Jimme K. Wiggers

Survival after resection of perihilar cholangiocarcinoma—development and external validation of a prognostic nomogram

BACKGROUNDnThe objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC).nnnPATIENTS AND METHODSnA nomogram was developed from 173 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA. The nomogram was externally validated in 133 patients treated at the Academic Medical Center (AMC), Amsterdam, The Netherlands. Prognostic accuracy was assessed with concordance estimates and calibration, and compared with the American Joint Committee on Cancer (AJCC) staging system. The nomogram will be available as web-based calculator at mskcc.org/nomograms.nnnRESULTSnFor all 306 patients, the median overall survival (OS) was 40 months and the median DSS 41 months. Median follow-up for patients alive at last follow-up was 48 months. Lymph node involvement, resection margin status, and tumor differentiation were independent prognostic factors in the derivation cohort (MSKCC). A nomogram with these prognostic factors had a concordance index of 0.73 compared with 0.66 for the AJCC staging system. In the validation cohort (AMC), the concordance index was 0.72, compared with 0.60 for the AJCC staging system. Calibration was good in the derivation cohort; in the validation cohort patients had a better median DSS than predicted by the model.nnnCONCLUSIONSnThe proposed nomogram to predict DSS after curative intent resection of PHC had a better prognostic accuracy than the AJCC staging system. Calibration was suboptimal because DSS differed between the two institutions. The nomogram can inform patients and physicians, guide shared decision making for adjuvant therapy, and stratify patients in future randomized, controlled trials.

Outcomes after Resection of Intrahepatic Cholangiocarcinoma: External Validation and Comparison of Prognostic Models

BACKGROUNDnPublished prognostic models for overall survival after liver resection for intrahepatic cholangiocarcinoma require external validation before use in clinical practice.nnnSTUDY DESIGNnFrom January 1993 to May 2013, consecutive patients who underwent resection of intrahepatic cholangiocarcinoma were identified from a prospective database. The Wang nomogram was derived in an Asian cohort (n = 367) and included clinicopathologic variables and preoperative CEA and cancer antigen 19-9 levels. The Hyder nomogram was derived in an Eastern and Western multicenter cohort (n = 514) using clinicopathologic variables only. The AJCC Cancer Staging System (7th ed) and the preoperative Fudan risk score were also evaluated. Prognostic performance was assessed in terms of discrimination, calibration, and stratification.nnnRESULTSnOne hundred and eighty-eight patients were included, with a median follow-up of 41 months. Median overall survival was 48.7 months and estimated 3-year and 5-year overall survival rates were 59% and 45%, respectively. Overall survival prediction accuracy, according to concordance-index calculation, was 0.72 with the Wang nomogram, 0.66 with the Hyder nomogram, 0.63 with the AJCC system, and 0.55 using the Fudan score. Both nomograms provided effective patient stratification in distinct survival groups.nnnCONCLUSIONSnBoth the Wang and Hyder nomograms provided accurate patient prognosis estimation after liver resection for intrahepatic cholangiocarcinoma and can be useful for decision making about adjuvant therapy. The Wang nomogram appears to be more appropriate in patients undergoing formal portal lymphadenectomy and requires preoperative CEA and cancer antigen 19-9 levels for optimal performance.

Recurrence Patterns and Disease-Free Survival after Resection of Intrahepatic Cholangiocarcinoma: Preoperative and Postoperative Prognostic Models

BACKGROUNDnLiver resection is the most effective treatment for intrahepatic cholangiocarcinoma. Recurrent disease is frequent; however, recurrence patterns are ill-defined and prognostic models are lacking.nnnSTUDY DESIGNnA primary cohort of 189 patients who underwent resection for intrahepatic cholangiocarcinoma was used for recurrence patterns analysis within and after 24 months. Based on independent factors for disease-free survival identified in Cox regression analysis, preoperative and postoperative models were developed using a recursive partitioning method. Models were externally validated using a multicenter cohort of 522 resected patients (Association Française de Chirurgie intrahepatic cholangiocarcinoma study group).nnnRESULTSnRecurrence within 24 months most often involved the liver (82.7%), and most recurrences after 24 months were strictly extrahepatic (61.1%). In multivariable analysis of the primary cohort, independent preoperative factors for disease-free survival were tumor size and multifocality (based on imaging); tumor size, multifocality, vascular invasion, and lymph node metastases (based on pathology) were independent postoperative factors. The preoperative model allowed patient classification into low-risk and high-risk groups for recurrence. In the validation cohort (nxa0= 522), high-risk patients had a greater likelihood of recurrence (hazard ratioxa0= 2.17; 95% CI, 1.74-2.72; p < 0.001). The postoperative model included tumor size, vascular invasion, and positive nodal disease on pathology and classified patients in low-, intermediate-, and high-risk groups in the primary cohort. As compared with low-risk patients in the validation cohort, intermediate- and high-risk patients were more likely to experience recurrence (hazard ratioxa0= 1.9; 95% CI, 1.41-2.47; p < 0.001 and hazard ratioxa0= 2.99; 95% CI, 2.08-4.31; p < 0.001, respectively).nnnCONCLUSIONSnRecurrence patterns are time dependent. Both models as developed and validated in this study classified patients in distinct recurrence risk groups, which can guide treatment recommendations.

Preoperative Risk Score to Predict Occult Metastatic or Locally Advanced Disease in Patients with Resectable Perihilar Cholangiocarcinoma on Imaging

BACKGROUNDnMany patients with resectable perihilar cholangiocarcinoma (PHC) on imaging are diagnosed intraoperatively with occult metastatic or locally advanced disease, precluding a curative-intent resection. This study aimed to develop and validate a preoperative risk score.nnnSTUDY DESIGNnPatients with resectable PHC on imaging who underwent operations in 2 high-volume centers (US and Europe) between 2000 and 2015 were included. Multivariable logistic regression analysis was used to develop the risk score. Cross-validation was used to validate the score, alternating the 2 centers as training and testing datasets.nnnRESULTSnOf 566 patients who underwent operations, 309 (55%) patients had a resection, and in 257 (45%) patients, a curative-intent resection was precluded due to distant metastasis (nxa0= 151 [27%]) or locally advanced disease (nxa0= 106 [19%]). Preoperative predictors included bilirubin >2 mg/dL, bile duct involvement on imaging, portal vein involvement on imaging (≥180 degrees), hepatic artery involvement on imaging (≥180 degrees), and suspicious lymph nodes on imaging. The new risk score (c-index 0.75 after cross-validation) provided significantly more accurate predictions than the Bismuth classification (c-index 0.62), Blumgart T-staging (c-index 0.67), and cTNM staging (c-index 0.68). The new risk score identified 4 risk groups for occult metastatic or locally advanced disease: low (14.7%), intermediate (29.5%), high (47.3%), and very high risk (81.3%). The preoperative score groups also predicted survival after operation, irrespective of intraoperative findings (pxa0<xa00.001).nnnCONCLUSIONSnThe validated risk score can predict occult distant metastatic or locally advanced PHC basedxa0on 5 preoperatively available factors. The score can be useful in preoperative shared decision making and selection of patients in neoadjuvant clinical trials.

In vitro detection of cholangiocarcinoma cells using a fluorescent protein-expressing oncolytic herpes virus

Pathological confirmation is desired prior to high-risk surgery for suspected perihilar cholangiocarcinoma (PHC), but preoperative tissue diagnosis is limited by poor sensitivity of available techniques. This study aimed to validate whether a tumor-specific enhanced green fluorescent protein (eGFP)-expressing oncolytic virus could be used for cholangiocarcinoma (CC) cell detection. Extrahepatic CC cell lines SK-ChA-1, EGI-1, TFK-1 and control cells (primary human liver cells) were exposed to the oncolytic herpes simplex type 1 virus NV1066 for up to 24u2009h in adherent culture. The technique was validated for cells in suspension and cultured cells that had been exposed to crude patient bile. Optimal incubation time of the CC cells with NV1066 at a multiplicity of infection of 0.1 was determined at 6–8u2009h, yielding 15% eGFP-expressing cells, as measured by flow cytometry. Cells were able to survive 2-h crude bile exposure and remained capable of producing eGFP following NV1066 infection. Detection of malignant cells was possible at the highest dilution tested (10 CC cells among 2 × 105 control cells), though hampered by non-target cell autofluorescence. The technique was not applicable to cells in suspension due to insufficient eGFP production. Accordingly, as yet the technique is not suitable for standardized clinical diagnostics in PHC.

Récidive après résection pour cholangiocarcinome intrahépatique : description, prédiction et prise en charge

Introduction La resection est le seul traitement curatif actuel des cholangiocarcinomes intrahepatiques (CCI). La recidive apres resection est frequente (53-79 %) et le plus souvent intrahepatique (IH). Les types de recidive des CCI sont cependant peu decrits. Methodes : A partir de 200 patients ayant eu une resection pour CCI entre 1993 et 2013, les types de recidive etaient retrospectivement decrits et leurs associations avec les donnees perioperatoires explorees. Resultats Parmi 189 patients avec un suivi median de 42 mois, 110 patients (58,5 %) avaient recidive, au niveau IH dans 75,4 % des cas (n = 83) et isolement en extra-hepatique (EH) dans 24,5 % des cas (n = 27). Environ 82 % des recidives avant 24 mois etaient IH (n = 76) alors que 61 % apres 24 mois etaient EH (n = 11 ; p 0,001). Conclusion La recidive avant 24 mois est majoritairement IH. Les patients a risque, identifies en pre ou postoperatoire, pourraient beneficier d’un traitement perioperatoire systemique ou intrahepatique. Declaration d’interet Les auteurs n’ont pas transmis de conflits d’interets.