Werner, Jens

ABSTRACT Background Living kidney donation is a crucial option for addressing the global organ shortage and providing kidney transplantation for patients suffering from end‐stage kidney disease. Ensuring donor safety necessitates a comprehensive preoperative assessment of kidney anatomy and function. This study evaluates the relationship between kidney volumes derived from deep learning‐based MRI volumetry, intraoperative kidney volume measurements, split renal function measured by renal scintigraphy, and post‐donation eGFR. Deep learning‐based MRI volumetry is hypothesized to be a reliable method with good correlation. Methods This retrospective study analyzed 178 living kidney donors. Deep learning MRI volumetry‐based kidney volumes were compared with intraoperative volumes of the explanted donor kidneys obtained using the water displacement method. Additionally, MRI‐based volume ratios were compared with scintigraphy‐based split renal function ratios to determine their ability to predict the kidney with poorer renal function and post‐donation eGFR. Results Deep learning‐based MRI volumetry strongly correlated with intraoperatively measured kidney volumes (Pearson's correlation; r = 0.7671; p < 0.0001), confirming its precision in volume estimation. Although MRI‐based kidney volume ratios demonstrated only a moderate correlation with scintigraphy‐based split renal function ratios ( r = 0.4798), MRI volumetry correlated with 1‐year post‐donation eGFR. It tended to be better than renal scintigraphy ( r = 0.6829 versus r = 0.6191). Conclusion Deep learning‐based MRI volumetry is a reliable, non‐invasive tool for estimating kidney volumes in living donors, offering a radiation‐free alternative for preoperative assessment. While it differs from renal scintigraphy in evaluating split renal function ratios, its correlation with post‐donation eGFR tends to be better, supporting its potential role in living kidney donor assessment.

Abstract Background: The neurokinin-1 receptor (NK1R) complex, activated by Substance P (SP), has emerged as a promising target. SP promotes cell growth, whereas its antagonist, Aprepitant (AP), used clinically for chemotherapy-induced nausea, has demonstrated anti-tumor activity. However, further insight on the anti-tumoral mechanisms after antagonistic targeting of the complex are required. Methods: We conducted bioinformatical analysis of public as well as own RNAseq data. Assays to assess cell proliferation and cell viability (MTT, scratch assays, colony formation) as well as apoptosis and autophagy were carried out. Metabolic changes were detected by SeaHorse analysis, ROS, NAD+/NADH, and MitoTracker. Results: Patient-derived organoid cultures showed reduced spheroid formation and altered morphology following AP treatment, while SP enhanced spheroid formation. SP promoted proliferation via Rho-kinase-dependent mechanisms and activated the ERK signaling pathway, with AP slightly reducing pERK levels. Further analyses revealed that AP induces apoptosis signaling without subsequent DNA fragmentation. Annexin V/PI staining indicated apoptosis induction after 24 hours, while subG1 analysis suggested a blockade in the apoptosis cascade. Prolonged AP exposure led to necrosis, which was mitigated by co-treatment with N-acetylcysteine. Western blot analysis confirmed caspase-9 and -3 activation but showed no PARP cleavage, likely due to high expression of inhibitors of apoptosis proteins (IAPs), such as XIAP. Conclusion: In conclusion, AP exhibits antiproliferative and cytotoxic effects in pancreatic tumor cells, potentially disrupting an autocrine/paracrine SP-NK1R feedback loop and altering metabolic resilience. Future studies should explore metabolic stress responses and investigate whether co-treatment could overcome incomplete apoptosis activation. Citation Format: Matthias Ilmer, Maximilian Viessmann, Bernhard Renz, Frank Braun, Jens Werner. Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B023.

Objective: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Background: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. Methods: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. Results: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population (https://rediscover.unipi.it/). Conclusions: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.

Objective: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. Background: : PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. Methods: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. Results: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. Discussions: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.