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.

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.

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.

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.

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.

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.

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.

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.

Extracorporeal shock wave lithotripsy for pancreatic duct stones in patients with chronic pancreatitis: Are we underutilizing a new technology?

The progressive inflammatory nature of chronic pancreatitis and its sparse therapeutic toolbox remain obstacles in offering patients durable solutions for their symptoms. Obstruction of the main pancreatic duct by either strictures or stones represents a scenario worthy of therapeutic focus, as nearly all patients with pancreatitis eventually have intraductal stones. A more recent option for removal of main duct stones is extracorporeal shock wave lithotripsy (ESWL). In an effort to explore the role of ESWL in a Canadian setting, we evaluated our initial experience over an 8-year period (2011-2019).

[Effect of pancreatic extracorporeal shock wave lithotripsy on chronic pancreatitis stones].

Objective: To analyze the therapeutic effect and safety of pancreatic extracorporeal shock wave lithotripsy(P-ESWL) for patients with chronic pancreatitis complicated by stones of the pancreatic duct and to investigate the influencing factors. Methods: A retrospective analysis was performed on clinical data from 81 patients with chronic pancreatitis complicated by pancreatic duct calculus treated with P-ESWL in the Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi 'an Jiaotong University from July 2019 to May 2022. There were 55 males(67.9%) and 26 females(32.1%). The age was (47±15)years (range: 17 to 77 years). The maximum diameter(M(IQR)) of the stone was 11.64(7.60) mm, and the CT value of the stone was 869 (571) HU. There were 32 patients (39.5%) with a single pancreatic duct stone and 49 patients(60.5%) with multiple pancreatic duct stones. The effectiveness, remission rate of abdominal pain, and complications of P-ESWL were evaluated. Student's t test, Mann Whitney U test, χ2 test, or Fisher's exact test was used to compare the characteristics between the effective and ineffective groups of lithotripsy. The factors influencing the effect of lithotripsy were analyzed by univariate and multivariate logistic regression analysis. Results: Eighty-one patients with chronic pancreatitis were treated with P-ESWL 144 times, with an average of 1.78 (95%CI:1.60 to 1.96) times per person. Among them, 38 patients(46.9%) were treated with endoscopy. There were 64 cases(79.0%) with effective removal of pancreatic duct calculi and 17 cases(21.0%) with ineffective removal. Of the 61 patients with chronic pancreatitis accompanied by abdominal pain, 52 cases(85.2%) had pain relief after lithotripsy. After lithotripsy treatment, 45 patients(55.6%) developed skin ecchymosis, 23 patients(28.4%) had sinus bradycardia, 3 patients(3.7%) had acute pancreatitis, 1 patient(1.2%) had a stone lesion, and 1 patient(1.2%) had a hepatic hematoma. Univariate and multivariate logistic regression analysis showed that the factors affecting the efficacy of lithotripsy included the age of patient(OR=0.92, 95%CI: 0.86 to 0.97), the maximum diameter of the stone(OR=1.12,95%CI:1.02 to 1.24) and the CT value of the stone(OR=1.44, 95%CI: 1.17 to 1.86). Conclusions: P-ESWL is effective in the treatment of patients with chronic pancreatitis complicated by calculi of the main pancreatic duct.Factors affecting the efficacy of lithotripsy include patient's age, maximum stone diameter, and CT value of calculi.

Hospital Frailty Risk Score (HFRS) Predicts Adverse Outcomes Among Hospitalized Patients with Chronic Pancreatitis.

INTRODUCTION: The prevalence of frailty among patients with chronic pancreatitis (CP) and its impact on clinical outcomes is unclear. We report the impact of frailty on mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the United States. METHODS: We extracted data on patients hospitalized with a primary or secondary diagnosis of CP from the Nationwide Readmissions Database 2019. We applied a previously validated hospital frailty risk scoring system to classify CP patients into frail and non-frail on index hospitalization and compared the characteristics of frail and non-frail patients. We studied the impact of frailty on mortality, readmission, and healthcare utilization. RESULTS: Of 56,072 patients with CP, 40.78% of patients were classified as frail. Frail patients experienced a higher rate of unplanned and preventable hospitalizations. Almost two-thirds of frail patients were younger than 65, and one-third had no or only single comorbidity. On multivariate analysis, frailty was independently associated with two times higher mortality risk (adjusted hazard ratio [aHR], 2.05; 95% CI 1.7-2.5). Frailty was also associated with a higher risk of all-cause readmission with an aHR of 1.07; (95% CI 1.03-1.1). Frail patients experienced a longer length of stay, higher hospitalization costs, and hospitalization charges. Infectious causes were the most common cause of readmission among frail patients compared to acute pancreatitis among non-frail patients. CONCLUSIONS: Frailty is independently associated with higher mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the US.

Development of a clinical score to estimate pancreatitis-related hospital admissions in patients with a new diagnosis of chronic pancreatitis: the trinity score.

BACKGROUND: The clinical course of chronic pancreatitis is unpredictable and there is no globally accepted score to predict the disease course. We developed a clinical score to estimate pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis. METHODS: We conducted a retrospective cohort study using two clinical chronic pancreatitis databases held in tertiary referral centres in Dublin, Ireland, and in Tarragona, Spain. Individuals diagnosed with chronic pancreatitis between 2007 and 2014 were eligible for inclusion. Candidate predictors included aetiology, body mass index, exocrine dysfunction, smoking and alcohol history. We used multivariable logistic regression to develop the model. RESULTS: We analysed data from 154 patients with newly diagnosed chronic pancreatitis. Of these, 105 patients (68%) had at least one hospital admission for pancreatitis-related reasons in the 6 years following diagnosis. Aetiology of chronic pancreatitis, body mass index, use of pain medications and gender were found to be predictive of more pancreatic-related hospital admissions. These predictors were used to develop a clinical score which showed acceptable discrimination (area under the ROC curve = 0.70). DISCUSSION: We developed a clinical score based on easily accessible clinical parameters to predict pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis.

Editorial for the Special Issue "Acute and Chronic Pancreatitis, Pancreatic Malignancies".

Pancreatic diseases, especially acute pancreatitis and pancreatic cancer, are associated with high rates of complications, difficult treatment that may not always be effective, and high mortality in complex cases [...].

Chronic pancreatitis and nutritional support.

Malnutrition in patients with chronic pancreatitis is common, but its evaluation is often missed in clinical practice. Pancreatic exocrine insufficiency is the single most important cause of malnutrition; therefore, it needs to be screened for and treated appropriately. Specific diet regimens in patients suffering from chronic pancreatitis are rarely reported in the literature. Patients suffering from chronic pancreatitis have a higher demand for energy but a lower caloric intake secondary to pancreatic exocrine insufficiency, combined with the malabsorption of liposoluble vitamin and micronutrients, which needs be corrected by appropriate dietary counselling. Diabetes is frequently observed in chronic pancreatitis and classified as type 3c, which is characterized by low levels of both serum insulin and glucagon; therefore, there is a tendency towards hypoglycaemia in patients treated with insulin. Diabetes contributes to malnutrition in chronic pancreatitis. Strategies to treat exocrine and endocrine insufficiency are important to achieve better control of the disease.