Anemia, Iron Deficiency, and Iron Regulators in Pancreatic Ductal Adenocarcinoma Patients: A Comprehensive Analysis.

Anemia and iron deficiency (ID) are common complications in patients with pancreatic ductal adenocarcinoma (PDAC), but their underlying causes remain unclear. This study investigated the incidence and characteristics of anemia and micronutrient deficiencies in PDAC patients before initiating chemotherapy. A total of 103 PDAC patients were included, comprising 67 in the palliative and 36 in the adjuvant groups. The overall incidence of anemia was 42.7% (n = 44), with comparable rates in both groups. Normocytic and normochromic anemia were predominant, with mild and moderate cases observed in 32% and 10.7% of the cohort, respectively. ID was evident in 51.4% of patients, with absolute ID more frequent in the adjuvant than in the palliative group (19.4% vs. 13.4%). Functional ID occurred more often in the palliative than in the adjuvant group (41.8% vs. 25%). Vitamin B12 and folate deficiency occurred in <5% (n = 5) of patients. Furthermore, 8.7% (n = 9) of patients had chronic kidney disease and anemia. To elucidate mechanisms of iron deficiency, the study explored the expression of iron regulators (hepcidin (HEP), ferroportin (FPN), and ZIP14 protein) and mitochondrial mass in PDAC tissue with immunohistochemical (IHC) staining and Perl's Prussian blue to detect iron deposits on available tumor samples (n = 56). ZIP14 expression was significantly higher in less advanced tumors (p = 0.01) and correlated with mitochondrial mass (p < 0.001), potentially indicating its role in local iron homeostasis. However, no significant impact of tissue iron regulators on patient survival was observed. Perl's Prussian blue staining revealed iron deposits within macrophages, but not in pancreatic duct cells. Furthermore, the GEPIA database was used to compare mRNA expression of iron regulators (HEP, FPN, and ZIP14) and other genes encoding iron transport and storage, including Transferrin Receptor Protein 1 (TfR1) and both ferritin chain subunits (FTH and FTL), in PDAC and normal pancreatic samples. FPN, TfR1, FTH, and FTL showed higher expression in tumor tissues, indicating increased iron usage by cancer. ZIP14 expression was higher in the pancreas than in PDAC and was correlated with FPN expression. The study highlights the importance of baseline iron status assessment in managing PDAC patients due to the high incidence of anemia and iron deficiency. Furthermore, ZIP14, in addition to HEP and FPN, may play a crucial role in local iron homeostasis in PDAC patients, providing valuable insights into the underlying mechanisms of iron dysregulation.

A TGF-ß/KLF10 signaling axis regulates atrophy-associated genes to induce muscle wasting in pancreatic cancer.

Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to effective cancer management. Many potential therapies have been proposed and tested-including appetite stimulants, targeted cytokine blockers, and nutritional supplementation-yet highly effective therapies are lacking. Innovative approaches to treating cancer cachexia are needed. Members of the Kruppel-like factor (KLF) family play wide-ranging and important roles in the development, maintenance, and metabolism of skeletal muscle. Within the KLF family, we identified KLF10 upregulation in a multitude of wasting contexts-including in pancreatic, lung, and colon cancer mouse models as well as in human patients. We subsequently interrogated loss-of-function of KLF10 as a potential strategy to mitigate cancer associated muscle wasting. In vivo studies leveraging orthotopic implantation of pancreas cancer cells into wild-type and KLF10 KO mice revealed significant preservation of lean mass and robust suppression of pro-atrophy muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other factors implicated in atrophy, calcium signaling, and autophagy. Bioinformatics analyses identified Transforming growth factor beta (TGF-ß), a known inducer of KLF10 and cachexia promoting factor, as a key upstream regulator of KLF10. We provide direct in vivo evidence that KLF10 KO mice are resistant to the atrophic effects of TGF-ß. ChIP-based binding studies demonstrated direct binding to Trim63, a known wasting-associated atrogene. Taken together, we report a critical role for the TGF-ß/KLF10 axis in the etiology of pancreatic cancer-associated muscle wasting and highlight the utility of targeting KLF10 as a strategy to prevent muscle wasting and limit cancer-associated cachexia.

Pancreatic cancer, depression, and spirituality in therapy: "Unio Mystica" and "Achrayut," 2 case reports.

OBJECTIVES: Pancreatic cancer is a major site of gastrointestinal tumors and remains a leading cause of cancer death in adults in the United States. There is also a strong association between pancreatic cancer and depression. When struggling with cancer, along the different phases of illness, a human being is confronted with manifold issues, which might profoundly interfere with their sense of meaning and purpose. METHODS: From this standpoint, several different therapeutic techniques have been designed to manage the psychological needs of the patients. Here we provide 2 clinical scenarios, where there was a strong religious correlation to the therapeutic techniques employed with patients suffering from pancreatic cancer. RESULTS: The 2 cases described showed some improvement in their overall life view and could recalibrate their expectations based on a strong religious foundation. SIGNIFICANCE OF RESULTS: The role of religion and spirituality in health has also received increasing attention in literature. Religion and spirituality can help patients with cancer find meaning in their illness, provide comfort in the face of existential fears, and receive support from a community of like-minded individuals. In effect, they also provide evidence toward the scope of and integrating the domain of spirituality into holistic cancer care.

Nutritional management of the patient with pancreatic cancer: from the diagnostic and therapeutic pathway to an integrated hospital-territory approach.

Abstract: Pancreatic cancer is associated to a high risk of malnutrition and neoplastic cachexia even at first diagnosis. Malnutrition is a negative prognostic factor for the outcome of surgery or medical oncology treatments. Despite the good awareness of the problem and the knowledge of the guidelines, the early recognition of malnutrition and its management are still uneven, mainly due to the lack of implementation of standardized and shared protocols and the shortage of dedicated clinical nutritionists and dieticians. An early and appropriate nutritional intervention is mandatory to improve the outcome of patients with pancreatic cancer at any stage of disease. The Mini Nutritional Assessment is useful tool to screen patients malnourished or at risk of malnutrition. The need for the establishment and implementation of an integrated hospital - territorial assistance as well as a home-delivered nutrition service is discussed.

Prophylactic Anticoagulation in Patients With Pancreatic Adenocarcinoma: A Single Tertiary Care Center Retrospective QI Project.

BACKGROUND/AIM: A well-known complication of pancreatic adenocarcinoma (PDAC) is venous thromboembolism (VTE). The Khorana score is used as a tool to help determine the role of primary prophylaxis (PPx) in cancer patients with VTE. This study compared outcomes in PDAC patients who received primary PPx (anticoagulation) versus those who did not. PATIENTS AND METHODS: PDAC patients from 2017-2019 at Allegheny General Hospital were retrospectively reviewed. Descriptive statistics were presented via medians with interquartile ranges for continuous variables and percentages for categorical variables. Predictors of VTE development were determined using univariable and multivariable logistic regression models. T-tests and Chi-square tests were used to compare means and percentages, respectively. RESULTS: A total of 102 patients with full VTE PPx data were reviewed. At least one VTE event was identified in 29 patients (28.2%). A total of 4 out of these 29 patients (13.8%) were on PPx anticoagulation. Death secondary to VTE occurred in one patient without PPx. Two (2.0%) patients experienced bleeding events of those prescribed VTE PPx. On univariable analysis, stage IV disease, planned surgery, and unresectable disease were predictors of VTE development. On multivariate analysis, total pancreatectomy was a predictor of VTE development. There was no difference in average time to progression amongst patients who had developed VTE versus those who did not. CONCLUSION: The Khorana score for VTE PPx in PDAC patients in underutilized.

Nursing Cooperation Pattern for Patients With Advanced Pancreatic Cancer and Abdominal Pain Undergoing Endoscopic Ultrasound-guided Celiac Plexus Neurolysis.

Context: Patients with pancreatic cancer (PC) at a late stage often suffer from severe abdominal pain due to the invasion of celiac plexus, and the analgesics they receive often have intolerable side effects. Endoscopic, ultrasound-guided, celiac plexus neurolysis (EUS-guided CPN) can have a good therapeutic effect. Objective: The study intended to evaluate the ability of two nursing cooperation patterns to reduce patients' pain, decrease operation times, increase operational efficiency, and increase nurses' satisfaction, for patients with advanced PC and abdominal pain who received EUS-guided CPN. Design: The research team designed a retrospective controlled study. Setting: The study took place at the Shenzhen People's Hospital of the Second Clinical Medical College of Jinan University in Shenzhen, China, and at the Changhai Hospital of the Second Military Medical University in Shanghai, China. Participants: Participants were 40 patients with advanced PC who received EUS-guided CPN at one of the two hospitals between January 2019 and January 2020. Intervention: Twenty participants at Changhai Hospital received the traditional nursing cooperation pattern and became the control group, and 20 participants at the Shenzhen People's Hospital received the new nursing cooperation pattern and became the intervention group. Outcome Measures: The study measured clinical data, nursing measures, diagnostic significance, and key points for the two patterns as well as compared the effects of the new nursing cooperation method to that of traditional nursing. If the measurement data met the requirements for normality, the team used the two independent sample t-test for the intergroup comparisons. If normality wasn't satisfied, the team used medians and interquartile ranges (IQRs) for expression and the rank sum test for the intergroup comparisons. Counting data were expressed using the constituent ratio, and team used the chi-square test for comparisons between groups. P < .05 was considered to be statistically significant. Results: The operations were successful, and no complications occurred. No significant difference existed in the pain scores between the control group and the intervention group (P > .05), while a significant difference occurred in the nurses' operation times and satisfaction. Not only were the scores for operation times for the control group (97) and the intervention group (59) significantly different, but also the nurses' satisfaction was significantly higher for the intervention group postintervention, at 83.35 ± 5.25, than for the control group, at 62.25 ± 8.18 (P < .001). Such a new nursing cooperation method could assist in patient's rehabilitation and increase nurses' satisfaction. Conclusions: The new nursing cooperation method for patients with advanced PC and abdominal pain undergoing EUS-guided CPN can reduce operation time and improve nurses' satisfaction.

Nutritional Support in Pancreatic Diseases.

This review summarizes the main pancreatic diseases from a nutritional approach. Nutrition is a cornerstone of pancreatic disease and is sometimes undervalued. An early identification of malnutrition is the first step in maintaining an adequate nutritional status in acute pancreatitis, chronic pancreatitis and pancreatic cancer. Following a proper diet is a pillar in the treatment of pancreatic diseases and, often, nutritional counseling becomes essential. In addition, some patients will require oral nutritional supplements and fat-soluble vitamins to combat certain deficiencies. Other patients will require enteral nutrition by nasoenteric tube or total parenteral nutrition in order to maintain the requirements, depending on the pathology and its consequences. Pancreatic exocrine insufficiency, defined as a significant decrease in pancreatic enzymes or bicarbonate until the digestive function is impaired, is common in pancreatic diseases and is the main cause of malnutrition. Pancreatic enzymes therapy allows for the management of these patients. Nutrition can improve the nutritional status and quality of life of these patients and may even improve life expectancy in patients with pancreatic cancer. For this reason, nutrition must maintain the importance it deserves.

Posterior Circular Stapled GastroJejunostomy After Duodenopancreatectomy.

Anastomotic fistulae are the most common and dreaded postoperative complications of pancreaticoduodenectomy. Delayed gastric emptying (DGE) and slow recovery of bowel function are contributing causes for postoperative pancreatic fistula (PoPF) that should be taken into consideration. The present study evaluates data from 17 consecutive cases that underwent pancreaticoduodenectomy for pancreatic adenocarcinoma with pancreaticojejunal anastomosis and circular stapled mechanical gastrojejunal anastomosis instead of the standard terminolateral technique. Three patients developed Grade A DGE (one also developed grade B PoPF) and one patient required reinsertion of the nasogastric tube due to Grade B PoPF. Overall, the incidence of DGE was 23.5%. Three patients developed Grade B pancreatic fistulae that were successfully managed conservatively. Twelve patients resumed early bowel movement within 4 days, two reinterventions were required for postoperative bleeding. Mean hospital stay was 11.5 days. Patients with DGE had a mean hospital stay of 14.5 days. No gastrojejunostomy leak was encountered. Mortality was nil. Therefore we consider the posterior circular stapled gastrojejunostomy a simple, reproducible, safe technical alternative for avoiding DGE and consequently help lower the risk of PoPF, increased costs associated with prolonged hospital stay and an improved postoperative quality of life.

Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.

OBJECTIVE: Cancer cachexia is a devastating chronic condition characterized by involuntary weight loss, muscle wasting, abnormal fat metabolism, anorexia, and fatigue. However, the molecular mechanisms underlying this syndrome remain poorly understood. In particular, the hypothalamus may play a central role in cachexia, given that it has direct access to peripheral signals because of its anatomical location and attenuated blood-brain barrier. Furthermore, this region has a critical role in regulating appetite and metabolism. METHODS: To provide a detailed analysis of the hypothalamic response to cachexia, we performed single-cell RNA-seq combined with RNA-seq of the medial basal hypothalamus (MBH) in a mouse model for pancreatic cancer. RESULTS: We found many cell type-specific changes, such as inflamed endothelial cells, stressed oligodendrocyes and both inflammatory and moderating microglia. Lcn2, a newly discovered hunger suppressing hormone, was the highest induced gene. Interestingly, cerebral treatment with LCN2 not only induced many of the observed molecular changes in cachexia but also affected gene expression in food-intake decreasing POMC neurons. In addition, we found that many of the cachexia-induced molecular changes found in the hypothalamus mimic those at the primary tumor site. CONCLUSION: Our data reveal that multiple cell types in the MBH are affected by tumor-derived factors or host factors that are induced by tumor growth, leading to a marked change in the microenvironment of neurons critical for behavioral, metabolic, and neuroendocrine outputs dysregulated during cachexia. The mechanistic insights provided in this study explain many of the clinical features of cachexia and will be useful for future therapeutic development.

Fat-Soluble Vitamin Deficiencies and Disruption of the Immune System in Pancreatic Cancer: A Vicious Cycle.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is currently an increasing contributor to cancer-related mortality. Despite advances in cancer treatment, PDAC survival rates have remained roughly unchanged over the years. Specifically, late diagnosis and insensitivity to currently available therapeutic regimens have been identified as the main causes for its poor survival. Pancreatic exocrine insufficiency (PEI) is a typical complication associated with PDAC diagnosis and pancreatic surgery. Pancreatic exocrine insufficiency, a major contributor to maldigestion in PDAC, is often not treated because it remains undetected because of lack of overt signs and symptoms. In this review, we will focus on the major consequences of PEI, including the inadequacy of lipase excretion, which results in deficiency of fat-soluble vitamins. Because PDAC is known for its immune-high jacking mechanisms, we describe key features in which deficiencies of fat-soluble vitamins may contribute to the aggressive biological behavior and immune evasion in PDAC. Because PEI has been shown to worsen survival rates in patients with PDAC, detecting PEI and the related fat-soluble vitamin deficits at the time of PDAC diagnosis is critical. Moreover, timely supplementation of pancreatic enzymes and fat-soluble vitamins may improve outcomes for PDAC patients.

Vitamin D deficiency and tumor aggressiveness in gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Data regarding vitamin D status in patients affected by gastroenteropancreatic (GEP) neuroendocrine tumor (NET) are limited and often showing contrasting results. The aim of the study was to evaluate the incidence of vitamin D deficiency (<20 ng/mL) in GEP-NET patients and compare the 25-hydroxyvitamin D (25(OH)D) levels with clinicopathological parameters and clinical outcome. METHODS: A retrospective cross-sectional study including 75 low grade (G1-G2) GEP-NETs and 123 healthy controls matched for age, sex, and body mass index, was performed. RESULTS: GEP-NET patients had significantly lower 25(OH)D levels compared to controls (17.9 ± 7.8 vs 24.2 ± 7.7 ng/mL, p < 0.0001). Ileal NETs were associated to lower 25(OH)D levels compared to other primary tumor sites (p = 0.049) and small bowel resection posed a significant increased risk of severe vitamin D deficiency (OR = 2.81, 95% CI = 1.25-3.37, p = 0.018). No correlation with somatostatin analogs treatment was found. 25(OH)D levels were significantly lower in G2 compared to G1 GEP-NETs (15.6 ± 7.8 vs 19.9 ± 7.4 ng/mL, p = 0.016) and in patients with progressive disease (12.6 ± 5.7 ng/mL) compared to those with stable disease (mean 21.5 ± 8.2 ng/mL, p = 0.001) or tumor free after surgery (19.6 ± 7.3 ng/mL, p = 0.002). Patients with vitamin D deficiency and insufficiency had shorter progression-free survival compared to those with sufficiency (p = 0.014), whereas no correlation was found with disease-specific survival. CONCLUSIONS: Vitamin D deficiency is highly prevalent among GEP-NETs and could be associated with high tumor grade and disease progression. Therefore, the monitoring of 25(OH)D levels is relevant in these patients and vitamin D supplementation should be considered in the management of GEP-NET patients with vitamin D deficiency or insufficiency.

Clinical nutrition as part of the treatment pathway of pancreatic cancer patients: an expert consensus.

PURPOSE: Malnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients. METHODS: A Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients. RESULTS: The panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment. CONCLUSIONS: There is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patients.

Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma.

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain.

In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.

Pancreatitis, Pancreatic Cancer, and Their Metabolic Sequelae: Projected Burden to 2050.

INTRODUCTION: Future burden has been modeled from population-based data for several common gastrointestinal diseases. However, as we enter the third decade in the 21st century, there are no such data on diseases of the pancreas holistically. The study aimed to estimate future incidence of pancreatitis, pancreatic cancer, diabetes of the exocrine pancreas (DEP), and exocrine pancreatic dysfunction (EPD) as well as years of life lost (YLL) due to premature death in individuals with those diseases up to 2050. METHODS: Historical New Zealand nationwide data on hospital discharge, pharmaceutical dispensing, cancer, and mortality were obtained. Annual incidence of each disease and annual YLLs due to premature death in individuals with each disease were calculated. A time series analysis using the stepwise autoregressive method was conducted. RESULTS: Pancreatitis yielded the highest projected incidence (123.7 per 100,000; 95% confidence interval, 116.7-130.7) and YLL (14,709 years; 13,642-15,777) in 2050. The projected incidence and YLL of pancreatic cancer were 18.6 per 100,000 (95% confidence interval, 13.1-24.1) and 14,247 years (11,349-17,144) in 2050, respectively. Compared with pancreatitis and pancreatic cancer, DEP and EPD yielded lower but more steeply increasing projected incidence rates and YLLs. DISCUSSION: The findings suggest that the burden of pancreatitis, pancreatic cancer, DEP, and EPD will rise in the next 3 decades unless healthcare systems introduce effective prevention or early treatment strategies for diseases of the pancreas and their sequelae.

Rivaroxaban thromboprophylaxis in ambulatory patients with pancreatic cancer: Results from a pre-specified subgroup analysis of the randomized CASSINI study.

BACKGROUND: Pancreatic cancer patients are at risk for venous thromboembolism (VTE); the value of thromboprophylaxis has not been definitively established. METHODS: This trial randomized cancer patients initiating a new regimen and at high risk for VTE (Khorana score ≥2) to rivaroxaban 10 mg or placebo up to day 180. This analysis examined the subset of pancreatic cancer patients. The primary efficacy endpoint was the composite of symptomatic deep-vein thrombosis (DVT), asymptomatic proximal DVT, any pulmonary embolism, and VTE-related death. The primary safety endpoint was International Society on Thrombosis and Haemostasis-defined major bleeding. RESULTS: In total, 49/1080 (4.5%) patients enrolled had baseline VTE on screening, with higher rates (24/362 [6.6%]) in pancreatic cancer and they were not randomized. Of 841 randomized patients, 273 (32.5%) had pancreatic cancer; 155/273 (57% in each arm) completed the double-blind period. The primary endpoint occurred in 13/135 (9.6%) patients in the rivaroxaban group and in 18/138 (13.0%) in the placebo group (hazard ratio [HR] = 0.70; 95% CI, 0.34-1.43; P = .328) in up-to-day-180 period and 5/135 (3.7%) patients receiving rivaroxaban and 14/138 (10.1%) receiving placebo in the intervention period (HR = 0.35; 95% CI, 0.13-0.97; P = .034). Major bleeding was similar (2 [1.5%] receiving rivaroxaban and 3 [2.3%] receiving placebo). Correlative biomarker studies demonstrated significant decline in D-dimer (weeks 8 and 16) in patients randomized to rivaroxaban compared to placebo (P < .01). CONCLUSIONS: In ambulatory pancreatic cancer patients, rivaroxaban did not result in significantly lower incidence of VTE or VTE-related death in the 180-day period. During the intervention period, however, rivaroxaban substantially reduced VTE without increasing major bleeding, suggesting benefit of rivaroxaban prophylaxis in this setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02555878.

Nutritional and immune impairments and their effects on outcomes in early pancreatic cancer patients undergoing pancreatoduodenectomy.

BACKGROUND & AIMS: Nutritional impairments are highly frequent in pancreatic cancer even in the early stages and have a significant impact on outcomes. The aim of this prospective study was to investigate immune and nutritional impairments, their interrelations and impacts on outcomes in an unselected cohort of patients scheduled for pancreatoduodenectomy due to suspicion of pancreatic cancer. METHODS: All consecutive patients scheduled for pancreatoduodenectomy at Vilnius University Hospital Santaros Klinikos between January 2016 and November 2018 were recruited into the study according to the inclusion/exclusion criteria. Patients were randomly allocated into the groups of nutritional intervention with immunonutrition vs. control and stratified into the groups of pancreatic ductal adenocarcinoma (PDAC) vs. other pancreatic tumors. Nutritional evaluation included screening (NRS 2002), anthropometric measurements, bioelectrical impedance analysis and lumbar skeletal muscle index (LSMI). Inflammatory indicators were measured before and after surgery. Surgical outcomes were assessed 30 days postoperatively using Comprehensive Complication Index (CCI). RESULTS: Although increased nutritional risk was identified in 22.4% of patients, 41.4% were finally diagnosed with cachexia. While cachexia was predominantly diagnosed in underweight patients, sarcopenia was detected across all BMI categories and 11.7% of obese patients had sarcopenia. Decreased LSMI was identified in 52.5% of patients as compared to decreased phase angle in 39% of patients and decreased fat free mass index in only 3.4% of patients. Regression model indicate a large effect of nutritional indicators on CCI (R2 coefficient 71.1%). In comparison to patients with other pancreatic tumors, patients with PDAC had a characteristic pattern of increased systemic inflammation prior to surgery and decreased inflammation postoperatively (p = 0.02). CONCLUSIONS: A high rate of nutritional impairments was identified in our cohort of patients with early pancreatic cancer, including abnormal body composition phenotypes. They produced negative effects on postoperative outcomes. The highest diagnostic rates were obtained with LSMI measurement, while the highest value for prognostication was attained with the inclusion of multiple objective nutritional state indicators.

Metabolic syndrome, metabolic components, and their relation to the risk of pancreatic cancer.

BACKGROUND: Components of the metabolic syndrome (MetS), such as elevated fasting glucose levels and abdominal obesity, have been suggested as potential risk factors for pancreatic cancer. However, data are still insufficient to assure the influence of MetS on incident pancreatic cancer. The objective of the current study was to investigate the association between MetS, metabolic components, and the risk of pancreatic cancer. METHODS: In the Korea National Health Information Database, 223,138 individuals who were without pancreatic cancer in 2009 were enrolled and followed until 2013. They were categorized into 4 groups according to the number of baseline metabolic components (0, 1, 2, 3, and 4-5). A multivariate Cox proportional hazard model was used to calculate the adjusted hazard ratios (HRs) and 95% CIs for incident pancreatic cancer according to the presence of MetS and the number of metabolic components. In addition, the risk of pancreatic cancer was evaluated in individuals who had a single metabolic component. RESULTS: The presence of MetS was significantly associated with incident pancreatic cancer (adjusted HR, 1.47; 95% CI, 1.19-1.81). The group with 4 or 5 baseline metabolic components had a higher risk of pancreatic cancer than the other groups (0 components: reference category; 1 component: adjusted HR, 0.94 [95% CI, 0.61-1.45]; 2 components: adjusted HR, 1.03 [95% CI, 0.68-1.56]; 3 components: adjusted HR, 1.35 [95% CI, 0.89-2.04]; 4-5 components: adjusted HR, 1.64 [95% CI, 1.06-2.51]). Regarding associations between the individual metabolic components and pancreatic cancer, no metabolic component alone had a statistically significant association with pancreatic cancer. CONCLUSIONS: MetS is a potential risk factor for pancreatic cancer. The presence of ≥4 metabolic components leads to a higher risk of pancreatic cancer even within categories of the MetS.

ß-Pentagalloyl-Glucose Sabotages Pancreatic Cancer Cells and Ameliorates Cachexia in Tumor-Bearing Mice.

Pancreatic cancer cells overexpress the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R). Activating these receptors, insulin and insulin-like growth factor-1 increase the growth and glycolysis of pancreatic cancer cells. The high glycolysis in pancreatic cancer cells increases whole-body energy expenditure and is therefore involved in the pathogenesis of cancer cachexia. The antagonism of IR and IGF1R may sabotage pancreatic cancer cells and attenuate cancer cachexia. Previous studies have shown that the intracellular regulating system of IR/IGF1R may be functionally interrelated to another intracellular system whose master regulator is hypoxia-inducible factor-1 (HIF-1). In this study, we investigated how the IR/IGF1R and HIF-1 systems are interrelated in pancreatic cancer cells. We also investigated whether a phytochemical, penta-O-galloyl- ß -D-glucose ( ß -PGG), antagonizes IR/IGF1R, sabotages pancreatic cancer cells and alleviates cancer cachexia. We found in MiaPaCa2 pancreatic cancer cells that IR/IGF1R activation increased both the α -subunit of HIF-1 and caveolin-1. This result suggests that IR/IGF1R, HIF-1 α , and caveolin-1 may constitute a feed-forward loop to mediate the effect of IR/IGF1R activation. ß -PGG inhibited IR/IGF1R activity and decreased glycolytic enzymes in MiaPaCa2 and Panc-1 pancreatic cancer cells. When MiaPaCa2 cells were transplanted in athymic mice, their growth was inhibited by ß -PGG or by a HIF-1 α inhibitor, rhein. ß -PGG and rhein also decreased glycolytic enzymes in the tumor grafts and reduced liver gluconeogenesis, skeletal-muscle proteolysis and fat lipolysis in the tumor carriers. Cancer-induced body-weight loss, however, was prevented by ß -PGG but not rhein. In conclusion, ß -PGG combats pancreatic cancer cells and cures cancer cachexia.