Long-Term Intake of Proton-Pump Inhibitors Could Be Associated with an Increased Incidence of Liver Cancer in Women.

BACKGROUND: Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs in gastroenterology. Although PPIs are mostly well tolerated, long-term PPI intake has been linked with diabetes mellitus, osteoporosis and infectious disease. In the present study, we evaluated a potential association between PPI intake and a subsequent diagnosis of liver cancer in a large real-world cohort of outpatients in Germany. METHODS: A total of 1766 patients with liver cancer, as well as 8830 propensity-score-matched controls, were identified from the Disease Analyzer database (IQVIA). The outcome of the study was the association between PPI use and a subsequent diagnosis of liver cancer, which was evaluated using multivariable logistic regression analyses. RESULTS: Overall, 42.9% of the liver cancer patients and 39.0% of the controls received at least one PPI prescription before the index date. PPI prescriptions at any time before the index date were associated with an increased risk of subsequent liver cancer (OR: 1.18; 95% CI: 1.06-1.31). The positive association was observed in all age groups, as well as in women and men, but only in women (OR: 1.30; 95% 1.09-1.55) did it reach the predefined level of significance (p < 0.01). When considering the duration of PPI therapy, only PPI therapy for at least two years was significantly associated with an increased risk of liver cancer (OR: 1.28; 95% 1.09-1.50). In an analysis stratified by age and sex, this association was strongest in the age group < 60 years (OR: 1.99; 95% 1.21-3.26). CONCLUSIONS: Our data suggest that long-term PPI intake in women as well as in patients < 60 years might be associated with an increased risk of liver cancer. These findings support current efforts to reduce the inappropriate use of PPIs in routine clinical practice and to link PPI prescribing to a clear medical indication.

MASLD-Related HCC-Update on Pathogenesis and Current Treatment Options.

Hepatocellular carcinoma (HCC) is a common complication of chronic liver diseases and remains a relevant cause of cancer-related mortality worldwide. The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocarcinogenesis is on the rise. Early detection of HCC has been crucial in improving the survival outcomes of patients with metabolic dysfunction-associated steatohepatitis (MASH), even in the absence of cirrhosis. Understanding how hepatocarcinogenesis develops in MASH is increasingly becoming a current research focus. Additive risk factors such as type 2 diabetes mellitus (T2DM), genetic polymorphisms, and intestinal microbiota may have specific impacts. Pathophysiological and epidemiological associations between MASH and HCC will be discussed in this review. We will additionally review the available tumor therapies concerning their efficacy in MASH-associated HCC treatment.

Associating Appendicitis with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Novel Insight into an Unexpected Connection.

BACKGROUND: The gut microbiome modulates the liver immune microenvironment and is deeply integrated into the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). Appendectomies, which are performed in almost all patients diagnosed with appendicitis, cause long-term alterations to the gut microbiome, providing a potential link with the development of MASLD. We therefore investigated a potential link between appendicitis and the presence of MASLD in a large cohort of outpatients in Germany. METHODS: The present study included 26,717 individuals with and 26,717 without appendicitis. Univariable Cox-regression analyses were conducted to assess the association between appendicitis and MASLD. RESULTS: During the long-term follow-up, 4.8% of patients with appendicitis and 3.4% of those in the non-appendicitis group were diagnosed with MASLD (p < 0.001), corresponding to an incidence of 5.4 (appendicitis cohort) versus 3.5 (non-appendicitis cohort) cases per 1000 patient years. These findings were confirmed in regression analysis, revealing a strong and statistically significant association between appendicitis and the development of MASLD (HR: 1.57; 95% CI: 1.39-1.78). This link was observed for all age groups and was independent of patients' sex. CONCLUSION: We provide evidence from a large cohort of outpatients in Germany suggesting a link between appendicitis and MASLD. This might help to better stratify patients according to their individual risk for the development of chronic liver diseases.

Liver transplantation meets gastrointestinal cancer.

Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.

Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab.

Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD.

Herpes zoster is not associated with subsequent gastrointestinal cancer: data from over 200,000 outpatients in Germany.

PURPOSE: Gastrointestinal (GI) cancers are an increasing global health challenge. Viral diseases play an important role in the development of GI cancers. For example, Epstein-Barr virus, which belongs to the human herpesvirus family, is a well-recognized risk factor for the development of gastric cancer. The purpose of this study was to investigate a possible association between varicella-zoster virus reactivation and subsequent diagnosis of GI cancer. METHODS: In this retrospective cohort study, a total of 103,123 patients with a first diagnosis of herpes zoster (HZ) between 2005 and 2021 were propensity score matched to a cohort of 103,123 patients without HZ. Patient data was extracted from the Disease Analyzer database (IQVIA). The incidence of GI cancer was compared as a function of HZ. Cox regression analysis was used to examine the association between HZ and GI cancer. RESULTS: Over a follow-up period of up to 10 years, the incidence of GI cancer did not differ between the two cohorts (HZ cohort 2.26 cases per 1000 patient-years vs. non-HZ cohort 2.37 cases per 1000 patient-years, p = 0.548). In regression analysis, HZ was not associated with an increased risk of developing GI cancer (HR: 0.97; 95% CI 0.89-1.05). Furthermore, no significant effect of the presence of HZ on the incidence of different GI cancer entities was found. CONCLUSION: In this retrospective cohort study consisting of well-matched patients, we observed no significant association between a HZ infection and the development of GI cancer during a long-term follow-up.

Prevalence of and factors associated with a treatment delay due to the COVID-19 pandemic in patients with gastrointestinal cancer in Europe.

BACKGROUND: Recent studies have raised the issue of delayed cancer care during the COVID-19 pandemic, but the extent of delays and cancellations in cancer treatment, screening and diagnosis varied widely by geographic region and study design, highlighting the need for further research. METHODS: We used the Oncology Dynamics (OD) database featuring data from a cross-sectional, partially retrospective survey to analyze treatment delays in 30,171 GI cancer patients from five European countries (Germany, France, UK, Spain, and Italy). Risk factors for treatment delays were identified using multivariable logistic regression models. RESULTS: Treatment delays were documented in 1342 (4.5%) of the study patients, with most patients having a delay of less than 3 months (3.2%). We observed decisive differences of treatment delay in relation to geographical, healthcare- and patient-related factors. Treatment delay was highest in France (6.7%) and Italy (6.5%) and lowest in Spain (1.9%, p < 0.001). 5.9% of patients treated at general hospitals but only 1.9% of those treated by office-based physicians experienced treatment delays (p < 0.001). Moreover, the difference between lines of therapy was highly significant and ranged from 7.2% for early-stage patients in primary therapy to 2.6% in advanced/metastatic cancer patients receiving 4th or later line therapy (p < 0.001). Finally, the proportion of cases with delayed treatments increased from 3.5% in asymptomatic patients (ECOG 0) to 9.9% in bedridden patients (ECOG IV, p < 0.001). Results were confirmed in multivariable logistic regression models. Our data highlight the problem of delayed treatment of tumor patients in the context of the COVID-19 pandemic. Identified risk factors for delayed treatment, such as poor general health or treatment in smaller hospitals, offer starting points for future concepts of "pandemic preparedness".

Are sleep disorders associated with the risk of gastrointestinal cancer?-A case-control study.

PURPOSE: Sleep disorders are among the most common health problems worldwide and are linked to a variety of physical and mental health problems. Recently, there has been increasing evidence of an association between sleep disorders and cancer risk. We aimed to investigate this association specifically for cancers of the gastrointestinal (GI) tract. METHODS: Using the DA database (IQVIA), adult patients diagnosed with GI cancer between January 2010 and December 2022 were retrospectively compared to a 1:1 propensity score-matched cohort of patients without cancer. The outcome of the study was the association between sleep disorders and subsequent diagnosis of GI cancer. To determine whether sleep disorders were more common in patients with GI cancer than in patients without GI cancer, logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). RESULTS: After matching, 37,161 cases with GI cancer and 37,161 controls without cancer were available for analysis. No association with cancer was found for sleep disorders in the overall history before the index date (OR 1.04; 95% CI 0.96-1.12), but considering sleep disorders documented within 1 year before the index date showed a positive association with GI cancer overall (OR 1.20; 95% CI 1.08-1.34). Stratified analyses by cancer site revealed higher odds of sleep disorders prior to diagnosis of gastric, pancreatic, and colorectal cancer. CONCLUSION: Our findings suggest that sleep disorders might be indicative of short-term health outcomes, including GI cancer, suggesting a role for sleep disorder screening in the context of cancer prevention efforts.

LiMAx Prior to Radioembolization for Hepatocellular Carcinoma as an Additional Tool for Patient Selection in Patients with Liver Cirrhosis.

BACKGROUND AND AIMS: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. PATIENTS AND METHODS: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. RESULTS: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child-Pugh score B 28 days after RE or with a deterioration in Child-Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child-Pugh score A or with stable Child-Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. CONCLUSION: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child-Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

Real-World Data for Lenvatinib in Hepatocellular Carcinoma (ELEVATOR): A Retrospective Multicenter Study.

Background: Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods: A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results: Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion: Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.

Sorafenib Versus Lenvatinib-Based Sequential Systemic Therapy for Advanced Hepatocellular Carcinoma: A Real-World Analysis.

The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.

Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort.

BACKGROUND AND AIMS: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. METHODS: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients' characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. RESULTS: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). CONCLUSION: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease - in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL).

68Ga-PSMA-11 PET/CT Improves Tumor Detection and Impacts Management in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. A growing number of local and systemic therapies are available, and accurate staging is critical for management decisions. We assessed the impact of neovasculature imaging by 68Ga-PSMA-11 PET/CT on disease staging, prognostic groups, and management of patients with HCC compared with staging with CT. Methods: Forty patients who received imaging with 68Ga-PSMA-11 PET/CT for HCC staging between September 2018 and September 2019 were retrospectively included. Management before and after PET scanning was assessed by standardized surveys. The presence of HCC was evaluated by 3 masked readers on a per-patient and per-region basis for PET/CT (PET criteria) and multiphase contrast-enhanced CT (CT criteria) in separate sessions. Lesions were validated by follow-up imaging or histopathology, and progression-free survival was recorded. Endpoints were detection rate and positive predictive value for 68Ga-PSMA-11 PET versus CT, interreader reproducibility, and changes in stage, prognostic groups, and management plans. Results: Median age was 65 y (range, 37-81 y), and median Child-Pugh score was 5 (range, 5-9). Most patients were treatment-naïve (27/40, 67.5%). The sensitivity of PET versus CT to identify liver lesions for patients with lesion validation was 31 of 32 (97%) for both modalities, whereas it was 6 of 6 (100%) versus 4 of 6 (67%), respectively, for extrahepatic lesions. PET and CT each had a positive predictive value of 100% at the liver level. PET versus CT stage was congruent in 30 of 40 (75%) patients; upstaging was seen in 8 of 40 patients (20%), whereas 2 of 40 (5%) had downstaging by PET. Intended management changed in 19 of 40 patients (47.5%); 9 of 19 of these patients were found to have detectable distant metastases (47.4%) and assigned stage 4 disease, most of whom were shifted to systemic therapy (8/9, 89%). Two patients underwent 177Lu-PSMA-617 radioligand therapy. Median progression-free survival was 5.2 mo for the entire cohort; 5.3 mo for PET M0, and 4.7 mo for PET M1 patients, respectively. Conclusion:68Ga-PSMA-11 PET demonstrated higher accuracy than CT in the detection of HCC metastases and was associated with a management change in about half the patient cohort.

Serum levels of soluble urokinase plasminogen activator receptor (suPAR) predict outcome after resection of colorectal liver metastases.

BACKGROUND: In colorectal cancer (CRC), the liver is the most common site of metastasis. Surgical resection represents the standard therapy for patients with colorectal liver metastases (CRLM). However, 5-year survival rates after resection do not exceed 50%, and despite existing preoperative stratification algorithms it is still debated which patients benefit most from surgical treatment. The soluble urokinase plasminogen activator receptor (suPAR) has recently evolved as a promising biomarker for distinct clinical conditions. Here, we examined a potential role of suPAR as a biomarker in patients undergoing resection of CRLM. RESULTS: Correlating with upregulated uPAR tissue expression in resected metastases, serum concentrations of suPAR were significantly elevated in CRLM patients compared to healthy controls. Importantly, patients with preoperative suPAR serum levels above the identified ideal cut-off value of 4.83 ng/ml showed a significantly reduced overall survival after resection of CRLM, both in right- and left-sided primary CRC. Moreover, multivariate Cox regression analysis revealed preoperative suPAR serum levels as a prognostic factor for mortality. Additionally, elevated preoperative suPAR but not creatinine levels were a predictor of acute kidney injury (AKI) after CRLM resection, correlating with a longer postoperative hospitalization. CONCLUSION: SuPAR represents a promising novel biomarker in CRLM patients that might help to guide preoperative treatment decisions regarding patients' outcome and to identify patients particularly susceptible to AKI. METHODS: Expression levels of uPAR were analyzed in CRLM tissue using RT-PCR and immunohistochemistry. SuPAR serum levels were measured by ELISA in 104 CRC patients undergoing hepatic resection for CRLM and 50 healthy controls.

IL-6 and IL-8 Serum Levels Predict Tumor Response and Overall Survival after TACE for Primary and Secondary Hepatic Malignancies.

While surgical resection represents the standard potentially curative therapy for liver cancer, transarterial chemoembolization (TACE) has evolved as a standard therapy for intermediate-stage hepatocellular carcinoma (HCC) as well as liver metastases. However, it is still not fully understood which patients particularly benefit from TACE. Cytokines represent a broad category of signaling molecules that might reflect concomitant inflammation as an adverse prognostic factor. Here, we evaluated the role of interleukin (IL)-6, IL-8, and CC-chemokine ligand (CCL)22 as biomarkers in the context of TACE treatment. Cytokine serum levels were analyzed by multiplex immunoassay in 54 patients (HCC: n = 44, liver metastases: n = 10) undergoing TACE as well as 51 healthy controls. Patients with primary and secondary liver cancer showed significantly elevated levels of IL-6 and IL-8 but not CCL22 compared to healthy controls. Interestingly, low pre-interventional levels of IL-6 and IL-8 were predictors for an objective response after TACE in binary logistic regression. In contrast, patients with high pre-interventional IL-6 and IL-8 serum levels not only poorly responded to TACE but had a significantly impaired overall survival. Serum levels of IL-6 and IL-8 represent promising biomarkers for patients undergoing TACE and might help to pre-interventionally identify patients who particularly benefit from TACE regarding objective treatment response and overall survival.

Elevated levels of circulating osteopontin are associated with a poor survival after resection of cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) represents a primary hepatic malignancy with incidence and mortality rising globally. Surgical treatment has remained the only potentially curative treatment option, but it is still unclear which patients benefit most from extended liver surgery, highlighting the need for new pre-operative stratification strategies. Osteopontin is a secreted extracellular glyco-phosphoprotein that has been associated with inflammation, metabolic disorders and cancer. Here, we examined the potential of circulating osteopontin serum levels as a diagnostic or prognostic biomarker in patients with CCA undergoing extended liver surgery. METHODS: Osteopontin expression levels were analysed in human and murine CCA tumour samples, using semi-quantitative reverse transcriptase PCR and immunohistochemistry. Osteopontin serum concentrations were measured by enzyme-linked immunosorbent assay in 107 patients with CCA undergoing elective tumour resection as well as 55 healthy controls. Results were correlated with clinical data. RESULTS: Correlating with an upregulation in CCA tumour cells and the tumour stroma, serum levels of osteopontin were elevated in patients with cholangiocarcinoma compared to healthy controls and patients with primary sclerosing cholangitis. Importantly, pre- and postoperative elevations of osteopontin showed a striking association with poor postoperative survival. CONCLUSIONS: Serum osteopontin concentrations represent a promising prognostic biomarker in patients resectable CCA which could help to guide preoperative treatment decisions and to identify patients that will particularly benefit from extended liver surgery. Lay summary: Extended liver surgery is the only potentially curative treatment for patients with cholangiocarcinoma (CCA/biliary cancer), but it is currently unclear which patients benefit most from surgery. Detecting serum levels of osteopontin - a specific secreted glycoprotein involved in multiple human diseases - in CCA patients might help to identify those patients that particularly benefit from tumour resection.