Disappearing colorectal liver metastases in the era of state-of-the-art triple-modality diagnostic imaging.

INTRODUCTION: Systemic therapy can result in disappearance of colorectal liver metastases in up to 40% of patients. This might be an overestimation caused by suboptimal imaging modalities. The aim of this study was to investigate the use of imaging modalities and the incidence, management and outcome of patients with disappearing liver metastases (DLMs). METHODS: This was a retrospective study of consecutive patients treated for colorectal liver metastases at a high volume hepatobiliary centre between January 2013 and January 2015 after receiving induction or neoadjuvant systemic therapy. Main outcomes were use of imaging modalities, incidence, management and longterm outcome of patients with DLMs. RESULTS: Of 158 patients included, 32 (20%) had 110 DLMs. Most patients (88%) had initial diagnostic imaging with contrast enhanced-CT, primovist-MR and FDG-PET and 94% of patients with DLMs were restaged using primovist-MR. Patients with DLMs had significantly smaller metastases and the median initial size of DLMs was 10 mm (range 5-61). In the per lesion analysis, recurrence after "watch & wait" for DLMs occurred in 36%, while in 19 of 20 resected DLMs no viable tumour cells were found. Median overall (51 vs. 28 months, p < 0.05) and progression free survival (10 vs. 3 months, p = 0.003) were significantly longer for patients with DLMs. CONCLUSION: Even state-of-the-art imaging and restaging cannot solve problems associated with DLMs. Regrowth of these lesions occurs in approximately a third of the lesions. Patients with DLMs have better survival.

European Society of Surgical Oncology's strategy for clinical research: Paving the way for a culture of research in cancer surgery.

As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities.

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.

Multicentre validation of a clinical prognostic score integrating the systemic inflammatory response to the host for patients treated with curative-intent for colorectal liver metastases: The Liverpool score.

BACKGROUND: This study aimed to create a new prognostic score integrating the systemic inflammatory response to predict survival in patients treated with curative intent for colorectal liver metastases (CLM). METHODS: We identified independent prognostic factors in patients who underwent liver surgery for CLM in a tertiary centre in the United Kingdom (UK) between 2010 and 2015. A pre- and a postoperative score (Liverpool score) were created by combining these factors to stratify patients into different risk groups. These new scores were validated in an international cohort of 219 patients from China and France. RESULTS: Multivariate cox regression analysis of the 364 patients of the UK cohort identified 6 preoperative and 1 postoperative prognostic factors for overall survival (OS): American society of anaesthesiologists (ASA) score, location and node status of the primary tumour, number and size of CLM, neutrophil-to-lymphocyte ratio (NLR) and resection margin. Both pre- and postoperative scores can be calculated with an online calculator at https://jscalc.io/calc/PXatrmjfrEFpYy2t. Using the pre-operative model on the UK cohort, median OS was 61.22 (50.23, not reached) months in the low-risk group (n = 162) and 30.36 (23.68, 35.95) months in the high-risk group (n = 162, p < 0.0001). The same difference was observed in the validation cohort. The Liverpool score outperformed previously published scoring system with a c-index of 0.619 pre-operatively and of 0.637 post-operatively. CONCLUSION: We developed a new prognostic score based on clinicopathologic characteristics including the site of the primary tumour location and on measurement of the systemic inflammatory response which could help to tailor patients' management.

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.

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).

Adherence to early mobilisation: Key for successful enhanced recovery after liver resection.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been proven effective in liver surgery. Adherence to the ERAS pathway is variable. This study seeks to evaluate adherence to key components of an ERAS protocol in liver resection, and identify the components associated with successful clinical outcomes. METHOD: All patients undergoing liver resections for two consecutive years were included in our ERAS pathway. Six key components of ERAS included preoperative assessment, nutrition and gastrointestinal function, postoperative analgesia, mobilisation and discharges. Successful accomplishment of ERAS was defined as hospital discharge by postop day (POD) 6. Adherences of these elements were compared between the successful and un-successful groups. RESULTS: During the studied period, 223 patients underwent liver resections, among which 103 had major hepatectomies. N = 147 patients (66%) were discharged within our ERAS protocol target (6 days). On multivariable analysis, sitting out of bed by POD 1 (p < 0.03), walking by POD 3 (p = 0.03), removal of urinary catheter by POD 3 (p < 0.01), and avoiding major complications (p < 0.01) were factors associated with successful completion to our ERAS protocol; whereas advanced age (p = 0.34) and discontinuation of PCA/epidural by POD 3 (p = 0.50) were not significant parameters. There was a significant difference in the length of stay (p < 0.01) following major and minor liver resection, of which the indications for surgery also varied significantly. There was no difference in hospital re-admission rate, and morbidity and mortality between major and minor liver resection. CONCLUSIONS: Facilitating early mobilisation and reducing postoperative complications are keys to successful outcomes of ERAS in liver resection.

Objective assessment of trainee operative experience in a tertiary hepatobiliary unit.

INTRODUCTION: Indicative numbers for completion of training (CCT) in the UK requires 35 upper Gastrointestinal/Hepatobiliary resections and 110 (50 non HPB trainees) cholecystectomies. We aim to identify whether the training experience in our centre meets the CCT requirements for hepatobiliary surgery and compare training opportunities to those in international fellowships. METHODS: We retrospectively reviewed our hospital's operating theatre database for all patients undergoing a liver or gallbladder resection between January 2008 and July 2015 using corresponding procedural codes and consultant name. The cohort was categorized based on case and primary operating surgeon. The training grade of the surgeon was split into junior registrar (ST3/5), senior registrar (ST6/8) and senior fellow (post-CCT). RESULTS: Over a 7.5 year period we performed 2301 hepatobiliary procedures. The senior fellows and senior registrars performed a median of 42 liver resections (range 15-94) and 77 (range 35-110) cholecystectomies as the primary operator in any given 12 month period. The academic output for the unit was 104 over this period, with a median publication rate of 1.34 papers/trainee in any given 12 months. 15/16 senior fellow/senior registrars went on to secure substantive hepatobiliary consultant posts. CONCLUSIONS: Our centre delivers in excess of the required operative volume and clinical competencies for CCT in Hepatobiliary surgery in a 12 month period and exposure of trainees to operative experience is commensurate to the best performing international fellowships.

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).

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.

Blood cultures in acute surgical admissions.

INTRODUCTION: Obtaining blood cultures prior to the administration of antimicrobial therapy was a key recommendation of the 2012 UK Surviving Sepsis Campaign. Few studies have examined the effect blood cultures have on clinical management and there have been none on acute surgical admissions. This retrospective study sought to evaluate the effect of blood cultures on clinical management in acute surgical admissions. METHODS: Data on acute surgical patients admitted between 1 January and 31 December 2012 were extracted from hospital records. Patients given intravenous antibiotics within 24 hours of admission were identified. Data collected included antibiotics administered, blood culture results, admission observations and white blood cell count. Case notes were reviewed for patients with positive cultures to establish whether the result led to a change in management. RESULTS: Of 5,887 acute surgical admissions, 1,346 received intravenous antibiotics within 24 hours and 978 sets of blood cultures were taken in 690 patients. The recommended two sets of cultures were obtained in 246 patients (18%). Patients who had blood cultures taken had the same in-hospital mortality as those who had none taken (3.6% vs 3.5%, p=0.97). Blood cultures were positive in 80 cases (11.6%). The presence of systemic inflammatory response syndrome did not increase positivity rates (12.9% vs 10.3%, p=0.28). Overall, cultures altered management in two patients (0.3%). CONCLUSIONS: Blood cultures rarely affect clinical management. In order to assess the additional value that blood cultures bring to sepsis management in acute surgical admissions, a prospective randomised trial focusing on outcome is needed.

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.

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.

Impact of specialized multi-disciplinary approach and an integrated pathway on outcomes in hilar cholangiocarcinoma.

AIMS: To assess the outcomes of patients with hilar cholangiocarcinoma following referral to a specialist multi-disciplinary team. METHODS: Over an 11-year period, patients referred with hilar cholangiocarcinoma were identified from a prospectively maintained registry. Collated data included demographics, operative findings and histo-pathological data. Survival differences and prognostic factors were determined. RESULTS: 345 patients were referred with hilar cholangiocarcinoma, of which 57 (16.5%) patients had surgery. Prior to 2008, of 143 patients referred, only 17 (11.9%) patients underwent surgery, compared to 40 (19.8%) of 202 patients referred from 2008 onwards (p = 0.051). In the surgery group, the majority of patients underwent left hemi-hepatectomy (n = 19). In addition, portal vein (n = 5), hepatic artery (n = 2) and inferior vena cava (n = 3) resections were performed. The R0 resection rate was 73.7%. The morbidity and mortality rates were 59.6% and 14.0%, respectively. The median disease-free survival was 16 (4-101) months. The presence of lymph node metastasis (p = 0.002) was the only predictor of poorer disease-free survival. The 5-year overall survival was 39.5% and was significantly better than that of the palliative group (p < 0.001). CONCLUSIONS: Surgery is the optimal treatment option for patients with hilar cholangiocarcinoma and is associated with better overall survival. Prompt referral to tertiary centres with a core team of clinicians to manage this difficult condition may allow more patients to come to potentially curative surgical resections.

The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection.

AIM: To determine the outcome of patients that underwent liver resection for metastases from uveal melanoma. METHODS: Over a 9-year period, patients referred with uveal melanoma metastases were included. Following treatment of primary uveal melanoma, high-risk patients were offered to be enrolled into a 6-monthly non-contrast liver magnetic resonance imaging (MRI) surveillance. Following detection of liver metastases, patients were staged with a contrast-enhanced (Primovist(®)) liver MRI, computer tomography (CT) of the thorax and staging laparoscopy. RESULTS: 155 patients were referred with uveal melanoma liver metastases, of which 17 (11.0%) patients had liver resection and one patient was treated with percutaneous radio-frequency ablation. The majority of patients undergoing liver resection were treated with multiple metastectomies (n = 8) and three patients had major liver resections. The overall median survival for patients treated with surgery/ablation was 27 (14-90) months, and this was significantly better compared to patients treated palliatively [median = 8(1-30) months, P < 0.001]. Following surgery, 11 patients had recurrent disease [median = 13(6-36) months]. Patients who had undergone a major liver resection had a significantly poorer disease-free survival (P = 0.037). CONCLUSIONS: Patients who can undergo surgical resection for metastatic uveal melanoma have a more favorable survival compared to those who do not.

FDG-PET-CT is effective in selecting patients with poor long term survivals for colorectal liver metastases.

AIMS: Having incorporated PET-CT as part of the staging process for colorectal liver metastases (CRLM) in our unit since 2008, this study aims to evaluate the survival outcomes of all patients managed by our specialist multi-disciplinary team (MDT). METHODS: All patients with colorectal liver metastases referred to a single liver MDT between 2008 and 2011 were examined. Overall survival (OS) for palliative groups due to occult extrahepatic disease detected by PET-CT (A) and those upfront palliative patients with extensive multi-site disease as identified on baseline CT or disease progression during chemotherapy (B), and resected (C) groups were evaluated and compared. Different extents of occult extrahepatic disease as characterised by PET-CT were also compared. RESULTS: 532 patients were included in the study. Median OS for group A (n = 80), B (n = 161) and C (n = 291) were 10.9, 12.0 and 46.7 months, with a 5-year OS approaching 6.5%, 6.1% and 43.0% respectively. There were significant differences in OS of C vs. A & B (p < 0.001). Single compartment metastases had a significant better survival outcomes than non-torso metastases (p = 0.04). CONCLUSION: This is the first report of OS of patients with CRLM excluded from surgery on the basis of PET-CT. We have confirmed that PET-CT is effective in selecting patients with occult extrahepatic disease, which has poor survival outcomes. However, a subgroup with single compartment extrahepatic disease has a better than expected outcome.

Tumour size and differentiation predict survival after liver resection for hepatocellular carcinoma arising from non-cirrhotic and non-fibrotic liver: a case-controlled study.

AIMS: The aims of this study were to assess the outcomes of patients who underwent potentially curative hepatic resection for hepatocellular carcinoma (HCC) in a background of non-cirrhotic/non-fibrotic livers, and to determine prognostic factors that influenced survival. METHODS: Over a 15-year period, all patients undergoing hepatectomy for HCC were identified. Collated data included demographics, laboratory analysis, operative findings and histo-pathological data. Survival differences between these factors following liver resection were determined. RESULTS: 57 patients were included with a median age of 70 years. The majority of patients underwent a hemi-hepatectomy or more radical resection (n = 37). Overall R0 resection rate was 90.4% (n = 51). The overall morbidity and mortality rates were 26.3% and 3.5%, respectively. The median follow-up period was 28 months. The 1-, 3- and 5- year disease-free survival was 65.4%, 41.8% and 39.1%, and the overall survival was 73.5%, 49.6% and 39.5%, respectively. AFP (p = 0.039) was the only predictor of poorer disease-free survival on univariate analysis. On multi-variable analysis, poorly differentiated tumour and large tumour size were independent predictors of overall survival. CONCLUSIONS: Liver resection is a feasible treatment option for HCC in non-cirrhotic/non-fibrotic livers with good survival outcome. Tumour size and differentiation are adverse predictors of outcome in these patients.

Renal cell carcinoma metastases to gallbladder.

A 74-year old man underwent a radical cholecystectomy for presumed gallbladder cancer. The histology of the resected specimen in fact revealed the lesion to be metastatic renal cell carcinoma from his resected right nephrectomy performed 14 years previously.