Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21–126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; p = 0.0048). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit.

Objectives: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder affecting virtually any organ. Type 1 autoimmune (type 1 AIP) is its pancreatic manifestation. To date, steroids are considered the first-line pancreatitis treatment. The CD20-binding antibody rituximab (RTX) appears a promising steroid-sparing therapy, although long-term data are lacking. We aimed to bridge this gap with a cohort of IgG4-RD patients treated with RTX and to assess the potential value of the Responder Index (RI) as a discriminatory score for disease activity. Methods: We retrospectively evaluated 46 patients from a tertiary referral centre who were diagnosed with IgG4-RD and/or type 1 AIP according to the International Consensus Diagnostic Criteria or Unifying-AIP criteria between June 2006 and August 2019. Results: Patients resembled previous cohorts in terms of characteristics, diagnosis, and therapeutic response. Thirteen of the 46 patients with IgG4-RD/type 1 AIP were treated with RTX pulse therapy due to relapse, adverse reactions to steroids, or high-risk constellations predicting a severe course of disease with multi-organ involvement. Median follow-up after diagnosis was 52 months for all subjects, and 71 months in IgG4-RD patients treated with RTX. While patients in the RTX group showed no significant response to an initial steroid pulse, clinical activity as measured by the RI significantly decreased in the short-term after RTX induction. Within 16 months, 61% of patients relapsed in the RTX group but responded well to re-induction. Clinical and laboratory parameters improved equally in response to RTX. Conclusion: RTX therapy in patients with IgG4-RD is an effective and safe treatment to induce treatment response and possible long-term remission. Repeated RTX administration after 6–9 months may be of value in reducing the risk of relapse. The RI appears to be a reasonable index to assess disease activity and to identify patients with IgG4-related disease who may benefit from B-cell-depleting therapy.

Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRAS^G12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRAS^G12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.

Abstract 339

Enteric infections represent a major health care challenge which is particularly prevalent in countries with restricted access to clean water and sanitation and lacking personal hygiene precautions, altogether facilitating fecal-oral transmission of a heterogeneous spectrum of enteropathogenic microorganisms. Among these, bacterial species are responsible for a considerable proportion of illnesses, hospitalizations, and fatal cases, all of which have been continuously contributing to ignite researchers interest in further exploring their individual pathogenicity. Beyond the universally accepted animal models, intestinal organoids are increasingly valued for their ability to mimic key architectural and physiologic features of the native intestinal mucosa. As a consequence, they are regarded as the most versatile and naturalistic in vitro model of the gut, allowing monitoring of adherence, invasion, intracellular trafficking, and propagation as well as repurposing components of the host cell equipment. At the same time, infected intestinal organoids allow close characterization of the host epitheliums immune response to enteropathogens. In this review, (i) we provide a profound update on intestinal organoid-based tissue engineering, (ii) we report the latest pathophysiological findings defining the infected intestinal organoids, and (iii) we discuss the advantages and limitations of this in vitro model.

Pancreatic cystic lesions are a frequent incidental finding in abdominal imaging. Despite its usually benign background, a small fraction exhibiting features suspicious for cancerous development demands continuous follow-up or surgical removal. Current guidelines advocate magnetic resonance imaging and endoscopic ultrasound to evaluate the risk of malignancy, whereas transabdominal ultrasound is perceived as subordinate imaging. The objective of this study was to analyze cyst detection rates of latest-generation ultrasound machines compared to magnetic resonance imaging, computed tomography, and endosonographic ultrasound and to determine inter-rater reliability. The results showed that large cysts facilitate their visualization by transabdominal ultrasound while detection rates are independent of the anatomical part of the pancreas in which they were sited. Changes in the pancreatic duct width, a connection to the pancreatic duct system, and the architectural characteristics of cysts are poorly recognized by transabdominal ultrasound compared to magnetic resonance imaging and endoscopic ultrasound. Computed tomography imaging is preferred over transabdominal ultrasound to detect calcifications and regional lymphadenopathy. Even if conducted by experienced investigators, transabdominal ultrasound examinations fail to agree with magnetic resonance imaging scans regarding cyst detection rates (κ = 0.093).