Starlinger, Patrick

Background Short-term outcomes after pancreatoduodenectomy (PD) are well-studied, but long-term reoperation rates and their indications remain poorly characterized. Methods A single-center retrospective chart review was performed on patients who underwent PD for pancreatic adenocarcinoma between 1/2011 and 12/2021. Reoperations occurring >90 days after PD were dichotomized to being related or unrelated to the index PD or pancreatic adenocarcinoma. The Kaplan-Meier analysis estimated the incidence of long-term reoperation at 1 and 5 years postoperatively. Results Six-hundred twenty-eight patients were included. The 5-year incidence of any additional operation >90 days after PD was 30.0% (95% CI 23.2-36.2%), and the 5-year incidence of any long-term related reoperation was 21.2% (95% CI 15.0-26.8%). The most common indications for reoperations by 5-year incidence were cancer recurrence (12.8%, 95% CI 7.6-17.7%), incisional hernia (6.2%, 95% CI 2.6-9.7%), small bowel obstruction (1.3%, 95% CI 0.2-2.4%), and leak, fistula, or infection (1.0%, 95% CI 0.1-2.0%). Of the examined risk factors, only 90-day reoperation was found to be predictive of long-term related reoperations ( P = 0.02). Additionally, the 5-year incidence of endoscopic or interventional radiology procedures was 20.2% (95% CI 14.5-25.4%). However, 40.9% (95% CI 33.6-47.3%) of patients required additional surgery or procedures of any kind between 90 days and 5 years after PD. Discussion Within 5 years of PD, one in three patients required additional surgery, and one in five had operations for related indications. Related reoperative indications included recurrence, hernia, PD-specific complications, and small bowel obstruction. However, the rates of each of these reoperations were relatively low.

Background: Corroborating evidence for the use of hypothermic oxygenated machine perfusion (HOPE) prior to orthotopic liver transplantation (OLT) suggests a beneficial effect in regard to biliary complications. Here, the authors aim to evaluate whether perfusion via portal vein alone (sHOPE) or via additional perfusion of the hepatic artery (dHOPE) have diverging impact on outcomes after OLT when compared to the use of static cold storage (SCS). Methods: Consecutive patients undergoing OLT at the Medical University of Vienna (2018–2023) were retrospectively analyzed. Donor organs were procured using SCS, or subjected to end-ischemic sHOPE or dHOPE. The severity of biliary complications was classified according to the degree of therapeutic intervention (endoscopic retrograde cholangiopancreatography or surgical revision). Results: Two hundred forty-seven patients were included (69 SCS, 76 sHOPE, and 102 dHOPE). Hospitalization was shorter for patients after HOPE (median in days: SCS=25 vs HOPE=20, P=0.019). Biliary complications were less frequent in patients after HOPE (SCS=37.7% vs HOPE=22.5%, P=0.015). A significantly lower incidence of surgical revisions for biliary complications was observed in the HOPE cohort (24.6% vs 11.8%, P=0.012). When evaluating outcome according to HOPE-modality, a significant reduction in biliary complications (P=0.006) and surgical revisions (P=0.002) was only observed in dHOPE patients in comparison to SCS. Further, only dHOPE was significantly associated with a reduced need for surgical revision for biliary complications upon univariable and multivariable logistic regression (odds ratio=0.336, P=0.011). Conclusion: HOPE leads to a reduction of biliary complications and associated surgical revisions. This effect seems to be primarily associated with use of dHOPE, while both methods appear as feasible options for preconditioning of donor grafts prior to OLT.

Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. However, their role in PHLF is still unknown. Methods: Our study included nine patients with hepatocellular carcinoma (HCC) undergoing PHx: three patients with PHLF, three patients undergoing the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure, and three matched controls without complications after PHx. Patient plasma was collected before PHx as well as 1 and 5 days after. EVs were isolated by ultracentrifugation, and extracted proteins were subjected to quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell lines. Results: We identified 2625 and quantified 2570 proteins in the EVs of PHx patients. Among these, 53 proteins were significantly upregulated and 32 were downregulated in patients with PHLF compared to those without PHLF. Furthermore, 110 proteins were upregulated and 78 were downregulated in PHLF patients compared to those undergoing ALPPS. The EV proteomic signature in PHLF indicates significant disruptions in protein translation, proteostasis, and intracellular vesicle biogenesis, as well as alterations in proteins involved in extracellular matrix (ECM) remodelling and the metabolic and cell cycle pathways, already present before PHx. Conclusions: Longitudinal proteomic analysis of the EVs circulating in the plasma of human patients undergoing PHx uncovers proteomic signatures associated with PHLF, which reflect dying hepatocytes and endothelial cells and were already present before PHx.

ABSTRACT Background Pancreatoduodenectomy (PD) for pancreatic cancer has a profound impact on patients' lives. However, the long‐term financial implications are poorly understood. Objective Assess the financial burden of long‐term survivors who underwent PD. Methods Patients who underwent PD between January 2011 and June 2019 were identified. To evaluate the long‐term financial burden, patients surviving ≥ 3 years post‐resection were prospectively surveyed using the Comprehensive Score for financial Toxicity (COST‐FACIT) and a customized institutionally developed questionnaire. A logistic regression model predicting high financial toxicity was used to identify predictive factors. Results Among 238 eligible patients, 137 (57.6%) responded. Responders had a median age of 66 (59–73) years, with 86.7% identifying as financial prosperous or comfortable. However, 33.3% experienced financial distress due to treatment costs, 27.3% demonstrated high financial toxicity on the COST‐FACIT survey, and 37.2% made sacrifices to afford treatment. Only 8.9% stated that the treatment costs influenced their decisions, and the majority (85.9%) did not discuss financial implications with healthcare providers. Multivariable analysis identified younger age as a risk factor for high financial toxicity. Conclusion One in three long‐term survivors experienced high financial toxicity, with younger age being a predictor. This emphasizes the need for efforts to provide comprehensive support and guidance to patients to navigate their oncological journey.

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While the precise etiology of PHLF remains elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored the theragnostic potential of extracellular high-mobility-group-box protein 1 (HMGB1), a key damage-associated molecular pattern (DAMP) released by hepatocytes, in liver recovery post LR in patients and animal models. Plasma from 96 LR patients and liver tissues from a subset of 24 LR patients were analyzed for HMGB1 levels, and associations with PHLF and liver injury markers were assessed. In a murine LR model, the HMGB1 inhibitor glycyrrhizin, was administered to assess its impact on liver regeneration. Furthermore, plasma levels of keratin-18 (K18) and cleaved cytokeratin-18 (ccK18) were quantified to assess suitability as predictive biomarkers for PHLF. Patients experiencing PHLF exhibited elevated levels of intrahepatic and circulating HMGB1, correlating with markers of liver injury. In a murine LR model, inhibition of HMGB1 improved liver function, reduced steatosis, enhanced regeneration and decreased hepatic cell death. Elevated levels of hepatic cell death markers K18 and ccK18 were detected in patients with PHLF and correlations with levels of circulating HMGB1 was observed. Our study underscores the therapeutic and predictive potential of HMGB1 in PHLF mitigation. Elevated HMGB1, K18, and ccK18 levels correlate with patient outcomes, highlighting their predictive significance. Targeting HMGB1 enhances liver regeneration in murine LR models, emphasizing its role in potential intervention and prediction strategies for liver surgery.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Abstract Background Perioperative morbidity and mortality remain a point of concern for the Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS) procedure. Post-hepatectomy liver failure (PHLF) after the second step poses the most significant risk factor for futile outcome. Recovery of liver function after the first step of ALPPS is critically important to allow for sufficient liver function after this surgery. The APRI+ALBI score has been proposed as an easily assessable score to monitor liver function and its dynamic recovery. Aims We explored if the APRI+ALBI score was able to assess liver function recovery after the first step of ALPPS and allow for optimal timing of the 2nd step. Methods Based on the ALPPS registry, patients from 2012 to 2020 with available APRI+ALBI score were included. Postoperative outcomes (PHLF A – C, PHLF B + C, 90-day mortality and severe morbidity) were defined as per standard definitions. The APRI/ALBI score was monitored perioperatively. Results Overall, 464 patients from 16 international participating centers in the ALPPS registry were included. Clinically relevant PHLF (B + C) was observed in 7.5 % and of these 63 % of patients ultimately died due to liver failure. The APRI+ALBI score immediately increased after each surgical intervention and continuously decrease thereafter. Failure of the APRI+ALBI score to decrease until the 2nd step of ALPPS predicted PHLF B+C (p = 0.001; AUC 0.78). Particularly patients with high APRI+ALBI scores and short interstage intervals were at risk to develop PHLF B+C. Conclusion The APRI+ALBI score objectifies liver function recovery after the 1st step of ALPPS and failure to sufficiently decreased is associated with a higher risk for PHLF B+C. This might allow for optimized planning of the 2nd step of ALPPS to allow for sufficient liver function recovery to minimize the risk for PHLF B+C and associated futile outcome.

Background: Platelets were shown to be relevant for liver regeneration. In particular, platelet-stored serotonin (5-HT) proved to be a pro-regenerative factor in this process. The present study aimed to investigate the perioperative course of 5-HT and evaluate associations with patient and graft outcomes after othotopic liver transplantation (OLT). Methods: 5-HT was quantified in plasma and serum of 44 OLT recipients perioperatively, and in their respective donors. Olthoff’s criteria for early allograft dysfunction (EAD) were used to evaluate postoperative outcomes. Results: Patients with higher donor intra-platelet 5-HT per platelet (IP 5-HT PP) values had significantly lower postoperative transaminases (ASAT POD1: p = 0.006, ASAT POD5: p = 0.006, ASAT POD10: p = 0.02, ALAT POD1: p = 0.034, ALAT POD5: p = 0.017, ALAT POD10: p = 0.04). No significant differences were seen between postoperative 5-HT values and the occurrence of EAD. A tendency was measured that donor IP 5-HT PP is lower in donor-recipient pairs that developed EAD (p = 0.07). Conclusions: Donor IP 5-HT PP might be linked to the postoperative development of EAD after OLT, as higher donor levels are correlated with a more favorable postoperative course of transaminases. Further studies with larger cohorts are needed to validate these findings.

The activation of the receptor tyrosine kinase Axl by Gas6 is a major driver of tumorigenesis. Despite recent insights, tumor cell-intrinsic and -extrinsic Axl functions are poorly understood in hepatocellular carcinoma (HCC). Thus, we analyzed the cell-specific aspects of Axl in liver cancer cells and in the tumor microenvironment. We show that tumor-intrinsic Axl expression decreased the survival of mice and elevated the number of pulmonary metastases in a model of resection-based tumor recurrence. Axl expression increased the invasion of hepatospheres by the activation of Akt signaling and a partial epithelial-to-mesenchymal transition (EMT). However, the liver tumor burden of Axl+/+ mice induced by diethylnitrosamine plus carbon tetrachloride was reduced compared to systemic Axl−/− mice. Tumors of Axl+/+ mice were highly infiltrated with cytotoxic cells, suggesting a key immune-modulatory role of Axl. Interestingly, hepatocyte-specific Axl deficiency did not alter T cell infiltration, indicating that these changes are independent of tumor cell-intrinsic Axl. In this context, we observed an upregulation of multiple chemokines in Axl+/+ compared to Axl−/− tumors, correlating with HCC patient data. In line with this, Axl is associated with a cytotoxic immune signature in HCC patients. Together these data show that tumor-intrinsic Axl expression fosters progression, while tumor-extrinsic Axl expression shapes an inflammatory microenvironment.