Background: The tumor microenvironment (TME) is composed of fibro-inflammatory cells and extracellular matrix (ECM) components. However, the exact contribution of the various TME compartments towards therapeutic response is unknown. Here, we aim to dissect the specific contribution of tumor-associated macrophages (TAMs) towards drug delivery and response in pancreatic ductal adenocarcinoma (PDAC). Methods: The effect of gemcitabine was assessed in human and murine macrophages, human pancreatic stellate cells (hPSCs), and tumor cells (L3.6pl, BxPC3 and KPC) in vitro. The drug metabolism of gemcitabine was analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Preclinical studies were conducted using Kras^G12D;p48-Cre and Kras^G12D;p53^172H;Pdx-Cre mice to investigate gemcitabine delivery at different stages of tumor progression and upon pharmacological TAM depletion. Results: Gemcitabine accumulation was significantly increased in murine PDAC tissue compared to pancreatic intraepithelial neoplasia (PanIN) lesions and healthy control pancreas tissue. In vitro, macrophages accumulated and rapidly metabolized gemcitabine resulting in a significant drug scavenging effect for gemcitabine. Finally, pharmacological TAM depletion enhanced therapeutic response to gemcitabine in tumor-bearing KPC mice. Conclusion: Macrophages rapidly metabolize gemcitabine in vitro, and pharmacological depletion improves the therapeutic response to gemcitabine in vivo. Our study supports the notion that TAMs might be a promising therapeutic target in PDAC.

As a member of the 11-gene “death-from-cancer” gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after Usp22 deletion in mice. We aimed to investigate the function of USP22 in intestinal inflammation as well as inflammation-associated CRC. We evaluated the effects of a conditional, intestine-specific knockout of Usp22 during dextran sodium sulfate (DSS)-induced colitis and in a model for inflammation-associated CRC. Mice were analyzed phenotypically and histologically. Differentially regulated genes were identified in USP22-deficient human CRC cells and the occupancy of active histone markers was determined using chromatin immunoprecipitation. The knockout of Usp22 increased inflammation-associated symptoms after DSS treatment locally and systemically. In addition, Usp22 deletion resulted in increased inflammation-associated colorectal tumor growth. Mechanistically, USP22 depletion in human CRC cells induced a profound upregulation of secreted protein acidic and rich in cysteine (SPARC) by affecting H3K27ac and H2Bub1 occupancy on the SPARC gene. The induction of SPARC was confirmed in vivo in our intestinal Usp22-deficient mice. Together, our findings uncover that USP22 controls SPARC expression and inflammation intensity in colitis and CRC.

Microorganisms have been increasingly implicated in the pathogenesis of malignant diseases, potentially affecting different hallmarks of cancer. Despite the fact that we have recently gained tremendous insight into the existence and interaction of the microbiome with neoplastic cells, we are only beginning to understand and exploit this knowledge for the treatment of human malignancies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with limited therapeutic options and a poor long-term survival. Recent data have revealed fascinating insights into the role of the tumoral microbiome in PDAC, with profound implications for survival and potentially therapeutic outcomes. In this review, we outline the current scientific knowledge about the clinical and translational role of the microbiome in PDAC. We describe the microbial compositions in healthy and tumoral pancreatic tissue and point out four major aspects of the microbiome in PDAC: pathogenesis, diagnosis, treatment, and prognosis. However, caution must be drawn to inherent pitfalls in analyzing the intratumoral microbiome. Among others, contamination with environmental microbes is one of the major challenges. To this end, we discuss different decontamination approaches that are crucial for clinicians and scientists alike to foster applicability and physiological relevance in this translational field. Without a definition of an exact and reproducible intratumoral microbial composition, the exploitation of the microbiome as a diagnostic or therapeutic tool remains theoretical.

Background and Aims: The incidence of acute pancreatitis is increasing in the Western world. About 10% of cases are caused by hypertriglyceridemia. Plasmapheresis was shown to reduce serum triglyceride (TG) levels, and current apheresis guidelines recommend its use in severe acute hypertriglyceridemia‐induced pancreatitis (HIP). However, data on safety and efficacy are lacking. This study aimed to evaluate the clinical efficacy of plasmapheresis in hypertriglyceridemia‐induced pancreatitis. Methods: This is a retrospective multicenter cohort study of patients hospitalized for an episode of hypertriglyceridemia‐induced pancreatitis from January 1, 2012 to December 31, 2022. The predefined composite primary endpoint was in‐hospital mortality and organ failure. To reduce allocation bias, we performed propensity score matching. Results: 245 episodes of hypertriglyceridemia‐induced pancreatitis from 13 German centers were included. Of those, 95 episodes were treated with plasmapheresis. After propensity score matching, the final cohort consisted of 60 well‐balanced pairs. Plasmapheresis was not associated with a difference in the primary composite outcome, in‐hospital mortality, and organ failure (8/60 vs. 5/60; χ ² (1) = 0.776; p = 0.378), nor was there any difference in the severity of pancreatitis episodes. It showed only a moderate reduction of serum triglyceride compared to the non‐plasmapheresis group, but a significantly longer hospital stay in the plasmapheresis group (12 days; IQR 14 vs. 9 days; IQR 11; U = 1356; Z = −2.46; p = 0.014). Conclusions: Plasmapheresis in patients with hypertriglyceridemia‐induced pancreatitis was not associated with a better clinical outcome compared with conservative treatment in this propensity score‐matched retrospective cohort study. Outside clinical studies, this costly and potentially complicative treatment should be considered with caution.

Chronic pancreatitis is a fibroinflammatory disease of the pancreas with heterogeneous clinical features and a significant socioeconomic burden. Assessing its aetiology and early diagnosis of associated complications remain challenging. Personalized therapy necessitates precise knowledge of the genetic, biological, and clinical differences within a patient population. In this context, the identification of the underlying aetiology represents an essential cornerstone. This review elucidates current standards for identifying underlying aetiologies and the diagnostic work‐up for idiopathic cases. It provides an overview of general therapeutic approaches and highlights individual treatment options. Additionally, the follow‐up management of pancreatitis‐associated complications, namely exocrine pancreatic insufficiency, post‐pancreatitis diabetes mellitus, pain management, pancreatic fluid collections, and pancreatic cancer risk, is summarized.

Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries. Despite advances in cancer treatment, the 5-year survival rate for patients with PDAC remains less than 5%. In recent years, neoadjuvant therapy (NAT) has emerged as a promising treatment option for many cancer types, including locally advanced PDAC, with the potential to improve patient outcomes. To analyze the role of NAT in the setting of locally advanced PDAC over the past decade, a systematic literature search was conducted using PubMed and Web of Science. The results suggest that NAT may reduce the local mass size, promote tumor downstaging, and increase the likelihood of resection. These findings are supported by the latest evidence-based medical literature and the clinical experience of our center. Despite the potential benefits of NAT, there are still challenges that need to be addressed. One such challenge is the lack of consensus on the optimal timing and duration of NAT. Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT. In conclusion, NAT has emerged as a promising treatment option for locally advanced PDAC. However, further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease. With continued advances in cancer treatment, there is hope of improving the outcomes of patients with PDAC in the future.