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ObjectivesTumour-associated macrophages play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages are known to mediate tumour progression and have been identified in invasive tumours and in early preinvasive pancreatic intraepithelial precursor lesions. We aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in a genetic mouse model of pancreatic cancer.MethodsKPC mice (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) were treated for 12 weeks with liposomal clodronate or control liposomes. Tumour and metastasis formation as well as alterations in local and circulating immune cells and cytokines were analysed.ResultsTreatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. While tumour incidence and growth were only slightly reduced, metastasis formation in the liver and lungs was significantly diminished after macrophage depletion. This antimetastatic effect was independent of the presence of an endogenous primary tumour, since reduced pulmonary colonisation was also detected in clodronate-pretreated mice after tail vein injection of syngeneic pancreatic cancer cell lines. Macrophage inhibition by liposomal clodronate was associated with significantly impaired angiogenesis, reduced circulating vascular endothelial growth factor levels and decreased circulating CD4+CD25+ T cells. These alterations could be confirmed in an independent macrophage depletion model using CD11b-diphtheria toxin receptor mice.ConclusionsPharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with impaired angiogenesis and reduced CD4+CD25+ T cell levels. Pharmacological targeting of infiltrating macrophages represents a promising novel tool for antimetastatic therapeutic approaches.

Cystic pancreatic lesions (CPL) pose a diagnostic challenge due to their morphological diversity and malignant potential. Given the limited study data, transabdominal ultrasound (TAUS) is currently not established for either primary diagnostics or CPL monitoring. This study compared the diagnostic accuracy of TAUS in the assessment of CPL to that of the reference method, endoscopic ultrasound (EUS), to identify patient subgroups suitable for TAUS monitoring. In a monocentric, retrospective analysis, patients with CPL who underwent EUS and TAUS within six months from 01/2016 to 06/2022 were included. Univariate and multiple logistic regression analyses were used to identify determinants for the detection of CPL via TAUS. Cross-method morphological assessments were analysed, and a patient-specific algorithm for selecting the appropriate monitoring method was developed. Among 105 patients, CPL were detected by both EUS and TAUS in 90 patients (86%). Patients with “TAUS negative” CPL ( n  = 15) exhibited greater body mass indices (BMI, p  = 0.002) and smaller CPL diameters ( p  = 0.043). The final multivariate model (BMI, age, CPL diameter) yielded an 85% accuracy in predicting CPL detectability by TAUS. TAUS could be a cost-effective and patient-friendly imaging method for the surveillance of CPL in selected patients.

The dolichyl-diphosphooligosaccharide-protein glycosyltransferase non-catalytic subunit (DDOST) is a key component of the oligosaccharyltransferase complex catalyzing N -linked glycosylation in the endoplasmic reticulum lumen. DDOST is associated with several cancers and congenital disorders of glycosylation. However, its role in pancreatic cancer remains elusive, despite its enriched pancreatic expression. Using quantitative mass spectrometry, we identify 30 differentially expressed proteins and phosphopeptides (DEPs) after DDOST knockdown in the pancreatic ductal adenocarcinoma (PDAC) cell line PA-TU-8988T. We evaluated DDOST / DEP protein–protein interaction networks using STRING database, correlation of mRNA levels in pancreatic cancer TCGA data, and biological processes annotated to DEPs in Gene Ontology database. The inferred DDOST regulated phenotypes were experimentally verified in two PDAC cell lines, PA-TU-8988T and BXPC-3. We found decreased proliferation and cell viability after DDOST knockdown, whereas ER-stress, ROS-formation and apoptosis were increased. In conclusion, our results support an oncogenic role of DDOST in PDAC by intercepting cell stress events and thereby reducing apoptosis. As such, DDOST might be a potential biomarker and therapeutic target for PDAC.

65 million people worldwide are estimated to suffer from long-term symptoms after their SARS-CoV-2 infection (Long COVID). However, there is still little information about the early recovery among those who initially developed Long COVID, i.e. had symptoms 4–12 weeks after infection but no symptoms after 12 weeks. We aimed to identify associated factors with this early recovery. We used data from SARS-CoV-2-infected individuals from the DigiHero study. Participants provided information about their SARS-CoV-2 infections and symptoms at the time of infection, 4–12 weeks, and more than 12 weeks post-infection. We performed multivariable logistic regression to identify factors associated with early recovery from Long COVID and principal component analysis (PCA) to identify groups among symptoms. 5098 participants reported symptoms at 4–12 weeks after their SARS-CoV-2 infection, of which 2441 (48%) reported no symptoms after 12 weeks. Men, younger participants, individuals with mild course of acute infection, individuals infected with the Omicron variant, and individuals who did not seek medical care in the 4–12 week period after infection had a higher chance of early recovery. In the PCA, we identified four distinct symptom groups. Our results indicate differential risk of continuing symptoms among individuals who developed Long COVID. The identified risk factors are similar to those for the development of Long COVID, so people with these characteristics are at higher risk not only for developing Long COVID, but also for longer persistence of symptoms. Those who sought medical help were also more likely to have persistent symptoms.

Introduction With a rising incidence and unchanged poor prognosis, pancreatic cancer is increasingly becoming a focus of gastroenterological oncology, but there is a lack of real‐world data. The aim of the current study was to investigate trends in survival and treatment patterns by analyzing German health claims data. Methods Pancreatic cancer patients diagnosed between 2010 and 2017 were identified from the German Pharmacoepidemiological Research Database (GePaRD, approximately 20% of the German population). Data on demographics, tumor treatment within 1 year after diagnosis, and survival were extracted. Results The study population comprised 23,339 patients with a median age of 74 years (IQR 66–80) and 44% with localized and 56% with metastatic disease. Overall, 52.4% received any chemotherapy, and curative intended resection was performed in 28.3%. Neoadjuvant and adjuvant therapy were performed in 4.4% and 58.7% of the cases, respectively. The median overall survival of the whole study population was 7.84 months. Patients diagnosed in the most recent period (2014–2017) had a significantly better prognosis (8.20 months (95% CI 7.97–8.43)) than patients who were diagnosed in the earlier period (2010–2013) (7.54 months (95% CI 7.31–7.70), p < 0.001), with an age‐, sex‐, and stage‐adjusted hazard ratio of 0.87 (95% CI 0.85–0.9). Over time, the most pronounced treatment trends have affected patients with localized disease, with increasing frequency of resection and neoadjuvant therapy and decreasing frequency of best supportive care. Conclusion This comprehensive insight into survival and treatment of pancreatic cancer in Germany shows presumably medically beneficial therapy trends with, however, only marginal improvements in prognosis to date. This study, one of the largest European real‐world investigations, provides a comprehensive analysis of treatment patterns and survival outcomes in pancreatic cancer. While curative‐intent therapies, such as neoadjuvant therapy and tumor resection, have increased and survival has improved over time, the prognosis remains poor.

IntroductionAutoimmune pancreatitis (AIP) mainly manifests in two distinct forms with different clinical, serological and prognostic characteristics. Previous studies indicated a higher risk of malignancy in AIP patients compared with the general population. However, a direct comparison of cancer incidence in AIP patients with controls from the general population has not been conducted yet.Methods and analysisThis is an international, multicentre, retrospective study on patients diagnosed with AIP after 2005. Retrospective data regarding demography, AIP characteristics and cancer incidence will be extracted from the medical files of AIP patients. The primary outcome is the standardised incidence ratio of any first invasive cancer after AIP diagnosis compared with the general population. The expected number of cancers in the general population will be determined using the ‘Cancer Incidence in Five Continents Volume XI’ registry. Secondary outcomes are the prevalence of all cancer diagnoses within 12 months prior to AIP diagnosis and AIP features associated with a cancer diagnosis.Ethics and disseminationThis study was approved by the ethics committees of the autoimmune pancreatitis, pancreatic and extrapancreatic cancer (AIPPEAR) core group centres (Halle (Saale), Germany; Aalborg, Denmark; Tartu, Estonia; Munich, Germany; Göttingen, Germany; Maribor, Slovenia, with the following reference numbers: 2023–204, 2023–0 29 953, 382 /T-3, 24–0768, 9/7/23, UKC-MB-KME 59/23, respectively). Where required, the study protocol will be reviewed and approved by the ethics committees of participating centres in compliance with local regulations. Data will be stored in an electronic case report form within REDCap. In this context, the AIPPEAR core group will share joint responsibility for the data. All results from this study will be submitted to international, peer-reviewed journals and presented at international conferences.Trial registration number NCT06328101.

Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5–77%) and neuropathy (range 0–22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials.

This study aimed to compare different pancreatic enzyme preparations (PEPs) available in Germany regarding particle geometry and size, and to evaluate enzyme activity under physiologically relevant conditions in vitro. Pancreatic endocrine insufficiency is characterized by deficiency of pancreatic enzymes resulting in maldigestion. It is orally treated by pancreatic enzyme replacement therapy. The formulations differ in their physical properties and enzyme release behavior, potentially resulting in inconsistent dosages and poor interchangeability of products. A total of 25 products were analyzed for particle size and number of particles per capsule. Enzyme activities of lipase, amylase, and protease were measured by digestion of olive oil emulsion, starch, and casein, respectively. To analyze enzyme release, gastric environments were simulated by incubating PEPs at pH 1, 4, or 5. Duodenal conditions were simulated by subsequent incubation at pH 6. Regarding physical properties and enzyme release kinetics, considerable differences between different PEPs were found. Furthermore, compared to the label claim, excess lipase activity was observed for most products, reaching up to 148%. These in vitro results suggest poor interchangeability of PEPs, potentially explained by physical and release characteristics. Physicians and patients should be aware of the potential gap between label claims and the real-life performance of different PEPs.

The CEL-HYB1 hybrid allele of the carboxyl ester lipase ( CEL ) gene and its pseudogene ( CELP ) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign. However, functional analysis revealed that Thr488 is the primary determinant of CEL-HYB1 misfolding and associated endoplasmic reticulum (ER) stress. To address this contradiction, we analyzed a cohort from Hungary and found significantly increased CEL-HYB1 carrier frequency in CP cases (9/319, 2.8%) versus controls (5/618, 0.8%), yielding an odds ratio of 3.6 (95% confidence interval 1.2–10.7, P  = 0.024). All CEL-HYB1 positive carriers from Hungary had the Thr488-Thr548 haplotype. We analyzed the haplotype distribution of reported CEL-HYB1 carriers from three European cohorts and found that 14/29 CP cases from Germany and 2/6 CP cases from Poland carried the Thr488-Ile548 haplotype, which was absent in CEL-HYB1 positive controls from Germany (n = 13) and Poland (n = 8). All patients (n = 17) and controls (n = 9) from France carrying CEL-HYB1 contained the Thr488-Thr548 haplotype. Functional studies using transfected cells indicated that both CEL-HYB1 haplotypes induced significant ER stress and the Thr488-Ile548 haplotype had a stronger effect. We conclude that the Thr488-Thr548 haplotype of CEL-HYB1 is widespread in Europe and increases CP risk by almost fourfold. In contrast, the Thr488-Ile548 haplotype is regionally restricted, but confers markedly stronger CP risk.