Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication.

BACKGROUND: Immunotherapy has emerged as a potent clinical approach for cancer treatment, but only subsets of cancer patients can benefit from it. Targeting lactate metabolism (LM) in tumor cells as a method to potentiate anti-tumor immune responses represents a promising therapeutic strategy. METHODS: Public single-cell RNA-Seq (scRNA-seq) cohorts collected from patients who received immunotherapy were systematically gathered and scrutinized to delineate the association between LM and the immunotherapy response. A novel LM-related signature (LM.SIG) was formulated through an extensive examination of 40 pan-cancer scRNA-seq cohorts. Then, multiple machine learning (ML) algorithms were employed to validate the capacity of LM.SIG for immunotherapy response prediction and survival prognostication based on 8 immunotherapy transcriptomic cohorts and 30 The Cancer Genome Atlas (TCGA) pan-cancer datasets. Moreover, potential targets for immunotherapy were identified based on 17 CRISPR datasets and validated via in vivo and in vitro experiments. RESULTS: The assessment of LM was confirmed to possess a substantial relationship with immunotherapy resistance in 2 immunotherapy scRNA-seq cohorts. Based on large-scale pan-cancer data, there exists a notably adverse correlation between LM.SIG and anti-tumor immunity as well as imbalance infiltration of immune cells, whereas a positive association was observed between LM.SIG and pro-tumorigenic signaling. Utilizing this signature, the ML model predicted immunotherapy response and prognosis with an AUC of 0.73/0.80 in validation sets and 0.70/0.87 in testing sets respectively. Notably, LM.SIG exhibited superior predictive performance across various cancers compared to published signatures. Subsequently, CRISPR screening identified LDHA as a pan-cancer biomarker for estimating immunotherapy response and survival probability which was further validated using immunohistochemistry (IHC) and spatial transcriptomics (ST) datasets. Furthermore, experiments demonstrated that LDHA deficiency in pancreatic cancer elevated the CD8+ T cell antitumor immunity and improved macrophage antitumoral polarization, which in turn enhanced the efficacy of immunotherapy. CONCLUSIONS: We unveiled the tight correlation between LM and resistance to immunotherapy and further established the pan-cancer LM.SIG, holds the potential to emerge as a competitive instrument for the selection of patients suitable for immunotherapy.

BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1.

Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix-loop-helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation-seq, RNA-seq, and high-throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40-SREBF1-stearoyl-CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40-mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma.

PURPOSE: Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy. METHODS: In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay). RESULTS: According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells. CONCLUSION: Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.

Hypoxia-induced long non-coding RNA LINC00460 promotes p53 mediated proliferation and metastasis of pancreatic cancer by regulating the miR-4689/UBE2V1 axis and sequestering USP10.

Long non-coding RNAs are considered to be key regulatory factors of oncogenesis and tumor progression. It is reported that LINC00460 plays the role of oncogene in some tumors. However, LINC00460's role and mechanism of action in pancreatic cancer have not yet been fully elucidated. We identified LINC00460 by analyzing data from the Gene Expression Omnibus database. The role of LINC00460 in proliferation and metastasis was examined using CCK8, colony formation, wound healing, and transwell assays. The potential mechanisms of LINC00460 in regulating mRNA levels were elucidated by RNA pull-down, RNA immunoprecipitation, Chromatin immunoprecipitation, Co-immunoprecipitation, and Immunofluorescence assays. The results showed that LINC00460 was upregulated in pancreatic cancer cells and tissues. Highly expressed LINC00460 is significantly related to short survival of pancreatic cancer patients. Inhibition of LINC00460 attenuated pancreatic cancer cell proliferation and metastasis, whereas its overexpression reversed this effect. Mechanically, LINC00460 is induced by hypoxia, through binding of the hypoxia-inducible factor 1-α in the promoter region of LINC00460. Furthermore, LINC00460 functioned as an miR-4689 sponge to regulate the downstream target gene UBE2V1, enhancing the stability of mutant p53 in pancreatic cancer cells. LINC00460 also further promotes pancreatic cancer development by sequestering USP10, a cytoplasmic ubiquitin-specific protease that deubiquitinates p53 and enhances its stability. Collectively, our study demonstrated that LINC00460 is a hypoxia-induced lncRNA that plays the role of oncogene in pancreatic cancer by modulating the miR-4689/UBE2V1 axis, sequestering USP10, and ultimately enhancing the stability of mutant p53.

A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1-hyperactivated pancreatic cancer.

The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis, chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer; however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1 degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and suggest a promising therapeutic strategy targeting the N1DARP-N1ICD interaction in Notch1-activated pancreatic cancer.

Comprehensive machine learning-generated classifier identifies pro-metastatic characteristics and predicts individual treatment in pancreatic cancer: A multicenter cohort study based on super-enhancer profiling.

Rationale: Accumulating evidence illustrated that the reprogramming of the super-enhancers (SEs) landscape could promote the acquisition of metastatic features in pancreatic cancer (PC). Given the anatomy-based TNM staging is limited by the heterogeneous clinical outcomes in treatment, it is of great clinical significance to tailor individual stratification and to develop alternative therapeutic strategies for metastatic PC patients based on SEs. Methods: In our study, ChIP-Seq analysis for H3K27ac was performed in primary pancreatic tumors (PTs) and hepatic metastases (HMs). Bootstrapping and univariate Cox analysis were implemented to screen prognostic HM-acquired, SE-associated genes (HM-SE genes). Then, based on 1705 PC patients from 14 multicenter cohorts, 188 machine-learning (ML) algorithm integrations were utilized to develop a comprehensive super-enhancer-related metastatic (SEMet) classifier. Results: We established a novel SEMet classifier based on 38 prognostic HM-SE genes. Compared to other clinical traits and 33 published signatures, the SEMet classifier possessed robust and powerful performance in predicting prognosis. In addition, patients in the SEMetlow subgroup owned dismal survival rates, more frequent genomic alterations, and more activated cancer immunity cycle as well as better benefits in immunotherapy. Remarkably, there existed a tight correlation between the SEMetlow subgroup and metastatic phenotypes of PC. Among 18 SEMet genes, we demonstrated that E2F7 may promote PC metastasis through the upregulation of TGM2 and DKK1. Finally, after in silico screening of potential compounds targeted SEMet classifier, results revealed that flumethasone could enhance the sensitivity of metastatic PC to routine gemcitabine chemotherapy. Conclusion: Overall, our study provided new insights into personalized treatment approaches in the clinical management of metastatic PC patients.

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1.

BACKGROUND: circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown. METHODS: Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified. RESULTS: CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1. CONCLUSIONS: We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.

Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway.

BACKGROUND: FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. METHODS: FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. RESULTS: FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. CONCLUSIONS: Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

Epigenetic silencing of LncRNA LINC00261 promotes c-myc-mediated aerobic glycolysis by regulating miR-222-3p/HIPK2/ERK axis and sequestering IGF2BP1.

Long noncoding RNAs have been identified as key regulators in the progression of various cancers. LINC00261 has been reported as a tumor suppressor in multiple cancers. However, its function and underlying mechanisms in pancreatic cancer remain largely unclear. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization was used to discover the subcellular location. The direct binding of LINC00261 to miR-222-3p was verified using a dual-luciferase reporter assay and RNA immunoprecipitation. LINC00261-binding proteins were detected using an RNA pulldown assay. LINC00261 was downregulated in pancreatic cancer tissues and cell lines. Its reduced expression was correlated with advanced pathological stage and poor prognosis. Forced expression of LINC00261 suppressed pancreatic cancer glycolysis and proliferation and induced cell cycle arrest and apoptosis. Mechanistically, downregulation of LINC00261 was caused by hypermethylation of the CpG island in the promoter region and EZH2-mediated histone H3 lysine 27 trimethylation. Moreover, LINC00261 exerted its biological function by binding to miR-222-3p to activate the HIPK2/ERK/c-myc pathway. In addition, LINC00261 could also reduce c-myc expression by sequestering IGF2BP1. Our study suggests that LINC00261 functions as a tumor suppressor in pancreatic cancer and identifies novel epigenetic and posttranscriptional regulatory mechanisms of LINC00261, which contribute to the targeted therapy of pancreatic cancer.

A Nomogram for Individual Prediction of Poor Prognosis After Radical Surgery in Patients with Primary Pancreatic Duct Adenocarcinoma.

BACKGROUND Pancreatic cancer is a highly malignant tumor characterized by poor prognosis. TNM stage cannot always provide accurate prediction of prognosis, which is vital for individualized treatment. Therefore, a novel way to identify patients with poor prognosis after radical surgery is urgently needed. MATERIAL AND METHODS The nomogram was established based on a discovery cohort that included 554 patients with PDAC who had received radical surgery from 2012 to 2016. The clinicopathological data were collected. Poor prognosis was evaluated using 25 features, in which appropriate features for a prediction model were identified. A prediction model incorporating the selected features was established. The discriminative capacity was assessed by C-index, calibration by calibration plot, and clinical usefulness by decision curve. The bootstrapping approach was used to perform internal validation. RESULTS Characteristics included in the nomogram were coronary artery disease and stroke history, elevated CA125, AJCC stage >II, R0 resection, operating time >6 h, poor differentiation, nerve invasion, length of stay >30 days, and postoperative complications. A C-index of 0.713 indicated good discrimination of the prediction model, and the calibration curve showed acceptable calibration. Survival analysis showed that this model had better discriminative capacity than the AJCC staging system and could distinguish relatively good prognosis from poor prognosis in patients at stage II (especially IIa) and IV. CONCLUSIONS Our study presents a valid and practical model to predict prognosis of pancreatic cancer patients, which contributes to individualized therapy by assisting surgeons to predict poor prognosis in patients who received radical surgery.

Construction and integrated analysis of a lncRNA-associated competing endogenous RNA network reveal functional lncRNAs in pancreatic cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) can serve as a competing endogenous RNA (ceRNA) in regulating gene expression in multiple cancers by sponging miRNA. However, this mechanism is poorly studied in pancreatic cancer. This study aims to identify functional lncRNAs and their potential regulatory mechanisms in pancreatic cancer. METHODS: Differentially expressed lncRNA (DE-lncRNA), miRNA (DE-miRNA) and mRNA (DE-mRNA) were analyzed using data from three datasets (GSE89139, GSE24279 and GSE62452) from the Gene Expression Omnibus (GEO). The lncRNA-miRNA-mRNA interactions were predicted using miRcode and Targetscan. Gene ontology (GO) and pathway analysis of DE-mRNAs were performed using clusterProfiler. Survival analysis was conducted using data from The Cancer Genome Atlas (TCGA) database. RESULTS: Three hundred sixty-six DE-lncRNAs, 28 DE-miRNAs and 330 DE-mRNAs from pancreatic cancer and adjacent tissue were identified. A ceRNA network including 75 DE-lncRNAs, 18 DE-miRNAs and 85 DE-mRNAs was constructed, among which 16 DE-lncRNAs were associated with overall survival and 13 DE-lncRNAs were correlated with tumor progression. Three functional lncRNAs, GABPB1-AS1, ST7-AS1 and PSMG3-AS1, were identified as key functional lncRNAs, and their differential expression and potential ceRNA regulatory mechanism were validated by qPCR using pancreatic cancer cell lines and tissues. CONCLUSIONS: Our study identifies novel lncRNAs associated with progression and prognosis of pancreatic cancer and contributes to better understanding of lncRNA-associated ceRNA regulatory mechanisms in pancreatic cancer.

INPP4B As A Prognostic And Diagnostic Marker Regulates Cell Growth Of Pancreatic Cancer Via Activating AKT.

BACKGROUND: Inositol polyphosphate 4-phosphatase type II (INPP4B), a member of the PI3K/Akt signaling pathway, plays a vital role in the initiation and progression of cancers. However, its biological role in pancreatic cancer remains largely undiscovered. Our study aimed to investigate the effects of INPP4B on proliferation in pancreatic cancer and its clinical relevance. MATERIALS AND METHODS: INPP4B expression data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clinicopathological and survival data were retrieved from the TCGA database. CCK8 and colony formation assays were performed to measure the proliferative capacity of pancreatic cancer. Tumor xenograft models were established to measure cancer proliferative abilities in vivo. RESULTS: INPP4B was upregulated in pancreatic cancer tissue compared with normal tissue. INPP4B knockdown inhibited cell proliferation and promoted apoptosis in pancreatic cancer in vitro and in vivo. INPP4B knockdown also reduced AKT phosphorylation. Moreover, INPP4B was associated with poor overall and disease-free survival, with Cox regression analysis showing that INPP4B could serve as an independent prognostic marker. ROC curve analysis showed that INPP4B possessed moderate diagnostic value. CONCLUSION: Collectively, INPP4B is an oncogenic gene in pancreatic cancer and could serve as a potential diagnostic marker and an independent prognostic marker, suggesting that it could be a novel therapeutic target for pancreatic cancer.

Predicting Selection Preference of Robotic Pancreaticoduodenectomy (RPD) in a Chinese Single Center Population: Development and Assessment of a New Predictive Nomogram.

BACKGROUND Robotic pancreaticoduodenectomy (RPD) is a novel type of minimally invasive surgery to treat tumors located at the head of the pancreas. This study aimed to construct a novel prediction model for predicting selection preference for RPD in a Chinese single medical center population. MATERIAL AND METHODS The clinical data from 451 pancreatic ductal adenocarcinoma patients were collected and analyzed from January 2013 to December 2016. Twenty-three items affecting clinical strategies were optimized by LASSO (least absolute shrinkage and selection operator) regression analysis and then were incorporated in multivariable logistic regression analysis. C-index was used for evaluating the discriminative ability. Decision curve was applied to determine clinical application of this model and the calibration of this nomogram was evaluated by calibration plot. The model was internally validated through bootstrapping validation. RESULTS Clinicopathological factors included in the model were age, history of diabetes mellitus, history of hypertension, history of heart, brain and kidney disease, history of abdominal surgery, symptoms (jaundice, accidental discovery and weight loss), anemia, elevated carcinoembryonic antigen (CEA), smoking, alcohol intake, American Society of Anesthesiologists (ASA) scores, vascular invasion, overweight, preoperative lymph node metastasis and tumor size >3.5 cm. A C-index of 0.831 indicated good discrimination and calibration of this model. Interval validation generated an acceptable C-index of 0.787. When surgical approach was determined at the threshold of preference possibility less than 63%, decision curve analysis indicated that this model had good clinical application value in this range. CONCLUSIONS This new nomogram could be conveniently used to predict the selection preference of robotic surgery for patients with pancreatic head cancer.

PRPF40A as a potential diagnostic and prognostic marker is upregulated in pancreatic cancer tissues and cell lines: an integrated bioinformatics data analysis.

BACKGROUND: Pre-mRNA processing factor 40 homolog A (PRPF40A) is an important protein involved in pre-mRNA splicing and is expressed in a variety of cell types. However, the function of PRPF40A in pancreatic cancer remains unclear. Therefore, our study is to investigate the role of PRPF40A in the pathogenesis of pancreatic cancer. MATERIALS AND METHODS: We extracted expression data and clinical information of PRPF40A from different online databases, including the Cancer Genome Atlas (TCGA), Oncomine and the Gene Expression Omnibus (GEO). Subsequently, samples were collected from patients to validate gene expression using qPCR, Western blotting and immunohistochemical (IHC) analyses. Receiver operating characteristic (ROC) and Kaplan-Meier curve were used to evaluate the diagnostic and prognostic potential. Colony formation assays and CCK-8 assays were performed to measure the proliferative capacity of pancreatic cancer. Finally, gene ontology (GO) and pathway enrichment analyses of co-expressed genes of PRPF40A were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). RESULTS: We found that PRPF40A was upregulated based on data from both the online databases and our samples. PRPF40A possessed a significant diagnostic value, and its overexpression was associated with poor prognosis. PRPF40A knockdown inhibited cell proliferation in pancreatic cancer. GO and pathway analysis showed that the co-expressed genes were mainly involved in viral processing, mRNA splicing and the AMPK signaling pathway. CONCLUSION: The results suggest that PRPF40A is an oncogene and can serve as a diagnostic and prognostic biomarker for pancreatic cancer. However, the underlying mechanisms remain to be elucidated.

Comparison of Radical Antegrade Modular Pancreatosplenectomy with Standard Retrograde Pancreatosplenectomy for Left-Sided Pancreatic Cancer: A Meta-Analysis and Experience of a Single Center.

BACKGROUND Radical antegrade modular pancreatosplenectomy (RAMPS) has been reported as a modified surgical technique used to achieve better margin resection and to retrieve more lymph nodes compared with standard retrograde pancreatosplenectomy (SRPS). MATERIAL AND METHODS A systematic literature review was performed to identify studies published in PubMed, EmBase, and Web of Science. Hazard ratio (HR), risk ratio (RR), weighted mean difference (WMD), and their 95% confidence intervals (95% CIs) were used as effect measures. In addition, the clinical data of 27 patients in our center were collected and retrospectively analyzed. RESULTS Seven studies containing 474 patients were finally enrolled in this meta-analysis. The pooled results showed that the RAMPS group had a better overall survival (OS) compared with the SRPS group (HR=0.65, 95% CI: 0.43-0.99, P=0.046; I²=41.8%, P=0.143). Significantly more lymph nodes were harvested in the RAMPS group compared with in the SRPS group (WMD=4.74, 95% CI: 0.36-9.12, P=0.034). Recurrence rate (RR=0.8, 95% CI: 0.66-0.98, P=0.028) and blood loss (WMD=-153.19 ml, 95% CI: -303.95 to -2.42, P=0.046) were both significantly reduced in the RAMPS group. Retrospective analysis results showed that only significantly more harvested lymph nodes were noted in the RAMPS group compared with the SRPS group (7.55±0.91 vs. 2.81±0.73, P=0.001). CONCLUSIONS Our study suggests that RAMPS has better prognosis and surgical outcomes than SRPS for left-sided pancreatic cancer. Nevertheless, more high-quality clinical trials are required to validate the result.

TRIANGLE operation for borderline resectable pancreatic cancer in total pancreatectomy.

BACKGROUND: Pancreatic cancer is a highly aggressive cancer featured by early metastasis and multiple chemoresistance. Surgical resection remains the only way for the radical cure of pancreatic cancer. The aim of this study was to assess the safety, feasibility and oncological effect of the Heidelberg TRIANGLE operation in total pancreatectomy (TP) for borderline resectable pancreatic cancer (BRPC). METHODS: Patients with BRPC eligible for TP were selected and underwent total pancreatectomy with Heidelberg TRIANGLE operation. Sharp dissection was applied to separate tumor and involved artery. Then we completely dissected the soft tissues surround celiac axis (CA) and superior mesenteric artery (SMA) in each case. If superior mesenteric vein (SMV) or portal vein (PV) were invaded by the tumor, resection and reconstruction of veins were performed. Operation time, blood loss, post-operative complications, perioperative mortality, number of lymph node examined and R0 resection rate were collected and analyzed. RESULTS: Nine BRPC patients underwent TRIANGLE operation in TP. No perioperative death occurred. 3 cases developed postoperative complications: biliary leakage and colon fistula in 1 case and lymphatic leakage in 2 cases. The R0 resection rate of operation was 88.89% (8/9). CONCLUSIONS: For patients with BRPC, upfront surgery should be encouraged when they were unwilling or unable to received neoadjuvant therapy. Especially for those patients with artery involvement eligible for TP, TRIANGLE operation can help to achieve arterial sparing resection. Thus, the risk of postoperative hemorrhage for vascular reconstruction and skeletonization can be reduced. After postoperative adjuvant therapy, the prognosis is acceptable.