Comprehensive characterization of complex glycosphingolipids in human pancreatic cancer tissues.

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-MS2. The major neutral GSL identified were GSL with the terminal blood groups A, B, H, Lea, Leb, Lex, Ley, P1, and PX2 determinants together with globo- (Gb3 and Gb4) and neolacto-series GSL (nLc4 and nLc6). 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 GM3 gangliosides were the predominant acidic GSL along with the minor sialyl-nLc4/nLc6 and sialyl-Lea/Lex. 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.

Pain Relief after Stereotactic Radiotherapy of Pancreatic Adenocarcinoma: An Updated Systematic Review.

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/ß: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.

Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China.

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.

Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway.

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.

RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival.

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.

Predictors of disease recurrence after curative surgery for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNENs): a systematic review and meta-analysis.

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.

Voluntary wheel running behaviour as a tool to assess the severity in a mouse pancreatic cancer model.

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.

Case Report: Insulinoma Presenting as Excessive Daytime Somnolence.

Currently, undiagnosed insulinomas remain a difficult clinical dilemma because its symptoms in most cases can easily be misdiagnosed as other diseases. In this article, we present the case of a 14-year-old girl who presented to our hospital with recurrent episodes of excessive daytime sleepiness and abnormal behavior during sleep that had been going on for 3 months. Insulinoma is a rare neuroendocrine tumor that causes excessive release of insulin, resulting in episodes of hypoglycemia. It usually manifests as autonomic sympathetic symptoms. These symptoms resolved rapidly with the administration of glucose. After successful removal of the tumor, daytime sleepiness and abnormal nighttime behavior of the patient did not reappear.

Plasma Hemoglobin and Red Blood Cell Mass Levels as Dynamic Prognostic Markers for Progression and Survival in Pancreatic Neuroendocrine Tumors.

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.

ANXA1 Contained in EVs Regulates Macrophage Polarization in Tumor Microenvironment and Promotes Pancreatic Cancer Progression and Metastasis.

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.

Nutritional status and functional status of the pancreatic cancer patients and the impact of adjacent symptoms.

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.

Psoas muscle mass, nutritional status, inflammation, and their relationship with prognosis in patients with pancreatic adenocarcinoma / Masa del músculo psoas, estado nutricional, inflamación y su relación con el pronóstico en pacientes con adenocarcinoma de páncreas

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. (AU)

Introducción:se ha demostrado que algunos factores se asocian a la supervivencia en los pacientes con adenocarcinoma de páncreas. Recientemente, algunos estudios sugirieron que la desnutrición, la masa muscular y la inflamación podrían afectar a la supervivencia de los pacientes con neoplasias malignas pancreáticas.Objetivo: investigar la asociación entre masa muscular del psoas, inflamación, estado nutricional en el momento del diagnóstico y supervivencia en pacientes con adenocarcinoma de páncreas. Métodos: este estudio retrospectivo incluyó a 219 pacientes diagnosticados de carcinoma de páncreas. Se evaluaron el estado nutricional, la inflamación y la masa del músculo psoas de los pacientes en el momento del diagnóstico. El estado nutricional de los pacientes se evaluó con el Índice Nutricional Pronóstico (PNI). El recuento de leucocitos y el cociente de neutrófilos/linfocitos (NLR) se emplearon para la evaluación de la inflamación. La masa del músculo psoas se calculó utilizando las imágenes de tomografía computarizada abdominal de los pacientes. Resultados: la edad media de los pacientes (80 mujeres y 139 hombres) fue de 66,6 ± 11,7 años. Según los resultados del PNI, 155 pacientes tenían un estado nutricional normal (70 %) mientras que 64 pacientes estaban desnutridos (30 %). La supervivencia de los pacientes con estado nutricional normal fue significativamente mayor que la de los pacientes desnutridos (p < 0,001). No hubo ninguna relación significativa entre el área del músculo psoas, el recuento de leucocitos, el NLR y el tiempo de supervivencia. Conclusión: la supervivencia de los pacientes con adenocarcinoma de páncreas con desnutrición en el momento del diagnóstico fue significativamente menor que la de los pacientes sin desnutrición. (AU)

Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy.

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.

JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

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.

Pancreatic cancer-derived exosomal microRNA-19a induces ß-cell dysfunction by targeting ADCY1 and EPAC2.

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 ß-cell dysfunction. The pancreatic ß 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 ß 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.

An exploratory study of body composition as a predictor of dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel.

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.

Psoas muscle mass, nutritional status, inflammation, and their relationship with prognosis in patients with pancreatic adenocarcinoma.

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.

INTRODUCCIÓN: Introducción: se ha demostrado que algunos factores se asocian a la supervivencia en los pacientes con adenocarcinoma de páncreas. Recientemente, algunos estudios sugirieron que la desnutrición, la masa muscular y la inflamación podrían afectar a la supervivencia de los pacientes con neoplasias malignas pancreáticas. Objetivo: investigar la asociación entre masa muscular del psoas, inflamación, estado nutricional en el momento del diagnóstico y supervivencia en pacientes con adenocarcinoma de páncreas. Métodos: este estudio retrospectivo incluyó a 219 pacientes diagnosticados de carcinoma de páncreas. Se evaluaron el estado nutricional, la inflamación y la masa del músculo psoas de los pacientes en el momento del diagnóstico. El estado nutricional de los pacientes se evaluó con el Índice Nutricional Pronóstico (PNI). El recuento de leucocitos y el cociente de neutrófilos/linfocitos (NLR) se emplearon para la evaluación de la inflamación. La masa del músculo psoas se calculó utilizando las imágenes de tomografía computarizada abdominal de los pacientes. Resultados: la edad media de los pacientes (80 mujeres y 139 hombres) fue de 66,6 ± 11,7 años. Según los resultados del PNI, 155 pacientes tenían un estado nutricional normal (70 %) mientras que 64 pacientes estaban desnutridos (30 %). La supervivencia de los pacientes con estado nutricional normal fue significativamente mayor que la de los pacientes desnutridos (p < 0,001). No hubo ninguna relación significativa entre el área del músculo psoas, el recuento de leucocitos, el NLR y el tiempo de supervivencia. Conclusión: la supervivencia de los pacientes con adenocarcinoma de páncreas con desnutrición en el momento del diagnóstico fue significativamente menor que la de los pacientes sin desnutrición.

Protein intake after the initiation of chemotherapy is an independent prognostic factor for overall survival in patients with unresectable pancreatic cancer: A prospective cohort study.

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.

CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.

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.

Expression patterns and prognostic significances of RRM1 and ERCC1 in pancreatic carcinoma and cholangiocarcinoma.

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.