Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management.

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

Current and future genomic applications for surgeons.

Genomics is a crucial part of managing surgical disease. This review focuses on some of the genomic advances that are available now and looks to the future of their application in surgical practice. Whole-genome sequencing enables unbiased coverage across the entire human genome of approximately three billion base pairs. Newer technologies, such as those that permit long-read sequence analysis, provide additional information in longer phased fragment and base pair epigenomic (methylomic) data. Whole-genome sequencing is currently available in England for cancers in children, teenagers and young adults, central nervous system tumours, sarcoma and haematological malignancies. Circulating tumour DNA (ctDNA), immunotherapy and pharmacogenomics have emerged as groundbreaking approaches in the field of cancer treatment. These are now revolutionising the way oncologists and surgeons approach curative cancer surgery. Cancer vaccines offer an innovative approach to reducing recurrence after surgery by priming the immune system to trigger an immune response. The Cancer Vaccine Launch Pad project facilitates cancer vaccine studies in England. The BNT122-01 trial is recruiting patients with ctDNA-positive high-risk colorectal cancer after surgery to assess the impact of cancer vaccines. The evolving landscape of cancer treatment demands a dynamic and integrated approach from the surgical multidisciplinary team. Immunotherapy, ctDNA, pharmacogenomics, vaccines, mainstreaming and whole-genome sequencing are just some of the innovations that have the potential to redefine the standards of care. The continued exploration of these innovative diagnostics and therapies, the genomic pathway evolution and their application in diverse cancer types highlights the transformative impact of precision medicine in surgery.

Postoperative surveillance after surgery for colorectal liver metastasis: a cross-sectional study.

INTRODUCTION: Colorectal liver metastases (CRLM) are associated with a high recurrence rate after surgery. There is paucity of high-quality evidence regarding the nature and overall benefit of surveillance after hepatectomy for CRLM. As part of a broader programme of research, this study aimed to assess current strategies for surveillance after liver resection for CRLM and outline surgeons' opinions regarding the benefit of postoperative surveillance. METHODS: An online survey was sent to clinicians performing surgery for CRLM at tertiary hepatobiliary centres in the UK. RESULTS: There were responses from a total of 23 centres (88% response rate); 15/23 centres used standardised surveillance protocols for all patients. Most centres followed patients up at six months, but there is variation in postoperative surveillance at 3, 9, 18 and beyond 60 months. Patient comorbidities, indeterminate findings on imaging, margin status and assessment of recurrence risk were identified as the major factors influencing personalised surveillance strategies. There was clear clinician equipoise regarding the costs and benefits of surveillance. CONCLUSION: There is heterogeneity in postoperative follow-up for CRLM in the UK. High-quality prospective studies and randomised trials are necessary to elucidate the value of postoperative surveillance and identify optimal follow-up strategies.

Defining enhanced recovery after resection of peri-hilar cholangiocarcinoma.

INTRODUCTION: Enhanced recovery after surgery (ERAS) for peri-hilar cholangiocarcinoma (pCCA) has not been described in the literature. This study examined patients undergoing pCCA resection within a standard post hepatectomy ERAS pathway to define achievable targets suitable for these patients. METHODS: Patients undergoing pCCA resection at University Hospital Aintree (January 2009-October 2017) were identified. Achievement of key ERAS outcomes was assessed. Patients were stratified on incidence of major complications and pre-operative cardiopulmonary exercise testing. Chi Square and Mann Whitney analyses were undertaken as appropriate. Achievable ERAS targets were derived from patients who did not develop a major complication. RESULTS: 46 patients underwent resection with enhanced recovery. Median age 65 (24 male: 22 female). Key ERAS outcomes in patients who did not experience major complications are described as medians (interquartile range): length of stay 8 days (6-13), duration critical care 2 days (2-4), inotropes 6 h (0-24), epidural 3 days (3-4), early mobilization day 1 (1-2), full mobilization day 3 (3-4), urinary catheter removal day 4 (3-5), NGT removal day 1 (1-2) and restoration oral nutrition day 2 (2-4). Patients deemed high risk pre-operatively or those who developed major complications post-operatively required significantly longer critical care (p = 0.008 and p = 0.002 respectively). Other ERAS targets remained achievable in similar timeframes. CONCLUSIONS: ERAS for pCCA is achievable. Applicable ERAS standards are defined which take into account minor complications. High risk patients and those with major complications can be appropriately managed in an ERAS pathway, though there is increased need for critical care support.

The way healthcare is funded is wrong: it should be linked to deaths as well as age, gender and social deprivation.

BACKGROUND: most spending on health occurs in the last few months of life. This study explored the number of deaths in England and their relationship to healthcare funding. METHODS: post hoc analysis Results: the number of deaths range from 3.3 to 15.1/1000/year, and the number of deaths per general practitioner from 5.2 to 27.3/year. Hospital deaths range from 12 to 52/1000 admissions. The correlation between the allocation index used for funding and deaths is not perfect and suggests that some regions may get up to17% less and others 14% more funding than is equitable. CONCLUSION: there is considerable variation in the prevalence of death throughout England. If healthcare funding considered the local number of deaths it would be more equitable.

Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management.

BACKGROUND: Next generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour. METHODS: We performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis. RESULTS: Exome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours. CONCLUSION: Only 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer.

Precision surgery for colorectal liver metastases: Opportunities and challenges of omics-based decision making.

Precision surgery involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient. For patients with colorectal liver metastases (CRLM), existing prognostic scoring systems rely on well-recognised histopathological features such as size and number of lesions. Advances in preoperative imaging algorithms mean that increasingly low volume disease can be detected, improving assessment of these factors. In addition, novel imaging modalities mean that underlying tumour biology and metabolic behaviour during therapy can be assessed. Molecular analysis of tumours can provide crucial prognostic information, with the critical role of RAS/RAF mutations in prognosis well recognised. The optimal source of tissue for this level of analysis is debated, with good concordance between primary and metastatic lesions for some recognised prognostic factors but marked discrepancies for a variety of other relevant mutations. As well as mutational heterogeneity between primary and metastatic lesions, heterogeneity within tumours and dynamic changes in tumour biology over time present a significant challenge in assessing tumour for prognostic biomarkers. Circulating tumour cells offer one potential method of longitudinal tumour analysis, but are limited by current technologies. This review article summarises some of the key advances in prognostication for patients with resectable colorectal liver metastases, as well as highlighting the potential limitations of such an approach.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Randomized clinical trial of prehabilitation before planned liver resection.

BACKGROUND: Patients with low fitness as assessed by cardiopulmonary exercise testing (CPET) have higher mortality and morbidity after surgery. Preoperative exercise intervention, or prehabilitation, has been suggested as a method to improve CPET values and outcomes. This trial sought to assess the capacity of a 4-week supervised exercise programme to improve fitness before liver resection for colorectal liver metastasis. METHODS: This was a randomized clinical trial assessing the effect of a 4-week (12 sessions) high-intensity cycle, interval training programme in patients undergoing elective liver resection for colorectal liver metastases. The primary endpoint was oxygen uptake at the anaerobic threshold. Secondary endpoints included other CPET values and preoperative quality of life (QoL) assessed using the SF-36®. RESULTS: Thirty-eight patients were randomized (20 to prehabilitation, 18 to standard care), and 35 (25 men and 10 women) completed both preoperative assessments and were analysed. The median age was 62 (i.q.r. 54-69) years, and there were no differences in baseline characteristics between the two groups. Prehabilitation led to improvements in preoperative oxygen uptake at anaerobic threshold (+1·5 (95 per cent c.i. 0·2 to 2·9) ml per kg per min) and peak exercise (+2·0 (0·0 to 4·0) ml per kg per min). The oxygen pulse (oxygen uptake per heart beat) at the anaerobic threshold improved (+0·9 (0·0 to 1·8) ml/beat), and a higher peak work rate (+13 (4 to 22) W) was achieved. This was associated with improved preoperative QoL, with the overall SF-36® score increasing by 11 (95 per cent c.i. 1 to 21) (P = 0·028) and the overall SF-36® mental health score by 11 (1 to 22) (P = 0·037). CONCLUSION: A 4-week prehabilitation programme can deliver improvements in CPET scores and QoL before liver resection. This may impact on perioperative outcome. REGISTRATION NUMBER: NCT01523353 (https://clinicaltrials.gov).

National survey on endoscopy training in the UK.

INTRODUCTION: Gastrointestinal (GI) endoscopy is an important skill for both gastroenterologists and general surgeons but concerns have been raised about the provision and delivery of training. This survey aimed to evaluate and compare the delivery of endoscopy training to gastroenterology and surgical trainees in the UK. METHODS: A nationwide electronic survey was carried out of UK gastroenterology and general surgery trainees. RESULTS: There were 216 responses (33% gastroenterologists, 67% surgeons). Gastroenterology trainees attended more non-training endoscopy lists (mean: 3.0 vs 1.2) and training lists than surgical trainees (mean: 0.9 vs 0.5). A significantly higher proportion of gastroenterologists had already achieved accreditation in gastroscopy (60.8% vs 28.9%), colonoscopy (66.7% vs 1.4%) and flexible sigmoidoscopy (33.3% vs 3.0%). More gastroenterology trainees aspired to achieve accreditation in gastroscopy (97.2% vs 79.2%), flexible sigmoidoscopy (91.7% vs 70.1%) and colonoscopy (88.8% vs 55.5%) by completion of training. By completion of training, surgeons were less likely than gastroenterologists to have completed the required number of procedures to gain accreditation in gastroscopy (60.3% vs 91.3%), flexible sigmoidoscopy (64.6% vs 68.6%) and colonoscopy (60.3% vs 70.3%). CONCLUSIONS: This survey highlights marked disparities between surgical and gastroenterology trainees in both aiming for and achieving accreditation in endoscopy. Without changes to the delivery and provision of training as well as clarification of the role of endoscopy training in a surgical training programme, future surgeons will not be able to perform essential endoscopic assessment of patients as part of their management algorithm.

Clinical follow-up does not improve survival after resection of stage I-III colorectal cancer: A cohort study.

INTRODUCTION: The benefit of clinical follow-up alongside CT & CEA in detecting recurrent colorectal cancer (CRC) remains unclear. Despite this, clinical review remains part of most surveillance protocols. This study assessed the efficacy of clinical follow-up in addition to CT/CEA in detecting disease recurrence. METHODS: Patients undergoing surgery for CRC at a single centre between 2009 and 2011 were identified. Follow-up included clinical review, CT and CEA for 5 years. The primary endpoint of the study was method of detection of recurrence. Secondary endpoints included detection of surgically treatable recurrence, compliance with follow-up, disease free survival and overall survival. RESULTS: 118 patients with stage I-III CRC were included. Only 68.9% of scheduled follow-up events were performed (76.6% clinical reviews, 76.2% CT scans and 60.4% CEA tests). At median follow-up of 36 months, 26 patients had developed recurrence (median DFS 45.8 months). 17 patients (14.7%) had died (median OS 49.3 months). Sensitivity and specificity of follow up modality in detecting recurrence were; CT (92.3%, 100%), CEA (57.7%, 100%), clinical review (23.0%, 27.2%). Addition of clinical review did not identify any disease recurrence that was not detected by scheduled CT. Eight patients (30.7%) had surgically treatable recurrence - all were identified by scheduled CT. CONCLUSION: The addition of CEA testing and clinical review to scheduled CT scanning offered no benefit in the detection of recurrent disease. Clinical review could be removed from follow-up protocols without any reduction in the detection of recurrent cancer.

Evaluation of a novel tissue stabilization gel to facilitate clinical sampling for translational research in surgical trials.

BACKGROUND: The aim was to establish the feasibility of using a tissue stabilization gel (Allprotect™) as an alternative to liquid nitrogen to facilitate collection of clinical samples for translational research. METHODS: Tumour samples from patients undergoing surgery for primary or metastatic colorectal cancer were either snap-frozen in liquid nitrogen or stored in Allprotect™ under a number of different conditions. Sample integrity was compared across different storage conditions by assessing biomolecule stability and function. DNA quality was assessed spectrophotometrically and by KRas genotyping by pyrosequencing. Total RNA retrieval was determined by nanodrop indices/RNA integrity numbers, and quality assessed by reverse transcription-PCR for two representative genes (high-mobility group box 1, HMGB1; carboxylesterase 1, CES1) and two microRNAs (miR122 and let7d). Western blot analysis of HMGB1 and CES1 was used to confirm protein expression, and the metabolic conversion of irinotecan to its active metabolite, SN-38, was used to assess function. RESULTS: Under short-term storage conditions (up to 1 week) there was no apparent difference in quality between samples stored in Allprotect™ and those snap-frozen in liquid nitrogen. Some RNA degradation became apparent in tissue archived in Allprotect™ after 1 week, and protein degradation after 2 weeks. CONCLUSION: In hospitals that do not have access to liquid nitrogen and -80°C freezers, Allprotect™ provides a suitable alternative for the acquisition and stabilization of clinical samples. Storage proved satisfactory for up to 1 week, allowing transfer of samples without the need for specialized facilities. Surgical relevance Access to clinical material is a fundamental component of translational research that requires significant infrastructure (research personnel, liquid nitrogen, specialized storage facilities). The aim was to evaluate a new-to-market tissue stabilization gel (Allprotect™), which offers a simple solution to tissue preservation without the need for complex infrastructure. Allprotect™ offers comparable DNA, RNA and protein stabilization to tissue snap-frozen in liquid nitrogen for up to 1 week. Degradation of biomolecules beyond this highlights its role as a short-term tissue preservative. Allprotect™ has the potential to increase surgeon participation in translational research and surgical trials requiring tissue collection.

A systematic review of the role of hepatectomy in the management of metastatic renal cell carcinoma.

AIM: This review sought to systematically appraise the literature to establish the role of hepatectomy in treating renal cell carcinoma hepatic metastases. METHOD: Medline and EMBASE were systematically searched for papers reporting survival of patients who underwent hepatectomy for metastatic renal cell carcinoma. RESULTS: Six studies containing 140 patients were included. There were no randomised controlled trials. Perioperative mortality was 4.3%, with reported morbidity between 13 and 30%. Patients with metachronous presentation, and a greater time interval between resection of primary tumour and development of metachronous metastases, appeared to have better survival. There was no difference in survival between patients with solitary and multiple metastases. CONCLUSION: Few patients with hepatic metastases from renal cell carcinoma are suitable for hepatectomy as metastatic disease is usually widespread. Selected patients may experience a survival benefit, but identifying these patients remains difficult.

Unexpected and unexplained increase in death due to neurological disorders in 2012 in England and Wales: is cytomegalovirus implicated?

In early 2012 deaths (all-cause mortality) in England and Wales showed an unexpected and unexplained increase which continued for 18 months before abating. The highest percentage increase in deaths was noted to be for neurological degenerations (mainly dementia, Alzheimer's, Parkinson's). This study seeks to understand why increased deaths should focus on these conditions and if an unrecognized infectious outbreak could be implicated. Cause of death statistics for England and Wales were compared for 2012 versus 2011 as was the diagnosis for first outpatient appointment and inpatient admissions for these conditions. Deaths for dementia, Alzheimer's and Parkinson's showed a 15% increase with associated age specificity. The increase could not be explained by changes in the coding relating to cause of death. The increase coincided with increased GP referral (as first outpatient attendance) and inpatient admission for a range of neurological conditions. These increases were also observed on previous occasions of a similar event where deaths peaked in 2003 and 2008. A cascade of debility leading to immobility and institutionalization along with specific immune impairments appears to render those suffering from neurological degenerations sensitive to infectious outbreaks and more specifically to the particular agent behind these events. These and other studies point to outbreaks of a previously uncharacterized agent with the outbreak peaking in 2003, 2008 and 2012 (and in other years prior to these dates). Cytomegalovirus is a potential candidate and the necessary research to test this hypothesis is outlined.

Controversies in the oncosurgical management of liver limited stage IV colorectal cancer.

Colorectal cancer is the fourth most common cancer diagnosis in the world (around 1.2 million diagnoses each year), and accounts for the second highest number of deaths. Over half of patients with colorectal cancer will develop liver metastases, with one quarter presenting in stage IV. There is growing evidence that patients with liver-limited disease represent a distinct biological cohort who will benefit from aggressive management. Only a minority of patients are technically resectable, but around 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease. Novel surgical techniques have been developed to allow more patients to undergo resection and there is also growing recognition that the chemotherapeutic manipulation of irresectable disease may bring some patients to resection with good long-term outcome. Perioperative chemotherapy can also improve long-term outcome through improved biological selection and destruction of occult micrometastases. This review outlines current oncosurgical treatment strategies for liver-limited stage IV colorectal cancer, and discusses some of the controversies surround the management of these complex patients.

Radiological assessment of response to neoadjuvant transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI(®)) for colorectal liver metastases does not predict tumour destruction or long-term outcome.

INTRODUCTION: Transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI(®)) allows targeted delivery of irinotecan direct to liver tissue and colorectal liver metastases (CRLM). Accurate assessment of tumour response to therapy is vital to guide optimal treatment. Preliminary work has suggested existing criteria for radiological response may not reflect pathological response after neoadjuvant DEBIRI. This study assessed the relationship between existing and novel radiological response criteria and pathological tumour response as well as long-term outcome. METHODS: Patients with easily resectable CRLM were treated with DEBIRI 4 weeks prior to resection and pathological tumour response graded using a validated system. Radiological response was assessed using RECIST and novel morphological response criteria. RESULTS: Twenty-two patients with 37 lesions were treated with DEBIRI. Median residual tumour was 20% (range 0-80), median necrosis 45% (10-100) and median fibrosis 10% (10-70). Twenty patients (91%) demonstrated stable disease by RECIST, with 11 (50%) demonstrating partial morphological response. Neither radiological response criteria correlated with pathological response. Overall median disease free survival (DFS) was 13.6 months (95% CI 4.7-22.5). Radiological response was not associated with DFS. CONCLUSION: Existing criteria reporting short-term radiological response to DEBIRI do not accurately predict pathological tumour response or long-term outcome. Further work is necessary to define the optimum timing and method of assessing response to DEBIRI.

Perioperative chemotherapy for resectable colorectal liver metastases: where now?

Following the publication of the EORTC trial (40983), perioperative chemotherapy has become the standard of care for all patients with resectable colorectal cancer liver metastases (CRLM). However recently presented data suggest that the earlier advantage seen in progression free survival (PFS) may not translate over into a meaningful overall survival (OS) advantage. At the other end of the spectrum, patients with irresectable but liver limited CRLM continue to be offered treatment based on improving PFS, at the expense of regimens with greater response rates (but maybe poorer PFS rates) that could bring them to potentially curative liver resection. We therefore argue that patients with liver limited CRLM should be managed in three separate groups: Group One: those with easily resectable disease who should be offered immediate surgery, followed by adjuvant therapy if considered appropriate. Group Two: those with borderline resectable or high recurrence risk CRLM who could be offered appropriate systemic neoadjuvant therapy prior to planned liver surgery. Group Three: those with inoperable but liver limited CRLM who should be offered the most effective and appropriate systemic therapy with the primary purpose of achieving maximal disease response (and not PFS) with the intention of conversion to surgical resectability with curative intent.

Microwave ablation with or without resection for colorectal liver metastases.

BACKGROUND: Ablation with or without resection for colorectal liver metastases has been suggested as a potential method of improving survival if complete surgical resection is not possible. This study assessed the safety and efficacy of surgical microwave ablation (MWA) with or without resection for colorectal liver metastases. METHODS: A retrospective case series was reviewed. Data was extracted for all patients treated with open MWA with or without resection for colorectal liver metastases. Endpoints included postoperative 30-day morbidity and mortality, local treatment failure, disease free survival and overall survival. RESULTS: A total of 43 patients with technically irresectable disease were treated with MWA; 28 underwent combined MWA and resection, whilst 15 underwent MWA as the sole treatment modality. Overall post-operative morbidity was 35%, 30-day postoperative mortality 2%. At a median follow-up of 15 months, local treatment failure was observed in 4% of ablated lesions. 3-year OS was 36% for MWA group, compared to 45% for the combined ablate/resect group with 3-year DFS of 32% and 8% respectively. CONCLUSION: Microwave ablation with or without resection is a safe and effective method of achieving local disease control. Ablation with or without resection is associated with good long-term outcomes, and may be a suitable treatment option for small non-resectable colorectal liver metastases.

Hepatic activation of irinotecan predicts tumour response in patients with colorectal liver metastases treated with DEBIRI: exploratory findings from a phase II study.

PURPOSE: The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI). METHODS: Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response. RESULTS: Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r (2) = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r (2) = 0.54, p = 0.01). CONCLUSION: This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response.

Routine staging laparoscopy has no place in the management of colorectal liver metastases.

AIMS: Staging laparoscopy has been recommended in the management of patients with colorectal liver metastases prior to hepatectomy in order to reduce the incidence and associated morbidity of futile laparotomies. The utility of staging laparoscopy has not been assessed in patients undergoing CT, PET-CT and MRI as standard preoperative staging. METHODS: All patients undergoing attempted open hepatectomy for colorectal liver metastases between 1/4/2008 and 31/3/2012 were identified from a prospectively maintained research database. All patients who underwent futile laparotomy were identified, with demographics and operative notes subsequently analysed. RESULTS: A total of 274 patients underwent attempted open hepatectomy during the study period. At laparotomy 12 (4.4%) patients were found to have irresectable disease. There were no unifying demographic factors within the patients undergoing futile laparotomy. CONCLUSIONS: With modern imaging, the potential yield of staging laparoscopy is low. Staging laparoscopy should not be used routinely, but may have a role in the case of specific clinical concerns.