SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing promotes resistance of pancreatic cancer to gemcitabine.

Serine/arginine-rich splicing factor 3 (SRSF3) regulates mRNA alternative splicing of more than 90% of protein-coding genes, providing an essential source for biological versatility. This study finds that SRSF3 expression is associated with drug resistance and poor prognosis in pancreatic cancer. We also find that SRSF3 regulates ANRIL splicing and m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrate that m6A methylation on lncRNA ANRIL is essential for the splicing. Moreover, our results show that SRSF3 promotes gemcitabine resistance by regulating ANRIL's splicing and ANRIL-208 (one of the ANRIL spliceosomes) can enhance DNA homologous recombination repair (HR) capacity by forming a complex with Ring1b and EZH2. In conclusion, this study establishes a link between SRSF3, m6A modification, lncRNA splicing, and DNA HR in pancreatic cancer and demonstrates that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.

A multicenter clinical study: personalized medication for advanced gastrointestinal carcinomas with the guidance of patient-derived tumor xenograft (PDTX).

BACKGROUND: Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. METHODS: Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. RESULTS: Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. CONCLUSION: The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.

CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer.

BACKGROUND: Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. METHODS: RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. RESULTS: CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. CONCLUSIONS: The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients.

SHCBP1 interacting with EOGT enhances O-GlcNAcylation of NOTCH1 and promotes the development of pancreatic cancer.

O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells.

Disordered Gut Microbiota in Children Who Have Chronic Pancreatitis and Different Functional Gene Mutations.

OBJECTIVES: Chronic pancreatitis (CP) is a serious condition whose pathogenic mechanism is unclear. Interactions of host genetic factors with gut microbiota have a role, but little is known, especially in children with CP (CCP), in which the external factors are less important. Our objective was to identify the main gut microbiota genera in CCP and to characterize the functional mutations of these patients. METHODS: We used 16S rRNA sequencing to compare the gut microbiota of healthy controls with patients who had CCP and different functional gene mutations. RESULTS: CCP is characterized by gut microbiota with remarkably reduced alpha diversity. Receiver operating characteristic curve analyses indicated that the abundances of 6 genera-Faecalibacterium, Subdoligranulum, Phascolarctobacterium, Bifidobacterium, Eubacerium, and Collinsella-were significantly decreased in CCP, with an area under curve (AUC) of 0.92 when considering all 6 genera together. Functional analysis of gut microbiota in CCP indicated reduced ribosomal activity, porphyrin and chlorophyll metabolism, starch and sucrose metabolism, and aminoacyl-tRNA biosynthesis, but an enrichment of phosphotransferase system pathways. The abundance of Butyricicoccus was significantly decreased in CCP in the presence of CFTR mutations when combined with mutations in CASR, CTSB, SPINK1, and/or PRSS1. The abundance of Ruminococcaceae was significantly increased in CCP when there were mutations in CASR, CTSB, SPINK1, and/or PRSS1. Patients with CCP but no gene mutations had greater abundances of Veillonella and reduced abundances of Phascolarctobacterium. DISCUSSION: CCP is associated with a depletion of probiotic gut microbiota, and CCP patients with different functional gene mutations have different gut microbiota.

Robotic pancreatectomy for solid pseudopapillary tumors in the pancreatic head: A propensity score-matched comparison and analysis from a single center.

BACKGROUND: Robotic surgery is the most advanced minimally invasive technique for the treatment of complicated solid pseudopapillary tumors (SPT). The aim of this study is to evaluate feasibility of robotic surgery for the treatment of SPTs in the pancreatic head. METHODS: A retrospective analysis of the clinical data of 83 SPTs in pancreatic head was conducted. Clinical characteristics were extracted and propensity score matching (PSM) was used to compare and evaluate mid-term outcomes of the two techniques. RESULTS: Pancreaticoduodenectomy (PD), duodenum-preserving partial pancreatic head resection (DPPHR-P) and tumor enucleation (En) were performed in 51, 24, and 8 patients, respectively. The robotic approach was associated with a significantly lower volume of blood loss, lower need for transfusion, and faster time to post-surgery recovery. Major complications and costs were comparable for both techniques. CONCLUSION: A robotic approach provides an alternative to open surgery for SPTs in the pancreatic head without increasing the incidence of clinically relevant pancreatic fistula (CRPF) or other major complications and with good patient outcomes.

Higher body mass index deteriorates postoperative outcomes of pancreaticoduodenectomy.

BACKGROUND: Previous studies presented controversies in impact of body mass index (BMI) on perioperative complications in pancreatectomy, and mainly focused on Western population. This study aimed to explore the impact of BMI on perioperative outcomes in Chinese patients undergoing pancreaticoduodenectomy. METHODS: Seven hundred and seven adult patients undergoing open pancreaticoduodenectomy between January 2005 and December 2016 at Ruijin Hospital were studied retrospectively and categorized as obese (BMI ≥25 kg/m2), overweight (BMI ≥23 kg/m2 and <25 kg/m2), or normal weight (BMI ≥18.5 kg/m2 and <23 kg/m2). Associations of these BMI groups with perioperative outcomes were evaluated. RESULTS: The overweight and obese groups experienced higher risk of clinically related postoperative pancreatic fistula (CR-POPF) (7.6% vs. 9.9% vs. 17.6%, P = 0.002) and re-operation (1.1% vs. 2.5%  vs. 5.1%, P = 0.017), and longer systemic inflammation response syndrome (SIRS) duration [2 (1-9) d vs. 2 (1-7) d vs. 3 (1-10) d, P = 0.003] and postoperative hospital stay [19 (2-84) d vs. 19 (7-158) d vs. 23 (8-121) d, P = 0.023] than the normal weight group did. The multiple logistic regression models showed obese as an independent risk factor for CR-POPF (P = 0.013). The multiple linear regression analysis confirmed BMI as a predictor for prolonged postoperative hospital stay (P = 0.005). CONCLUSIONS: Higher BMI results in higher morbidity of Chinese patients undergoing open pancreaticoduodenectomy. Pancreaticoduodenectomy is still a safe surgery procedure for overweight and obese patients, with intensive perioperative management.

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma.

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.

Silencing of long noncoding RNA LINC00958 prevents tumor initiation of pancreatic cancer by acting as a sponge of microRNA-330-5p to down-regulate PAX8.

Pancreatic cancer (PC) represents a relatively rare but severe malignancy worldwide. Accumulated studies have emphasized the potential of long noncoding RNA (lncRNA) as therapeutic strategies for several human cancers. Thus, we aimed to investigate whether a novel non-coding RNA regulatory circuitry involved in PC. Aberrantly expressed lncRNAs and mRNAs were screened out of microarray database. Following the determination of RNA expression, PANC-1 and BxPC-3 PC cells were adopted, after which the expression of miR-330-5p, PAX8 and LINC00958 were subsequently altered. RNA crosstalk was validated by dual-luciferase reporter gene assay. In order to detect whether LINC00958 could act as ceRNA to competitively sponge miR-330-5p and regulate PAX8, subcellular location of LINC00958 and interaction between LINC00958 and miR-330-5p were measured by FISH and RNA pull down respectively. The epithelial mesenchymal transition (EMT) process, cell invasion, and tumor growth were determined in vitro and in vivo. LINC00958 and PAX8 were up-regulated, while miR-330-5p was down-regulated during PC. LINC00958 mainly expressed in the cytoplasm and LINC00958 competitively sponged miR-330-5p. Upregulated miR-330-5p or downregulated PAX8 inhibited the EMT process as well as the invasion and metastasis ability of the PC cells. Moreover, the results indicated that miR-330-5p negatively targeted PAX8, and LINC00958 ultimately showcasing its ability to bind to miR-330-5p through its interaction with AGO2. Therefore, silencing of LINC00958 may bind to miR-330-5p to inhibit PAX8 in a competitive fashion, thereby preventing the progression of PC.

Baicalein induces the apoptosis of HCT116 human colon cancer cells via the upregulation of DEPP/Gadd45a and activation of MAPKs.

Baicalein has efficient antitumor properties and has been reported to promote the apoptosis of several human cancer cell lines. Decidual protein induced by progesterone (DEPP), a transcriptional target of Forkhead Box O, was originally identified from the human endometrial stromal cell cDNA library. However, the expression and physiological functions of DEPP in human colon cancer cells remain to be fully elucidated. In the present study, it was reported that baicalein stimulated apoptosis and morphological changes of HCT116, A549 and Panc­1 cells in a dose-dependent manner. It also upregulated the mRNA and protein levels of DEPP and growth arrest and DNA damage-inducible 45α (Gadd45a). In addition, the overexpression of DEPP promoted mitogen-activated protein kinase (MAPK) phosphorylation. To further investigate the role of DEPP and Gadd45a in baicalein-induced apoptosis, HCT116 cells were transfected with small interfering RNA against either DEPP or Gadd45a as in vitro models. Through an Annexin V/PI double staining assay, it was observed that baicalein-induced apoptosis was impaired by the inactivation of either DEPP or Gadd45a, which in turn restricted the baicalein-induced activation of caspase­3 and caspase­9 and phosphorylation of MAPKs. In addition, the inhibition of c­Jun N­terminal kinase (JNK)/p38 activity with SP600125/SB203580 decreased the expression of Gadd45a, whereas the inactivation of extracellular signal-regulated kinase with SCH772984 had no effect on the expression of Gadd45a. Taken together, these results demonstrated that baicalein induced the upregulation of DEPP and Gadd45a, which promoted the activation of MAPKs with a positive feedback loop between Gadd45a and JNK/p38, resulting in a marked apoptotic response in human colon cancer cells. These results indicated that baicalein is a potential antitumor drug for the treatment of colon cancer.

Robot-assisted duodenum-preserving pancreatic head resection with pancreaticogastrostomy for benign or premalignant pancreatic head lesions: a single-centre experience.

BACKGROUND: The purpose of this study was to compare short- and long-term outcomes of modified robot-assisted duodenum-preserving pancreatic head resection (RA-DPPHR) versus robot-assisted pancreaticoduodenectomy (RA-PD). METHODS: Matched for age, sex, ASA classification, tumour size, history of abdominal surgery and pathological type, 34 patients undergoing RA-DPPHR and 34 patients undergoing RA-PD between January 2010 and December 2016 were retrospectively analyzed. RESULTS: The RA-DPPHR group had shorter surgical time (188.2 vs. 386.3 min, p < 0.001) and less blood loss (168.2 vs. 386.3 ml, p = 0.026) but higher complication rate (47.1% vs. 32.4%, p = 0.105) and pancreatic fistula rate (32.4% vs. 17.6%, p = 0.161). Hospital mortality was 2.9%. Exocrine insufficiency was lower in the RA-DPPHR group (3.0% vs. 24.2%, p = 0.027). Endocrine insufficiency was observed in one RA-DPPHR patient and 5 RA-PD patients (p = 0.197). CONCLUSIONS: Modified RA-DPPHR benefits in terms of better conservation of exocrine and endocrine pancreatic functions at the expense of a significant morbidity and non-zero mortality.

MicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/ß-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells.

The study aims to verify the hypothesis that up-regulation of microRNA-300 (miR-300) targeting CUL4B promotes apoptosis and suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells by regulating the Wnt/ß-catenin signaling pathway. Pancreatic cancer tissues and adjacent tissues were collected from 110 pancreatic cancer patients. Expression of miR-300, CUL4B, Wnt, ß-catenin, E-cadherin, N-cadherin, Snail, GSK-3ß, and CyclinD1 were detected using qRT-PCR and Western blot. CFPAC-1, Capan-1, and PANC-1 were classified into blank, negative control (NC), miR-300 mimics, miR-300 inhibitors, siRNA-CUL4B, and miR-300 inhibitors + siRNA-CUL4B groups. The proliferation, migration, invasion abilities, the cell cycle distribution, and apoptosis rates were measured in CCK-8 and Transwell assays. Pancreatic cancer tissues showed increased CUL4B expression but decreased miR-300 expression. When miR-300 was lowly expressed, CUL4B was upregulated which in-turn activated the Wnt/ß-catenin pathway to protect the ß-catenin expression and thus induce EMT. When miR-300 was highly expressed, CUL4B was downregulated which in-turn inhibited the Wnt/ß-catenin pathway to prevent EMT. Weakened cell migration and invasion abilities and enhanced apoptosis were observed in the CUL4B group. The miR-300 inhibitors group exhibited an evident increase in growth rate accompanied the largest tumor volume. Smaller tumor volume and slower growth rate were observed in the miR-300 mimics and siRNA-CUL4B group. Our study concludes that lowly expressed miR-300 may contribute to highly expressed CUL4B activating the Wnt/ß-catenin signaling pathway and further stimulating EMT, thus promoting proliferation and migration but suppressing apoptosis of pancreatic cancer cells.

Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance.

Pancreatic cancer is one of the most fatal types of cancer and is associated with a dismal prognosis. Gemcitabine-based chemotherapy is clinically used for the treatment of advanced pancreatic cancer. However, many forms of pancreatic cancer have acquired resistance to gemcitabine. In order to prevent patients from suffering from the side effects of chemotherapy and to have the chance to receive more effective intervention, assessment of whether the patient pancreatic cancer cells are resistant to gemcitabine before clinical practice is crucial. Recently, patient-derived xenograft (PDX) models have been regarded as a practical approach for preclinical drug resistance test. In the present study, we harvested tumor specimens from 28 pancreatic cancer patients to establish PDX models. The tumor formation rate of the xenografts was 100%, several of which could be re-implanted in nude mice for more than 10 passages. Primary cells were further obtained from the PDX xenografts to determine their morphological features and evaluate their proliferation rate, migration capacity and angiopoietic ability. In addition, the sensitivities of the primary cells and PDX xenografts to gemcitabine were correlated with each other. When compared to the gemcitabine-sensitive cells, the gemcitabine-resistant cells had a higher level of MCF2L expression, suggesting that MCF2L plays an important role in gemcitabine resistance.

Up-regulation of chemokine receptor CCR4 is associated with Human Hepatocellular Carcinoma malignant behavior.

Studies indicate that the chemokine receptor is responsible for poor prognosis of hepatocellular carcinoma (HCC) patients. In this study, we initially demonstrated that CCR4 is overexpressed in HCC specimens, and its elevation in HCC tissues positively correlates with tumor capsule breakthrough and vascular invasion. Although overexpression of CCR4 failed to influent proliferation of HCC cells in vitro apparently, the prominent acceleration on HCC tumor growth in vivo was remarkable. The underlying mechanism may be involved in neovascularization. Interestingly, different from effect on proliferation, CCR4 overexpression could trigger HCC metastasis both in vitro and in vivo also induced HCC cell epithelial-mesenchymal transition (EMT) as well. Then we identified matrix metalloproteinase 2 (MMP2) as a direct target of CCR4 which plays an important role in CCR4-mediated HCC cell invasion, which was up-regulated by ERK/AKT signaling. Positive correlation between CCR4 and MMP2 expression was also observed in HCC tissues. In conclusion, our study suggested that chemokine receptor CCR4 promotes HCC malignancy and facilitated HCC cell metastases via ERK/AKT/MMP2 pathway. These findings suggest that CCR4 may be a potential new diagnostic and prognostic marker in HCC, and targeting CCR4 may be a potential therapeutic option for blocking HCC metastasis.

Robot-assisted laparoscopic versus open middle pancreatectomy: short-term results of a randomized controlled trial.

OBJECTIVE: This first prospective randomized controlled trial was performed to compare short-term outcomes of robot-assisted laparoscopic middle pancreatectomy (RA-MP) with open middle pancreatectomy (OMP). BACKGROUND: RA-MP is a novel minimally invasive surgical technique for benign or borderline tumors in the pancreatic neck or body. Its short-term effectiveness and safety remain unknown, compared to OMP. METHODS: Patients eligible for MP from August 2011 to November 2015 were randomized into the RA-MP or OMP group. The primary endpoint was length of hospital stay (LOS). Secondary endpoints were intraoperative parameters, and postoperative and recovery variables. RESULTS: A total of 100 patients were included into the study to analyze primary and secondary endpoints. Demographic characteristics and pathological parameters were similar in both groups. Furthermore, LOS was significantly shorter (15.6 vs. 21.7 days, P = 0.002), median operative time was reduced (160 vs. 193 min, P = 0.002), median blood loss was lower (50 vs. 200 mL, P < 0.001), rate of clinical postoperative pancreatic fistula (POPF) was lower (18 vs. 36.0 %, P = 0.043), nutritional status recovery was better, off-bed return to activity was expedited (3.1 vs. 4.6 days, P < 0.001), and resumption of bowel movement was faster (3.5 vs. 5.0 days, P < 0.001) in the RA-MP group, compared to the OMP group. CONCLUSION: RA-MP was associated with significantly shorter LOS, reduced operative time, blood loss and clinical POPF rate, and expedited postoperative recovery, compared to OMP.

Robotic Enucleation for Benign or Borderline Tumours of the Pancreas: A Retrospective Analysis and Comparison from a High-Volume Centre in Asia.

BACKGROUND: Enucleation is increasingly performed for benign or borderline tumours of the pancreas because it is a parenchyma-sparing and less invasive procedure compared to conventional pancreatectomy, which reduces the risk of exocrine and endocrine insufficiency. This study retrospectively evaluated and compared the pre-, intra-, and post-operative clinical characteristics after open and robotic approaches for pancreatic enucleation. METHODS: Fifty-six cases of enucleation for benign or borderline tumours of the pancreas treated from March 2010 to July 2015 were identified by a retrospective search. These included 25 patients who underwent an open approach and 31 patients who underwent a robotic approach. The clinical characteristics were extracted and compared. RESULTS: The two groups had a similar location and pathology of the tumour. The robotic group had a significantly shorter operation time and significantly less blood loss than the open group. The rates of clinical pancreatic fistula (PF) formation and major complications were similar. The robotic approach could be applied for a tumour on the right side of the pancreas without increasing the incidence of clinical PF or other major complications. The patients with clinical PF had a significantly shorter distance between the lesion and the main pancreatic duct (MPD). CONCLUSION: Robotic enucleation appears to be a feasible and safe approach for benign or borderline tumours of the pancreas and was associated with similarly favourable surgical outcomes as the open approach. Identifying and avoiding the MPD is an important step during enucleation.

TMEM45B promotes proliferation, invasion and migration and inhibits apoptosis in pancreatic cancer cells.

In the present study, we focused on the expression and biological functions of TMEM45B in pancreatic cancer tissues and cell lines. Real-time PCR and Western blotting were used to examine the expression levels of TMEM45B in pancreatic cancer tissues and cell lines. The functions of TMEM45B were evaluated using CCK-8, flow cytometry and transwell analysis. Our results showed that TMEM45B exhibited high expression in pancreatic cancer tissues and cell lines compared with the normal pancreatic tissues and cells. Using gene set enrichment analysis (GSEA), we found that TMEM45B may regulate multiple genes involved in the cell cycle and metastasis pathways. Downregulation of TMEM45B by RNA interference significantly reduced proliferation, invasion and migration of SW1990 and PANC-1 cells, accompanied by the induction of cell cycle arrest and apoptosis, whereas overexpression of TMEM45B promoted proliferation, invasion and migration of CFPAC-1 cells as well as apoptosis inhibition. Taken together, our study provides evidence that TMEM45B is an oncogene involved in the tumorigenesis of pancreatic cancer and may represent a new molecular target for pancreatic cancer treatment.

Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors.

BACKGROUND: The optimal surgical management of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) is still controversial. Here, we evaluated the impact of lymph node status on postoperative recurrence in patients with NF-PNET and the potential of preoperative variables for predicting lymph node metastasis (LNM). METHODS: In this mono-institutional retrospective cohort study conducted in 100 consecutive patients who underwent NF-PNET resection between January 2004 and December 2014, we evaluated risk factors for survival using the Kaplan-Meier method and the Cox regression model. Predictors of LNM were evaluated using the logistic regression model, and the power of predictive models was evaluated using receiver operating characteristic curve analysis. RESULTS: Five-year disease-free survival of resected NF-PNET was 64.1%. LNM was independently associated with postoperative recurrence (hazard ratio = 3.995, P = 0.003). Multivariate analysis revealed tumor grade as an independent factor associated with LNM (G2 vs. G1: odds ratio [OR] =6.287, P = 0.008; G3 vs. G1: OR = 12.407, P = 0.001). When tumor grade was excluded, radiological tumor diameter >2.5 cm (OR = 5.430, P = 0.013) and presence of symptoms (OR = 3.366, P = 0.039) were significantly associated with LNM. Compared to neoplasms with radiological diameter >2.5 cm (32.1%), tumors ≤2.5 cm had an obviously lower risk of LNM (7.7%), indicating the reliability of this parameter in predicting LNM (area under the curve, 0.693). Incidentally discovered NF-PNETs ≤2.5 cm were associated with a low-risk of LNM and excellent survival. CONCLUSIONS: LNM is significantly associated with postoperative recurrence. Radiological tumor diameter is a reliable predictor of LNM in NF-PNETs. Our results indicate that lymphadenectomy in small (≤2.5 cm) NF-PNETs is not routinely necessary.

New variation of right recurrent laryngeal nerve: cases report.

The recognition of variation in recurrent laryngeal nerves is important for both surgeons and the prognosis of patients undergoing surgery of the neck. Here, we reported a new variation of the right recurrent laryngeal nerves in five patients with thyroid surgery. The new variation is characterized by the additional ascending intracranial branches after division of laryngeal branches.

Robotic approach improves spleen-preserving rate and shortens postoperative hospital stay of laparoscopic distal pancreatectomy: a matched cohort study.

BACKGROUND: Spleen preservation (SP) is beneficial for patients undergoing distal pancreatectomy of benign and borderline tumors; however, the conventional laparoscopy approach (C-LDP) is less effective in controlling splenic vessel bleeding. The benefits of the robotic-assisted approach (RA-LDP) in SP have not been clearly described. This study aimed to evaluate whether a robotic approach could improve SP rate and effectiveness/safety profile of laparoscopic distal pancreatectomy (LDP). METHODS: Matched for scheduled SP, age, sex, ASA classification, tumor size, tumor location, and pathological type, 69 patients undergoing RA-LDP and 50 undergoing C-LDP between January 2005 and May 2014 were included. Main outcome measures included SP rate, operative time (OT), blood loss, transfusion frequency, morbidity, postoperative hospital stay (PHS), and oncologic safety. RESULTS: Among matched patients scheduled for SP, RA-LDP was associated with significantly higher overall (95.7 vs. 39.4%) and Kimura SP rates (72.3 vs. 21.2%), shorter OT (median 120 vs. 200 min), less blood loss (median 100 vs. 300 mL), lower transfusion frequency (2.1 vs. 18.2%), and shorter mean PHS (10.2 vs. 14.5 days). Among matched patients scheduled for splenectomy, RA-LDP was associated with similar OT, blood loss, transfusion frequency, and PHS. The two approaches were similar in overall morbidity, frequency of pancreatic fistula, and oncologic outcome among patients undergoing splenectomy for malignant tumors. CONCLUSIONS: RA-LDP was associated with a significantly better SP rate and reduced OT, blood loss, transfusion requirement, and PHS for patients undergoing SP compared to C-LDP, but offered less benefits for patients undergoing splenectomy.