Neuropancreatology: The Nervous System and Pain Management in Pancreatic Diseases.

The intricate network of the pancreatic nervous system plays a fundamental role in physiologic functions of the endocrine and exocrine pancreas. Several pancreatic diseases affect the normal functionality of the pancreatic nervous system. This chronic derangement leads to anatomical alterations, such as neural hypertrophy and increased nerve density. Perineural invasion is a prominent feature of pancreatic cancer, contributing to cancer progression and metastasis. Despite the fact that these pathogenic mechanisms are still incompletely studied and understood, the constant occurrence of these alterations highlights their importance in the pathophysiology of the pancreatic diseases. The occurrence of anatomical changes is strictly linked to the appearance of pain. Pancreatic pain has peculiar features, and its management is complex in clinical practice. In the present review, the evidence on lifestyle, pharmacological and interventional approaches for the management of pancreatic pain is presented. Analgesic therapy is the cornerstone of pain treatment. However, it is important to identify the individual characteristic of the patients and personalize the approach to pain management. Nevertheless, the incomplete efficacy of these strategies makes this field an area of unmet needs. The study of neuroplasticity is crucial to understand the mechanisms that regulate the pathophysiology of pancreatic diseases. Several trials testing new drugs with specific neuromodulatory effects are ongoing. However, further studies are needed to investigate crucial targets to develop novel therapies for the modulation of the nervous system and the prevention of complications of pancreatic diseases. This comprehensive review summarizes the importance of the nervous system in pancreatic diseases with a special focus on its anatomy and physiology, its pathophysiological features and clinical relevance in pancreatic disease, the treatment of pancreatic pain, and the identification of future trends of research.

Immunohistochemical Evaluation of the Expression of Specific Membrane Antigens in Patients with Pancreatic Ductal Adenocarcinoma.

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of this study was to evaluate the expression of six membrane antigens on PDAC (CA 19-9, mucin 1 and 4 (MUC1, MUC4), mesothelin (MSLN), Annexin A10 (ANXA10), Glypican-1 (GPC-1)) and their correlation with oncologic outcomes. (2) Methods: Immunohistochemical staining for CA 19.9, MUC1, MUC4, MSLN, ANXA10, and GPC-1 of surgical samples of 50 consecutive patients with PDAC was performed. Antigen expression for tumor, ductal, and acinar tissues was classified according to the histo-score (H-score) by two pathologists. (3) Results: Recurrence rate was 47% and 18 patients (36%) deceased (median follow-up 21.5 months). Immunostaining for CA 19-9 and MUC1 showed a significantly higher expression in the neoplastic tissue compared to non-tumor ductal and acinar tissues (p < 0.001). MUC4, MSLN, ANXA10, and GPC-1 were selectively expressed in the neoplastic tissue (p < 0.001). A CA 19-9 H-score value >270 was independently associated with a worse overall survival (p = 0.05) and disease-free survival (p = 0.05). (4) Conclusions: CA 19-9 and MUC1 are highly expressed in PDAC cells. The histological expression of CA 19-9 may predict prognosis. MUC4, MSLN, ANXA10, and GPC-1 are selectively expressed by neoplastic tissue and may represent a potential histological biomarker of disease.

Dynamic contrast enhanced ultrasound in gastrointestinal diseases: A current trend or an indispensable tool?

Contrast enhanced ultrasound (CEUS) has been widely implemented in clinical practice because of the enormous quantity of information it provides, along with its low cost, reproducibility, minimal invasiveness, and safety of the second-generation ultrasound contrast agents. To overcome the limitation of CEUS given by the subjective evaluation of the contrast enhancement behaviour, quantitative analysis of contrast kinetics with generation of time-intensity curves has been introduced in recent years. The quantification of perfusion parameters [named as dynamic-CEUS (D-CEUS)] has several applications in gastrointestinal neoplastic and inflammatory disorders. However, the limited availability of large studies and the heterogeneity of the technologies employed have precluded the standardisation of D-CEUS, which potentially represents a valuable tool for clinical practice in management of gastrointestinal diseases. In this article, we reviewed the evidence exploring the application of D-CEUS in gastrointestinal diseases, with a special focus on liver, pancreas, and inflammatory bowel diseases.

The Role of Transabdominal Ultrasound Elastography in Gastrointestinal Non-Liver Diseases: Current Application and Future Prospectives.

Ultrasound imaging is the first-line investigation for patients with abdominal symptoms, as it effectively depicts the gastrointestinal tract and enables the diagnosis of multiple pathological conditions. Among different recent ultrasound technological advancements, elastography enables the evaluation of various tissue characteristics, such as neoplastic transformation or fibroinflammatory status. In recent years, ultrasound elastography has been utilized extensively for the study of liver diseases and in numerous other clinical settings, including gastrointestinal diseases. Current guidelines suggest the use of transabdominal ultrasound elastography to characterize bowel wall lesions, to assess gastrointestinal contractility, to diagnose and grade chronic pancreatitis; however, no specific indications are provided. In the present paper, we summarize the evidence concerning the application of different ultrasound elastography modalities in gastrointestinal non-liver diseases.

Shear Wave Dispersion in Chronic Liver Disease: From Physical Principles to Clinical Usefulness.

The development of new applications in ultrasound (US) imaging in recent years has strengthened the role of this imaging technique in the management of different pathologies, particularly in the setting of liver disease. Improved B-mode imaging (3D and 4D), contrast-enhanced US (CEUS) and especially US-based elastography techniques have created the concept of multiparametric ultrasound (MP-US), a term borrowed from radiological sectional imaging. Among the new elastography techniques, shear wave dispersion is a newly developed imaging technology which enables the assessment of the shear waves' dispersion slope. The analysis of the dispersion qualities of shear waves might be indirectly related to the tissue viscosity, thus providing biomechanical information concerning the pathologic state of the liver such as necroinflammation. Some of the most recent US devices have been embedded with software that evaluate the dispersion of shear waves/liver viscosity. In this review, the feasibility and the clinical applications of liver viscosity are reviewed based on the preliminary findings of both animal and human studies.

Correlation between a New Point-Shear Wave Elastography Device (X+pSWE) with Liver Histology and 2D-SWE (SSI) for Liver Stiffness Quantification in Chronic Liver Disease.

BACKGROUND: The aim of this study was to investigate the feasibility, the correlation with previously validated 2D-SWE by supersonic imagine (SSI), and the accuracy in fibrosis-staging of a novel point shear-wave elastography device (X+pSWE) in patients with chronic liver disease. METHODS: This prospective study included 253 patients with chronic liver diseases, without comorbidities potentially affecting liver stiffness. All patients underwent X+pSWE and 2D-SWE with SSI. Among them 122 patients also underwent liver biopsy and were classified according to histologic fibrosis. Agreement between the equipment was assessed with Pearson coefficient and Bland-Altman analysis, while receiver operator characteristic curve (ROC) analysis with Youden index was used to establish thresholds for fibrosis staging. RESULTS: A very good correlation was found between X+pSWE and 2D-SWE with SSI (r2 = 0.94; p < 0.001), with X+pSWE average liver stiffness values 0.24 kPa lower than those obtained with SSI. AUROC of X+pSWE for the staging of significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4) using SSI as a reference standard was 0.96 (95% CI, 0.93-0.99), 0.98 (95% CI, 0.97-1) and 0.99 (95% CI, 0.98-1), respectively. The best cut-off values for diagnosing fibrosis ≥F2, ≥F3 and F4 were, respectively, 6.9, 8.5 and 12 for X+pSWE. According to histologic classification, X+pSWE correctly identified 93 out of 113 patients (82%) for F ≥ 2 and 101 out of 113 patients (89%) for F ≥ 3 using the aforementioned cut-off values. CONCLUSION: X+pSWE is a useful novel non-invasive technique for staging liver fibrosis in patients with chronic liver disease.

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.

Extracellular Vesicles: Novel Potential Therapeutic Agents in Inflammatory Bowel Diseases.

Patients affected by inflammatory bowel diseases (IBD) can nowadays benefit from a growing number of pharmacological options. However, in moderate-to-severe cases, the therapeutic response is still far from optimal, and treatment changes and optimizations are often required. Thus, researchers in this field are strongly engaged in studies aiming to identify new potential therapeutic targets. Extracellular vesicles (EVs) are tiny subcellular bodies with a phospholipid bilayer envelope containing bioactive molecules, which are released from different cells and are involved in intercellular communication. Recent pre-clinical data show their emerging role in the pathogenesis and treatment of IBD. In our review, we summarize current evidence about the function of EVs as active therapeutic agents in ulcerative colitis and Crohn's disease, analyzing the properties of EVs derived from different cellular sources and the mechanisms through which they may improve intestinal inflammation.

Direct oral anticoagulant administration in cirrhotic patients with portal vein thrombosis: What is the evidence?

In recent years, the traditional concept that cirrhosis-related coagulopathy is an acquired bleeding disorder has evolved. Currently, it is known that in cirrhotic patients, the hemostatic system is rebalanced, which involves coagulation factors, fibrinolysis and platelets. These alterations disrupt homeostasis, skewing it toward a procoagulant state, which can lead to thromboembolic manifestations, especially when hemodynamic and endothelial factors co-occur, such as in the portal vein system in cirrhosis. Portal vein thrombosis is a common complication of advanced liver cirrhosis that negatively affects the course of liver disease, prognosis of cirrhotic patients and success of liver transplantation. It is still debated whether portal vein thrombosis is the cause or the consequence of worsening liver function. Anticoagulant therapy is the mainstay treatment for acute symptomatic portal vein thrombosis. In chronic portal vein thrombosis, the role of anticoagulant therapy is still unclear. Traditional anticoagulants, vitamin K antagonists and low-molecular-weight heparin are standard-of-care treatments for portal vein thrombosis. In the last ten years, direct oral anticoagulants have been approved for the prophylaxis and treatment of many thromboembolic-related diseases, but evidence on their use in cirrhotic patients is very limited. The aim of this review was to summarize the evidence about the safety and effectiveness of direct oral anticoagulants for treating portal vein thrombosis in cirrhotic patients.

Fecal Microbiota Transplantation in Patients with HBV Infection or Other Chronic Liver Diseases: Update on Current Knowledge and Future Perspectives.

Liver disease and gut dysbiosis are strictly associated, and the pathophysiology of this bidirectional relationship has recently been the subject of several investigations. Growing evidence highlights the link between gut microbiota composition, impairment of the gut-liver axis, and the development or progression of liver disease. Therefore, the modulation of gut microbiota to maintain homeostasis of the gut-liver axis could represent a potential instrument to halt liver damage, modify the course of liver disease, and improve clinical outcomes. Among all the methods available to achieve this purpose, fecal microbiota transplantation (FMT) is one of the most promising, being able to directly reshape the recipient's gut microbial communities. In this review, we report the main characteristics of gut dysbiosis and its pathogenetic consequences in cirrhotic patients, discussing the emerging data on the application of FMT for liver disease in different clinical settings.

Delta-Procalcitonin and Vitamin D Can Predict Mortality of Internal Medicine Patients with Microbiological Identified Sepsis.

Background: The management of septic patients hospitalized in Internal Medicine wards represents a challenge due to their complexity and heterogeneity, and a high mortality rate. Among the available prognostic tools, procalcitonin (PCT) is considered a marker of bacterial infection. Furthermore, an association between vitamin D deficiency and poor sepsis-related outcomes has been described. Objectives: To evaluate the prognostic accuracy of two consecutive PCT determinations (Delta-PCT) and of vitamin D levels in predicting mortality in a population of patients with microbiological identified sepsis admitted to Internal Medicine wards. Methods: This is a sub-analysis of a previous prospective study. A total of 80 patients had at least two available consecutive PCT determinations, while 63 had also vitamin D. Delta-PCT was defined as a reduction of PCT > 50% after 48 h, >75% after 72 h, and >85% after 96 h. Mortality rate at 28- and 90-days were considered as main outcome. Results: Mortality rate was 18.7% at 28-days and 30.0% at 90-days. Baseline PCT levels did not differ between survived and deceased patients (28-days: p = 0.525; 90-days: p = 0.088). A significantly higher proportion of survived patients showed Delta-PCT (28-days: p = 0.002; 90-days: p < 0.001). Delta-PCT was associated with a lower 28-days (p = 0.007; OR = 0.12, 95%CI 0.02-0.46) and 90-days mortality (p = 0.001; OR = 0.17, 95%CI 0.06-0.48). A significantly higher proportion of deceased patients showed severe vitamin D deficiency (28-days: p = 0.047; 90-days: p = 0.049). Severe vitamin D deficiency was associated with a higher 28-days (p = 0.058; OR = 3.95, 95%CI 1.04-19.43) and 90-days mortality (p = 0.054; OR = 2.94, 95%CI 1.00-9.23). Conclusions: Delta-PCT and vitamin D represent two useful tests for predicting prognosis of septic patients admitted to Internal Medicine wards.

The use of procalcitonin for the management of sepsis in Internal Medicine wards: current evidence.

Procalcitonin (PCT) is a circulating polypeptide produced in response to bacterial infections. Studies conducted in the Intensive Care Unit (ICU) setting have demonstrated its utility as a biomarker of bacterial infection and sepsis. Thus, PCT is widely used to distinguish between sepsis and SIRS, and to guide antibiotic therapy. At present sepsis represents a frequent diagnosis among patients admitted to internal medicine (IM) departments. Basing on the knowledge derived from ICU studies, the use of PCT has become routine in non-intensive wards, contributing to improve the management of sepsis. However, some differences between the two populations of patients - the IM being older, affected by multiple chronic comorbidities and lacking of invasive monitoring - could limit the generalizability of ICU results. Most of the studies on PCT conducted in the IM setting have focused on chronic obstructive pulmonary disease, pneumonia and sepsis. Although PCT represents one of the best biomarker available in routine clinical practice, there are uncertainties on the optimal cut-offs to be used for starting or discontinuing antibiotic treatment in patients with suspected bacterial infection or sepsis, for predicting outcome and on the role of PCT variations during antibiotic treatment. Moreover, several diseases can produce an elevation of PCT levels, thus producing false positive results. This represents a narrative review summarizing current evidences on PCT for the management of sepsis in an Internal Medicine wards, highlighting differences with ICU, with a special focus on the role of PCT variations as predictor of outcomes in non-ICU wards.