M. Gaspersz

Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.

A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: A competing risk analysis in a national cohort

BACKGROUND & AIMS Frail patients with low model for end-stage liver disease (MELD) scores may be under-prioritised. Low skeletal muscle mass, namely sarcopenia, has been identified as a risk factor for waiting list mortality. A recent study proposed incorporating sarcopenia in the MELD score (MELD-Sarcopenia score). We aimed to investigate the association between sarcopenia and waiting list mortality, and to validate the MELD-Sarcopenia score (i.e. MELD + 10.35 * Sarcopenia). METHODS We identified consecutive patients with cirrhosis listed for liver transplantation in the Eurotransplant registry between 2007-2014 and measured skeletal muscle mass on computed tomography. A competing risk analysis was used to compare survival of patients with and without sarcopenia, and concordance (c) indices were calculated to assess performance of the MELD and MELD-Sarcopenia score. We created a nomogram of the best predictive model. RESULTS We included 585 patients with a median MELD score of 14 (interquartile range 9-19), of which 254 (43.4%) were identified as having sarcopenia. Median waiting list survival was shorter in patients with sarcopenia than those without (p <0.001). This effect was even more pronounced in patients with MELD ≤15. The discriminative performance of the MELD-Sarcopenia score (c-index 0.820) for three-month mortality was lower than MELD score alone (c-index 0.839). Apart from sarcopenia and MELD score, other predictive variables were occurrence of hepatic encephalopathy before listing and recipient age. A model including all these variables yielded a c-index of 0.851. CONCLUSIONS Sarcopenia was associated with waiting list mortality in liver transplant candidates with cirrhosis, particularly in patients with lower MELD scores. The MELD-Sarcopenia score was successfully validated in this cohort. However, incorporating sarcopenia in the MELD score had limited added value in predicting waiting list mortality. LAY SUMMARY In this study among patients with liver cirrhosis listed for liver transplantation, low skeletal muscle mass was associated with mortality on the waiting list, particularly in patients who were listed with low priority based on a low MELD score. However, adding these measurements to the currently used system for donor and organ allocation showed no added value.

Evidence of good prognosis of hepatocellular adenoma in post-menopausal women

BACKGROUND & AIMS Hepatocellular adenoma (HCA) is a rare benign liver tumor, which typically develops in women in their reproductive phase and is associated with the use of oral contraceptives. The aim of this study was to evaluate whether follow-up of HCA can be safely terminated after the occurrence of menopause. Secondary, we studied the impact of the diagnosis HCA on health-related quality of life (HRQoL). METHODS This was a cross-sectional cohort study, including 48 post-menopausal women with HCA. Patients underwent ultrasound examination and the size of HCA was compared to size at the last follow-up imaging (CT, MRI or ultrasound). HRQoL was evaluated by the Liver Disease Symptom Index 2.0 and Short Form 12. RESULTS Median time since last follow-up was 60.5months. In 44 patients 43.5% of the lesions were undetectable, 32.6% were stable in size and 19.6% became smaller. Mean diameter of HCA was 17.2mm compared to 35.9mm at last follow-up (p<0.001). There was a positive correlation between difference in size and time since last follow-up (p<0.001). No significant effect of HCA subtype on difference in size was found. Regarding HRQoL, study patients scored significantly lower on the mental component summary score compared to the general female Dutch population. CONCLUSIONS HCA diameter became significantly smaller after the occurrence of menopause and as time progresses, this regression increased. This suggests that routine follow-up of HCA <5cm in post-menopausal women after subsequent follow-up is not required. Notably we found that patients mental HRQoL was inferior to that of the general population. LAY SUMMARY In this study we investigated if hepatocellular adenoma, a benign tumor of the liver that is found mostly in women and is associated with female hormones, regresses in size after the occurrence of menopause in female patients over 50years of age. We made an ultrasound of the liver lesion and found that the average size of the adenomas becomes significantly smaller. This could mean that female patients with a small (<5cm) hepatocellular adenoma who are post-menopausal do not have to remain in follow-up. CLINICAL TRIAL NUMBER MEC-2015-385.

Low skeletal muscle mass is associated with increased hospital expenditure in patients undergoing cancer surgery of the alimentary tract

Background Low skeletal muscle mass is associated with poor postoperative outcomes in cancer patients. Furthermore, it is associated with increased healthcare costs in the United States. We investigated its effect on hospital expenditure in a Western-European healthcare system, with universal access. Methods Skeletal muscle mass (assessed on CT) and costs were obtained for patients who underwent curative-intent abdominal cancer surgery. Low skeletal muscle mass was defined based on pre-established cut-offs. The relationship between low skeletal muscle mass and hospital costs was assessed using linear regression analysis and Mann-Whitney U-tests. Results 452 patients were included (median age 65, 61.5% males). Patients underwent surgery for colorectal cancer (38.9%), colorectal liver metastases (27.4%), primary liver tumours (23.2%), and pancreatic/periampullary cancer (10.4%). In total, 45.6% had sarcopenia. Median costs were €2,183 higher in patients with low compared with patients with high skeletal muscle mass (€17,144 versus €14,961; P<0.001). Hospital costs incrementally increased with lower sex-specific skeletal muscle mass quartiles (P = 0.029). After adjustment for confounders, low skeletal muscle mass was associated with a cost increase of €4,061 (P = 0.015). Conclusion Low skeletal muscle mass was independently associated with increased hospital costs of about €4,000 per patient. Strategies to reduce skeletal muscle wasting could reduce hospital costs in an era of incremental healthcare costs and an increasingly ageing population.

The new European Society of Cardiology guidelines on myocardial revascularisation: an appraisal

The latest European Society of Cardiology (ESC) guidelines on myocardial revascularisation are reviewed. The nearly 300 recommendations make it difficult to apply them in their totality. The authors would propose 20–30 recommendations per guideline based on sound clinical evidence. Also, the scope of the current guidelines is very wide as it includes topics already incorporated in other guidelines, such as strategies for pre-intervention diagnosis and imaging as well as on secondary prevention. Some recommendations in the new guidelines are sensible and will not be disputed. In particular, the encouragement of a balanced multidisciplinary decision process (the ‘heart team’) is welcome. Although coronary revascularisation in unstable high risk patients is well accepted, this is less the case for the low risk patient with chest pain. This issue is controversial and a balanced discussion of the pros and cons of percutaneous coronary intervention is missing. Despite convincing evidence indicating lack of benefit of percutaneous coronary intervention for chronic total occlusion, this procedure is not discouraged. Lastly, most committee members were interventional cardiologists or cardiac surgeons. Guideline committees should be representative of the whole group of professionals as the interpretation of the evidence by specialists may be biased. There may be a role for procedure oriented guidelines but, in that case, the items at issue should remain confined to matters directly related to technical aspects of the procedure.

Inflammatory and multiple hepatocellular adenoma are associated with a higher BMI

Aim To identify patient and lesion characteristics associated with the occurrence of single or multiple hepatocellular adenoma (HCA). Patients and methods Using a tertiary centre database, we retrospectively collected information on patient and lesion characteristics, management and follow-up of all patients with HCA included between 2001 and 2016. Patients were classified into three groups; patients with a single HCA, 2–9 HCA and at least 10 HCA. Results A total of 458 patients were diagnosed with HCA, including 121 (26.4%) with single HCA, 235 (51.3%) with 2–9 HCA and 102 (22.3%) with at least 10 HCA. Significant differences in the mean BMI were found, with the highest BMI in patients with more than 10 HCA (P<0.05). The mean BMI was significantly higher in patients with inflammatory HCA compared with steatotic HCA (31 vs. 26, respectively, P<0.05). Steatotic HCA were more often single lesions (22/55, 40%), whereas patients with inflammatory HCA were often diagnosed with multiple lesions (122/166, 73%). Conclusion Our series show a significantly higher BMI and frequency of inflammatory HCA in patients with multiple HCA compared with single HCA.

Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin

Abstract Background: Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not. Methods: Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). Results: We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CI = 6.7–12.5), 9.5 months (95%CI = 7.7–11.3) and 7.6 months (95%CI = 5.0–10.2), respectively. Median PFS was 6.0 months (95%CI = 4.4–7.6) in group I and 5.1 months (95%CI = 3.7–6.5) in group II. Toxicity and number of dose reductions (p = .974) were comparable between the two chemotherapy groups. Conclusion: First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II).

Growth of Focal Nodular Hyperplasia is Not a Reason for Surgical Intervention, but Patients Should be Referred to a Tertiary Referral Centre

BackgroundWhen a liver lesion diagnosed as focal nodular hyperplasia (FNH) increases in size, it may cause doubt about the initial diagnosis. In many cases, additional investigations will follow to exclude hepatocellular adenoma or malignancy. This retrospective cohort study addresses the implications of growth of FNH for clinical management.MethodsWe included patients diagnosed with FNH based on ≥2 imaging modalities between 2002 and 2015. Characteristics of patients with growing FNH with sequential imaging in a 6-month interval were compared to non-growing FNH.ResultsGrowth was reported in 19/162 (12%) patients, ranging from 21 to 200%. Resection was performed in 4/19 growing FNHs; histological examination confirmed FNH in all patients. In all 15 conservatively treated patients, additional imaging confirmed FNH diagnosis. No adverse outcomes were reported. No differences were found in characteristics and presentation of patients with growing or non-growing FNH.ConclusionThis study confirms that FNH may grow significantly without causing symptoms. A significant increase in size should not have any implications on clinical management if confident diagnosis by imaging has been established by a tertiary benign liver multidisciplinary team. Liver biopsy is only indicated in case of doubt after state-of-the-art imaging. Resection is deemed unnecessary if the diagnosis is confirmed by multiple imaging modalities in a tertiary referral centre.

A preoperative prognostic model to predict surgical success in patients with perihilar cholangiocarcinoma: GASPERSZ et al.

Patients with resectable perihilar cholangiocarcinoma (PHC) on imaging have a substantial risk of metastatic or locally advanced disease, incomplete (R1) resection, and 90‐day mortality. Our aim was to develop a preoperative prognostic model to predict surgical success, defined as a complete (R0) resection without 90‐day mortality, in patients with resectable PHC on imaging.

Low Skeletal Muscle Density Is Associated with Early Death in Patients with Perihilar Cholangiocarcinoma Regardless of Subsequent Treatment

Background: Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Methods: Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Results: Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7–9.3) and high (HR 12.1, 95% CI 8.1–16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03–3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44–1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. Conclusion: A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death.