: Cancer patients experience weight loss for a variety of reasons, commencing with the tumor's metabolism (Warburg effect) and proceeding via cachexia to loss of appetite. In pancreatic cancer, ...several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.
Cancer cachexia is a multifactorial syndrome that is characterised by a loss of skeletal muscle mass, is commonly associated with adipose tissue wasting and malaise, and responds poorly to ...therapeutic interventions. Although cachexia can affect patients who are severely ill with various malignant or non-malignant conditions, it is particularly common among patients with pancreatic cancer. Pancreatic cancer often leads to the development of cachexia through a combination of distinct factors, which, together, explain its high prevalence and clinical importance in this disease: systemic factors, including metabolic changes and pathogenic signals related to the tumour biology of pancreatic adenocarcinoma; factors resulting from the disruption of the digestive and endocrine functions of the pancreas; and factors related to the close anatomical and functional connection of the pancreas with the gut. In this review, we conceptualise the various insights into the mechanisms underlying pancreatic cancer cachexia according to these three dimensions to expose its particular complexity and the challenges that face clinicians in trying to devise therapeutic interventions.
IgG4-related diseases of the digestive tract Löhr, J-Matthias; Vujasinovic, Miroslav; Rosendahl, Jonas ...
Nature reviews. Gastroenterology & hepatology,
03/2022, Letnik:
19, Številka:
3
Journal Article
Recenzirano
IgG4-related conditions affecting the digestive tract are part of a multi-organ fibro-inflammatory disorder termed IgG4-related disease (IgG4-RD), with autoimmune pancreatitis and IgG4-related ...cholangitis being the most prominent manifestations. Gastrointestinal symptoms include jaundice, weight loss, abdominal pain, biliary strictures, and pancreatic and hepatic masses that mimic malignant diseases. IgG4-RD manifestations occur less frequently elsewhere in the digestive tract, namely in the oesophagus, retroperitoneum or intestine. Evidence-based European guidelines frame the current state-of-the-art in the diagnosis and management of IgG4-related digestive tract disease. Diagnosis is based on histology (if available), imaging, serology, other organ involvement and response to therapy (HISORt criteria). Few biomarkers beyond serum IgG4 concentrations are reliable. The first-line therapy (glucocorticoids) is swiftly effective but disease flares are common at low doses or after tapering. Second-line therapy might consist of other immunosuppressive drugs such as thiopurines or rituximab. Further trials, for example, of anti-CD19 drugs, are ongoing. Although an association between IgG4-RD and the development of malignancies has been postulated, the true nature of this relationship remains uncertain at this time.
Abstract Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year ...survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.
New strategies are required for the discovery of unknown bioactive molecules produced by gut microbiota in the human host. Herein, we utilize a chemoselective probe immobilized to magnetic beads for ...analysis of carbonyls in human fecal samples. We identified 112 metabolites due to femtomole analysis and an increased mass spectrometric sensitivity by up to six orders of magnitude.
New chemoselective method permits detection of 112 metabolic ketones and aldehydes in human samples due to significantly increased mass spectrometric sensitivity.
The microbiome has a fundamental impact on the human host's physiology through the production of highly reactive compounds that can lead to disease development. One class of such compounds are ...carbonyl‐containing metabolites, which are involved in diverse biochemical processes. Mass spectrometry is the method of choice for analysis of metabolites but carbonyls are analytically challenging. Herein, we have developed a new chemical biology tool using chemoselective modification to overcome analytical limitations. Two isotopic probes allow for the simultaneous and semi‐quantitative analysis at the femtomole level as well as qualitative analysis at attomole quantities that allows for detection of more than 200 metabolites in human fecal, urine and plasma samples. This comprehensive mass spectrometric analysis enhances the scope of metabolomics‐driven biomarker discovery. We anticipate that our chemical biology tool will be of general use in metabolomics analysis to obtain a better understanding of microbial interactions with the human host and disease development.
Chemoselective probes based on stable isotope labeling allow for highly sensitive mass spectrometric quantification and detection of metabolites at attomole quantities in three human sample types.
Resections for intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Overall survival (OS) for conventional pancreatic ductal adenocarcinoma (PDAC) is well known but OS for ...invasive IPMN (inv-IPMN) is not as conclusive. This study aims to elucidate potential differences in clinicopathology and OS between these tumor types and to investigate if the raised number of resections have affected outcome.
Consecutive patients ≥18 years of age resected for inv-IPMN and PDAC at Karolinska University Hospital between 2009 and 2018 were included. Clinicopathological variables were analyzed in multivariable regression models. Outcome was assessed calculating two-year OS, estimating OS using the Kaplan-Meier model and comparing survival functions with log-rank test.
513 patients were included, 122 with inv-IPMN and 391 with PDAC. During the study period both the proportion resected inv-IPMN and two-year OS, irrespective of tumor type, increased (2.5%–45%; p < 0.001 and 44%–57%; p = 0.005 respectively). In Kaplan-Meier survival analysis inv-IPMN had more favorable median OS (mOS) compared to PDAC (33.6 months vs 19.3 months, p = 0.001). However, in multivariable Cox Regression analysis, tumor type was not a predictor for death, but so were resection period, tumor subtype and N-stage (all p < 0.001).
In this large single center observational cohort study, inv-IPMN seemed to have favorable survival outcome compared to PDAC, but after adjusting for predictors for death this benefit vanished. The combination of a pronounced increase in resected inv-IPMN and a concurrent hazard abatement for death within 2 years during the study period proved to be a principal factor.
Five plus Three for the Pancreas Löhr, J-Matthias; Pantel, Klaus
Clinical cancer research,
04/2023, Letnik:
29, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Preneoplastic high-risk lesions in the pancreas need to be differentiated from low-risk lesions warranting surveillance and eventually surgical intervention. Imaging is used so far; however, certain ...imaging features are subject to interpretation and hence have their intrinsic flaws. In a recent article, a liquid biopsy with protein and RNA markers demonstrates differentiation based on a blood test. See related article by Zhang et al., p. 1535.
Gut microbiota significantly impact human physiology through metabolic interaction. Selective investigation of the co-metabolism of bacteria and their human host is a challenging task and methods for ...their analysis are limited. One class of metabolites associated with this co-metabolism are
-sulfated compounds. Herein, we describe the development of a new enzymatic assay for the selective mass spectrometric investigation of this phase II modification class. Analysis of human urine and fecal samples resulted in the detection of 206 sulfated metabolites, which is three times more than reported in the Human Metabolome Database. We confirmed the chemical structure of 36 sulfated metabolites including unknown and commonly reported microbiota-derived sulfated metabolites using synthesized internal standards and mass spectrometric fragmentation experiments. Our findings demonstrate that enzymatic sample pre-treatment combined with state-of-the-art metabolomics analysis represents a new and efficient strategy for the discovery of unknown microbiota-derived metabolites in human samples. Our described approach can be adapted for the targeted investigation of other metabolite classes as well as the discovery of biomarkers for diseases affected by microbiota.
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