INTRODUCTION: Preoperative characterization of pancreatic cystic lesions (PCLs) remains inaccurate when based on morphology alone. We aimed to determine whether integrating complementary imaging (cross-sectional imaging plus endoscopic ultrasound) and clinical history, particularly history of pancreatitis, improves diagnostic accuracy compared with single-modality imaging. METHODS: This retrospective study included consecutive patients with PCLs treated at a tertiary referral center (test cohort) and a confirmatory cohort from a second hospital. Preoperative diagnostic accuracy was assessed in patients with histological confirmation. Multivariable logistic regression identified independent predictors of correct preoperative diagnosis. Additionally, a secondary multivariable logistic regression analysis included all patients using final diagnosis at follow-up (mean 2.4 ± 0.3 years) was performed. RESULTS: In the test cohort, 258 patients were analyzed; 59 (23%) had histological confirmation. Overall preoperative accuracy was 63% (validation cohort: 68%). No significant difference was observed between MRI, CT or endoscopic ultrasound alone. Complementary imaging was independently associated with higher diagnostic accuracy in multivariable analysis, as was main pancreatic duct dilation. In the full cohort, a history of acute or chronic pancreatitis was the only independent predictor of correct diagnosis and strongly predicted pseudocysts (80% vs. 10% without pancreatitis; p<0.00001). Combining complementary imaging with pancreatitis history further improved overall diagnostic accuracy and significantly increased detection of malignant PCLs compared with MRI alone (p=0.03). CONCLUSION: Diagnostic accuracy of PCLs is limited with single-modality imaging. A stepwise strategy integrating complementary imaging and clinical history, particularly a history of pancreatitis, significantly improves identification of malignant lesions and may refine guideline-based management.

INTRODUCTION:Autoimmune pancreatitis (AiP) is an inflammatory disease typically treated with corticosteroids. But repeated corticosteroid treatment (CST) can cause significant side effects, raising the need for better management strategies. This study investigated the role of "conventional" autoantibodies in monitoring disease activity and progression in AiP to establish individualized treatment strategies. METHODS:The study examined 55 AiP patients from the University Medical Centre Mannheim (Germany) and aimed to correlate "conventional" autoantibodies with disease severity, relapse risk, and other clinical parameters by analyzing 769 treatment appointments. RESULTS:A total of 56% of AiP patients have elevated levels of "conventional" autoantibodies, particularly smooth muscle antibody, anti-neutrophil cytoplasmic antibodies (ANCA), and rheumatoid factor. Rheumatoid factor was especially elevated in AiP type 1, whereas ANCA was elevated in AiP type 2. Increased disease activity is assumed in case of high AiP activity score, before (vs. after) CST, in the case of emergency (vs. elective) treatment, and in the presence of other organ involvement. Autoantibodies were found to correlate with these clinical markers of disease activity. Furthermore, symptomatic inflammatory bowel disease in AiP type 2 was associated with increased ANCA titers. The presence of a focal mass was especially associated with an increase in rheumatoid factor. Notably, patients with elevated autoantibodies at baseline and particularly those with insufficient reduction of autoantibody titers after CST had a higher likelihood of relapse. CONCLUSION:While conventional autoantibodies are not diagnostic for AiP, they are useful in monitoring disease activity and predicting relapse. Testing for autoantibodies could help guide individual treatment decisions.

Pain is one of the most frequent and debilitating symptoms associated with pancreatic ductal adenocarcinoma (PDAC). More than 60% of patients suffer from significant pain at diagnosis. The prevalence increases during the progression of the disease and is associated with anorexia, weight loss, and impaired social interactions. The pathophysiology of pain includes the combined effects of tumor growth and spread, perineural invasion, neuroimmune interactions, peripheral nerve remodeling, and central nervous system sensitization. Pain is additionally modulated by comorbid conditions, such as anxiety or depression, as well as treatment-related toxicity. Previous reports have used simple unidimensional scales to assess pain intensity, but as pain in PDAC is multidimensional, there is a need to develop new and robust instruments to assess pain. The treatment follows the World Health Organization three-step analgesic ladder. Non-opioid analgesics can be used to improve pain, but strong opioids are often used to relieve pain and suffering. When opioids are used, there should be a focus on the management of the side effects. Patients with anxiety and depression may benefit from treatment with selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, and tricyclic antidepressants that also have effects on pain. In some cases, more experimental drugs such as ketamine may be used. Celiac plexus neurolysis and local irradiation therapies are supplementary methods used to treat PDAC pain, but the response is unpredictable, and the durability is relatively short. The reduced survival associated with celiac ganglia injection, especially in patients with advanced disease, has also tempered enthusiasm.

Mechanisms of pancreatic pain are insufficiently understood, and quantitative sensory testing (QST) may help to identify the underlying mechanisms. Accordingly, this study assessed comprehensive somatosensory profiles encompassing nociceptive and nonnociceptive parameters in 70 patients with distinct pancreatic diseases, namely acute (n = 23), chronic (n = 20), or autoimmune pancreatitis (n = 10) and pancreatic cancer (n = 17) and compared it with 30 healthy control subjects by standardized QST (protocol of the German research network on neuropathic pain). Patients with pancreatic diseases presented significant somatosensory deficits in all thermal and tactile detection and pain thresholds in the pancreatic viscerotome (Th10), when compared with a remote control area (dermatome C5) or reference data of matched healthy controls ( P < 0.05- P < 0.0001). Unaltered vibration detection emphasizes the strictly regional character of losses. Loss of sensitivity paralleled the occurrence of paradoxical heat sensation (Th10 vs C5; P < 0.05), an indicator of thermal integration deficit. Punctate hyperalgesia or pain to light touch, the hallmark signs of spinal central sensitization were mostly absent and pain summation remained unchanged ( P > 0.05). Stratification of patients revealed that somatosensory deficits were significantly more pronounced in acute compared with chronic pancreatitis (eg, cold and warm detection thresholds: −2.19 ± 1.42 vs −1.10 ± 1.23 and −1.30 ± 1.68 vs −0.11 ± 1.80 z-values; P < 0.05 each). Notably, blunt pressure hyperalgesia, the only somatosensory parameter exhibiting significant gain compared with the patients' remote C5 segment, was a frequent finding only in acute, but not in chronic pancreatitis. The somatosensory phenotype of patients with distinct pancreatic disorders was characterized by a wide array of sensory losses being most severe in acute pancreatitis.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

INTRODUCTION:United European Gastroenterology (UEG) Guidelines on immunoglobulin G4 (IgG4)-related digestive disease provides evidence-based recommendations for the diagnosis and management of IgG4-related digestive disease. The aim of this study is to evaluate the adherence to recommendations of this IgG4 guideline across centers in Europe. PATIENTS AND METHODS:Questionnaire-based data related to organ involvement, diagnosis, treatment and follow-up of newly diagnosed patients with IgG4-related digestive diseases over a 3-year period, were collected from 14 centers in 11 European countries. RESULTS:One hundred and ninety-nine patients (76% males) were included. Median age at diagnosis was 64 years. Most of the patients had concomitant pancreatic and biliary tree involvement (46%), followed by isolated pancreatic involvement (33.5%), isolated biliary tree involvement (18.5%), esophageal involvement (1.5%) or bowel (0.5%) involvement. Most of the patients (64%) underwent a combination of computed tomography and magnetic resonance imaging at diagnosis. Among the 158 autoimmune pancreatitis patients with or without concomitant bile duct involvement, treatment was performed according to guidelines in 115 patients (73%; moderate adherence). Follow-up assessment was performed between 2 and 4 weeks in 75 patients (47%, partial adherence). Among 37 patients with liver- or biliary tree involvement, 29 patients were treated according to guidelines (78%; full adherence). In the follow-up of patients with isolated liver- or biliary tree involvement, we observed moderate adherence in 21 (57%). Disease monitoring for activity and damage using the IgG4 responder activity index was utilized in only 3/14 centers (poor adherence). CONCLUSIONS:IgG4-related digestive disease is restricted to the pancreas and bile ducts in the majority of patients. Even in specialist centers with an interest in IgG4-related digestive disease, UEG guideline treatment adherence was moderate, follow-up at 2-4 weeks was only partial, and monitoring for disease activity was poor. These findings highlight the need for ongoing education and improved adherence to monitoring among healthcare providers.

BACKGROUND:Biliary acute pancreatitis (AP) during pregnancy is a challenging situation, and current guidelines for AP, pregnancy care, and surgery do not specifically address its management. This study investigated the safety and effectiveness of cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) during pregnancy in AP. METHODS:This international retrospective multicenter cohort study encompassed questions related to demographic information, clinical presentation, management strategies, timing of cholecystectomy, approaches to the procedure, complications, and outcomes. Continuous variables were summarized as medians with interquartile ranges, and categorical variables as frequencies and percentages. Group comparisons used Welch's t-test, Pearson's chi-squared, or Fisher's exact tests. RESULTS:A total of 101 cases from 14 countries and 19 centers were enrolled. Cholecystectomy after mild AP during pregnancy had a lower rate of readmission due to recurrent AP or other gallstone-related complications compared with those who did not undergo surgery after a mild AP during pregnancy (0% vs. 24%; n = 0/17 vs. n = 12/49, p = 0.027). Cholecystectomy performed during pregnancy was associated with a low surgical complication rate, identical to that seen in postpartum procedures (12% vs. 10%; n = 2/17 vs. n = 3/30; p > 0.999). Preterm birth occurred in 7.1% (n = 1/14) of patients with cholecystectomy versus 11% (n = 5/45) without. Fetal loss after surgery occurred only in the first trimester (n = 3/17 vs. n = 1/49). No difference was seen in readmission (5%, n = 1/21 vs. 27%, n = 4/15; p = 0.138), fetal loss (5%, n = 1/21 vs. 27%, n = 4/15; p = 0.138) and preterm birth (6%, n = 1/17 vs. 8%, n = 1/12; p > 0.999) between the surgical and ERCP groups. The fetal loss (9.1%, n = 2/22 vs. 5.4%, n = 4/74; p = 0.618) and preterm birth rates (5.9%, n = 1/17 vs. 12%, n = 8/65; p = 0.677) did not significantly differ between patients with and without ERCP during pregnancy. CONCLUSION:Cholecystectomy is effective and safe in pregnant patients during the second or third trimester in cases of mild biliary pancreatitis. ERCP is safe in any trimester.

BACKGROUND & AIMS:Type 1 autoimmune pancreatitis (AIP) is a relapsing remitting disorder that often requires multiple treatment courses. Our aims were to assess the efficacy of maintenance treatment in preventing relapse and to develop the PrescrAIP risk score predicting relapse risk and the benefit of maintenance treatment. METHODS:We retrospectively analyzed patients meeting international diagnostic criteria for type 1 AIP who reached partial or complete remission after initial treatment. The primary outcome was disease relapse, defined as recurrence of symptoms and/or radiologic findings. We developed a multivariable prediction model using Cox proportional hazards regression, performed internal and internal-external validation, and built a predictive nomogram. RESULTS:We included 577 patients (68% male). During a median follow-up of 34 months (interquartile range, 13-69 months), we observed 154 relapses. The overall 3-year relapse risk was 28% (95% confidence interval [CI], 24%-32%), lower in patients receiving maintenance treatment than in those without (22% vs 35%; P < .001). The final PrescrAIP model incorporated protective factors (maintenance treatment, prior surgery, focal mass, female sex) and risk factors (biliary involvement, other organ involvement, IgG4 elevation, allergy, jaundice, acute pancreatitis). The model showed moderate discrimination (Concordance index, 0.69) and good calibration. Internal-external validation yielded Concordance index values ranging from 0.64 to 0.71. Maintenance treatment significantly reduced relapse in patients with a PrescrAIP score >155, but not in those with lower scores. CONCLUSIONS:Maintenance therapy reduced relapse only in patients at high relapse risk. Once externally validated, the PrescrAIP score may guide personalized maintenance treatment decisions.

Background In liver cirrhosis, prognosis is profoundly affected by renal function. This study evaluates the usefulness of renal stiffness measurement by point-shear wave elastography and renal perfusion by duplex. Methods In this case-control study, organ stiffness was quantified using point-shear wave elastography and duplex sonography to calculate the arterial resistive (RI) and pulsatility indices (PI) in 123 patients, including patients with liver cirrhosis with (LC+A) and without ascites (LC-A) and patients without liver cirrhosis (NLC). Results PI and RI were significantly increased in LC-A and LC+A compared to NLC (p<0.001) and correlated with MELD and Child Pugh scores. Point-shear wave elastography showed significantly lower renal stiffness in LC+A compared to LC-A (p<0.01) and NLC (p<0.001). Renal stiffness correlated inversely with MELD and Child Pugh scores.Reduced renal stiffness, but not PI or RI, was associated with the presence of hepatorenal syndrome (p<0.001). Reduced renal stiffness was associated with an increased risk of death due to complications of liver cirrhosis within 3 years (p<0.01). Conclusion Point-shear wave elastography and duplex sonography correlate with progression of liver cirrhosis, but only shear wave elastography represents a valuable prognostic tool for hepatorenal syndrome and mortality in patients with liver cirrhosis.

Background: Transcutaneous point-shear wave elastography (p-SWE) performed using an acoustic radiation force impulse can be used to quantify pancreatic stiffness in chronic pancreatitis (CP). We aimed to evaluate its usefulness to diagnose and monitor CP. Methods: 175 participants were included in this prospective study including patients with CP (n = 65), liver cirrhosis (LC; n = 60), alcohol abuse (n = 10) and healthy controls (n = 40). Point-shear wave elastography of the pancreas was performed and quantified as median shear wave velocity (SWV). In the same way, p-SWE of the spleen served as a marker of portal hypertension. The M-ANNHEIM Severity score was used as global marker for disease activity in CP. Results: Compared to healthy controls, pancreatic SWV was significantly elevated in CP (1.38 vs. 0.96 m/s; p < 0.0001, MWU-test). Pancreatic SWV was increased in alcoholic CP but not in hereditary CP. Receiver operating characteristic analysis revealed 1.2 m/s as the optimal cut-off to identify non-heredity-CP subjects (90% specificity; 81% sensitivity; 92% positive predictive value). Pancreatic SWV correlated significantly with the M-ANNHEIM Severity score, severity of CP-typical complications (both p < 0.05, linear regression analysis), morphological changes of the pancreas and need for hospital treatment (both p < 0.05, MWU-test) but not with exocrine or endocrine insufficiency. Pancreatic SWV >1.7 m/s was identified to predict M-ANNHEIM Severity score >= 11 points. Pancreatic SWV was also elevated in LC (1.42 m/s; p < 0.001), correlating with increased splenic SWV. Conclusion: Transcutaneous pancreatic p-SWE represents a bedside, cost-effective and non-invasive tool which adds valuable information to the process of diagnosing and monitoring CP. By portal hypertension, an increased pancreatic SWV must be expected.

BACKGROUND & AIMS:Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS:We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS:We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS:Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

There are several overlapping clinical practice guidelines in acute pancreatitis (AP), however, none of them contains suggestions on patient discharge. The Hungarian Pancreatic Study Group (HPSG) has recently developed a laboratory data and symptom-based discharge protocol which needs to be validated. (1) A survey was conducted involving all members of the International Association of Pancreatology (IAP) to understand the characteristics of international discharge protocols. (2) We investigated the safety and effectiveness of the HPSG-discharge protocol. According to our international survey, 87.5% (49/56) of the centres had no discharge protocol. Patients discharged based on protocols have a significantly shorter median length of hospitalization (LOH) (7 (5;10) days vs. 8 (5;12) days) p < 0.001), and a lower rate of readmission due to recurrent AP episodes (p = 0.005). There was no difference in median discharge CRP level among the international cohorts (p = 0.586). HPSG-protocol resulted in the shortest LOH (6 (5;9) days) and highest median CRP (35.40 (13.78; 68.40) mg/l). Safety was confirmed by the low rate of readmittance (n = 35; 5%). Discharge protocol is necessary in AP. The discharge protocol used in this study is the first clinically proven protocol. Developing and testifying further protocols are needed to better standardize patients’ care.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the pancreatic cancer field. A histological hallmark of PDAC is perineural invasion (PNI), whereby cancer cells invade surrounding nerves, providing an alternative route for metastatic spread. The extent of PNI has been positively correlated with early tumor recurrence and reduced overall survival. Multiple studies have shown that mechanisms involved in PNI are also involved in tumor spread and pain generation. Targeting these pathways has shown promising results in alleviating pain and reducing PNI in preclinical models. In this review, we will describe the mechanisms and future treatment strategies to target this mutually trophic interaction between cancer cells to open novel avenues for the treatment of patients diagnosed with PDAC.