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

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.M.H. is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z). L.B. is supported by an EMBO Postdoctoral Fellowship (EMBO ALTF 794-2014) and Marie-Curie Postdoctoral Fellowship (grant no. 656193_H2020-MSCA-IF-2014). G.M. was supported by a Marie Curie Initial Training Network (Marie Curie ITN WntsApp 608180) and a H2020 LSMF4LIFE grant (ECH2020-668350). This work was funded by an NC3Rs International prize, a Beit Prize, a Cambridge Cancer Center-pump priming award (CRUK-RG83267) and, partially, by a NC3Rs project grant (NC/R001162/1), all of them awarded to M.H. Work at the L.J.W.v.d.L lab was funded by the research program InnoSysTox (project number 114027003), by the Netherlands Organisation for Health Research and Development (ZonMw), and part of the research program financed by the Dutch Digestive Foundation (MLDS-Diagnostics project number D16-26). Work in the M.J.G. lab is funded by the Wellcome Trust (102696), Stand Up To Cancer (SU2C-AACRDT1213) and Cancer Research UK (C44943/A22536)

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

Validation of the Mayo Clinic Staging System in Determining Prognoses of Patients With Perihilar Cholangiocarcinoma

BACKGROUND & AIMS: Most systems for staging perihilar cholangiocarcinoma (PHC) have been developed for the minority of patients with resectable disease. The recently developed Mayo Clinic system for staging PHC requires only clinical and radiologic variables, but has not yet been validated. We performed a retrospective study to validate the Mayo Clinic staging system. METHODS: We identified consecutive patients with suspected PHC who were evaluated and treated at 2 tertiary centers in The Netherlands, from January 2002 through December 2014. Baseline characteristics (performance status, carbohydrate antigen 19-9 level) used in the staging system were collected from medical records and imaging parameters (tumor size, suspected vascular involvement, and metastatic disease) were reassessed by 2 experienced abdominal radiologists. Overall survival was analyzed using the Kaplan-Meier method and comparison of staging groups was performed using the log-rank test and Cox proportional hazard regression analysis. Discriminative performance was quantified by the concordance index and compared with the radiologic TNM staging of the American Joint Committee on Cancer (7th ed). RESULTS: PHCs from 600 patients were staged according to the Mayo Clinic model (23 stage I, 80 stage II, 357 stage III, and 140 stage IV). The median overall survival time was 11.6 months. The median overall survival times for patients with stages I, II, III, and IV were 33.2 months, 19.7 months, 12.1 months, and 6.0 months, respectively; with hazard ratios of 1.0 (reference), 2.02 (95% confidence interval [CI], 1.14-3.58), 2.71 (95% CI, 1.59-4.64), and 4.00 (95% CI, 2.30-6.95), respectively (P <.001). The concordance index score was 0.59 for the entire cohort (95% CI, 0.56-0.61). The Mayo Clinic model performed slightly better than the radiologic American Joint Committee on Cancer TNM system. CONCLUSIONS: In a retrospective study of 600 patients with PHC, we validated the Mayo Clinic system for staging PHC. This 4-tier staging system may aid clinicians in making treatment decisions, such as referral for surgery, and predicting survival time

Conditional survival in patients with unresectable perihilar cholangiocarcinoma

Conditional survival is the life expectancy from a point in time for a patient who has survived a specific period after presentation. The aim of the study was to estimate conditional survival for patients with unresectable perihilar cholangiocarcinoma. Patients with unresectable perihilar cholangiocarcinoma from two academic hospitals in the Netherlands between 2002 and 2012 were assessed. A multivariable Cox proportional hazards analysis was performed to identify risk factors associated with overall survival. Survival was estimated using the Kaplan-Meier method to evaluate factors associated with overall survival. In total, 572 patients were included. Overall survival was 42% at one year and 6% at three years. The conditional chance of surviving three years was 15% at 1 year and increased to 38% at 2 years. Independent poor prognostic factors for overall survival were age ≥65 years, tumor size >3 cm on imaging, bilirubin levels (>250 μmol/L), CA19-9 level at presentation (>1000 U/ml), and suspected distant metastases on imaging. The conditional survival of patients with and without these prognostic factors was comparable after patients survived the first two or more years. The conditional chance of surviving for patients with unresectable perihilar cholangiocarcinoma increases with time. Poor prognostic factors become less relevant once patients have survived two year

The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma

Background: Although several classifications of perihilar cholangiocarcinoma (PHC) include vascular involvement, its prognostic value has not been investigated. Our aim was to assess the prognostic value of unilateral and main/bilateral involvement of the portal vein (PV) and hepatic artery (HA) on imaging in patients with PHC. Methods: All patients with PHC between 2002 and 2014 were included regardless of stage or management. Vascular involvement was defined as apparent tumor contact of at least 180 degrees to the PV or HA on imaging. Kaplan-Meier method with log-rank test was used to compare overall survival (OS) between groups. Cox regression was used for multivariable analysis. Results: In total, 674 patients were included with a median OS of 12.2 (95% CI 10.6-13.7) months. Patients with unilateral PV involvement had a median OS of 13.3 (11.0-15.7) months, compared with 14.7 (11.7-17.6) in patients without PV involvement (p = 0.12). Patients with main/bilateral PV involvement had an inferior median OS of 8.0 (5.4-10.7, p <0.001) months. Median OS for patients with unilateral HA involvement was 10.6 (9.3-12.0) months compared with 16.9 (13.2-20.5) in patients without HA involvement (p <0.001). Patients with main/bilateral HA involvement had an inferior median OS of 6.9 (3.3-10.5, p <0.001). Independent poor prognostic factors included unilateral and main/bilateral HA involvement, but not PV involvement. Conclusion: Both unilateral and main HA involvement are independent poor prognostic factors for OS in patients presenting with PHC, whereas PV involvement is no

Treatment outcomes.

<p>Treatment outcomes.</p

Eligibility for Liver Transplantation in Patients with Perihilar Cholangiocarcinoma

Background: Liver transplantation (LT) has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (pCCA) in the Mayo Clinic with a reported 5-year overall survival (OS) of 53% on intention-to-treat analysis. The objective of this study was to estimate eligibility for LT in a cohort of pCCA patients in two tertiary referral centers. Methods: Patients diagnosed with pCCA between 2002 and 2014 were included from two tertiary referral centers in the Netherlands. The selection criteria used by the Mayo Clinic were retrospectively applied to determine the proportion of patients that would have been eligible for LT. Results: A total of 732 consecutive patients with pCCA were identified, of whom 24 (4%) had PSC-associated pCCA. Overall, 154 patients had resectable disease on imaging and 335 patients were ineligible for LT because of lymph node or distant metastases. An age limit of 70 years led to the exclusion of 50 patients who would otherwise be eligible for LT. After applying the Mayo Clinic criteria, only 34 patients (5%) were potentially eligible for LT. Median survival from diagnosis for these 34 patients was 13 months (95% CI 3–23). Conclusion: Only 5% of all patients presenting with pCCA were potentially eligible for LT under the Mayo criteria. Without transplantation, a median OS of about 1 year was observed

Total hospital costs by skeletal muscle mass in sex-specific quartiles.

<p>The total hospital costs significantly decreased per skeletal muscle index sex-specific quartile (<i>P</i> = 0.029).</p