 Served as a Potential Oncogene and Promoted Resistance of Hepatocellular Carcinoma to Oxaliplatin by Directly Sponging miR-6783-3p.

BACKGROUND: Oxaliplatin (L-OHP)-based chemotherapy, such as FOLFOX4 (5-fluorouracil, leucovorin, and L-OHP), improves the prognosis of patients with late-stage Hepatocellular Carcinoma (HCC). However, the development of resistance to L-OHP leads to the failure of chemotherapy. The aim of this study was to investigate the role of linc01559 and miR-6783-3p in regulating resistance to L-OHP. METHODS: Quantitative reverse transcription-polymerase chain reaction was used to determine the expression profile. The Cell Counting Kit-8 test and wound healing assay were also used. Dual-luciferase reporter gene assay, RNA pull-down assay, and RNA immunoprecipitation were used to evaluate the interaction between linc01559 and miR-6783-3p. RESULT: linc01559 expression was associated with response to FOLFOX4, as well as miR-1343-3p and miR- 6783-3p expression in vivo. A nomogram, including linc01559 and miR-1343-3p, precisely and accurately predicted the overall survival of patients with HCC. Regarding the in vitro tests, linc01559 showed higher expression in L-OHP-resistant cell lines, whereas miR-6783-3p was downregulated. Knockdown of linc01559 led to decreased proliferation and migration ability, and increased expression of miR-6783-3p; however, it did not influence the expression of miR-1343-3p. We also found that linc01559 directly interacted with miR-6783-3p. Furthermore, linc01559 and miR-6783-3p regulated the viability of L-OHP-resistant cells following treatment with L-OHP. CONCLUSION: linc01559 promoted the proliferation of HCC by sponging miR-6783-3p. This suggests that linc01559/miR-6783-3p may be key factors in regulating resistance and response to L-OHP. Moreover, they may be potential therapeutic targets for improving sensitivity to L-OHP in patients with HCC.

Comprehensive analysis and experimental verification of LINC01314 as a tumor suppressor in hepatoblastoma.

Hepatoblastoma (HB), as a common pediatric liver malignancy, is composed of a variety of subgroups with different clinical outcomes. Long-noncoding RNA (lncRNA) has crucial roles in cancer biology. However, the association between lncRNA and HB has not been fully investigated. In this study, we screened lncRNA expression profiles that were annotated from the GSE75271 dataset. A total of 225 differentially expressed lncRNAs (DELs) were identified based on comparison between three prognostic subgroups, and seven of them (XR_241302, XR_923061, NR_038322, XR_951687, XR_934593, NR_120317 and XR_93406) that exhibited highly predictive accuracies were selected for functional analysis. Weighted gene correlation network analysis (WGCNA) was employed to predict the biological functions of the seven DELs. The Hippo-YAP signaling pathway was predicted to be the most statistically significant predicted pathway associated with the seven DELs. Furthermore, we performed in vitro experiments to validate the biological function of one DEL, NR_120317 (LINC01314). Our results showed decreased proliferation and migration activities of HB cells overexpressing LINC01314. Moreover, mechanistic investigations revealed that LINC01314 overexpression inhibited nuclear translocation of YAP, by inducing MST1 expression and promoting phosphorylation of LATS1 and YAP, consequently downregulating the expression of cell cycle regulatory proteins (MCM7 and cyclin D1). Taken together, our findings provide evidence for LINC01314 as a potential biomarker and anti-cancer therapeutic target in patients with HB.

Identification of differentially expressed genes, lncRNAs and miRNAs which are associated with tumor malignant phenotypes in hepatoblastoma patients.

Hepatoblastoma (HB) is one of the most common hepatic malignancies in the pediatric population. HB are composed of a variety of tumors, which derived from different origins and had varying clinical outcomes. However, the unclear underlying mechanisms of HB limited exploring novel biomarkers and effective therapeutic targets. We searched microarray datasets on Gene Expression Omnibus (GEO) database and selected GSE75271 and GSE75283 datasets for comprehensive analysis. Weighted gene correlation network analysis (WGCNA) was employed to identify genes which were associated with tumor malignant phenotypes, including HB subtypes, Cairo classification and tumor stage. Coexpression analysis of identified genes was also performed and lncRNA-miRNA-mRNA network was finally conducted. Our results showed that a total of 22 lncRNAs, 13 miRNAs and 66 mRNAs were identified to be associated with tumor malignant phenotypes. Mechanistically, these molecules might promote the malignant phenotypes via regulating metabolic pathways. Among of them, 6 miRNAs (hsa-miR-106b, hsa-miR-130b, hsa-miR-19a, hsa-miR-19b, hsa-miR-20a and hsa-miR-301a), 8 lncRNAs (NR_102317, XR_245338, XR_428373, XR_924945, XR_929728, XR_931611, XR_935074 and XR_946696), and 6 mRNAs (EGFR, GAREM, INSIG1, KRT81, SAR1B and SDC1) were selected to conduct a lncRNA-miRNA-mRNA network. Taken together, our findings provide evidence for exploring molecular mechanisms of HB. Those identified malignant phenotype-associated molecules might be potential biomarkers and anti-cancer therapeutic targets in future.

Effect of coronary-caval shunt combined with partial pericardial devascularisation on oesophageal and gastric variceal bleeding caused by portal hypertension.

BACKGROUND/AIMS: To investigate the effect of coronary-caval shunt combined with partial pericardial devascularisation on oesophageal and gastric variceal bleeding caused by portal hypertension. MATERIALS AND METHODS: Between January 2005 and January 2015, coronary-caval shunt operations combined with partial pericardial devascularisation were performed electively on 15 cirrhotic patients with portal hypertension. All of these patients had a history of oesophageal and gastric variceal bleeding. The clinical and follow-up data of these patients were reviewed retrospectively. Another 15 patients receiving non-surgical treatments in a similar follow-up period were used as controls to compare the preventive effects of different treatment strategies on rebleeding. RESULTS: All of the 15 surgical procedures were performed successfully, and no severe complications occurred. Among these, autogenous splenic veins were used as bridge vessels in 6 cases, whereas the coronary vein and inferior vena cava were anastomosed directly in 9 cases. All surgical patients were followed up from 5 months to 10 years with an average of 63 months; 2 patients died due to liver failure induced by reactivation of hepatitis B virus and oesophageal/gastric variceal rebleeding, respectively. The rebleeding rates for surgical and non-surgical patients were 6.7% and 66.7% (p < 0.05), respectively, whereas the 5-year survival rates for the two groups were 85.7% and 33.3% (p < 0.05), respectively. CONCLUSION: Patients with oesophageal and gastric variceal bleeding caused by portal hypertension may benefit from a coronary-caval shunt combined with partial pericardial devascularisation due to decreased coronary vein pressure, unaffected hepatic blood inflow, and reduced incidence of rebleeding.

Extracellular miRNA-21 as a novel biomarker in glioma: Evidence from meta-analysis, clinical validation and experimental investigations.

Evidence is accumulating highlighting the importance of extracellular miRNA as a novel biomarker for diagnosing various kinds of malignancies. MiR-21 is one of the most studied miRNAs and is over-expressed in cancer tissues. To explore the clinical implications and secretory mechanisms of extracellular miR-21, we firstly meta-analyzed the diagnostic efficiency of extracellular miR-21 in different cancer types. Eighty-one studies based on 59 articles were finally included. In our study, extracellular miR-21 was observed to exhibit an outstanding diagnostic accuracy in detecting brain cancer (area under the summary receiver operating characteristic curve or AUC = 0.94), and this accuracy was more obvious in glioma diagnosis (AUC = 0.95). Our validation study (n = 45) further confirmed the diagnostic and prognostic role of miR-21 in cerebrospinal fluid (CSF) for glioma. These findings inspired us to explore the biological function of miR-21. We next conducted mechanistic investigations to explain the secretory mechanisms of extracellular miR-21 in glioma. TGF-ß/Smad3 signaling was identified to participate in mediating the release of miR-21 from glioma cells. Further targeting TGF-ß/Smad3 signaling using galunisertib, an inhibitor of the TGF-ß type I receptor kinase, can attenuate the secretion of miR-21 from glioma cells. Taken together, CSF-based miR-21 might serve as a potential biomarker for diagnosing brain cancer, especially for patients with glioma. Moreover, extracellular levels of miR-21 were affected by exogenous TGF-ß activity and galunisertib treatment.

Prognostic significance of preoperative platelet count in patients with gallbladder cancer.

AIM: To investigate the prognostic value of preoperative platelet count (PLT) in patients with primary gallbladder cancer (GBC). METHODS: The clinical data of 223 GBC patients after surgery was retrospectively reviewed. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cutoff point for PLT. Univariate and multivariate survival analyses were performed to identify the factors associated with the prognosis. RESULTS: The ROC curve showed that the optimum cutoff point for PLT was 178 × 10(9)/L, and the entire cohort was stratified into group A with PLT > 178 × 10(9)/L and group B with PLT ≤ 178 × 10(9)/L. Group A had a better survival than group B (P < 0.001). There was an obvious difference between the two groups in terms of the differentiation degree, advanced tumor stage, lymph node metastasis (P < 0.001) and pathological type (P < 0.05). The univariate analysis demonstrated that tumor location, differentiation degree, TNM stage, Nevin stage, lymph node metastasis and PLT were associated with overall survival (P < 0.001). In the multivariate analysis, PLT (P = 0.032), lymph node metastasis (P = 0.007), tumor location (P < 0.001) and TNM stage (P = 0.005) were independent prognostic factors. CONCLUSION: PLT is closely correlated with GBC prognosis and could be used to identify the population with a poorer prognosis after surgery.

Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene. Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China. This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China, and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies. METHODS: An epidemiological investigation of family members was done to collect the general information. A retrospective study of clinical VHL cases was launched to collect the relative clinical data. Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family. The VHL gene screening was performed by directly analyzing DNA sequence output. At last, we summarized the VHL gene mutation in China by the literature review. RESULTS: A five-generation North-western Chinese family afflicted with VHL disease was traced in this research. The family consisted of 38 living family members, of whom nine were affected. The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas (8), central nervous system hemangioblastomas (3), pancreatic endocrine tumors (2), pancreatic cysts (3), renal cysts (4), and paragangliomas (2). A linkage analysis resulted in a high maximal LOD score of 8.26 (theta = 0.0) for the marker D3S1263, which is in the same chromosome region as VHL. Sequence analysis resulted in the identification of a functional C>T transition mutation (c. 499 C>T, p.R167W) located in exon 3 of the 167 th codon of VHL. All affected individuals shared this mutation, whereas the unaffected family members and an additional 100 unrelated healthy individuals did not. To date, 49 mutations have been associated with this disease in Chinese populations. The most frequent VHL mutations in China are p.S65 W, p.N78 S, p.R161Q and p.R167 W. CONCLUSIONS: The results supported the notion that the genomic sequence that corresponds to the 167 th residue of VHL is a mutational hotspot. Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.

[Research progress of emodin anti-gallbladder carcinoma].

Emodin is an effective active ingredient extracted from Chinese herbal medicine, which has the function of antimicrobial, anti-inflammatory, antioxidant and scavenging oxygen free radicals, inhibiting platelet aggregation, improving microcirculation, protecting various organs and tissues as well as a wide range of anti-tumor effect. Primary biliary gallbladder is a common malignant tumor resection rate and lack of effective adjuvant treatment. It has been confirmed that emodin has broad spectrum antitumor effect, whereas, whether it has curative effect in the treatment of gallbladder carcinoma there is no reliable clinical trials confirmed that its resistance to gallbladder carcinoma function needs further experimental research. In this review, we report the research progress of emodin anti-gallbladder carcinoma.

Down-regulation of FoxM1 inhibits viability and invasion of gallbladder carcinoma cells, partially dependent on inducement of cellular senescence.

AIM: To investigate the effect of knockdown of Forkhead box M1 (FoxM1) on the proliferation and invasion capacities of human gallbladder carcinoma (GBC)-SD cells. METHODS: Four FoxM1 shRNAs were transfected into GBC-SD cells with Lipofectamine 2000 to select the appropriate shRNA for down-regulation of FoxM1. A recombinant lentivirus for shFoxM1 (Lv-shFoxM1), which expresses FoxM1-specific shRNA, and a negative control carrying green fluorescent protein, which expresses a scrambled RNA, were constructed. After transfection with the recombinant adenovirus and screened with puromycin, RT-PCR and Western blot were utilized to evaluate the inhibition efficiency. Cell viability was evaluated by MTT assay, and cell migration and invasion were assessed using the Transwell system. Cells were suspended in serum-free medium and seeded into Transwell inserts either uncoated (for migration assay) or coated (for invasion assay) with growth factor-reduced Matrigel. To verify the involvement of FoxM1 in the senescence of tumor cells, staining of senescence ß-galactosidase (SA ß-gal), the widely used biomarker of cellular senescence, was also performed. RESULTS: After successful transfection of four FoxM1 small interfering RNAs (shRNAs) with Lipofectamine 2000, the shF1822 was selected as the most appropriate shRNA according to its obvious inhibitory effect. The recombinant adenovirus was then constructed with the shF1822 and successfully transfected into the GBC-SD cells, resulting in the significant inhibition of FoxM1 expression at both the mRNA and protein levels, compared with the negative control (P < 0.05). After transfection, down-regulation of FoxM1 significantly inhibited cell viability according to the MTT assay (P < 0.05). In addition, Transwell migration and invasion assays also suggested the suppression of invasion ability of the transfected cells. SA ß-gal staining showed that down-regulation of FoxM1 could induce more senescent GBC cells (P < 0.05), suggesting the possible involvement of the senescence process of the FoxM1-deficient cells in GBC. CONCLUSION: FoxM1 is functionally involved in viability of GBC cells, partially dependent on the inducement of cellular senescence, and is a potential target for GBC therapy.

Epidemiological study of a von Hippel-Lindau family in northwest China.

von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBL) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts. We encountered a large VHL family in northwest China and conducted a systematic screening of the family members based on their epidemiological and clinical characteristics. A self-designed questionnaire was used to collect the general sociodemographic and health information of the family members. For the preliminary family screening, physical examination and abdomen B ultrasonography were performed. The suspected patients were subjected to cranial computerized tomography and fundus examination. The clinical data of the patients with confirmed VHL disease were collected from hospital records. A total of 63 lineal descendants in six generations were observed in the family (generations O, A, B, C, D, E), including 9 dead suspected cases (6 males, 3 females) and 10 living cases (2 males, 8 females). Among the 10 living cases, 4, 2, 1, 3, 4, 8, and 2 manifested HBLs of the CNS, PETs, RCC, pancreatic cysts, renal cysts, pheochromocytomas (4 hemi and 4 bilateral), and paragangliomas, respectively. Data showed that the morbidity of VHL disease in generation C was lower than that in generation B, but the age of onset was younger. This study is the first to report VHL disease in northwest China and VHL-associated PET cases in Chinese. Therefore, follow-up checkups of the family should be focused on younger generations. Proper family screening protocols should be followed for the treatment of patients with VHL disease.

Dubin-Johnson syndrome with cholecystolithiasis and choledocholithiasis.

INTRODUCTION: Dubin-Johnson syndrome (DJS) is unusual during common medical work. Moreover, cholecystolithiasis and choledocholithiasis involvement has not been reported. PRESENTATION OF CASE: We describe a case of DJS complicated by cholecystolithiasis and choledocholithiasis. A 49-year-old man accepted by outpatient complained with intermittent cramping pain in right upper abdomen. It is diagnosed as cholecystolithiasis and choledocholithiasis. We found the dark greenish liver when the operation was performed. Liver biopsy confirms the DJS. DISCUSSION: It is the firstly reported case DJS related to the cholecystolithiasis and choledocholithiasis. CONCLUSION: Cholecystolithiasis and choledocholithiasis may develop in DJS. DJS is possible a reason for cholecystolithiasis and choledocholithiasis, not just likely a chance occurrence.