Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

Contrast enhanced endoscopic ultrasound detects early therapy response following anti-TNF-therapy in patients with ulcerative colitis.

BACKGROUND AND AIM: Though colonoscopy plays a crucial role in assessing active ulcerative colitis (aUC), its scope is limited to the mucosal surface. Endoscopic ultrasound (EUS) coupled with contrast-enhancement (dCEUS) can precisely quantify bowel wall thickness and microvascular circulation, potentially enabling the quantitative evaluation of inflammation.We conducted a prospective, longitudinal study to assess therapy response using dCEUS in aUC patients undergoing treatment with adalimumab (ADA) or infliximab (IFX). METHODS: 30 ADA- and 15 IFX-treated aUC patients were examined at baseline and at 2, 6, 14 weeks of therapy and 48 weeks of follow-up. Bowel wall thickness (BWT) was measured by EUS in the rectum. Vascularity was quantified by dCEUS using Rise Time (RT) and Time To Peak (TTP). Therapy response was defined after 14 weeks using the Mayo Score. RESULTS: Patients with aUC displayed a mean BWT of 3.9±0.9 mm. In case of response to ADA/IFX a significant reduction in BWT was observed after 2 weeks (p=0.04), whereas non-responders displayed no significant changes. The TTP was notably accelerated at baseline and significantly normalised by week 2 in responders (p=0.001), while non-responders exhibited no significant alterations (p=0.9). At week 2, the endoscopic Mayo score did not exhibit any changes, thus failing to predict treatment responses. CONCLUSION: dCEUS enables the early detection of therapy response in patients with aUC, which serves as a predictive marker for long term clinical success. Therefore, dCEUS serves as a diagnostic tool for assessing the probability of future therapy success.

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

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.

International Consensus Recommendations for Safe Use of LAMS for On- and Off-Label Indications Using a Modified Delphi Process.

INTRODUCTION: The study aimed to develop international consensus recommendations on the safe use of lumen-apposing metal stents (LAMSs) for on- and off-label indications. METHODS: Based on the available literature, statements were formulated and grouped into the following categories: general safety measures, peripancreatic fluid collections, endoscopic ultrasound (EUS)-biliary drainage, EUS-gallbladder drainage, EUS-gastroenterostomy, and gastric access temporary for endoscopy. The evidence level of each statement was determined using the Grading of Recommendations Assessment, Development, and Evaluation methodology.International LAMS experts were invited to participate in a modified Delphi process. When no 80% consensus was reached, the statement was modified based on expert feedback. Statements were rejected if no consensus was reached after the third Delphi round. RESULTS: Fifty-six (93.3%) of 60 formulated statements were accepted, of which 35 (58.3%) in the first round. Consensus was reached on the optimal learning path, preprocedural imaging, the need for airway protection and essential safety measures during the procedure, such as the use of Doppler, and measurement of the distance between the gastrointestinal lumen and the target structure. Specific consensus recommendations were generated for the different LAMS indications, covering, among others, careful patient selection, the preferred size of the LAMS, the need for antibiotics, the preferred anatomic location of the LAMS, the need for coaxial pigtail placement, and the appropriate management of LAMS-related adverse events. DISCUSSION: Through a modified international Delphi process, we developed general and indication-specific experience- and evidence-based recommendations on the safe use of LAMS.

High prevalence of incidental endoscopic findings at routine endoscopy after atrial fibrillation ablation: Do we need a screening endoscopy for the upper gastrointestinal tract in the general population?

INTRODUCTION: High-power short-duration ablation (HPSD) is an effective therapy for atrial fibrillation with thermal esophageal injury as a rare but relevant side effect. AIM AND METHODS: In this retrospective single-center analysis we evaluated the incidence and relevance of ablation-induced findings and the prevalence of ablation-independent incidental gastrointestinal findings. For 15 months all patients undergoing ablation were screened by postablation esophagogastroduodenoscopy. Pathological findings were followed up and treated if necessary. RESULTS: 286 consecutive patients (66±10 years; 54.9% male) were included. 19.6% of patients showed ablation-associated alterations (10.8% esophageal lesions, 10.8% gastroparesis, 1.7% both findings). Logistic multivariable regression analysis confirmed an influence of lower BMI on the occurrence of RFA-associated endoscopic findings (OR 0.936, 95% CI 0.878-0.997, p<0.05). 48.3% of patients demonstrated incidental gastrointestinal findings. In 1.0% neoplastic lesions were present, 9.4% showed precancerous lesions and in 4.2% neoplastic lesions of unknown dignity were found requiring further diagnostics or therapy. 18.1% of patients demonstrated findings associated with a potentially increased risk of bleeding under anticoagulation. Patients with clinically relevant incidental findings were significantly more often male, 68.8% vs. 49.5% (p<0.01). CONCLUSION: HPSD ablation is safe, no devasting complication occurred in any patient. It resulted in 19.6% ablation-induced thermal injury whereas incidental findings of the upper GI tract were found in 48.3% of patients. Due to the high prevalence of 14.7% of findings requiring further diagnostics, therapy, or surveillance in a cohort that is mimicking the general population, screening endoscopy of the upper GI tract seems to be reasonable in the general population.

NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer.

The emergence of resistance to systemic therapies in pancreatic ductal adenocarcinoma (PDAC) is still a major obstacle in clinical practice. Both, constitutive and inducible NF-κB activity are known as key players in this context. To identify differentially expressed and TRAIL resistance mediating NF-κB target genes, TRAIL sensitive and resistant PDAC cell lines were analyzed by transcriptome assays. In this context, A20 was identified as an NF-κB/RelA inducible target gene. Translational PDAC tissue analysis confirmed the correlation of elevated A20 protein expression with activated RelA expression in PDAC patients. In in vitro experiments, an elevated A20 expression is accompanied by a specific resistance toward TRAIL-mediated apoptosis but not to chemotherapeutic-induced cell death. This TRAIL resistance was attributed to A20´s E3-ligase activity-mediating Zink finger domain. Furthermore, the ubiquitin-binding scaffold protein p62 was identified as indispensable for the TRAIL-mediated apoptosis-inducing pathway affected by A20. The results of this study identify A20 as a possible therapeutic target to affect resistance to TRAIL-induced apoptosis in PDAC cells.

Incidence of ablation-induced esophageal lesions and gastroparesis in patients undergoing ablation index guided high power short duration atrial fibrillation ablation.

INTRODUCTION: Aim of this study was to evaluate the incidence of ablation-induced endoscopically detected esophageal lesions (EDEL) and gastroparesis in patients undergoing high-power short-duration (HPSD) atrial fibrillation (AF) ablation using different target ablation index (AI) values. METHODS AND RESULTS: Consecutive patients undergoing AF ablation were included. Radiofrequency (RF) ablation was performed using HPSD ablation (50 W, target AI of 320 and 350 (group 1) and 380 (group 2) at posterior wall). Postablation endoscopy was performed in all patients. In total, 233 patients (66.8 ± 10 years; 52% male) were included consecutively (n = 137 patients in group 1 and n = 96 patients in group 2). Mean AI values und RF time at posterior wall was significantly higher and longer in group 2 compared to group 1 patients (413 ± 9 vs. 392 ± 19 AI, p < 0.01; 9.0 ± 0.8 s vs. 7.8 ± 0.7 s, p < 0.01). Esophageal endoscopy revealed esophageal lesions or gastroparesis in 43 of 233 patients (18.5%) in the total cohort (13.1% in group 1 and 26.0% in group 2; p = 0.02). Incidence of EDEL was 8.0% and 13.5% in group 1 and group 2, respectively. According to logistic analysis incidence of EDEL and/or gastroparesis was significantly lower in patients with a higher body mass index and higher in group 2 patients compared to group 1 patients. CONCLUSION: The incidence of EDEL or gastroparesis in patients undergoing HPSD AF ablation was 18.5% in the total cohort. The risk of EDEL and gastroparesis was associated with a higher AI target value of 380 compared to 320 and 350 at posterior wall and was reversely associated with body mass index.

AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer.

Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination.

Tumor-related death is primarily caused by metastasis; consequently, understanding, preventing, and treating metastasis is essential to improving clinical outcomes. Metastasis is mainly governed by the dissemination of tumor cells in the systemic circulation: so-called circulating tumor cells (CTCs). CTCs typically arise from epithelial tumor cells that undergo epithelial-to-mesenchymal transition (EMT), resulting in the loss of cell-cell adhesions and polarity, and the reorganization of the cytoskeleton. Various oncogenic factors can induce EMT, among them the transforming growth factor (TGF)-ß, as well as Wnt and Notch signaling pathways. This entails the activation of numerous transcription factors, including ZEB, TWIST, and Snail proteins, acting as transcriptional repressors of epithelial markers, such as E-cadherin and inducers of mesenchymal markers such as vimentin. These genetic and phenotypic changes ultimately facilitate cancer cell migration. However, to successfully form distant metastases, CTCs must primarily withstand the hostile environment of circulation. This includes adaption to shear stress, avoiding being trapped by coagulation and surviving attacks of the immune system. Several applications of CTCs, from cancer diagnosis and screening to monitoring and even guided therapy, seek their way into clinical practice. This review describes the process leading to tumor metastasis, from the generation of CTCs in primary tumors to their dissemination into distant organs, as well as the importance of subtyping CTCs to improve personalized and targeted cancer therapy.

The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression.

Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric surgery, we recently demonstrated the strong enrichment of differentially methylated heat shock factor 1 (HSF1) binding sites (>400-fold) in the process of liver remodeling, indicating a crucial role of HSF1 in modulating central aspects of NAFLD pathogenesis. Using cellular models of NAFLD, we were able to show that HSF1 is activated during fat accumulation in hepatocytes, mimicking conditions in patients before bariatric surgery. This induction was abolished by starving the cells, mimicking the situation after bariatric surgery. Regarding this connection, carnitine palmitoyltransferase 1 isoform A (CTP1a), a central regulator of lipid beta-oxidation, was identified as a HSF1 target gene by promoter analysis and HSF1 knockdown experiments. Finally, pharmacological activation of HSF1 through celastrol reduced fat accumulation in the cells in a HSF1-dependent manner. In conclusion, we were able to confirm the relevance of HSF1 activity and described a functional HSF1-CPT1a pathway in NAFLD pathogenesis.

Endoscopic Management of Anastomotic Leakage after Esophageal Surgery: Ten Year Analysis in a Tertiary University Center.

BACKGROUND/AIMS: Anastomotic leakage after esophageal surgery remains a feared complication. During the last decade, management of this complication changed from surgical revision to a more conservative and endoscopic approach. However, the treatment remains controversial as the indications for conservative, endoscopic, and surgical approaches remain non-standardized. METHODS: Between 2010 and 2020, all patients who underwent Ivor Lewis esophagectomy for underlying malignancy were included in this study. The data of 28 patients diagnosed with anastomotic leak were further analyzed. RESULTS: Among 141 patients who underwent resection, 28 (19.9%) developed an anastomotic leak, eight (28.6%) of whom died. Thirteen patients were treated with endoluminal vacuum therapy (EVT), seven patients with self-expanding metal stents (SEMS) four patients with primary surgery, one patient with a hemoclip, and three patients were treated conservatively. EVT achieved closure in 92.3% of the patients with a large defect and no EVT-related complications. SEMS therapy was successful in clinically stable patients with small defect sizes. CONCLUSION: EVT can be successfully applied in the treatment of anastomotic leakage in critically ill patients, while SEMS should be limited to clinically stable patients with a small defect size. Surgery is only warranted in patients with sepsis with graft necrosis.

Important role of Nfkb2 in the KrasG12D-driven carcinogenesis in the pancreas.

BACKGROUND: Oncogenic Kras initiates and drives carcinogenesis in the pancreas by complex signaling networks, including activation of the NFκB pathway. Although recent evidence has shown that oncogenic gains in Nfκb2 collaborate with Kras in the carcinogenesis, no data at the level of genetics for the contribution of Nfκb2 is available so far. METHODS: We used Nfkb2 knock-out mice to decipher the role of the gene in Kras-driven carcinogenesis in vivo. RESULTS: We show that the Nfkb2 gene is needed for cancer initiation and progression in KrasG12D-driven models and this requirement of Nfkb2 is mechanistically connected to proliferative pathways. In contrast, Nfκb2 is dispensable in aggressive pancreatic ductal adenocarcinoma (PDAC) models relying on the simultaneous expression of the Kras oncogene and the mutated tumor suppressor p53. CONCLUSIONS: Our data add to the understanding of context-dependent requirements of oncogenic Kras signaling during pancreatic carcinogenesis.

The safety and efficacy of a new 20-mm lumen apposing metal stent (lams) for the endoscopic treatment of pancreatic and peripancreatic fluid collections: a large international, multicenter study.

BACKGROUND: Lumen apposing metal stent (LAMS) allows an easy access to peripancreatic fluid collections (PPFCs) and the possibility of performing direct endoscopic necrosectomy (DEN). The aim of our study was to evaluate the safety and efficacy of a new 20-mm LAMS in the management of PPFCs. This novel stent represents the largest diameter LAMS available on the market to date. METHODS: This is an international, multicenter retrospective study involving 20 centers. Consecutive patients who underwent EUS-guided PPFC drainage using a 20-mm LAMS were included. Primary outcomes were technical and clinical success. Secondary outcomes were rate and the severity of adverse events. RESULTS: A total 105 patients underwent PPFC drainage using the new 20-mm LAMS and 106 LAMS were placed. Technical success was 100% (106/106). 7/105 patients died due to causes not related to the stent. Clinical success was achieved in 92/98 patients (93.9%). Significant adverse events occurred in 8/98 patients (8.16%): 4 cases (4.08%) of bleeding, 3 cases (3.06%) of suprainfection, 1 case of gastric outlet obstruction. CONCLUSIONS: This multicenter study demonstrated acceptable rates of technical and clinical success using a new 20-mm LAMS for PPFC, including walled-off pancreatic necrosis (WOPN). The results of our study suggest that a new 20-mm LAMS is non-inferior in terms of safety, efficacy, and adverse events as compared to smaller diameter LAMS in the management of PPFCs, including pancreatic psuedocysts (PP) and WOPN. Randomized controlled studies will be needed to determine the ideal size of LAMS need to achieve the greatest clinical benefit with the minimized risk exposure for this high-risk patient population.

Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer.

With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer.

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells †.

Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these "reverse Warburg" cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies "reverse Warburg "PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance.

Endoscopic ultrasound-guided drainage of pancreatic walled-off necrosis using 20-mm versus 15-mm lumen-apposing metal stents: an international, multicenter, case-matched study.

BACKGROUNDS: Endoscopic ultrasound (EUS)-guided placement of lumen-apposing metal stents (LAMSs) has gained popularity for the treatment of pancreatic walled-off necrosis (WON). We compared the 20-mm and 15-mm LAMSs for the treatment of symptomatic WON in terms of clinical success and adverse events. METHODS: We conducted a retrospective, case-matched study of 306 adults at 22 tertiary centers from 04/2014 to 10/2018. A total of 102 patients with symptomatic WON who underwent drainage with 20-mm LAMS (cases) and 204 patients who underwent drainage with 15-mm LAMS (controls) were matched by age, sex, and drainage approach. Conditional logistic regression analysis was performed to compare clinical success (resolution of WON on follow-up imaging without reintervention) and adverse events (according to American Society for Gastrointestinal Endoscopy criteria). RESULTS: Clinical success was achieved in 92.2 % of patients with 20-mm LAMS and 91.7 % of patients with 15-mm LAMS (odds ratio 0.92; P = 0.91). Patients with 20-mm LAMS underwent fewer direct endoscopic necrosectomy (DEN) sessions (mean 1.3 vs. 2.1; P < 0.001), despite having larger WON collections (transverse axis 118.2 vs. 101.9 mm, P = 0.003; anteroposterior axis 95.9 vs. 80.1 mm, P = 0.01). There was no difference in overall adverse events (21.6 % vs. 15.2 %; P = 0.72) and bleeding events (4.9 % vs. 3.4 %; P = 0.54) between the 20-mm and 15-mm LAMS groups, respectively. CONCLUSIONS: The 20-mm LAMS showed comparable clinical success and safety profile to the 15-mm LAMS, with the need for fewer DEN sessions for WON resolution.