Novel therapeutics to treat chronic pancreatitis: targeting pancreatic stellate cells and macrophages.

INTRODUCTION: Chronic pancreatitis (CP) is a persistent, recurrent, and progressive disorder that is characterized by chronic inflammation and irreversible fibrosis of the pancreas. It is associated with severe morbidity, resulting in intense abdominal pain, diabetes, exocrine and endocrine dysfunction, and an increased risk of pancreatic cancer. The etiological factors are diverse and the major risk factors include smoking, chronic alcoholism, as well as other environmental and genetic factors. The treatment and management of CP is challenging, and no definitive curative therapy is currently available. AREAS COVERED: This review paper aims to provide an overview of the different cell types in the pancreas that is known to mediate disease progression and outline potential novel therapeutic approaches and drug targets that may be effective in treating and managing CP. The information presented in this review was obtained by conducting a NCBI PubMed database search, using relevant keywords. EXPERT OPINION: In recent years, there has been an increased interest in the development of novel therapeutics for CP. A collaborative multi-disciplinary approach coupled with a consistent funding for research can expedite progress of translating the findings from bench to bedside.

The Importance of Early Detection and Minimally Invasive Treatment of Pseudoaneurysms Due to Chronic Pancreatitis: Case Report.

The occurrence of the pseudoaneurysm of visceral arteries in the field of chronic pancreatitis is a very rare complication that represents a life-threatening condition. The higher frequency of this complication is in the necrotic form of pancreatic inflammation, especially in patients with formed peripancreatic necrotic collections. The degradation of the arterial wall leads to bleeding and transforms these necrotic collections into a pseudoaneurysm. Urgent endovascular angioembolization is the first choice in the therapeutic approach as a valid minimally invasive solution with very satisfactory immediate and long-term outcomes. This successfully avoids open surgery, which is associated with a high mortality rate in these patients, especially in acute-on-chronic pancreatitis.

Endoscopic Retrograde Cholangiopancreatography for Management of Chronic Pancreatitis.

Management of symptomatic chronic pancreatitis (CP) has shifted its approach from surgical procedures to minimally invasive endoscopic procedures. Increased experience and advanced technology have led to the use of endoscopic retrograde cholangiopancreatography (ERCP) as a therapeutic tool to provide pain relief and treat CP complications including pancreatic stones, strictures, and distal biliary strictures, pseudocysts, and pancreatic duct fistulas. In this article the authors will discuss the use of ERCP for the management of CP, its complications, recent advancements, and techniques from the most up to date literature available.

Pancreatolithiasis: Does Management Depend on Clinical Manifestations?

BACKGROUND Pancreatic calculi (PC) or pancreatolithiasis refers to the presence of stones in the main pancreatic duct (MPD), side branches, or parenchyma of the pancreas. It is highly associated with chronic pancreatitis (CP), and is present in 50-90% of those patients. The stone formation can be attributed to a diversity of factors, all of them leading to obstruction in the duct, hypertension of its distal part, increased intraductal and parenchymal pressure, and inflammation, causing the standard symptom, epigastric pain. Immediate restoration of pancreatic secretion flow is of utmost importance and can be achieved with both endoscopic and surgical techniques. Endoscopic techniques include endoscopic retrograde cholangiopancreatography (ERCP) combined, if possible, with extracorporeal shock wave lithotripsy (ESWL), while surgical techniques consist of drainage and resection procedures. The choice of treatment for PC depends on the location, size, and number of stones, and the existence of other complications. CASE REPORT We present 2 cases that were diagnosed with PC, in which clinical symptoms, laboratory results, and imaging examinations were different, suggesting the variety of manifestations pancreatolithiasis can cause. Each patient was treated differently, according to their clinical situation and the presence or absence of complications. Both patients were discharged and fully recovered. CONCLUSIONS The management of pancreatolithiasis can be demanding in some cases, mostly when there are complications. The purpose of this case report is to indicate the importance of personalized treatment for each patient, as different approaches to the same medical condition should be easily identified and successfully treated.

Pancreatic Cancer: Rapid Evidence Review.

Pancreatic cancer is relatively uncommon and carries a poor prognosis because patients often develop signs or symptoms at a late stage of illness. Patients with a family history, especially those with genetic syndromes, are at a significantly increased risk of pancreatic cancer. Modifiable risk factors include smoking, heavy alcohol use, and obesity. Although patients at increased risk should be screened, screening is not recommended for asymptomatic people at average risk. The differential diagnosis for a symptomatic patient is broad, including gastroesophageal reflux disease, gastritis, peptic ulcer disease, chronic pancreatitis, biliary dyskinesia, cholelithiasis, gastroparesis, or constipation. Initial serologic testing should include transaminase and bilirubin levels, and in patients with midepigastric pain, lipase levels. Pancreas-protocol, contrast-enhanced abdominal computed tomography is the imaging test of choice. Carbohydrate antigen 19-9 is the most studied cancer marker and moderately accurate in patients suspected of having cancer; however, the positive predictive value is 0.9% in asymptomatic patients. Treatment includes neoadjuvant or adjuvant chemotherapy and surgery if the cancer is resectable. The treatment approach is best determined by a multidisciplinary, high-volume center. For a patient undergoing chemotherapy, nutritional and psychosocial support and palliation of symptoms should be goals during treatment.

Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Management of chronic pancreatitis.

Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine pancreatic function. The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma. This review summarizes the latest evidence on the diagnosis and management of chronic pancreatitis and its manifestations. In particular, this review discusses advances in understanding of the role of genetic disorders in the mechanisms of the disease and surgical options for patients refractory to medical therapy. Furthermore, clinical trials are under way to develop medical therapeutics.

ESPEN practical guideline on clinical nutrition in acute and chronic pancreatitis.

Both acute and chronic pancreatitis are frequent diseases of the pancreas, which, despite being of benign nature, are related to a significant risk of malnutrition and may require nutritional support. Acute necrotizing pancreatitis is encountered in 20 % of patients with acute pancreatitis, is associated with increased morbidity and mortality, and may require artificial nutrition by enteral or parenteral route, as well as additional endoscopic, radiological or surgical interventions. Chronic pancreatitis represents a chronic inflammation of the pancreatic gland with development of fibrosis. Abdominal pain leading to decreased oral intake, as well as exocrine and endocrine failure are frequent complications of the disease. All of the above represent risk factors related to malnutrition. Therefore, patients with chronic pancreatitis should be considered at risk, screened and supplemented accordingly. Moreover, osteoporosis and increased facture risk should be acknowledged in patients with chronic pancreatitis, and preventive measures should be considered.

Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitis.

BACKGROUND: Extracorporeal shockwave lithotripsy (ESWL) and/or endoscopic retrograde cholangiopancreatography (ERCP) are recommended as first-line therapy for painful uncomplicated chronic pancreatitis with obstructed main pancreatic duct (MPD) in the pancreas head/body. However, predictors of pain relief after ESWL are unknown. We evaluated independent predictors of persistent pain in patients who underwent ESWL for chronic pancreatitis. METHODS: 640 consecutive adult patients with chronic pancreatitis, who underwent successful ESWL with ERCP and pancreatic duct (PD) stent placement, were followed for 12 months. The pain was assessed at baseline and at 12 months using the Izbicki Pain Score, with a score decrease of >50% considered pain relief. Independent predictors of pain relief were derived from logistic regression analysis. RESULTS: Of 640 patients (mean age 36.71 [SD 12.19] years; 60.5% men), 436 (68.1%) had pain relief and 204 (31.9%) had persistent pain. On univariate analysis, older age, male sex, alcohol and tobacco intake, longer duration of symptoms, dilated MPD and MPD stricture were associated with persistent pain at 12 months (P<0.05). Consumption of alcohol (odds ratio [OR] 1.93, 95%CI 1.26-2.97), tobacco (OR 4.09, 95%CI 2.43-6.90), duration of symptoms (OR 1.02, 95%CI 1.01-1.04), MPD size (OR 1.22, 95%CI 1.11-1.33), and MPD stricture (OR 8.50, 95%CI 5.01-14.42) were independent predictors of persistent pain. CONCLUSIONS: Alcohol, tobacco, duration of symptoms, MPD size and stricture were independent predictors of persistent pain after successful ESWL. A multidisciplinary team approach that includes behavioral therapy and surgical options should be considered for such patients.

Daily Pain Experiences in Chronic Pancreatitis: Identifying Pain Phenotypes.

OBJECTIVES: Pain, the hallmark symptom of chronic pancreatitis (CP), remains difficult to assess. To capture the variability of pain that patients can experience day to day, this study used pain diaries to describe daily pain experiences and identify pain phenotypes. METHODS: This study is a secondary data analysis from a pilot trial examining cognitive behavioral therapy for pain treatment in CP. Before treatment, patients completed an online daily pain diary using the Brief Pain Inventory for 7 days. Using indicators of pain magnitude, pain variability, pain synchrony along with least, worst, and average pain intensity levels, we identified pain patterns using K-means clustering. RESULTS: Of 30 patients in the pilot trial, a total of 27 patients (mean age of 49.8 years, 80% women) had complete data to include in this report. Four clusters were identified: cluster 1, lowest pain magnitude (n = 3); cluster 2, moderate pain magnitude and high pain variability (n = 4); cluster 3, moderate pain magnitude and low pain variability (n = 9); and cluster 4, highest pain magnitude and lowest pain variability (n = 11). CONCLUSIONS: Daily pain diaries offer a novel way of evaluating the dynamic pain experiences in CP. Although 4 distinct pain patterns were identified, further studies are needed to validate these findings.

Long-Term Follow-up of Disabled Patients With Chronic Pancreatitis: Evaluation of Clinical Characteristics, Outcomes, and Predictors.

BACKGROUND/AIMS: Patients with chronic pancreatitis (CP) often report a poor quality of life and may be disabled. Our study identifies clinical characteristics, predictors and outcomes in CP patients with disability. METHODS: A review of established CP patients followed in our Pancreas Center between January 1, 2016 and April 30, 2021. Patients were divided into 2 groups based on disability. Univariate analysis was performed to identify differences in demographics, risk factors, comorbidities, complications, controlled medications, and resource utilization. Multivariate analysis was conducted to identify predictors for disability. RESULTS: Out of 404 CP patients, 18% were disabled. These patients were younger (53.8 vs. 58.8, P =0.001), had alcoholic CP (54.1% vs. 30%; P <0.001), more recurrent pancreatitis (83.6% vs. 61.1%; P =0.001), chronic abdominal pain (96.7% vs. 78.2%; P =0.001), exocrine pancreatic insufficiency (83.6% vs. 55.5%; P <0.001), concurrent alcohol (39.3% vs. 23.3%; P =0.001) and tobacco abuse (42.6% vs. 26%; P =0.02), anxiety (23% vs. 18.2%; P <0.001), and depression (57.5% vs. 28.5%; P <0.001). A higher proportion was on opiates (68.9% vs. 43.6%; P <0.001), nonopiate controlled medications (47.5% vs. 23.9%; P <0.001), neuromodulators (73.3% vs. 44%; P <0.001), and recreational drugs (27.9% vs. 15.8%; P =0.036). Predictors of disability were chronic pain (OR 8.71, CI 2.61 to 12.9, P < 0.001), celiac block (OR 4.66, 2.49 to 8.41; P <0.001), neuromodulator use (OR 3.78, CI 2.09 to 6.66; P <0.001), opioid use (OR3.57, CI 2.06 to 6.31; P < 0.001), exocrine pancreatic insufficiency (OR3.56, CI 1.89 to 6.82; P <0.001), non-opioid controlled medications (OR 3.45, CI 2.01 to 5.99; P <0.001), history of recurrent acute pancreatitis (OR 2.49, CI 1.25 to 4.77; P <0.001), depression (OR 2.26, CI 1.79 to 3.01; P <0.001), and active smoking (OR1.8, CI 1.25 to 2.29; P <0.001). CONCLUSION: CP patients with disability have unique characteristics and predictors, which can be targeted to reduce disease burden and health care expenditure in this population.

Managing complications of chronic pancreatitis: a guide for the gastroenterologist.

INTRODUCTION: Chronic pancreatitis is a heterogeneous and complex syndrome that, in most cases, causes pain as a cardinal symptom and affects both the morphology and function of the pancreas, leading to several serious complications. AREAS COVERED: The present review, based on a non-systematic PubMed search updated to June 2023, aims to present the current available evidence on the role of gastroenterologists in the diagnosis and treatment of both local and systemic complications by either endoscopic or medical treatments. EXPERT OPINION: At diagnosis and during chronic pancreatitis follow-up, particular care is needed to consider not only the clinically manifest signs and symptoms of the disease, such as pain, jaundice, gastrointestinal obstruction, and pseudocysts, which require multidisciplinary discussion to establish the best treatment option (endoscopic or surgical), but also less evident systemic complications. Pancreatic exocrine and endocrine insufficiency, together with chronic inflammation, addiction, and dysbiosis, contribute to malnutrition, sarcopenia, and osteopathy. These complications, in turn, increase the risk of infection, thromboembolic events, and death. Patients with chronic pancreatitis also have an increased risk of psychiatric disorders and pancreatic cancer onset. Overall, patients with chronic pancreatitis should receive a holistic evaluation, considering all these aspects, possibly through multidisciplinary care in dedicated expert centers.

Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention.

Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.

Management of Pancreatic Duct Stones: Nonextracorporeal Approach.

Chronic pancreatitis (CP) is an ongoing inflammatory disease with most patients developing pancreatic calculi during their course of disease. Extracorporeal shock wave lithotripsy (ESWL) is a first-line treatment option in patients with large lumen obstructing pancreatic duct (PD) stones. In patients with CP and PD dilatation, digital single-operator pancreatoscopy (DSOP)-guided lithotripsy seems to be an appealing option to ESWL and surgery. DSOP-guided lithotripsy for the treatment of large symptomatic PD-stones has been demonstrated to be safe, technically, and clinically effective, and should be regarded as an alternative endoscopic treatment of certain patients.

Management of Benign Biliary Stricture in Chronic Pancreatitis.

Endoscopic therapy is the first line of management for chronic pancreatitis (CP)-related benign biliary strictures. Multiple plastic stents (MPS) exchanged at regular intervals and temporary placement of fully covered self-expanding metal stents (FCSEMS) are preferred modalities of endotherapy. FCSEMS placement is non-inferior to MPS and requires fewer sessions of endoscopic retrograde cholangiopancreatography than MPS placement. The presence of head calcifications, severe CP, and length of stricture are predictors of failure or recurrence after endotherapy. Failure of endotherapy should be considered after 1 year when surgery should be considered.

Advances in the Management of Pain in Chronic Pancreatitis.

PURPOSE OF REVIEW: The data on recent advances in managing chronic pancreatitis (CP) pain is limited. This review highlights the role of endotherapy and the advances in the overall management of pain in CP. RECENT FINDINGS: Of late, pancreatic biodegradable stents have been used in endotherapy with appreciable success. These include slow, medium, and fast degrading stents, which optimize the overall management of CP and could prevent the need for multiple procedures. Endoscopic ultrasound-guided celiac plexus block is reserved in selected patients to treat debilitating pain. Total pancreatectomy with islet autotransplantation in small duct disease has shown promising results. The indications for treating pain in CP with endoscopy and surgery need to be better defined. The complexity of pain control due to the incomplete understanding of pathomorphology makes the management of CP challenging. The current treatment methods are still evolving. Therapy aims to reduce pain, optimize recovery, maintain quality of life, and meet postoperative needs. Initial management includes lifestyle modification, nutrition optimization, risk factor reduction with abstinence from alcohol, cessation of tobacco and smoking. Supportive medical management involves the judicial use of analgesics, neuromodulators, antioxidants, pancreatic enzyme replacement for insufficiency, and diabetes management. Patients with intractable pain are ideal for therapeutic intervention. Being less invasive with an acceptable complication rate makes endotherapy the preferred first-line treatment. If found to be cost-effective, biodegradable stents can reduce the overall cost. Unfortunately, if patients remain symptomatic, surgery is preferred in case of failure or recurrence. For optimal results, appropriate patient selection is vital to maximizing outcomes.

Endotherapy in pediatric pancreatitis.

PURPOSE OF REVIEW: Some children with acute recurrent and chronic pancreatitis stand to benefit from therapeutic endoscopic interventions. The purpose of this review is to summarize specific endoscopic therapies used for these conditions and highlight areas of future research. RECENT FINDINGS: Multicenter collaboration and consortium efforts have provided more data now than ever on the technical outcomes and safety of therapeutic endoscopic procedures for pancreatitis in children. Indications are growing but more research is needed to help guide patient selection. SUMMARY: Advanced endoscopic procedures including endoscopic retrograde cholangiopancreatography, endoscopic-ultrasound guided therapies, and single-operator pancreatoscopy may be used in patients with acute recurrent or chronic pancreatitis to manage pancreatic duct obstruction or local complications including pseudocysts and walled-off necrosis. Patient and procedural factors differ between adults and children. Access to these procedures for younger children is growing, and technical outcomes and adverse event rates appear similar between adults and children.