Background: KRAS circulating tumor DNA (ctDNA) has shown biomarker potential for pancreatic ductal adenocarcinoma (PDAC) but has not been applied in clinical routine yet. We aim to improve clinical applicability of ctDNA detection in PDAC and to study the impact of blood-draw site and time point on the detectability and prognostic role of KRAS mutations.Methods: 221 blood samples from 108 PDAC patients (65 curative, 43 palliative) were analyzed. Baseline peripheral and tumor-draining portal venous (PV), postoperative, and follow-up blood were analyzed and correlated with prognosis.Results: Significantly higher KRAS mutant detection rates and copy numbers were observed in palliative compared to curative patients baseline blood (58.1% vs 24.6%; P = 0.002; and P < 0.001). Significantly higher KRAS mutant copies were found in PV blood compared to baseline (P < 0.05) samples. KRAS detection in pre- and postoperative and PV blood were significantly associated with shorter recurrence-free survival (all P < 0.015) and identified as independent prognostic markers. KRAS ctDNA status was also an independent unfavorable prognostic factor for shorter overall survival in both palliative and curative cohorts (hazard ratio [HR] 4.9, P = 0.011; HR 6.9, P = 0.008).Conclusions: KRAS ctDNA detection is an independent adverse prognostic marker in curative and palliative PDAC patients—at all sites of blood draw and a strong follow-up marker. The most substantial prognostic impact was seen for PV blood, which could be an effective novel tool for identifying prognostic borderline patients—guiding future decision-making on neoadjuvant treatment despite anatomical resectability. In addition, higher PV mutant copy numbers contribute to an improved technical feasibility.

Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.

Background: Circulating Cancer Associated Macrophage-like cells (CAMLs) have been described as novel liquid biopsy analytes and unfavorable prognostic markers in some tumor entities, with scarce data for Pancreatic Ductal Adenocarcinomas (PDAC). Methods: Baseline and follow-up blood was drawn from resected curative (n = 36) and palliative (n = 19) PDAC patients. A microfluidic size-based cell enrichment approach (Parsortix^TM) was used for CAML detection, followed by immunofluorescence staining using pan-keratin, CD14, and CD45 antibodies to differentiate between CAMLs, circulating tumor cells (CTCs), and leukocytes. Results: CAMLs were detectable at baseline in 36.1% of resected patients and 47.4% of palliative PDAC patients. CAML detection was tumor stage independent. Follow-up data indicated that detection of CAMLs (in 45.5% of curative patients) was an independent prognostic factor for shorter recurrence-free survival (RFS) (HR: 4.3, p = 0.023). Furthermore, a combined analysis with CTCs showed the detectability of at least one of these cell populations in 68.2% of resected patients at follow-up. The combined detection of CAMLs and CTCs was also significantly associated with short RFS (HR: 8.7, p = 0.003). Conclusions: This pilot study shows that detection of CAMLs in PDAC patients can provide prognostic information, either alone or even more pronounced in combination with CTCs, which indicates the power of liquid biopsy marker analyses.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal cancers, with only 20% of patients qualifying for curative treatment at diagnosis. Three‐dimensional tumor organoids capturing patient‐specific features of PDAC serve as a valuable disease model. We employed this technology to assess drug sensitivities of patient‐derived tumor organoids to clinically relevant drugs and combinations, evaluated culture success rates, and correlated in vitro data with clinicopathological and follow‐up information. Tumor organoid cultures were established from PDAC patients undergoing surgical resection (or liver biopsy) and follow‐up at a single medical center. Patient‐derived cultures displaying sustained growth were analyzed regarding their molecular subtype and utilized for functional drug sensitivity testing (f‐DST). Correlative analyses of our PDAC patient cohort (n = 67; n = 42 patients with curative tumor resection and n = 25 palliative patients) revealed a link between tumor organoid growth and reduced patient survival. Furthermore, drug sensitivity profiles (obtained of 10 patient‐derived cultures) revealed notable inter‐individual differences and mirrored clinical responses to administered drug therapies. f‐DST was applicable across tumor organoid cultures of both classical and basal subtype, according to the Purity Independent Subtyping of Tumors (PurIST) classifier. This pilot study confirms the feasibility of deriving and maintaining tumor organoid cultures from heterogeneous samples. Cultures displaying sustained proliferation correlated positively with advanced‐stage tumors (Tumour, Node, Metastasis (UICC) stages III and IV). Individual patient case analyses integrating in vitro drug sensitivity profiles with clinical follow‐up data suggest that f‐DST using tumor organoids could guide future therapeutic strategies. In summary, tumor organoids offer insights into patient‐specific responses to treatment, highlighting the potential of precision medicine in managing this challenging cancer.

(1) Background: Abdominal compartment syndrome (ACS) is a life-threatening situation and is associated with high mortality in the intensive care unit (ICU). Decompressive laparotomy represents the last therapeutic option. This cohort study aims to optimize the selection of ICU patients suffering from ACS who benefit from decompressive laparotomy. (2) Methods: All available data from adult patients treated at the 12 ICUs of a university hospital between 2011 and 2019 were included. Outcome parameters for patients with and without extracorporeal membrane oxygenation (ECMO) were compared. (3) Results: 207 ICU patients with ACS undergoing surgery were identified. Laparotomy resulted in immediate improvement of organ functions in 15% of patients, who then survived more frequently. The overall mortality rate in our cohort was 69%. The group of ECMO patients—including va- and vv-ECMO—showed significantly less organ function improvement and a higher mortality rate of 79% compared to a better postoperative improvement and a lower mortality rate of 62% in non-ECMO patients. (4) Conclusions: There are ICU patients who benefit from decompressive laparotomy—nevertheless, mortality is high. Non-ECMO patients have a better prognosis than ECMO patients. Our findings can support clinical decision-making on emergency surgery and the development of future guidelines.

Intraductal papillary mucinous neoplasms (IPMNs) are potential precursor lesions of pancreatic cancer. We assessed the efficacy of screening for KRAS proto‐oncogene, GTPase (KRAS), and GNAS complex locus (GNAS) mutations in cell‐free DNA (cfDNA)—using digital droplet polymerase chain reaction (ddPCR) and circulating epithelial cell (CEC) detection—as biomarkers for risk stratification in IPMN patients. We prospectively collected plasma samples from 25 resected patients at risk of malignant progression, and 23 under clinical surveillance. Our findings revealed KRAS mutations in 10.4% and GNAS mutations in 18.8% of the overall cohort. Among resected IPMN patients, KRAS and GNAS mutation detection rates were 16.0% and 32.0%, respectively, whereas both rates were 4.0% in conservatively managed IPMN. GNAS mutations in cfDNA were significantly more prevalent in resected IPMN (P = 0.024) compared with IPMN under surveillance. No CECs were detected. The absence of KRAS and GNAS mutations could be a reliable marker for branch duct IPMN without worrisome features. The emergence of GNAS mutations could prompt enhanced imaging surveillance. Neither the presence of established worrisome features nor GNAS or KRAS mutations appear effective in identifying high‐grade dysplasia among IPMN patients.