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Remodeling (re-engineering) of a tumor's stroma has been shown to improve the efficacy of anti-tumor therapies, without destroying the stroma. Even though it still remains unclear which stromal component/-s and what characteristics hinder the reach of nanoparticles deep into cancer cells, we hypothesis that mechanisms behind stroma's resistance to the penetration of nanoparticles rely heavily on extrinsic mechanical forces on stromal cells and cancer cells. Our hypothesis has been formulated on the basis of our previous study which has shown that changes in extracellular matrix (ECM) stiffness with tumor growth influence stresses exerted on fibroblasts and cancer cells, and that malignant cancer cells generate higher stresses on their stroma. This study attempts to establish a distinct identification of the components' remodeling on the distribution and magnitude of stress within a tumor tissue which ultimately will impact the resistance of stroma to treatment. In this study, our objective is to construct a three-dimensional in silico model of a pancreas tumor tissue consisting of cancer cells, stromal cells, and ECM to determine how stromal remodeling alters the stresses distribution and magnitude within the pancreas tumor tissue. Our results show that changes in mechanical properties of ECM significantly alter the magnitude and distribution of stresses within the pancreas tumor tissue. Our results revealed that these stresses are more sensitive to ECM properties as we see the stresses reaching to a maximum of 22,000 Pa for softer ECM with Young's modulus of 250 Pa. The stress distribution and magnitude within the pancreas tumor tissue does not show high sensitivity to the changes in mechanical properties of stromal cells surrounding stiffer cancer cells (PANC-1 with Young's modulus of 2400 Pa). However, softer cancer cells (MIA-PaCa-2 with (Young's modulus of 500 Pa) increase the stresses experienced by stiffer stromal cells and for stiffer ECM. By providing a unique platform to dissect and quantify the impact of individual stromal components on the stress distribution within a tumor tissue, this study serves as an important first step in understanding of which stromal components are vital for an efficient remodeling. This knowledge will be leveraged to overcome a tumor's resistance against the penetration of nanoparticles on a per-patient basis., (© 2024. The Author(s).)

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a common cancer with a poor prognosis and is associated with a high prevalence of cachexia, a metabolic syndrome of muscle wasting due to complex mechanisms. In addition to loss of muscle mass, cancer patients also experience functional deterioration. The aim of this study is to determine whether there is an association between muscle mass and function and clinical outcomes, particularly survival., Methods: We performed a prospective cohort study including all patients with PDAC at Monash Health from March 2016 to December 2017. We conducted body composition analysis for myopenia and handgrip strength testing. We constructed Kaplan-Meier curves to estimate whether myopenia and low hand grip strength were associated with poorer survival., Results: Myopenia was not associated with a significant difference in PDAC-specific survival (log-rank P = 0.60). However, low handgrip strength was associated with significantly worse PDAC-specific survival compared with other patients (log-rank hazard ratio, 1.88; 95% confidence interval, 1.15-3.09; P = 0.004)., Conclusions: The relationship between survival in PDAC and handgrip strength, but not anatomical muscle mass, suggests that functional testing of strength may be important in prognostication of patients with PDAC, alongside existing tools such as the Eastern Cooperative Oncology Group performance status., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related deaths worldwide, accounting for 90% of primary pancreatic tumors with an average 5-year survival rate of less than 10%. PDAC exhibits aggressive biology, which, together with late detection, results in most PDAC patients presenting with unresectable, locally advanced, or metastatic disease. In-depth lipid profiling and screening of potential biomarkers currently appear to be a promising approach for early detection of PDAC or other cancers. Here, we isolated and characterized complex glycosphingolipids (GSL) from normal and tumor pancreatic tissues of patients with PDAC using a combination of TLC, chemical staining, carbohydrate-recognized ligand-binding assay, and LC/ESI-MS 2 . The major neutral GSL identified were GSL with the terminal blood groups A, B, H, Le a , Le b , Le x , Le y , P1, and PX2 determinants together with globo- (Gb 3 and Gb 4 ) and neolacto-series GSL (nLc 4 and nLc 6 ). We also revealed that the neutral GSL profiles and their relative amounts differ between normal and tumor tissues. Additionally, the normal and tumor pancreatic tissues differ in type 1/2 core chains. Sulfatides and GM 3 gangliosides were the predominant acidic GSL along with the minor sialyl-nLc 4 /nLc 6 and sialyl-Le a /Le x . The comprehensive analysis of GSL in human PDAC tissues extends the GSL coverage and provides an important platform for further studies of GSL alterations; therefore, it could contribute to the development of new biomarkers and therapeutic approaches., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the content of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe pain is frequent in patients with locally advanced pancreatic ductal adenocarcinoma (PDCA). Stereotactic body radiotherapy (SBRT) provides high local control rates in these patients. The aim of this review was to systematically analyze the available evidence on pain relief in patients with PDCA. We updated our previous systematic review through a search on PubMed of papers published from 1 January 2018 to 30 June 2021. Studies with full available text, published in English, and reporting pain relief after SBRT on PDCA were included in this analysis. Statistical analysis was carried out using the MEDCALC statistical software. All tests were two-sided. The I2 statistic was used to quantify statistical heterogeneity (high heterogeneity level: >50%). Nineteen papers were included in this updated literature review. None of them specifically aimed at assessing pain and/or quality of life. The rate of analgesics reduction or suspension ranged between 40.0 and 100.0% (median: 60.3%) in six studies. The pooled rate was 71.5% (95% CI, 61.6−80.0%), with high heterogeneity between studies (Q2 test: p < 0.0001; I2 = 83.8%). The rate of complete response of pain after SBRT ranged between 30.0 and 81.3% (median: 48.4%) in three studies. The pooled rate was 51.9% (95% CI, 39.3−64.3%), with high heterogeneity (Q2 test: p < 0.008; I2 = 79.1%). The rate of partial plus complete pain response ranged between 44.4 and 100% (median: 78.6%) in nine studies. The pooled rate was 78.3% (95% CI, 71.0−84.5%), with high heterogeneity (Q2 test: p < 0.0001; I2 = 79.4%). A linear regression with sensitivity analysis showed significantly improved overall pain response as the EQD2α/β:10 increases (p: 0.005). Eight papers did not report any side effect during and after SBRT. In three studies only transient acute effects were recorded. The results of the included studies showed high heterogeneity. However, SBRT of PDCA resulted reasonably effective in producing pain relief in these patients. Further studies are needed to assess the impact of SBRT in this setting based on Patient-Reported Outcomes.

Purpose: Patients submitted to curative surgery for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) exhibit a variable risk of disease relapse. Aims of this meta-analysis were to estimate the rate of disease recurrence and to investigate the risk factors for disease relapse in patients submitted to curative surgery for NF-PanNENs., Methods: Medline/Pubmed and Web of Science databases were searched for relevant studies. A meta-regression analysis was performed to investigate the source of recurrence rate heterogeneity. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CI) were used to assess the effect of each possible prognostic factor on disease-free survival., Results: Fifteen studies, involving 2754 patients submitted to curative surgery for NF-PanNENs, were included. The pooled rate of disease recurrence was 21% (95% CI 15-26%). Study quality (Odds ratio, OR 0.94, P = 0.016) and G3-PanNENs rate (OR 2.18, P = 0.040) independently predicted the recurrence rate variability. Nodal metastases (HR 1.63, P < 0.001), tumor grade G2-G3 (G1 versus G2: HR 1.72, P < 0.001, G1 versus G3 HR 2.57, P < 0.001), microvascular (HR 1.25, P = 0.046) and perineural (HR 1.29, P = 0.019) invasion were identified as significant prognostic factors. T stage (T1-T2 versus T3-T4, P = 0.253) and status of resection margins (R0 versus R1, P = 0.173) did not show any significant relationship with NF-PanNENs recurrence., Conclusion: Disease relapse occurs in approximately one out of five patients submitted to curative surgery for NF-PanNENs. Nodal involvement, tumor grade, microvascular and perineural invasion are relevant prognostic factors, that should be taken into account for follow-up and for possible trials investigating adjuvant or neoadjuvant treatments., (© 2021. Italian Society of Endocrinology (SIE).)

The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization., Competing Interests: SB, HL, NS, LZ, PS, AA, MW, RS, VB, YZ, AN, MP, CH No competing interests declared, CL CAL has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015), (© 2022, Boyer et al.)

Importance: A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited., Objective: To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China., Design, Setting, and Participants: This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021., Main Outcomes and Measures: Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups., Results: A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort., Conclusions and Relevance: In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.

The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies' datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.

Laboratory animals frequently undergo routine experimental procedures such as handling, restraining and injections. However, as a known source of stress, these procedures potentially impact study outcome and data quality. In the present study, we, therefore, performed an evidence-based severity assessment of experimental procedures used in a pancreatic cancer model including surgical tumour induction and subsequent chemotherapeutic treatment via repeated intraperitoneal injections. Cancer cell injection into the pancreas was performed during a laparotomy under general anaesthesia. After a four-day recovery phase, mice received either drug treatment (galloflavin and metformin) or the respective vehicle substances via daily intraperitoneal injections. In addition to clinical scoring, an automated home-cage monitoring system was used to assess voluntary wheel running (VWR) behaviour as an indicator of impaired well-being. After surgery, slightly elevated clinical scores and minimal body weight reductions, but significantly decreased VWR behaviour were observed. During therapy, body weight declined in response to chemotherapy, but not after vehicle substance injection, while VWR activity was decreased in both cases. VWR behaviour differed between treatment groups and revealed altered nightly activity patterns. In summary, by monitoring VWR a high impact of repeated injections on the well-being of mice was revealed and substance effects on well-being were distinguishable. However, no differences in tumour growth between treatment groups were observed. This might be due to the severity of the procedures uncovered in this study, as exaggerated stress responses are potentially confounding factors in preclinical studies. Finally, VWR was a more sensitive indicator of impairment than clinical scoring in this model., Competing Interests: The authors have declared that no competing interests exists.

There are scarce data on readily available markers enabling immediate risk stratification and personalized management in patients with advanced pancreatic neuroendocrine tumors. This study explores the association of red blood cells-related parameters as prognostic markers in patients harboring pancreatic neuroendocrine tumors. Retrospective analysis of a tertiary medical center database, acquiring data of patients with pancreatic neuroendocrine tumors including demographics, tumor-related parameters and consecutive imaging results, vital status at last follow-up, and red blood cells parameters at baseline, last follow-up, and dynamics (last/baseline ratio). Univariate and multivariable analyses were performed. Sixty-seven patients were identified (mean age at diagnosis of 63±11 years, 56.7% males). Patients with disease progression had lower hemoglobin, red blood cells mass values and hematocrit at the last evaluation (p<0.001 for all comparisons), with red blood cells mass level<3.9 m/μl and a 6% and 9% relative reduction in hemoglobin and hematocrit levels, respectively, associated with an increased risk for disease progression. Similarly, patients deceased during the study period had lower hemoglobin, red blood cells mass values and hematocrit (p<0.03 for all) than those alive, at last follow-up. Eleven percent reduction in hemoglobin level was noted indicating a higher mortality risk (p=0.04). Negative hemoglobin and hematocrit dynamics were independently associated with increased risk for disease progression (p=0.03 and 0.049, respectively). In conclusion, decrease in red blood cells mass, hemoglobin and/or hematocrit levels are all associated with poor prognosis in patients with pancreatic neuroendocrine tumors. We suggest utilizing these parameters as complementary follow-up prognostic markers to radiologic imaging in this patients population., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Aims: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC., Methods: DDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival., Results: The nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2-pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC., Conclusion: These results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer. Abbreviations : AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.

Rationale & Aims: Pancreatic cancer (PC) is the third most common type of gastrointestinal tract cancer in Europe and the fourth leading cause of death by cancer. Its initial stage is asymptomatic Therefore, the diagnosis tends to be late leading to locally advanced stages that presuppose late and debilitating symptoms, which consequently makes the Nutritional Status (NS) get worse. The weight loss (WL), malnutrition, and oncologic cachexia, which are quite prevalent in PC patients, reflect a poor prognosis. We aimed to track and evaluate the NS and Functional Status (FS) of PC patients (hospitalized patients - HP and Day Hospital patients - DHP) and associate NS with symptoms with nutritional impact and FS., Methods: Observational cohort study in PC patients from Garcia de Orta Hospital. NS was tracked and evaluated using Nutritional Risk Screening (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA). To assess FS we used the Eastern Cooperative Oncology Group (ECOG), Karnofsky Performance Scale Index (KPSI) and Handgrip Dynamometer (HGD)., Results: 41 PC patients (30-HP and 11-DHP). 29 patients in stage IV of the tumor. 24 with a WL >10% in the last 6 months. 37 manifest symptoms with nutritional impact. 30 to 34 malnourished according to the GLIM criteria and PG-SGA, respectively. 11 in ECOG level 2 and corresponding KPSI, 10 in level 3 and 8 in level 4. 28 patients had a value of HGD below the 10th percentile. NRS-2002, PG-SGA and GLIM criteria were positively correlated with the symptoms (p < 0.01), % WL (p < 0.01) and ECOG (p < 0.01) and negatively correlated with HGS (p < 0.05 - NRS-2002; p < 0.01 - PG-SGA and GLIM criteria)., Conclusions: PC patients manifest debilitating symptoms with nutritional impact, namely severe WL and anorexia, which in turn lead to deterioration of the NS and FS. It is an oncology population with high nutritional risk and a higher prevalence of malnutrition, associated with severe % WL and symptoms and a sharp decline in FS., Competing Interests: Conflict of interest No conflict of interests., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Active hexose-correlated compound (AHCC) is a standardized extract from cultured Lentinula edodes mycelia, used as a potent biological response modifier in cancer treatment. We evaluated the nutritional effect of AHCC, given during neoadjuvant therapy, to patients with pancreatic ductal adenocarcinoma (PDAC). Thirty patients with resectable or borderline-resectable PDAC received neoadjuvant therapy with gemcitabine plus S-1. We compared, retrospectively, the outcomes of 15 patients who received AHCC combined with neoadjuvant therapy with those of 15 patients who did not receive AHCC combined with neoadjuvant therapy. The median changes of the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) were significantly better in the AHCC group. The relative dose intensity of neoadjuvant therapy was also significantly higher in the AHCC group. Thus, AHCC may improve the nutritional status during neoadjuvant therapy of patients with pancreatic ductal adenocarcinoma. To validate these results and examine the long-term impact of AHCC, a prospective phase II study for PDAC is ongoing., (© 2021. Springer Nature Singapore Pte Ltd.)

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published., (© 2021. The Author(s).)

Introduction: Introduction: some factors have been shown to be associated with survival in patients with pancreatic adenocarcinoma. Recently, some studies suggested that malnutrition, muscle mass, and inflammation might have an effect on survival in patients with pancreatic malignancy. Objectives: to investigate the association between psoas muscle mass, inflammation, nutritional status at the time of diagnosis, and survival in patients with pancreatic adenocarcinoma. Methods: this retrospective study included 219 patients diagnosed with pancreatic carcinoma. The nutritional status, inflammation, and psoas muscle mass of the patients at the time of diagnosis were evaluated. Nutritional status was assessed using the Prognostic Nutritional Index (PNI). Leucocyte count and neutrophil/lymphocyte ratio (NLR) were used for inflammation assessment. Psoas muscle mass was calculated by using abdominal computed tomography images of the patients. Results: the mean age of patients (80 female and 139 male) was 66.6 ± 11.7 years. According to the PNI results, 155 patients had a normal nutritional status (70 %), whereas 64 patients were malnourished (30 %). The survival of the patients with normal nutritional status was significantly longer than that of those who were malnourished (p < 0.001). There was no significant relationship between psoas muscle area, leucocyte count, NLR, and survival time. Conclusion: the survival of pancreatic adenocarcinoma patients with malnutrition at the time of diagnosis was significantly shorter than for patients without malnutrition.

The tumor microenvironment (TME) is a dynamic system where nontumor and cancer cells intercommunicate through soluble factors and extracellular vesicles (EVs). The TME in pancreatic cancer (PC) is critical for its aggressiveness and the annexin A1 (ANXA1) has been identified as one of the oncogenic elements. Previously, we demonstrated that the autocrine/paracrine activities of extracellular ANXA1 depend on its presence in EVs. Here, we show that the complex ANXA1/EVs modulates the macrophage polarization further contributing to cancer progression. The EVs isolated from wild type (WT) and ANXA1 knock-out MIA PaCa-2 cells have been administrated to THP-1 macrophages finding that ANXA1 is crucial for the acquisition of a protumor M2 phenotype. The M2 macrophages activate endothelial cells and fibroblasts to induce angiogenesis and matrix degradation, respectively. We have also found a significantly increased presence of M2 macrophage in mice tumor and liver metastasis sections previously obtained by orthotopic xenografts with WT cells. Taken together, our data interestingly suggest the relevance of ANXA1 as potential diagnostic/prognostic and/or therapeutic PC marker.

Pancreatic cancer is one of the malignant tumors with poor prognosis. The molecular mechanisms of pancreatic oncogenesis and malignant progression are not fully elucidated. Several key signaling pathways, such as Notch, Wnt and hedgehog pathways, are important to drive pancreatic carcinogenesis. Recently, noncoding RNAs, especially circular RNAs (circRNAs), have been characterized to participate into pancreatic cancer development. Therefore, in this review article, we describe the association between circRNAs and pancreatic cancer prognosis. Moreover, we discuss how circRNAs are involved in regulation of cellular processes in pancreatic cancer, including proliferation, apoptosis, cell cycle, migration, invasion, EMT, metastasis, angiogenesis, drug resistance and immune escape. Furthermore, we mention that several compounds could regulate the expression of circRNAs, indicating that targeting circRNAs by compounds might be helpful for treating pancreatic cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins., Methods: We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017-2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes., Results: Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352-9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019)., Conclusion: Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes., (© 2021. The Author(s).)

Background: Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). Solute carrier family 45 member A4 (SLC45A4) is a H + -dependent sugar cotransporter. The role of SLC45A4 in PDA, especially in TP53 mutant PDA, remains poorly understood., Methods: We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium], colony formation and 5-ethynyl-2'-deoxyuridine (Edu) assays were performed to investigate the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization. Extracellular acidification rate and oxygen consumption rate assays were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNA-sequencing and gene set enrichment analysis were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blotting was performed to evaluate the activation of glycolysis, as well as the AMPK pathway and autophagy., Results: SLC45A4 was overexpressed in PDA for which the expression was significantly higher in TP53 mutant PDA than that in wild-type PDA tissues. Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production, which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice., Conclusions: The present study found that SLC45A4 prevents autophagy via AMPK/ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA., (© 2021 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.)

New-onset diabetes mellitus has a rough correlation with pancreatic cancer (PaC), but the underlying mechanism remains unclear. This study aimed to explore the exosomal microRNAs and their potential role in PaC-induced β-cell dysfunction. The pancreatic β cells were treated with isolated exosomes from PaC cell lines, SW1990 and BxPC-3, before measuring the glucose-stimulated insulin secretion (GSIS), validating that SW1990 and BxPC-3 might disrupt GSIS of both β cell line MIN6 and primary mouse pancreatic islets. The difference in expression profiles between exosomes and exosome-free medium of PaC cell lines was further defined, revealing that miR-19a secreted by PaC cells might be an important signaling molecule in this process. Furthermore, adenylyl cyclase 1 (Adcy1) and exchange protein directly activated by cAMP 2 (Epac2) were verified as the direct targets of exogenous miR-19a, which was involved in insulin secretion. These results indicated that exosomes might be an important mediator in the pathogenesis of PaC-DM, and miR-19a might be the effector molecule. The findings shed light on the pathogenesis of PaC-DM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Body composition is increasingly being studied as a method of predicting chemotherapy toxicity. Our study aimed to evaluate associations of body composition with treatment toxicity in a group of pancreatic cancer patients treated with gemcitabine plus nab-paclitaxel., Methods: A retrospective review was performed for all patients who received first-line gemcitabine plus nab-paclitaxel for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014 to 2017. Total lean body mass (LBM) was derived from measurements of muscle surface area at L3 on baseline computed tomography (CT) scans. Optimal stratification, or minimal p-value analysis, was used to assess for a threshold of nab-paclitaxel dose per LBM (mg/kg) associated with a higher risk of dose-limiting toxicity (DLT)., Results: 152 patients were included in the study, of whom 62 (40.8%) experienced DLT. nab-Paclitaxel dose/LBM ranged from 0.98 to 8.76 mg/kg. A threshold for nab-paclitaxel dose/LBM that optimally predicted risk of DLT was identified at 5.83 mg/kg. Above this cut-off, 18/31 (58.1%) patients experienced DLT, compared to 44/121 (36.4%) patients below (p = 0.028). Patients above this cut-off had a higher incidence of peripheral neuropathy compared to those below, though this was not statistically significant based on an adjusted p-value threshold (48.4 vs. 29.8% respectively, p = 0.050). Body mass index, body surface area, and absolute initial doses of nab-paclitaxel or gemcitabine did not significantly impact likelihood of DLT., Conclusions: nab-Paclitaxel dose normalized to LBM, based on CT-derived measures of skeletal muscle, has potential to predict risk of chemotherapy toxicity. Chemotherapy dosing based on body composition, rather than conventional anthropometric measures, may be effective in reducing treatment toxicity., Competing Interests: Conflict of interest None declared., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation, and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor-promoting (Ym1 + , Fizz + , Arg1 + ) phenotype, increases fibrosis, and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells., Competing Interests: VP, AF, LB, HD, JE, TL, BE, PS No competing interests declared, (© 2021, Pandey et al.)

The α-actinin family of actin cross-linking proteins have been implicated in driving tumor cell metastasis through regulation of the actin cytoskeleton; however, there has been little investigation into whether these proteins can influence tumor cell growth. We demonstrate that α-actinin 1 and 4 are essential for nutrient uptake through the process of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC) cells, and inhibition of these proteins decreases tumor cell survival in the presence of extracellular protein. The α-actinin proteins play essential roles throughout the macropinocytic process, where α-actinin 4 stabilizes the actin cytoskeleton on the plasma membrane to drive membrane ruffling and macropinosome internalization and α-actinin 1 localizes to actin tails on macropinosomes to facilitate trafficking to the lysosome for degradation. In addition to tumor cell growth, we also observe that the α-actinin proteins can influence uptake of chemotherapeutics and extracellular matrix proteins through macropinocytosis, suggesting that the α-actinin proteins can regulate multiple tumor cell properties through this endocytic process. In summary, these data demonstrate a critical role for the α-actinin isoforms in tumor cell macropinocytosis, thereby affecting the growth and invasive potential of PDAC tumors.

Background & Aims: This study was conducted to investigate the nutritional status and longitudinal dietary intake during the course of chemotherapy, and their relationships with the survival in patients with unresectable pancreatic cancer., Methods: A prospective cohort study was conducted in 38 patients with unresectable pancreatic cancer receiving chemotherapy between January 2018 and November 2019. Subjective global assessment was used to assess the nutritional status, and the dietary intake was assessed monthly, for up to 12 months, using a brief self-administered diet history questionnaire. The primary outcome was overall survival, and the secondary outcome was progression-free survival. Cox regression analysis was performed to identify independent prognostic factors., Results: Moderate or severe malnutrition was found in 34.2% of the participants. Daily protein intake was significantly higher in the survivor group than in the deceased group at one month after the initiation of chemotherapy (1.4 ± 0.7 g/kg/day vs. 0.9 ± 0.5 g/kg/day, p = 0.019), while the baseline nutritional intakes were similar between the two groups. Univariate analysis identified weight loss >3.5%, energy intake <25 kcal/kg/day, protein intake <1.1 g/kg/day, and malnutrition as possible poor prognostic factors. Multivariate analysis identified protein intake <1.1 g/kg/day (hazard ratio [HR]: 9.03, 95%CI: 1.45-56.32, p = 0.018) as an independent poor prognostic factor., Conclusions: Insufficient protein intake was identified as an independent poor prognostic factor in patients with unresectable pancreatic cancer receiving chemotherapy. Improving the dietary protein intake could be a useful therapeutic approach in patients with advanced pancreatic cancer receiving chemotherapy., Competing Interests: Conflicts of interest YN have received grants or contracts from Taiho Pharmaceutical, Yakult Honsha, Eisai, Sumitomo Dainippon Pharma. They had no role in designing the study, data collection or analysis, interpretation of the data, or writing the manuscript., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The survival benefit of chemotherapy compared to best supportive care (BSC) after percutaneous transhepatic biliary drainage (PTBD) was evaluated in patients with pancreatic or biliary tract cancer., Patients and Methods: A retrospective registry study was conducted at a tertiary-level university hospital. The endpoint was survival measured from the PTBD and the initiation of chemotherapy., Results: Among 158 patients (mean age=74 years, range=43-93 years; 51.9% women), 82 (51.9%) had pancreatic cancer and 76 (48.1%) had biliary tract cancer. After PTBD, 32 (20.3%) patients received chemotherapy and had a median survival of 11.7 months; 126 (79.7%) patients received only BSC resulting in a median survival of 1.7 months. The hazard ratio for survival at 1 year for patients who received chemotherapy compared to BSC was 0.22 (95% confidence interval=0.12-0.41, p<0.001)., Conclusion: After PTBD, patients with pancreatic or biliary tract cancer should be critically evaluated by an oncologist to determine whether chemotherapy is possible, as it seems to significantly improve survival compared to BSC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Aggressive pancreatobiliary tumors often require oxaliplatin-based therapies, instead of standard gemcitabine-based therapy and biomarker studies at diagnosis to decide the appropriate therapeutic regimen. The ribonucleotide Reductase catalytic subunit M1 (RRM1) and excision repair cross-complementing gene-1 (ERCC1) are related to DNA synthesis and repair and essential in this regard. However, apart from the therapeutic benefit, their prognostic implication is controversial., Methods: In this retrospective study, paraffin-embedded tissue from 51 cases of pancreatic cancer and 29 cases of cholangiocarcinoma were evaluated for RRM1 and ERCC1 expression by immunohistochemical technique along with 18 control pancreatic and biliary tissues. The semiquantitatively H score was calculated based on stain distribution and stain intensities., Results: Both RRM1 and ERCC1 expression were high in tumor epithelium than in controls (RRM1: the difference was statistically significant in cholangiocarcinoma (P = 0.008); ERCC1: the difference was statistically significant both in pancreatic and cholangiocarcinoma (P < 0.05)]. However, no correlation was noted between RRM1 and ERCC1-low and high tumors with histological markers of prognosis and overall survival in these patients., Conclusions: The present study adds further evidence against the controversy that if RRM1 and ERCC1 expression in pancreatic and biliary carcinomas have any prognostic significance apart from their proven therapeutic benefits in these tumors., Competing Interests: None

Purpose: To evaluate and compare the nutritional factors and clinical outcomes of pancreaticoduodenectomy between elderly and non-elderly patients., Methods: This retrospective study evaluated 122 consecutive patients who underwent pancreaticoduodenectomy from April 2008 to April 2020. Preoperative and postoperative nutritional factors (prognostic nutritional index), complication rates, and survival rates were compared between the elderly (≥ 80 years) and non-elderly (< 80 years) patient groups. Changes in nutrition markers were evaluated before surgery to 1 year after surgery., Results: A total of 20 elderly patients (16.4%) and 102 non-elderly patients (83.6%) underwent pancreaticoduodenectomy. Elderly patients had a significantly lower preoperative prognostic nutritional index than did non-elderly patients. At 3 months postoperatively, elderly patients had a lower albumin level and prognostic nutritional index. The median length of hospital stay was significantly longer (39.9 vs. 27 days, P = 0.004), the rate of death due to other diseases was higher, and the overall survival rate was significantly lower (1-/3-/5 year overall survival rates: 78.1%/26.7%/13.3% vs. 87.1%/54.4%/46.7%; log-rank test, P = 0.003) in the elderly group than in the non-elderly group., Conclusions: The results suggest that careful patient selection and optimal perioperative care are necessary to determine whether pancreaticoduodenectomy is indicated for elderly patients.

Pancreatic neuroendocrine neoplasms (pNENs) are slow growing cancers of increasing incidence that lack effective treatments once they become metastatic. Unfortunately, nearly half of pNEN patients present with metastatic liver tumors at diagnosis and current therapies fail to improve overall survival. Pre-clinical models of pNEN metastasis are needed to advance our understanding of the mechanisms driving the metastatic process and for the development of novel, targeted therapeutic interventions. To model metastatic dissemination of tumor cells, human pNEN cell lines (BON1 and Qgp1) stably expressing firefly luciferase (luc) were generated and introduced into NSG immunodeficient mice by intracardiac (IC) or intravenous (IV) injection. The efficiency, kinetics and distribution of tumor growth was evaluated weekly by non-invasive bioluminescent imaging (BLI). Tumors formed in all animals in both the IC and IV models. Bioluminescent Qgp1.luc cells preferentially metastasized to the liver regardless of delivery route, mimicking the predominant site of pNEN metastasis in patients. By comparison, BON1.luc cells most commonly formed lung tumors following either IV or IC administration and colonized a wider variety of tissues than Qgp1.luc cells. These models provide a unique platform for testing candidate metastasis genes and anti-metastatic therapies for pNENs.

Objectives: Exocrine pancreatic insufficiency is a frequent and clinically relevant complication of pancreatic cancer probably secondary to pancreatic duct obstruction. We aimed at evaluating the impact of endoscopic pancreatic drainage on pancreatic function in patients with unresectable pancreatic cancer., Methods: A double-blind, prospective, randomized, single-center, interventional study was designed. Patients undergoing endoscopic retrograde cholangiopancreatography for jaundice secondary to unresectable pancreatic cancer were randomized to biliary drainage (group A) or biliopancreatic drainage (group B). Pancreatic function was evaluated by 13C-mixed triglyceride breath test before and 2 weeks after endoscopic retrograde cholangiopancreatography. Breath test result is expressed as 13C-cumulative recovery rate. Abdominal symptoms and nutritional markers were evaluated as secondary outcomes., Results: Twenty patients were included. Sixteen patients had exocrine pancreatic insufficiency, and 13 completed the study (7 in group A and 6 in group B). The median absolute improvement of 13C-cumulative recovery rate was of 23.75% (interquartile range, 9.62-31.74) after biliopancreatic drainage compared with -1.92% (interquartile range, -4.17 to 13.92) after biliary drainage (P = 0.015). Nutritional markers improved after biliopancreatic drainage, but not after biliary drainage., Conclusions: Biliopancreatic and not biliary endoscopic drainage is associated with a significant improvement of exocrine pancreatic function in patients with unresectable pancreatic cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Diet and exercise interventions may help reverse malnutrition and muscle wasting common in pancreatic cancer. We performed a scoping review to identify the knowledge gaps surrounding diet and exercise interventions. We searched PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, Embase, ProQuest Theses and Dissertations, and Google Scholar using the umbrella terms of "pancreatic cancer," "diet/nutrition," and "exercise." Included were articles reporting on ambulatory adults with diagnosed pancreatic cancer. Excluded were studies examining prevention and/or risk, animal, or cell lines. Of the 15,708 articles identified, only 62 met the final inclusion criteria. Almost half of the articles were randomized controlled studies (n = 27). Most studies were from the United States (n = 20). The majority examined dietary interventions (n = 41), with 20 assessing the use of omega-3 fatty acids. Exercise interventions were reported in 13 studies, with 8 examining a diet and exercise intervention. Most studies were small and varied greatly in terms of study design, intervention, and outcomes. We identified 7 research gaps that should be addressed in future studies. This scoping review highlights the limited research examining the effect of diet and exercise interventions in ambulatory patients with pancreatic cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients' anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

Hypoxia and nutrient starvation (H/NS) microenvironment, a notable characteristic of pancreatic carcinoma, plays a critical role in cell death resistance and tumor recurrence. However, its role in ferroptosis remains to be classified. Here, we found that H/NS contributed to the pancreatic cancer cell ferroptosis resistance depending on the altered intracellular lipid compositions. Mechanistically, H/NS induced the upregulation of stearoyl-CoA desaturase 1 (SCD1), which promoted monounsaturated fatty acids (MUFAs) synthesis and protected against lipid peroxidation. Surprisingly, SCD1 showed a strong correlation with antiferroptosis gene expression. Moreover, short-hairpin RNA-based knockdown of SCD1 enhanced erastin-induced ferroptosis in vitro under H/NS. Finally, our results demonstrate the synergistic effect of erastin and A939572, a special SCD1 inhibitor, in dictating pancreatic carcinoma subcutaneous ferroptotic death. Taken together, our findings reveal a new role of the H/NS microenvironment against ferroptosis and suggest a potential therapeutic strategy for overcoming ferroptosis resistance in pancreatic cancer cells., Competing Interests: The authors declare no conflict of interests., (Copyright © 2021 Jie Gao et al.)

A significant number of pancreatic cancer cases are due to modifiable risk factors, with many being attributed to increased body fatness. This has sparked investigators to examine the role played by high dietary fat intake in pancreatic cancer development and the mechanisms driving this connection. However, there is currently no consensus on how dietary fat quantity and composition specifically affect pancreatic carcinogenesis. The objective of this narrative review is to discuss the link between high total fat consumption and fatty acid composition (saturated, mono-, or poly-unsaturated fats) with pancreatic cancer incidence and progression. Following our detailed analysis of the strengths and weaknesses of recent preclinical and human studies, we discuss existing research gaps and opportunities, and provide recommendations for future studies. Numerous studies suggest that diets high in omega-3 polyunsaturated fatty acids are associated with reduced pancreatic cancer risk. However, the current evidence appears insufficient for a general conclusion regarding the impact of other types of fat in pancreatic carcinogenesis, with many studies providing inconclusive findings due to study limitations. Thus, we recommend future studies to include detailed methodology of the animal experiments, not limited to the diet composition, type of ingredients, formulations, and administration of the diets. Moreover, human studies should include a diverse population and well-characterized biomarkers for accurate determination of dietary fat intake. Ultimately, this will aid the study rigor, and improve our understanding of the impact of fat quantity and composition in pancreatic carcinogenesis., (Copyright © 2020. Published by Elsevier Inc.)

Background: The geriatric nutritional risk index (GNRI), originally developed as a nutritional assessment tool to evaluate mortality and morbidity in older hospitalized patients (i.e., those aged ≥65 years), is regarded as a prognostic factor in several cancers. Body composition is also an important consideration when predicting the prognosis of patients with cancer. This study aimed to investigate the relationship between the GNRI and psoas muscle volume (PMV) for survival outcomes in patients with pancreatic cancer., Methods: This retrospective study evaluated the prognostic significance of the GNRI and PMV in 105 consecutive patients aged ≥65 years who underwent pancreatectomy for histologically confirmed pancreatic cancer. The patients were divided into high (GNRI > 98) and low GNRI groups (GNRI ≤98), and into high (PMV > 61.5 mm 3 /m 3 for men and 44.1 mm 3 /m 3 for women) and low PMV (PMV ≤ 61.5 mm 3 /m 3 for men and 44.1 mm 3 /m 3 for women) groups., Results: Both the 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly greater among patients in the high GNRI group than among patients in the low GNRI group. Similarly, both the 5-year OS and RFS rates were significantly greater among patients in the high PMV group than among patients in the low PMV group. Patients were stratified into three groups: those with both high GNRI and high PMV; those with either high GNRI or high PMV (but not both); and those with both low GNRI and low PMV. Patients with both low GNRI and low PMV had a worse 5-year OS rate, compared with patients in other groups (P <  0.001). The C-index of the combination of the GNRI and PMV for predicting 5-year OS was greater than the C-indices of either the GNRI or PMV alone. Multivariate analysis revealed that the combination of the GNRI and PMV was an independent prognostic factor in patients aged ≥65 years with pancreatic cancer (P = 0.003)., Conclusions: The combination of the GNRI and PMV might be useful to predict prognosis in patients aged ≥65 years with pancreatic cancer.

Background: Recently, a few studies have reported different results regarding the relationship between metabolic health and obesity phenotype and several cancers. We examined the effects of metabolic health and obesity phenotype on pancreatic cancer using a nationwide population-based cohort database., Methods: Using the Korean National Health Insurance Service-Health Screening Cohort, we enrolled 347,434 Korean adults who underwent a health examination between 2009 and 2010 and were followed until 2015. This population was divided into four groups based on metabolically healthy status and body mass index (BMI): metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO)., Results: Over a median follow-up of 6.1 (5.5-6.5) years, 886 individuals were diagnosed with pancreatic cancer. The adjusted HRs for incident pancreatic cancer were 1.52 [95% confidence interval (CI) 1.27-1.81] and 1.34 (95% CI, 1.12-1.61) for the MUNW and MUO phenotypes (compared with the MHNW phenotype) after adjusting for various confounding factors. However, compared with the MHNW phenotype, the MHO phenotype did not show an elevated risk of pancreatic cancer. Moreover, the HR for pancreatic cancer gradually increased with an increase in number of metabolically unhealthy components, even after adjusting for BMI ( P trend < 0.001)., Conclusions: Regardless of BMI, metabolically unhealthy phenotype demonstrated significantly increased risk of pancreatic cancer, whereas obese individuals with metabolically healthy phenotype did not., Impact: These findings suggest that metabolically unhealthy phenotype might represent a potential risk factor for pancreatic cancer occurrence independent of obesity., (©2020 American Association for Cancer Research.)

Abstract: The aim of this study was to examine the health-related effects of exercise in patients with pancreatic cancer (PanCa) through a systematic review of current evidence. Studies were obtained through searching PubMed, Web of Science, PsycINFO, Embase, CINAHL Plus, and Cochrane Library databases with additional hand searches. All intervention-based studies were included if it involved (1) adult patients with PanCa, (2) exercise training, and (3) findings in quality of life, cancer-related fatigue, psychological distress, and physical function. The review protocol was registered in PROSPERO: CRD42020154684. Seven trials described in 9 publications were included consisting of 201 patients with early-stage and advanced PanCa. Participants were required to perform supervised and/or home-based, low- to moderate-intensity resistance and/or aerobic exercise for 12 to 35 weeks or duration of neoadjuvant therapy. There were no exercise-related adverse events with a reported retention rate of 71% to 90% and exercise attendance of 64% to 96%. The programs were consistently associated with improvements in cancer-related fatigue, psychological distress, and physical function, with mixed effects on quality of life. Exercise training seems to be safe and feasible and may have a beneficial effect on various physical and psychological outcomes in patients with PanCa. Further work with rigorous study designs is required to consolidate and advance current findings., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. We developed PIC-IT, a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size - including single-metastatic cells - which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising microcolonies revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for an inflammatory-response phenotype associated with NF-κB/AP-1 signaling. Pharmacological inhibition of NF-κB depleted microcolonies but had no effect on macrometastases, suggesting microcolonies are particularly dependent on this pathway. PIC-IT thus enables systematic investigation of metastatic heterogeneity. Moreover, the technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible., Competing Interests: YS, JL, PK, AM, NL, CL, PR, BS No competing interests declared, (© 2021, Sela et al.)

Napabucasin, undergoing multiple clinical trials, was reported to inhibit the signal transducer and transcription factor 3 (STAT3). To better elucidate its mechanism of action, we designed a napabucasin-based proteolysis targeting chimera (PROTAC), XD2-149 that resulted in inhibition of STAT3 signaling in pancreatic cancer cell lines without inducing proteasome-dependent degradation of STAT3. Proteomics analysis of XD2-149 revealed the downregulation of the E3 ubiquitin-protein ligase ZFP91. XD2-149 degrades ZFP91 with DC 50 values in the nanomolar range. The cytotoxicity of XD2-149 was significantly, but not fully, reduced with ZFP91 knockdown providing evidence for its multi-targeted mechanism of action. The NQO1 inhibitor, dicoumarol, rescued the cytotoxicity of XD2-149 but not ZFP91 degradation, suggesting that the NQO1-induced cell death is independent of ZFP91. ZFP91 plays a role in tumorigenesis and is involved in multiple oncogenic pathways including NF-κB and HIF-1α.

Background:  Neuroendocrine tumors (NET) diagnosed during pregnancy are extremely rare. This case report describes diagnosis and treatment of a metastasized pancreas NET that became symptomatic in the second trimester., Case Description:  A 33-year-old patient presented to the emergency department in the 19 th week of pregnancy (WOP) with persistent diarrhea. Laboratory tests showed a pronounced hypercalcemia (3.53 mmol/l). Imaging revealed a mass in the pancreatic corpus/tail with extensive liver metastasis. Histologically, a NET (G2, SSTR-positive) with paraneoplastic parathormone-related-peptide secretion was found to be the cause of hypercalcemia. Under a treatment with octreotide, calcium values normalized and diarrhea stopped. After delivery of a healthy child (32.WOP via cesarean section) tumor progress was found. The pancreatic mass was resected completely, the liver metastases as far as possible. Postoperatively, in a CT scan, residual suspicious liver lesions could be found, and a palliative therapy with lanreotide was initiated. With this treatment, the patient has been asymptomatic for one year, and serum calcium remained normal. The child developed normally., Discussion:  This unusual case shows that even in extensively metastasized symptomatic NETs during pregnancy, there may be sufficient diagnostic and therapeutic options that allow for a continuation of pregnancy in close interdisciplinary cooperation under careful risk-benefit assessment for mother and child., Competing Interests: JS erhielt Vortragshonorare von Novartis und Ipsen und nahm an Advisory Boards von Novartis und ADVANZ Pharma teil. Die anderen Autoren erklären, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The controlling nutritional status (CONUT) score was developed as a nutritional score that can be calculated from the serum albumin level, total cholesterol concentration, and total lymphocyte count. The aim of this study was to assess the prognostic factors for the overall survival (OS) of pancreatic cancer patients following a curative resection and to compare the CONUT score with other prognostic factors to demonstrate its utility. Between January 2007 and December 2015, 307 consecutive patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) were divided into a low CONUT group (LC; CONUT score ≤ 3) and a high CONUT group (HC; CONUT score ≥ 4) according to the results of their preoperative blood examination. The clinicopathological characteristics and prognosis of the patients were evaluated retrospectively. The prognostic factors of PDAC were detected using multivariate analyses. The LC and HC groups included 279 and 28 patients, respectively. The overall survival of the LC group was better than that of the HC group (LC, median survival time [MST] 27.9 months, 5-year survival rate 33.4%, respectively; HC, 13.9 months, 6.7%, p < 0.001). The multivariate analyses showed that age ≥ 70 years, lymph node metastasis, absence of postoperative adjuvant chemotherapy, CA19-9 ≥ 200 U/ml, and a preoperative CONUT score ≥ 4 were independently associated with poor survival. However, the Glasgow prognostic score, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and prognostic nutritional index were not significant factors. The CONUT score may be useful for predicting the long-term survival of patients with PDAC.

The specific role and mechanism of ferroptosis in the development of pancreatic cancer (PC) remain to be elucidated. The present study aimed to investigate the effects of the overexpression of the KAI1 gene on the ferroptosis of the human PC cell line MIA PaCa‑2. MIA PaCa‑2 cells infected with pCMV‑KAI1 and selected by G418 and KAI1 protein were analyzed by western blotting. The MIA PaCa‑2 cells with a stable expression of the KAI1 gene were termed MIA PaCa‑2‑KAI1. The proliferative capacities of MIA PaCa‑2 and MIA PaCa‑2‑KAI1 cells were detected using Cell Counting Kit‑8. The reactive oxygen species (ROS) in the cells were compared by flow cytometry. The expressions of ferroportin (FPN) and glutathione peroxidase 4 (GPX4) protein were analyzed by western blotting. The KAI1 stable expression cell line was confirmed and relabeled as MIA PaCa‑2‑KAI1. No significant differences in the proliferation of MIA PaCa‑2 and MIA PaCa‑2‑KAI1 were identified. Following treatment with a ferroptosis blocker, the increase in the proliferation of MIA PaCa‑2‑KAI1 (from 2.06±0.02 to 2.75±0.02) was more evident compared with MIA PaCa‑2 (from 2.94±0.02 to 2.95±0.02; P&lt;0.05). The ROS in MIA PaCa‑2‑KAI1 was significantly higher compared with MIA PaCa‑2 (P&lt;0.05). FPN and GPX4 protein demonstrated higher expression levels in MIA PaCa‑2‑KAI1 compared with MIA PaCa‑2. Moreover, KAI1 exerted an obvious promotion effect on FPN expression. This study identified that the high expression of the KAI1 gene promoted the occurrence of ferroptosis in PC cells through its extensive effect on FPN and GPX4. KAI1‑induced ferroptosis did not significantly inhibit the proliferation of PC cells.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity., (© 2021 Purohit et al.; Published by Cold Spring Harbor Laboratory Press.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1 + tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1 + and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1 + cells in vivo, revealing the essential roles of Dclk1 + cells in expansion of pancreatic neoplasia in all progressive stages., Competing Interests: TM, AF, NG, MT, KI, YH, SO, YN, YY, TY, KT, SU, DS, TC, HS No competing interests declared, (© 2021, Maruno et al.)

Purpose: To identify the direct effects and functional mechanisms of SHP1, plus its relationship with STAT3 in pancreatic cancer., Methods: Immunohistochemistry and Western blot assays were used to test SHP1 expression in pancreatic cancer. The functions of SHP1 in pancreatic cancer cells were analyzed by cell viability, colony formation, flow cytometric analysis of apoptosis, migration and invasion assays. Co-immunoprecipitation, combined with shotgun mass spectrometry, verified the direct or indirect interactions with JAK1 and p-STAT3(Ser727). Non-labeling and quantitative proteomics analysis evaluated the effect of SHP1 on protein expression levels. PRM phosphorylation modification of quantitative proteomics analysis confirmed p-STAT3(Ser727) levels., Results: SHP1 was missing or weakly expressed in human pancreatic ductal adenocarcinoma tissues and cells: PANC-1, AsPC-1, BxPC-3, and SW1990. SHP1 inhibited cell proliferation and migration. SHP1 had a slight effect on the protein expression level of PANC-1 cells. The level of p-STAT3(Ser727) was decreased by SHP1 at 0.53 multiple. Co-IP analysis revealed no direct or indirect interactions between SHP1and p-STAT3(Ser727) in protein complex patterns., Conclusion: These results suggest that SHP1 negatively regulate pancreatic cancer cells progression. It inhibits STAT3 activation by decreasing STAT3 phosphorylation at serine 727.

Background: Weight change offers the simplest indication of a patient's recovery after an operation. There have been no studies that have thoroughly investigated postoperative weight dynamics after pancreatectomy. The aim of this study was to define postoperative weight change after a pancreatectomy and determine factors associated with optimal and poor weight trajectories., Methods: From 2004 to 2019, 1,090 proximal (65%) and distal (35%) pancreatectomies were performed in patients with adequate data in the medical records. Patient weights were acquired preoperatively and at postoperative months 1, 3, and 12. Optimal (top quartile, weight restoration) and poor (bottom quartile, persistent weight loss) postoperative weight cohorts were identified at 1 year postoperatively., Results: The median percentage weight change 1 year postpancreatectomy was -6.6% (interquartile range: -1.4% to -12.5%), -7.8% for proximal pancreatectomy, and -4.2% for distal pancreatectomy. For most patients (interquartile range cohort), the median percentage weight change at 1, 3, and 12 months was -6.2%, -7.2%, and -6.6%. The independent factors associated with weight restoration were age <65, nonobesity (body mass index <30kg/m 2 ), receiving total parenteral nutrition/total enteral nutrition preoperatively, experiencing preoperative weight loss >10%, distal pancreatectomy, not undergoing vascular resection, and no readmission within 30 days. Conversely, persistent weight loss was associated with American Society of Anesthesiologists classes III to IV, obesity, malignancy, proximal pancreatectomy, blood loss ≥350mL, and experiencing readmission within 30 days. Focusing on pancreatic ductal adenocarcinoma (n = 372) patients, the factors associated with persistent weight loss were obesity, proximal pancreatectomy, and experiencing recurrence within 1 year; however, weight cohorts were not associated with overall survival for pancreatic ductal adenocarcinoma patients., Conclusion: These data define weight kinetics after pancreatectomy. Ultimately, postoperative weight trajectories appear to be largely predetermined but may be mitigated by limiting readmissions and complications. Clinicians should use these data to identify patients who continue to lose weight between the first and third month postoperatively with a high suspicion for the requirement of nutritional monitoring or other interventions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Loss of body weight is often seen in pancreatic cancer and also predicts poor prognosis. Thus, maintaining muscle mass is an essential treatment goal. The primary aim was to investigate whether progressive resistance training impacts muscle and adipose tissue compartments. Furthermore, the effect of body composition on overall survival (OS) was investigated., Methods: In the randomized SUPPORT-study, 65 patients were assigned to 6-month resistance training (2x/week) or a usual care control group. As secondary endpoint, muscle strength of the upper and lower extremities was assessed before and after the intervention period. Routine CT scans were assessed on lumbar L3/4 level for quantification of total-fat-area, visceral-fat-area, subcutaneous-fat-area, intramuscular-fat-area, visceral-to-subcutaneous fat ratio (VFR), muscle-area (MA), muscle-density and skeletal-muscle-index (SMI). OS data were retrieved., Results: Of 65 patients, 53 had suitable CT scans at baseline and 28 completed the intervention period with suitable CT scans. There were no significant effects observed of resistance training on body composition (p>0.05; effect sizes ω2p <0.02). Significant moderate to high correlations were found between MA and muscle strength parameters (r = 0.57-0.85; p<0.001). High VFR at baseline was a predictor of poor OS (VFR≥1.3 vs. <1.3; median OS 14.6 vs. 45.3 months; p = 0.012). Loss of muscle mass was also a predictor of poor OS (loss vs. gain of SMI; median OS 24.6 vs. 50.8 months; p = 0.049)., Conclusion: There is anabolic potential in patients with resectable pancreatic cancer. A progressive resistance training may help patients to maintain their muscle mass and avoid muscle depletion. CT-quantified muscle mass at the level of L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. A high VFR at baseline and a high loss of muscle mass are predictors of poor OS. Registered on ClinicalTrials.gov (NCT01977066)., Competing Interests: The authors have declared that no competing interests exist.

Aims: The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies., Main Methods: The ER expression status in PANC-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ERα-selective agonist propylpyrazoletriol (PPT), ERβ-selective agonist diarylpropionitrile (DPN), ERα over-expressed SW1990 cells, ERα knock-out PANC-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ERα in pancreatic cancer. The phosphorylation of ERα-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied., Key Findings: PANC-1 cells expressed much more ERα than SW1990 cells, and ERβ level was with less diversity. Accordingly, the proliferation of PANC-1 rather than SW1990 cells could be stimulated by E2, and only PANC-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ERα with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety., Significance: This study showed the important roles of ERα in tumor progression and endocrine therapies of pancreatic cancer in women., (Copyright © 2020 Elsevier Inc. All rights reserved.)