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BMC Cancer May 2018Malnutrition and weight loss are commonly observed in patients with pancreatic cancer and contribute to poor survival. Pancreatic exocrine insufficiency (PEI), which can... (Comparative Study)
Comparative Study
BACKGROUND
Malnutrition and weight loss are commonly observed in patients with pancreatic cancer and contribute to poor survival. Pancreatic exocrine insufficiency (PEI), which can be caused by ductal obstruction by a tumor, causes maldigestion and malabsorption of nutrients, thus contributing to malnutrition in these patients. In this study, we evaluated the effects of pancreatic enzyme replacement therapy (PERT) on survival in patients with unresectable pancreatic cancer.
METHODS
A retrospective analysis was conducted on a database of patients with unresectable, pathologically confirmed pancreatic cancer. All patients were evaluated for palliative chemotherapy and received the optimal palliative care. Patients were divided into two groups: Group 1 received standard therapy; Group 2 underwent additional evaluation of the pancreatic function and therapy with PERT, if needed. Survival (median and 95% confidence interval [CI]) was analyzed using Kaplan-Meier and Cox regression; groups were compared using the log-rank test.
RESULTS
Overall, 160 patients with unresectable pancreatic cancer were included in the analysis (mean age: 70.5 years [range 28-100]; gender: 57.5% male; tumor stage: 78.7% Stage IV). Eighty-six patients (53.75%) were in Group 1 and 74 (46.25%) were in Group 2. Age, gender, tumor size, location and stage, weight loss, and serum CA 19-9 were similar between groups. Ninety-three (58.1%) patients received palliative chemotherapy; 46.5% in Group 1 and 71.6% in Group 2 (P < 0.001). Forty-nine (66.2%) patients in Group 2 and none in Group 1 received PERT. Survival in Group 2 (189 days, 95% CI 167.0-211.0 days) was significantly longer than in Group 1 (95.0 days, 95% CI 75.4-114.6 days) (HR 2.117, 95% CI 1.493-3.002; P < 0.001). Chemotherapy and PERT were significantly and independently associated with longer survival in a model controlled by age and tumor stage. In patients with significant weight loss at diagnosis (> 10% bodyweight within 6 months), PERT was associated with longer survival (HR 2.52, 95% CI 1.55-4.11; P < 0.001).
CONCLUSIONS
In patients with unresectable pancreatic cancer, PERT in patients with PEI was associated with longer survival compared with those not receiving PERT, especially in those experiencing significant weight loss. This finding should guide future prospective clinical trials of similar interventions.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Malnutrition; Middle Aged; Palliative Care; Pancreas; Pancreatic Neoplasms; Pancrelipase; Retrospective Studies; Survival Analysis; Treatment Outcome; Weight Loss
PubMed: 29728096
DOI: 10.1186/s12885-018-4439-x -
Journal of Cystic Fibrosis : Official... Sep 2016Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF).
METHODS
Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h).
RESULTS
96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar.
CONCLUSIONS
Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393.
Topics: Adolescent; Adult; Cystic Fibrosis; Double-Blind Method; Drug Monitoring; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Agents; Humans; Intestinal Absorption; Male; Pancreas; Pancreatic Function Tests; Pancrelipase; Treatment Outcome
PubMed: 27013382
DOI: 10.1016/j.jcf.2016.02.010 -
Journal of Cystic Fibrosis : Official... Jan 2009Maldigestion in cystic fibrosis (CF) affects approximately 90% of patients. As soon as pancreatic insufficiency is identified, enzyme supplementation is prescribed even... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Maldigestion in cystic fibrosis (CF) affects approximately 90% of patients. As soon as pancreatic insufficiency is identified, enzyme supplementation is prescribed even with breast fed infants. A pancreatic enzyme preparation developed particularly for infants, Creon for children (CfC), contains smaller granules to be administered with a dosing spoon (5000 lipase units per scoop).
PATIENTS AND METHODS
In a prospective, randomised, multi-centre study, 40 infants and toddlers received both CfC and Creon 10000 (C10) for two weeks each in a cross-over design. Dosing of pancreatic enzymes was continued as applied before the study. The primary endpoint was the parents' treatment preference. Secondary endpoints included coefficient of fat absorption (CFA), clinical symptoms and safety parameters.
RESULTS
20 parents (51%) from the N=39 intent to treat sample preferred CfC, 9 (23%) preferred C10, and 10 (26%) had no preference The applied doses led to a mean CFA with similar results for both treatments (77.8% vs. 78.7%). Gastrointestinal symptoms were reported on a number of study days, and some children had abnormal results for laboratory parameters of malabsorption. Safety and tolerability of the preparations were good and all these parameters were comparable for both treatments.
CONCLUSION
Those parents who had a preference favoured CfC over C10. Both enzyme preparations improved malabsorption to a similar degree, although the applied dosages could have been too low in some children reflected in a suboptimal CFA. These data support the use of CfC for young patients with cystic fibrosis improving the daily care of this cohort detected mainly now through neonatal screening programmes.
Topics: Administration, Oral; Child, Preschool; Consumer Behavior; Cross-Over Studies; Cystic Fibrosis; Female; Gastrointestinal Agents; Humans; Infant; Lipid Metabolism; Male; Microspheres; Pancrelipase; Parents; Treatment Outcome
PubMed: 18718819
DOI: 10.1016/j.jcf.2008.07.003 -
PloS One 2012We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage...
BACKGROUND
We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD≤2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes.
METHODOLOGY/PRINCIPAL FINDINGS
Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, p<9.8×10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (p<0.002, p<0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas.
CONCLUSIONS
We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 5; Denmark; Diabetes Mellitus, Type 1; Family Health; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Immunohistochemistry; Islets of Langerhans; Linkage Disequilibrium; Lod Score; Pancrelipase; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT1A; Reverse Transcriptase Polymerase Chain Reaction; Sweden; Ubiquitin-Protein Ligases
PubMed: 22563461
DOI: 10.1371/journal.pone.0035439 -
The American Journal of Pathology Apr 2011Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial...
Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node-like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin(+) T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell-rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter-CXCL13-transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell-rich zone.
Topics: Animals; Chemokine CXCL13; Dendritic Cells; Fibroblasts; Humans; Inflammation; Insulin; Ligands; Lymph Nodes; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancrelipase; Promoter Regions, Genetic; Rats; Stromal Cells
PubMed: 21435450
DOI: 10.1016/j.ajpath.2010.12.039 -
HPB : the Official Journal of the... Oct 2017Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not... (Observational Study)
Observational Study
BACKGROUND
Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not routinely used, and effects upon post-operative survival are unclear.
METHODS
This review of patients undergoing PD for periampullary malignancy sought to test for an association between PERT and overall survival, with post-hoc subgroup analysis performed after stratifying patients by the year of surgery, pancreatic duct width and tumour type.
RESULTS
Some 202/469 (43.1%) patients received PERT. After accounting for pathological variables and chemotherapy, PERT use was found to be independently associated with improved survival on multivariable analysis [HR 0.72 (95% CI: 0.52-0.99), p = 0.044] and on propensity matched analysis (p = 0.009). The effect of PERT upon improved survival was predominantly observed amongst patients with a dilated pancreatic duct (≥3 mm).
DISCUSSION
PERT use was independently associated with improved survival following PD for cancer. The validity of this observation is supported by an effect largely confined to those patients with a dilated pancreatic duct. The nutritional status of patients undergoing PD for cancer needs further investigation and the effects of PERT require verification in further clinical studies.
Topics: Aged; Bile Duct Neoplasms; Disease Progression; Disease-Free Survival; Duodenal Neoplasms; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pancrelipase; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 28711377
DOI: 10.1016/j.hpb.2017.05.009 -
Cell Metabolism Jan 2008CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain...
CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain enigmatic. Here we show that CAPS2(-/-) and CAPS1(+/-);CAPS2(-/-) mice, despite having increased insulin sensitivity, are glucose intolerant and that this effect is attributable to a marked reduction of glucose-induced insulin secretion. This correlates with diminished Ca(2+)-dependent exocytosis, a reduction in the size of the morphologically docked pool, a decrease in the readily releasable pool of secretory vesicles, slowed granule priming, and suppression of second-phase (but not first-phase) insulin secretion. In beta cells of CAPS1(+/-);CAPS2(-/-) mice, the lowered insulin content and granule numbers were associated with an increase in lysosome numbers and lysosomal enzyme activity. We conclude that although CAPS proteins are not required for Ca(2+)-dependent exocytosis to proceed, they exert a modulatory effect on insulin granule priming, exocytosis, and stability.
Topics: Animals; Calcium; Calcium-Binding Proteins; Electrophysiology; Exocytosis; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lysosomes; Mice; Mice, Knockout; Microscopy, Confocal; Microscopy, Electron, Transmission; Nerve Tissue Proteins; Pancrelipase
PubMed: 18177725
DOI: 10.1016/j.cmet.2007.11.009 -
Regulation of translation initiation by insulin and amino acids in skeletal muscle of neonatal pigs.American Journal of Physiology.... Jul 2003Previous studies have shown that intravenous infusion of insulin and/or amino acids reproduces the feeding-induced stimulation of muscle protein synthesis in neonates...
Previous studies have shown that intravenous infusion of insulin and/or amino acids reproduces the feeding-induced stimulation of muscle protein synthesis in neonates and that insulin and amino acids act independently to produce this effect. The goal of the present study was to delineate the regulatory roles of insulin and amino acids on muscle protein synthesis in neonates by examining translational control mechanisms, specifically the eukaryotic translation initiation factors (eIFs), which enable coupling of initiator methionyl-tRNAi and mRNA to the 40S ribosomal subunit. Insulin secretion was blocked by somatostatin in fasted 7-day-old pigs (n = 8-12/group), insulin was infused to achieve plasma levels of approximately 0, 2, 6, and 30 microU/ml, and amino acids were clamped at fasting or fed levels or, at the high insulin dose, below fasting. Both insulin and amino acids increased the phosphorylation of ribosomal protein S6 kinase (S6K1) and the eIF4E-binding protein (4E-BP1), decreased the binding of 4E-BP1 to eIF4E, increased eIF4E binding to eIF4G, and increased fractional protein synthesis rates but did not affect eIF2B activity. In the absence of insulin, amino acids had no effect on these translation initiation factors but increased the protein synthesis rates. Raising insulin from below fasting to fasting levels generally did not alter translation initiation factor activity but raised protein synthesis rates. The phosphorylation of S6K1 and 4E-BP1 and the amount of 4E-BP1 bound to eIF4E and eIF4E bound to eIF4G were correlated with insulin level, amino acid level, and protein synthesis rate. Thus insulin and amino acids regulate muscle protein synthesis in skeletal muscle of neonates by modulating the availability of eIF4E for 48S ribosomal complex assembly, although other processes also must be involved.
Topics: Algorithms; Amino Acids; Amino Acids, Branched-Chain; Animals; Animals, Newborn; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factor-4F; Female; Glucose Clamp Technique; Hypoglycemic Agents; Immunoblotting; Insulin; Muscle Proteins; Muscle, Skeletal; Pancrelipase; Phosphorylation; Protein Biosynthesis; RNA, Messenger; Swine
PubMed: 12637260
DOI: 10.1152/ajpendo.00563.2002 -
Transplant International : Official... 2022
Topics: Abdomen; Humans; Pancreas; Pancrelipase; Reperfusion; Research Design
PubMed: 35497885
DOI: 10.3389/ti.2022.10038 -
Molecules (Basel, Switzerland) Nov 2019Enzymatic inhibitions of crude extracts and their constituents from Zingiberaceae against both rat intestinal α-glucosidase and porcine pancreatic lipase were...
Enzymatic inhibitions of crude extracts and their constituents from Zingiberaceae against both rat intestinal α-glucosidase and porcine pancreatic lipase were investigated. Structure-activity relationships using their derivatives were also investigated. The rhizomes extract of mango ginger, showed remarkable inhibitory activity in the screening test. Two natural labdane diterpenes and and a drimane sesquiterpene were major constituents isolated from this hexane extract. Among them, ()-labda-8(17),12-diene-15,16-dial () was the most prominent compound and showed inhibitory activity against both α-glucosidase and lipase. Derivatives - from compound were prepared and evaluated using inhibitory assays with these enzymes. The reduced derivative maintained α-glucosidase inhibitory activity, but had decreased pancreatic lipase inhibitory activity compared with parent compound . Other tested derivatives of compound , including acetates - and oxidative derivatives , had very weak α-glucosidase inhibitory activity. Most of these compounds showed moderate pancreatic lipase inhibitory activity. However, only sesquiterpene albicanal () showed drastically decreased pancreatic lipase activity compared with . These findings suggested that molecular size was essential for enzymatic inhibitory activities of these compounds. These results demonstrated that mango ginger may be useful for the prevention of obesity and being overweight.
Topics: Animals; Diterpenes; Enzyme Activation; Enzyme Inhibitors; Zingiber officinale; Glycoside Hydrolase Inhibitors; Molecular Structure; Pancrelipase; Plant Extracts; Rats; alpha-Glucosidases
PubMed: 31717689
DOI: 10.3390/molecules24224071