The ratio of skeletal muscle mass to body mass index combined with inflammatory immune markers to stratify survival of pancreatic cancer after pancreatoduodenectomy.

BACKGROUND: We sought to combine skeletal muscle index and inflammatory immune markers to stratify long-term survival in patients with pancreatic cancer after pancreatoduodenectomy (PD). METHODS: A total of 581 patients with pancreatic cancer underwent PD were included, and divided into the training and validation cohort. Image analysis of computed tomography scans was used to calculate the ratio of skeletal muscle (SM) area to body mass index (BMI). Naples prognostic score (NPS) was calculated from blood-test inflammatory immune markers. Propensity score matching (PSM) analysis was performed to minimize biases of clinicopathological characteristics. To estimate the overall survival (OS), a nomogram was developed using the training cohort. The predictive accuracy of nomogram was estimated by concordance index (C-index), calibration curve, and receiver operating characteristics (ROC) curve. RESULTS: After PSM analysis, SM/BMI ratio, NPS, lymph node metastasis, TNM stage, surgical margin, tumor grade and adjuvant therapy were independent predictors of OS, which were all assembled into nomogram. The SM/BMI ratio was the best single-predictor for 3- and 5-year OS, with an AUC of 0.805 (95% CI: 0.755-0.855) and 0.812 (95% CI: 0.736-0.888), respectively. Harrell's c-index of the nomogram in the training cohort was 0.786 (95% CI: 0.770-0.802), and the area under ROC curve of 1-year, 3- and 5-year OS prediction were 0.869 (95%CI: 0.837-0.901), 0.846 (95%CI: 0.810-0.882) and 0.849 (95%CI: 0.801-0.896). CONCLUSIONS: The nomogram based on SM/BMI ratio and NPS had excellent predictive performance, which should be incorporated to conventional risk scores to stratify survival of patients with PDAC after PD.

Targeting the alterations of ARID1A in pancreatic cancer: tumorigenesis, prediction of treatment, and prognostic value.

The chromatin remodeling gene AT-rich interactive domain 1A (ARID1A), encoding a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is one of the most frequently mutated chromatin regulators across a broad spectrum of cancers. Most of the ARID1A alterations are inactivating, leading to the loss or reduced expression of the protein. Recently, ARID1A has been demonstrated as a tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC), as its inactive alterations attribute to carcinogenesis. Importantly, ARID1A alterations are revealed as predictive biomarkers for the selection of targeted therapy and immune checkpoint blockade (ICB) therapy. In PDAC, the application of ARID1A alterations in stratifying patients for precise treatment has also been widely explored in preclinical and early clinic studies with encouraging preliminary results. Furthermore, the prognostic value of ARID1A mutations in PDAC has been suggested by various studies. In this review, we focus on the functions of ARID1A alterations in PDAC, particularly their functions during carcinogenesis and their predictive value in treatment selection and prognosis, to provide a comprehensive overview on our current understanding of ARID1A alterations in PDAC.

The Impact of Preoperative and Postoperative Malnutrition on Outcomes for Ampullary Carcinoma After Pancreaticoduodenectomy.

PURPOSE: The aim of this study was to investigate the effect of preoperative and postoperative malnutrition on postoperative short- and long-term outcomes for ampullary carcinoma after pancreatoduodenectomy (PD). METHODS: Data were collected retrospectively from 511 patients with ampullary carcinoma who underwent PD between June 2012 and June 2019. Nutritional status before and at 3, 6, and 12 months after operation was assessed by the scored Patient-Generated Subjective Global Assessment (PG-SGA). The patients were classified into well-nourished, moderately malnourished, and severely malnourished group according to the PG-SGA score. Propensity score matching (PSM) was performed to adjust baseline characteristics between preoperative group A (well-nourished and moderately malnourished group) and group B (severely malnourished group). After PSM, clinicopathological variables and postoperative complications were compared between the two groups. Univariate and multivariate Cox analysis was also conducted to investigate the prognostic factors of overall survival of patients with ampullary carcinoma who underwent PD. RESULTS: Preoperatively, 122 (23.9%) patients were classified into well-nourished group, 189 (37.0%) into moderately malnourished group, and 200 (39.1%) into severely malnourished group. After PSM analysis, the incidence of overall postoperative complications was higher in group B than that in group A (50.5% vs. 32.5%, p < 0.001). Multivariate Cox proportional hazards regression model showed that severe malnutrition (PG-SGA score >9 scores) before operation [hazard ratio (HR) = 1.508; 95% CI, 1.103-2.061; p = 0.01] and at 6 months (HR = 4.148; 95% CI, 2.523-6.820; p < 0.001) and 12 months (HR = 5.272; 95% CI, 3.630-7.656; p < 0.001) after operation was an independent prognostic factor of patients who underwent PD for ampullary carcinoma. CONCLUSIONS: Severe malnutrition before and at 6 and 12 months after operation significantly affects the long-term survival of patients with ampullary carcinoma who underwent PD. Additionally, the preoperative malnutrition was closely related to postoperative complications.

Long Noncoding Competing Endogenous RNA Networks in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial-mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.

A randomised, multicentre trial of somatostatin to prevent clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.

BACKGROUND: Prophylactic somatostatin to reduce the incidence of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy remains controversial. We assessed the preventive efficacy of somatostatin on clinically relevant postoperative pancreatic fistula in intermediate-risk patients who underwent pancreaticoduodenectomy at pancreatic centres in China. METHODS: In this multicentre, prospective, randomised controlled trial, we used the updated postoperative pancreatic fistula classification criteria and cases were confirmed by an independent data monitoring committee to improve comparability between centres. The primary endpoint was the rate of clinically relevant postoperative pancreatic fistula within 30 days after pancreaticoduodenectomy. RESULTS: Eligible patients (randomised, n = 205; final analysis, n = 199) were randomised to receive postoperative intravenous somatostatin (250 µg/h over 120 h; n = 99) or conventional therapy (n = 100). The primary endpoint was significantly lower in the somatostatin vs control group (n = 13 vs n = 25; 13% vs 25%, P = 0.032). There were no significant differences for biochemical leak (P = 0.289), biliary fistula (P = 0.986), abdominal infection (P = 0.829), chylous fistula (P = 0.748), late postoperative haemorrhage (P = 0.237), mean length of hospital stay (P = 0.512), medical costs (P = 0.917), reoperation rate (P > 0.99), or 30 days' readmission rate (P = 0.361). The somatostatin group had a higher rate of delayed gastric emptying vs control (n = 33 vs n = 21; 33% vs 21%, P = 0.050). CONCLUSIONS: Prophylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy. TRIAL REGISTRATION: NCT03349424.

Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models.

PURPOSE: Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. EXPERIMENTAL DESIGN: In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA-based high-content screening was implemented to validate the function of the deregulated genes. RESULTS: The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. CONCLUSIONS: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.

Predictive factors of postoperative pancreatic fistula after laparoscopic pancreatoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) continues to be a major contributor to morbidity after pancreaticoduodenectomy (PD), but it remains unclear what risk factors can precisely predict the development of CR-POPF after laparoscopic pancreatoduodenectomy (LPD). We thus aimed to identify the risk factors for predicting CR-POPF after LPD. METHODS: A total of 388 consecutive patients who underwent LPD at our institution between July 2014 and December 2018 were identified. All data, including pre-, intra-, and postoperative risk factors associated with CR-POPF defined by the International Study Group of Pancreatic Fistula, were collected retrospectively. To evaluate the predictive performance of the risk factor models, areas under the receiver operating characteristic curve (ROC) were determined. RESULTS: CR-POPF was observed in 31 patients (8.0%) with significant association observed with body mass index (BMI), visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA), intra-abdominal fat thickness, main pancreatic duct width, soft pancreatic texture, operative time, underlying pathology, and albumin (Alb) on postoperative days (POD) 1--3. Multivariate analyses revealed that VFA >82 cm2 [odds ratio (OR) =11.088; P=0.029], main pancreatic duct width <3 mm (OR =7.701; P=0.001), soft pancreatic texture (OR =12.543; P=0.022), and operative time >320 min (OR =6.061; P<0.001) were independent risk factors for CR-POPF after LPD. Areas under the ROC curve (AUC) analysis revealed the pancreatic texture was the strongest single predictor (AUC =0.854) of CR-POPF, and pancreatic texture + pancreatic duct width was the best two-predictor model (AUC =0.904). Meanwhile, our findings indicated an association between the TFA >221 cm2 (OR =8.637; P=0.001) and VFA >82 cm2 (OR =7.009; P<0.001) with soft pancreatic texture. CONCLUSIONS: Soft pancreatic texture, VFA >82 cm2, main pancreatic duct width <3 mm, and operative time >320 min were independent predictive risk factors of CR-POPF for LPD.

Adrenocorticotropic Hormone-Producing Pancreatic Neuroendocrine Neoplasms: A Systematic Review.

OBJECTIVE: Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasm (ACTHoma) is an exceedingly rare type of pancreatic neuroendocrine neoplasm (pNEN) that often causes ectopic adrenocorticotropic hormone syndrome. These neoplasms have been found to be very aggressive and challenging to treat. The current systematic review aimed to analyze the clinical features, immunohistochemical characteristics, diagnosis, therapy, and prognosis of ACTHoma. METHODS: A systematic review of the English- and Chinese-language literature was performed. PubMed, EMBASE, and Wanfang databases were searched to identify articles about ACTHoma in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. RESULTS: A total of 210 studies encompassing 336 patients diagnosed with ACTHoma were selected for the systematic review, including 16 Chinese patients. CONCLUSION: ACTHoma was more common in women (66.4%), and the mean age was 44.7 years. Tumors were generally large, and the mean tumor size was 4.43 cm. The incidence of clinical manifestations was: hypokalemia, 69.3%; diabetes, 63.2%; weakness, 60.1%, hypertension, 56.4%; moon face 41.1%; and edema, 37.4%. These tumors are more commonly found in the tail of pancreas, and the most frequent site of metastasis was the liver. The pNENs or other functioning pNENs could evolve into ACTHoma. ACTHoma is a very rare disease, and the mean follow-up time was 28.3 months.

Prognostic significance of preoperative Naples prognostic score on short- and long-term outcomes after pancreatoduodenectomy for ampullary carcinoma.

BACKGROUND: The Naples prognostic score (NPS) is an effective and objective tool to assess the immune-nutritional status of patients with malignant tumors. The aim of this study was to investigate the clinical significance of preoperative NPS on short- and long-term outcomes after pancreatoduodenectomy (PD) for ampullary carcinoma. METHODS: We retrospectively analyzed 404 consecutive patients with ampullary carcinoma who underwent PD between January 2012 and June 2018. Preoperative NPS was calculated from serum albumin and total cholesterol concentrations, and the neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio (LMR). Patients were then divided into three groups according to their NPS. Clinicopathological variables, postoperative outcomes, and survival data were compared between the three groups. Univariate and multivariate Cox analysis of overall survival (OS) and recurrence-free survival (RFS) were also conducted, and time-dependent receiver operating characteristic (ROC) curves were created to evaluate the discriminatory ability of the prognostic scoring systems. RESULTS: Patients with higher NPS had worse prognosis, and significant OS difference (group 0 vs. 1, P=0.02; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001) and RFS difference (group 0 vs. 1, P=0.088; group 1 vs. 2, P<0.001; group 0 vs. 2, P<0.001). Multivariate analysis revealed that NPS was an independent significant predictor of OS (grade 2 vs. grade 1 or 0, hazard ratio: 3.067; P<0.001) and RFS (grade 2 vs. grade 1 or 0, hazard ratio: 2.732; P<0.001). The time-dependent receiver operating curve analysis showed that NPS had better prognostic performance for OS and RFS than other prognostic models. Additionally, significant differences in the incidence of postoperative morbidity were observed between the three groups, and the NPS was an independent risk factor of overall postoperative complications (grade 2 vs. grade 1 or 0, odds ratio: 1.692; P=0.02). CONCLUSIONS: The NPS was an independent predictor of overall- and RFS in patients undergoing PD for ampullary carcinoma, and was independently associated with the incidence of postoperative complications.

OLR1 Promotes Pancreatic Cancer Metastasis via Increased c-Myc Expression and Transcription of HMGA2.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, the mechanisms of metastasis in pancreatic cancer remain unclear. Oxidized low-density lipoprotein receptor 1 (OLR1), a lectin-like scavenger receptor that recognizes several ligands, such as oxidized low-density lipoprotein, was previously reported in cardiovascular and metabolic diseases. The role and mechanism of OLR1 in pancreatic cancer is unclear. In this study, we found that OLR1 expression was significantly higher in pancreatic cancer tissues than that in adjacent normal tissues and closely associated with reduced overall survival. OLR1 promoted proliferation and metastasis of pancreatic cancer cells in vitro and in vivo. Mechanistically, OLR1 increased HMGA2 transcription by upregulating c-Myc expression to promote the metastasis of pancreatic cancer cells. In addition, patients with pancreatic cancer with high expression of OLR1-c-Myc-HMGA2 axis showed worse prognosis compared with patients with low expression of OLR1-c-Myc-HMGA2 axis. IMPLICATIONS: Our findings suggested that the OLR1-c-Myc-HMGA2 axis promotes metastasis of pancreatic cancer cells and may serve as potential therapeutic targets and prognosis markers for patients with pancreatic cancer.

Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer.

BACKGROUND: Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. METHODS: Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. RESULTS: Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. CONCLUSION: Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.

BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.

BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

Glucagonoma and the glucagonoma syndrome.

Glucagonoma is an extremely rare pancreatic α-islet cell tumor and is often accompanied by certain clinical symptoms including necrotizing migratory erythema (NME), diabetes, weight loss and anemia. The objectives of the current review were to discern the clinical features, diagnosis, treatment and prognosis of glucagonoma by evaluating 623 reported cases. A 1998 study reviewed 407 cases and 216 cases were reported in studies published after 1998. The current review consisted of 268 males and 339 females, with an average age of 52.4 years. The male-to-female ratio was 0.79. The incidence of typical clinical findings were as follows: NME, 82.4% (350/425); diabetes, 68.5% (291/425); weight loss, 60.2% (256/425); anemia, 49.6% (211/425); and glossitis or stomatitis or cheilitis, 41.2% (175/425). A total of 499 cases reported the location of the tumor as the pancreas and 64.1% (320/499) involved the pancreatic tail. Tumor size was recorded in 58.3% (126/216) cases reported after 1998 and average tumor size was 5.0 cm. Metastasis was detected in 49.2% of patients (293/595 for whom metastasis or no metastasis were recorded) upon diagnosis. These patients were older than those without metastasis (average age, 54.0 years old vs. 50.8 years old). The average time between symptoms and diagnosis of glucagonoma was 31.4 months. Glucagonoma is a very rare disease. It is important for clinicians to learn more about this disease to be able to diagnose and treat it as early as possible, thus improving patient prognosis.

PD-1/PD-L1 and immunotherapy for pancreatic cancer.

Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.

The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer.

Pancreatic cancer, which is often asymptomatic, is currently one of the most common causes of cancer-related death. This phenomenon is most likely due to a lack of early diagnosis, a high metastasis rate and a disappointing chemotherapy outcome. Thus, improving treatment outcomes by overcoming chemotherapy resistance may be a useful strategy in pancreatic cancer. Various underlying mechanisms involved in the chemoresistance of pancreatic cancer have been investigated. Notably, non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a pivotal role in regulating sensitivity to chemotherapy in pancreatic cancer. In this review, we highlight recent evidence regarding the role of miRNAs and lncRNAs in the chemoresistance of pancreatic cancer, including their expression levels, targets, biological functions and the regulation of chemoresistance, and discuss the potential clinical application of miRNAs and lncRNAs in the treatment of pancreatic cancer.

PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value.

BACKGROUND: The effects of PIM-1 on the progression of pancreatic cancer remain unclear, and the prognostic value of PIM-1 levels in tissues is controversial. Additionally, the expression levels and clinical value of PIM-1 in plasma have not been reported. METHODS: The effects of PIM-1 on biological behaviours were analysed. PIM-1 levels in tissues and plasma were detected, and the clinical value was evaluated. RESULTS: We found that PIM-1 knockdown in pancreatic cancer cells suppressed proliferation, induced cell cycle arrest, enhanced apoptosis, resensitized cells to gemcitabine and erlotinib treatment, and inhibited ABCG2 and EZH2 mRNA expression. Our results indicated that PIM-1 and the EGFR pathway formed a positive feedback loop. We also found that PIM-1 expression in pancreatic cancer tissues was significantly upregulated and that a high level of expression was negatively associated with prognosis (P = 0.025, hazard ratio [HR] =2.113, 95 % confidence interval: 1.046-4.266). Additionally, we found that plasma PIM-1 levels in patients with pancreatic cancer were significantly increased and could be used in the diagnosis of pancreatic cancer. High plasma PIM-1 expression was an independent adverse prognostic factor for pancreatic cancer (P = 0.037, HR = 1.87, 95 % CI: 1.04-3.35). CONCLUSION: Our study suggests that PIM-1 contributes to malignancy and has diagnostic and prognostic value in pancreatic cancer.

miR-497 expression, function and clinical application in cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression by binding to the 3' untranslated region (3'-UTR) of their target mRNAs. Recent studies show that miR-497 plays an important role in various cancers. Here, we summarize the existing studies of miR-497 as following: (1) miR-497 expression in cancer; (2) regulation mechanisms of miR-497 expression; (3) function of miR-497 in cancer; (4) direct targets of miR-497; (5) Clinical applications of miR-497. Recent analyses verify that miR-497 mainly suppresses tumors; however, it also acts as an oncogene in several cancers. Increasing evidence indicates that miR-497 can serve as a diagnostic and prognostic biomarker and is a promising therapeutic target for future clinical applications.