Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

BACKGROUND: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. METHODS: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. RESULTS: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). CONCLUSION: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Resection of Liver Metastases in Colorectal Cancer in the Era of Expanding Systemic Therapy.

About 25% of patients with colorectal cancer develop liver metastases after resection of the primary tumor, and surgical resection of the metastases offers the only opportunity for long-term survival. However, only 20% of patients present with resectable disease. Deciding which patients should be offered surgery, and which should receive additional treatment in the form of perioperative chemotherapy, is complex. For the majority of patients who present with technically irresectable liver-limited disease, systemic downsizing chemotherapy offers the only opportunity to reach surgery and potential cure. Molecular analysis of tumor tissue is improving patient stratification, allowing more appropriate treatment selection, but is not yet a regular part of clinical practice. Decision making is limited by a lack of clear prospective evidence, and so multidisciplinary team assessment is essential to optimize outcomes.

RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases.

OBJECTIVE: To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). BACKGROUND: The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. METHODS: Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients. RESULTS: A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. CONCLUSIONS: Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.

Preoperative Leucocyte-Based Inflammatory Scores in Patients with Colorectal Liver Metastases: Can We Count on Them?

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have been identified as potential prognostic factors for overall survival (OS) in primary colorectal cancer, and there is a growing interest in their use in colorectal liver metastases (CLMs). However, optimal cut-off values for these ratios have not been defined by making comparison between series difficult. This study aimed to confirm the prognostic value of inflammatory scores in patients undergoing resection for CLM. METHODS: We retrospectively analysed data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We assessed the reproducibility of previously published ratios and determined new cut-off values using the Cut-off Finder web-based tool. Relations between cut-off values and OS were analysed with Kaplan-Meier log-rank survival analysis and multivariate Cox models. RESULTS: Three hundred and forty-three patients had full preoperative blood tests for calculation of NLR, PLR and LMR. The number of cut-off values which showed a significant discrimination for OS was 49/249 (19.7%) for NLR, 28/316 (8.9%) for PLR and 22/214 (10.3%) for LMR, all with a scattered nonlinear distribution. CONCLUSIONS: This study showed that inflammatory scores expressed as ratios do not seem to be consistently reliable prognostic markers in patients with resectable CLM.

Evaluation of the utility of prognostic models for patients with resected hilar cholangiocarcinoma.

BACKGROUND: Several prognostic systems have been proposed to guide management strategies post-resection for patients with hilar cholangiocarcinoma. The objective of this study was to evaluate the efficacy of these conventional prognostic models, with respect to Overall Survival (OS), on patients in a modern single-centre resectional cohort. METHOD: Patients diagnosed with hilar cholangiocarcinoma, referred to a supra-regional tertiary referral centre between February 2009 and February 2016, were retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. RESULTS: Two-hundred and one patients were assessed for suitability for surgery. Eighty-three (41%) patients considered to have potentially resectable disease underwent surgical assessment of resectability. Fifty-six (68%) patients proceeded to resection. Multivariate analysis demonstrated that pre-operative Serum CA 19-9 (p = 0.007), Radiological Arterial Involvement (p = 0.005) and Amsterdam Medical Centre (AMC) prognostic model score (p = 0.032) retained significance in association with OS. Multivariate models developed from this cohort out-performed the conventional prognostic systems for OS. CONCLUSION: The cohort-derived multivariate models demonstrated significantly improved prognostic capability compared to conventional systems in explaining OS.

A modified TNM staging system for non-metastatic colorectal cancer based on nomogram analysis of SEER database.

BACKGROUND: To revise the American Joint Committee on Cancer TNM staging system for colorectal cancer (CRC) based on a nomogram analysis of Surveillance, Epidemiology, and End Results (SEER) database, and to prove the rationality of enhancing T stage's weighting in our previously proposed T-plus staging system. METHODS: Total 115,377 non-metastatic CRC patients from SEER were randomly grouped as training and testing set by ratio 1:1. The Nomo-staging system was established via three nomograms based on 1-year, 2-year and 3-year disease specific survival (DSS) Logistic regression analysis of the training set. The predictive value of Nomo-staging system for the testing set was evaluated by concordance index (c-index), likelihood ratio (L.R.) and Akaike information criteria (AIC) for 1-year, 2-year, 3-year overall survival (OS) and DSS. Kaplan-Meier survival curve was used to valuate discrimination and gradient monotonicity. And an external validation was performed on database from the Second Affiliated Hospital of Zhejiang University (SAHZU). RESULTS: Patients with T1-2 N1 and T1N2a were classified into stage II while T4 N0 patients were classified into stage III in Nomo-staging system. Kaplan-Meier survival curves of OS and DSS in testing set showed Nomo-staging system performed better in discrimination and gradient monotonicity, and the external validation in SAHZU database also showed distinctly better discrimination. The Nomo-staging system showed higher value in L.R. and c-index, and lower value in AIC when predicting OS and DSS in testing set. CONCLUSION: The Nomo-staging system showed better performance in prognosis prediction and the weight of lymph nodes status in prognosis prediction should be cautiously reconsidered.

Validation of clinical prognostic scores for patients treated with curative-intent for recurrent colorectal liver metastases.

BACKGROUND: Scoring systems were developed to stratify patients with colorectal liver metastases considered for liver resection into different risk groups. Such scores have never been evaluated in recurrent liver metastases. The aim of this study was to evaluate whether these scores are applicable to patients with recurrent colorectal liver metastases and treated with curative intent. METHODS: We retrospectively analyzed data from 375 consecutive patients who underwent liver surgery for colorectal liver metastases between June 2010 and August 2015. Seventy-three patients developed liver-limited recurrence treated with curative intent. The predictive value of 6 scores (Fong, Sofocleous, Nagashima, Nordlinger, Konopke, and the Basingstoke index) was assessed in this set of patients. RESULTS: Median follow-up was 36.2 months. Overall survival and progression-free survival were 33.6 and 5.6 months, respectively. When scores were applied for OS, none showed a significant stratification between patients, although Nagashima's score showed a significant difference in overall survival between patients from the low-risk group and those from the intermediate- and high-risk groups (40.8 vs 30.5 months, P = 0.039). For PFS, only Fong's score showed a statistically significant stratification (6.6 vs 4.7 months, P = 0.027). CONCLUSION: Scoring systems are of limited-value in stratifying patients operated on for recurrent colorectal liver metastases.

Defining the Optimal Use of Ablation for Metastatic Colorectal Cancer to the Liver Without High-Level Evidence.

OPINION STATEMENT: The role of physical interventions (surgical resection and surgical/radiological ablation) for liver metastases of colorectal cancer has changed dramatically over the last 10-15 years. Whereas in the 1990s, when only those patients with up to three unilobar metastases were considered for any form of such intervention, our present approach to these physical interventions is determined by how much viable disease-free liver can be preserved (most authorities accepting 25-30% disease-free future remnant liver volume) and the possibility of further such interventions if the disease recurs in the liver. There is increasing evidence that for smaller tumours (<3 cm diameter), ablation therapy may be therapeutically the equivalent of surgical resection and possibly safer in high-risk patients with multiple comorbidities. Therefore, we now consider the use of such ablation therapies (with or without surgical resection) to be clinically effective when treating patients with multiple bilobar metastases that have shown good radiologic response to prior systemic therapy.

Evolution of surgical microwave ablation for the treatment of colorectal cancer liver metastasis: review of the literature and a single centre experience.

Surgical resection is the gold standard treatment for colorectal liver metastasis, with reported five-year survival rates of 40 %. Unfortunately, despite progress in systemic therapies and surgical techniques, only 20-30 % of patients can be offered this potentially curative treatment modality. Ablative therapies have recently been suggested to treat unresectable lesions or to extend the margins of resectability. Additionally, cases of local recurrence after hepatic surgery might require alternative strategies and options for re-intervention. Microwave ablation (MWA) has recently become a matter of particular interest for such indications. We, herein, present a review of the literature published between January 1999 and June 2013 from a database search with the following keywords: microwave, ablation, liver metastases, colorectal neoplasm, resection, hepatectomy, colonic neoplasm, cancer. Furthermore, we provide insight based on our own data for 28 consecutive patients who underwent hepatic resection combined with MWA from 2005 to 2012 in a single centre.

When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations.

AIM: To determine the benefits and risks of hepatic resection versus non-resectional liver-directed treatments in patients with potentially resectable neuroendocrine liver metastases. METHODS: A systematic review identified 1594 reports which alluded to a possible liver resection for neuroendocrine tumour metastases, of which 38 reports (all retrospective), comprising 3425 patients, were relevant. RESULTS: Thirty studies reported resection alone, and 16 studies reported overall survival (OS). Only two studies addressed quality-of-life (QoL) issues. Five-year overall survival was reported at 41-100%, whereas 5-year progression-free survival (PFS) was 5-54%. We identified no robust evidence that a liver resection was superior to any other liver-directed therapies in improving OS or PFS. There was no evidence to support the use of a R2 resection (debulking), with or without tumour ablation, to improve either OS or QoL. There was little evidence to guide sequencing of surgery for patients presenting in Stage IV with resectable disease, and none to support a resection of asymptomatic primary tumours in the presence of non-resectable liver metastases. CONCLUSION: Low-level recommendations are offered to assist in the management of patients with neuroendocrine liver metastases, along with recommendations for future studies.

Determination of the optimal echocardiographic scoring system to quantify carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) is an important complication of metastatic neuroendocrine disease, requiring regular monitoring to enable intervention prior to right heart failure. We aimed to identify the most appropriate echocardiographic scoring systems for the quantitative assessment of CHD. METHODS: In this prospective study conducted between April and October 2012 in two European Neuroendocrine Tumor Society (ENETS) Centres of Excellence, patients with neuroendocrine tumours with liver metastases and/or carcinoid syndrome underwent transthoracic echocardiography and blood sampling for serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA). Each patient was assessed according to six echocardiographic scoring systems. The individual scoring systems' feasibility, observer variability, sensitivity, specificity and correlation with the concentration biomarkers were determined. RESULTS: 100 patients were included; 21% had echocardiographic evidence of CHD. All scores discriminated highly between those with/without CHD, with no single score performing significantly better than another. The severity, determined using all of the scoring systems, correlated with the concentration of both biomarkers, but the strongest correlations were seen between the Bhattacharyya score and serum NT-proBNP. CONCLUSION: All scoring systems are comparable in terms of sensitivity and specificity for the detection of CHD. There is a variation in the feasibility of the scoring systems due to varying complexity of the score components. All scores correlate with NT-proBNP and plasma 5-HIAA. The Westberg score appears to be the most optimal scoring system for use in screening of CHD whereas the more complex scoring systems are more suited to the patient with established disease who may require surgical intervention.

Enhanced recovery in the resection of colorectal liver metastases.

BACKGROUND: There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM). METHODS: A multimodal ERAS program was introduced in 2/2008. Consecutive patients undergoing hepatectomy for CRLM between 2/2008 and 9/2012 were included in the study. Data were collected prospectively. Retrospective analysis compared an early ERAS cohort (2/2008-4/2010) with a later cohort with a matured ERAS program (5/2010-8/2012). RESULTS: Length of stay reduced as experience of ERAS increased (Log-rank χ(2) = 10.43, P = 0.001). Although median length of stay remained unchanged (6 days), the probability of hospitalization beyond 10 days was 25% in the early cohort compared with 7% in the later cohort. Critical care utilization reduced over time (75.5% vs. 54.7%, P < 0.0001). Complications occurred in 38.2%, with no difference in between cohorts. One postoperative death occurred in the early cohort (<0.3%). CONCLUSIONS: This study suggests that as experience of ERAS evolves, there is a progressive reduction in hospitalization and critical care admission. This is without any increase in morbidity and mortality.

Cardiopulmonary exercise testing before liver surgery.

BACKGROUND: Cardiopulmonary exercise testing (CPET) assessed "poorer" fitness correlates with poorer outcomes in blinded studies. Whether this correlation will persist when CPET is utilized to stratify care as part of a multi-modal enhanced recovery after surgery (ERAS) program is unclear. This study examined whether CPET variables were associated with postoperative morbidity in patients undergoing hepatectomy within an ERAS program. OBJECTIVES AND METHODS: Data were prospectively collected on patients undergoing elective hepatectomy between October 2009 and April 2011. The relationships between CPET derived variables; postoperative complications and length of stay were investigated. RESULTS: Of 267 patients undergoing surgery, 197 had undergone standard cycle ergometer CPET. The relative oxygen uptake [VO2 (ml kg(-1) min(-1))] and ventilatory equivalent of CO2 (VE/VCO2) at the anaerobic threshold (AT) were not associated with complications or length of stay. Greater absolute oxygen uptake at AT [VO2 at AT (L min(-1) )] was associated with early hospital discharge [OR 2.16 (95% CI 1.18-3.96), P = 0.013] on multivariable analysis. CONCLUSIONS: When CPET is used to delineate perioperative management a low relative oxygen uptake [VO2 (ml kg(-1) min(-1) )] at the AT does not place patients at significantly higher risk of postoperative complications. This suggests CPET assessed "poor" fitness should not be used as a barrier to surgical intervention.

Liver resection with concomitant inferior vena cava resection: experiences without veno-venous bypass.

PURPOSE: Liver resection offers the chance of a cure for liver cancer. However, when extended hepatectomies were performed in combination with resection of the inferior vena cava (IVC), the procedures were reported to have a surgical mortality rate in excess of 5 %. While most of these operations were performed with the use of veno-venous bypass, this study presents our experience performing the procedure without the bypass. METHODS: Data were collected from a prospectively maintained database. A retrospective evaluation of a consecutive series of concomitant IVC and liver resections was performed. RESULTS: Five hundred and seventy-five liver resections were performed between June 2008 and November 2011. Eleven patients (1.9 %) underwent concomitant IVC and liver resections. One patient required segmental IVC replacement, and four IVC defects were closed using a bovine pericardial patch without bypass. Only one patient had histologically confirmed IVC invasion. There was no postoperative mortality. Nine postoperative complications occurred in five patients. No complications in terms of IVC patency were seen. Five patients had disease recurrence, one of whom died within 12 months of surgery. CONCLUSION: Concomitant liver and IVC resection is safe without using a bypass procedure, with acceptable short-term results. Meticulous technique, careful patient selection and a specialized anesthetic team are key to obtaining low postoperative morbidity and mortality rates and an acceptable oncological outcome.

Management of incidental and suspicious gallbladder cancer: focus on early referral to a tertiary centre.

OBJECTIVES: This study was conducted to assess the management of incidental gallbladder cancer and indeterminate gallbladder lesions. Its secondary aim referred to the devising of a management pathway for these patients. METHODS: Patients referred with incidental gallbladder cancer and indeterminate gallbladder lesions during 2002-2011 were identified from a prospectively maintained database. Collated data included operative findings, histopathological data and survival outcomes. RESULTS: The study included a total of 104 patients, 40 of whom had incidental gallbladder cancer following cholecystectomy. In this group, the index cholecystectomy was considered curative (T-is/T1a stage) in three patients; 11 patients underwent further resection, and 26 patients were inoperable. One-, 3- and 5-year overall survival rates were 91.1%, 91.0% and 60.7%, respectively, in patients who underwent re-resection. Of the 64 patients with indeterminate gallbladder lesions, 54 patients underwent modified radical cholecystectomy. Seven patients were found to have gallbladder cancer. One-, 3- and 5-year overall survival rates were 85.9%, 43.1% and 42.8%, respectively. Five-year overall survival in patients treated with surgery for gallbladder cancer was 59.9%. CONCLUSIONS: The majority of patients with incidental gallbladder cancer were not amenable to further potentially curative resection. The radiological suspicion of gallbladder cancer should lead to prompt referral to a tertiary hepatobiliary unit for further management.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Metal stents: a bridge to surgery in hilar cholangiocarcinoma.

BACKGROUND: Obstructive jaundice in patients with hilar cholangiocarcinoma is a known risk factor for hepatic failure after liver resection. Plastic stents are most widely used for preoperative drainage. However, plastic stents are known to have limited patency time and therefore, in palliative settings, the self-expanding metal stent (SEMS) is used. This type of stent has been shown to be superior because it allows for rapid biliary decompression and a reduced complication rate after insertion. This study explores the use of the SEMS for biliary decompression in patients with operable hilar cholangiocarcinoma. METHODS: A retrospective evaluation of a prospectively maintained database at a tertiary hepatobiliary referral centre was carried out. All patients with resectable cholangiocarcinoma were recorded. RESULTS: Of 260 patients referred to this unit with cholangiocarcinoma between January 2008 and April 2012, 50 patients presented with operable cholangiocarcinoma and 27 of these had obstructive jaundice requiring stenting. Ten patients were initially treated with SEMSs; no stent failure occurred in these patients. Seventeen patients initially received plastic stents, seven of which failed in the interval between stent placement and laparotomy. These stents were replaced by SEMSs in four patients and by plastic stents in three patients. Median time to laparotomy was 45 days and 68 days in patients with SEMSs and plastic stents, respectively. CONCLUSIONS: Self-expanding metal stents provide adequate and rapid biliary drainage in patients with obstruction caused by hilar cholangiocarcinoma. No re-interventions were required. This probably reflects the relatively short interval between stent placement and laparotomy.

Segmental and lobar administration of drug-eluting beads delivering irinotecan leads to tumour destruction: a case-control series.

BACKGROUND: Irinotecan-loaded drug-eluting beads represent a novel drug delivery method that allows for the locoregional delivery of irinotecan to colorectal liver metastases (CRLM). The method has shown impressive response rates. However, the pathological response to this treatment has not previously been demonstrated. METHODS: Patients with easily resectable CRLM were treated with drug-eluting beads delivering irinotecan (DEBIRI) 4 weeks prior to resection. Pathological tumour response was graded using a validated system. The intraoperative detection of previously unidentified disease allowed for the assessment of pathological responses directly attributable to bead treatment. RESULTS: In Patient 1, segmental embolization of the target lesion in segment VIII resulted in 100% necrosis (0% viability). An untreated lesion in segment IV was found to be 30% viable. In Patient 2, subsegmental embolization of the target lesion in segment VI resulted in 60% necrosis and 40% fibrosis (0% viability). An untreated lesion in segment VI remained 60% viable. In Patient 3, lobar embolization of the target lesion in segment II resulted in 0% viability. Two further lesions within the treated hemiliver, both with 0% viability, and one lesion in the untreated hemiliver with 45% viability were discovered at laparotomy. CONCLUSIONS: This series demonstrates the effectiveness of DEBIRI in the treatment of CRLM. High rates of tumour destruction are possible, even with the proximal lobar administration of DEBIRI. Lobar administration appears to be an appropriate method of delivery for integration into future therapeutic regimens.

Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.