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Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT).MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes.A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically.The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.

Background Sarcomas are a heterogenous set of soft tissue cancers with an estimated incidence of up to 5.0 cases per 100,00 worldwide. Retroperitoneal sarcomas (RPS) account for up to 20% of these. The aetiology behind the pathogenesis is not truly understood, but to date, surgery remains the only curative treatment. Owing to resistance, systemic chemotherapy only plays a role in attempts to downstage the tumour, or in the palliative setting. RPS are slow growing and owing to the lack of symptoms have variable presentation. The ability to excise RPS traditionally was limited by vascular invasion, which increases the complexity of the resection and poses uncertainty about the long-term oncological benefit. Although small, emerging case series over the last couple of decades have established the feasibility of multi-visceral resection with vascular reconstruction. Here we present our outcomes comparing multi-visceral resections with single organ resections with vascular reconstructions. Methods All patients who underwent excision of a retroperitoneal sarcoma between January 2005 and April 2021 were included in the analysis. Patients were identified from a database which was prospectively completed by the operating surgeon. Data collected included patient demographics, clinicopathologic characteristics and intra-operative variables. Endpoints included perioperative morbidity and mortality, oncological clearance status, recurrence status, and survival. Complications were graded using the Clavien-Dindo classification. All patients were discussed in a local multi-disciplinary team meeting. When aortic/iliac artery involvement was suspected on pre-operative imaging (Computer Tomography or Magnetic Resonance Imaging), patients were referred appropriately to vascular for further pre-operative discussion regarding treatment and/or conduit plans. Continuous data was presented as medians (range) and compared using ANOVA (analysis of variance). Survival probabilities were calculated using the Kaplan-Meier method and log-rank test. Normally distributed data was assessed with the Student's t-test, and skewed data with Mann-Whitney test. A two-sided p value < 0.05 was considered significant. Results From January 2005 to April 2021, 122 patients underwent 170 operations for RPS resections. 112 (68.9%) underwent a visceral resection (90 (53.0%) multi-visceral (MVR) and 22 (15.9%) single organ (SOR)). In the MVR group, 23 (25.6%) involved a synchronous vascular resection with a complete resection margin in 94.7%. In the SOR group, 6 (27.3%) underwent a synchronous vascular resection with a 96.3% complete resection margin. Multi-visceral resections included 39 nephrectomies, 33 segmental colectomies, 16 liver resections, 16 splenectomies, pancreatic resections in 19, and partial gastrectomy in 12 cases. The inferior vena cava was resected in 17 and 5 cases in the MVR and SOR group, respectively. Aortic and iliac artery resection and reconstruction with Dacron graft took place in 4 cases. Histologically, leiomyosarcomas and dedifferentiated liposarcomas were the most common subtype, accounting for 33 and 30 (36.7% and 33.3%) in the MVR group and 10 and 6 (37.0% and 22.2%) in the SOR group, respectively. Overall 5-year survival for all resections was 60%. There was no significant difference in complication rate[HM1] [AR2], length of stay, 30-day mortality (2% and 1%) or 1- (71.1% and 77.8%) or 3-year (33.3% and 25.9%) survival between the MVR and SOR groups. Conclusions RPS are prone to localised invasion as well as into surrounding viscera. Although traditionally, these patients may not have been deemed suitable for surgical intervention, our case series shows multi-visceral resections with vascular resections can be undertaken safely with no impact on overall survival. The series also highlights the need for a multi-disciplinary surgical approach to address the technical complexities of the operation. In conclusion, the need for multi-visceral resection or vascular resection and reconstruction should not deter surgical treatment, and these cases should be managed within a MDT with appropriate surgical expertise.

Background The liver is the only visceral organ with regenerative capabilities. This ensures maintenance of the liver-to-bodyweight ratio required for homeostasis. Failure of this mechanism can be fatal. Precipitants to liver failure include infection, drug toxicity and surgical resection. Post-hepatectomy liver failure (PHLF) is associated with small for size syndrome i.e., insufficient post hepatectomy liver volume. The mechanisms by which liver failure occurs on a molecular basis are not yet fully understood, but theories include uncontrolled apoptosis from unrivalled superoxide radical formation causing irreparable oxidative stress. A major research focus of liver regeneration has been modulating the anti-oxidative response to any form of liver injury, but identifying pathways involved in dysfunctional liver regeneration after surgery have yet to be elucidated. Nuclear factor erythoid 2-related factor 2 (Nrf2) is an anti-oxidant transcription factor which promotes liver regeneration. Using a murine partial hepatectomy model, we have shown that pharmacological stimulation of Nrf2 increases the rate of post hepatectomy liver regeneration. Furthermore glutathione (GSH – a downstream target of Nrf2), has been linked with impaired liver regeneration when deficient. In this study, we present data on GSH analysis in liver tissue taken from patients undergoing hepatectomy. Methods Liver parenchyma was collected ex-vivo from patients undergoing liver resection (National Research Ethics Service approval 11/NW/0327). Additionally, isolated RNA from hepatic parenchyma from patients undergoing liver resections was received from collaborators at the Medical University of Vienna, Austria. From liver tissue, protein was isolated using a standard protocol and immunoblotting performed; RNA was isolated using a Monarch RNA preparation kit (NEB, UK), and quantitative PCR was performed. GSH levels in liver tissue were analysed using a standard enzyme recycling method. Relevant targets were identified based on their response to anti-oxidative stress as defined in literature. Primers were designed based on internally validated sequences and antibodies were purchased externally. qPCR was performed using the fluorescent dye, SYBR Green with a ViiA 7 Real-Time PCR system (ThermoFisher). Immunoblotting consisted of transferring separated by weight proteins onto a membrane which was then blocked in 5% milk, with primary and then secondary antibody incubation. Chemiluminescence was applied and bands were visualised using a ChemiDoc (BioRad). Bands were quantified using ImageJ software, and expressed in relation to actin. PHLF was classified according to the ISGLS criteria. Control patients (with no PHLF) were matched for demographic and clinico-pathologic variables (major resection as per the Brisbane criteria). Results Protein expression and GSH expression was measured in liver tissue from 23 patients. Of these, 10 had no PHLF, 4, 3 and 6 were classified as having Grades A, B, and C PHLF respectively. Additional isolated RNA samples yielded 11 with no PHLF, and 14 PHLF (4, 7 and 3, grade A, grade B and grade C, respectively) patients. A GSH assay showed no change in expression between those without PHLF and those with grade A and grade B, but patients who had grade C PHLF had significantly lower levels of GSH (p=0.0040). With respect to gene expression, GCLC, encoding the enzyme glutamate cysteine ligase catalytic subunit, the first rate limiting enzyme of glutathione synthesis, was also significantly lower in patients with grade C compared to those without PHLF of grade A/B (p=0.0206). Protein expression showed significantly reduced levels of GCLC when comparing grade C with patients without PHLF. Furthermore, samples taken at 2 timepoints (pre-parenchymal transection, and then 2 hours later from the resection margin) have shown a decrease in GCLC gene expression in patients who have grade C PHLF. Conclusions Our results have shown that patients who have grade C PHLF (who all died from acute liver failure post-operatively), have significantly lower levels of GSH in liver tissue taken at the time of resection. There is already a weight of evidence showing activation of the transcription factor Nrf2 (encoding GSH) enhances liver regeneration, however this is not without off target effects. Although not known to promote oncogenesis, in vitro studies have shown that persistent overstimulation of Nrf2 promotes cancer cell growth and proliferation, in part by improving the chemoresistance of cancer cells. This effect is theorised to be due to metabolic reprogramming of cancer cells, resulting in elevated levels of metabolic enzymes involved in cell proliferation.Whilst it is appreciated that liver failure is multi-factorial, targeting genes that promote liver regeneration may reduce the risk of failure. Identifying and targeting individual genes which are involved in liver regeneration may help to overcome potentially deleterious off target effects. This data suggests that GSH is a potential therapeutic target reducing the risk of PHLF.

Background The unique regenerative capacity of the liver permits curative surgery for patients with liver malignancy. However, extensive resections with a small future remnant liver risks post hepatectomy liver failure. Attempts to stimulate pre-resection liver regeneration have been refined over the last two decades. Techniques such as portal vein ligation/embolization, hepatic vein embolization and ALPPS are in clinical use. All these interventions aim to promote liver regeneration via a subtle anti-oxidative response in the contralateral lobe. The anti-oxidant transcription factor, nuclear erythoid 2-related factor 2 (Nrf2), has been strongly linked to enhancing liver regeneration. Furthermore, modulating Nrf2 pharmacologically has been shown to enhance liver regeneration, both structurally and functionally, in animal models of partial hepatectomy. Several Nrf2 activators (bardoxolone methyl (CDDO-Me), dimethyl fumarate, sulphoraphane) are in various phases of clinical trials, but each has potential unwanted off-target effects. One method to circumvent these effects would be to be use gene-specific therapy. Small activating RNA (saRNA), is a novel therapy using small RNA molecules to upregulate a specific gene. Here we present identification of a lead saRNA candidate to upregulate Nrf2. Methods We obtained several human and mouse specific saRNAs, with different sequences, all designed to target Nrf2. Human specific saRNA was screened using a hepatoma cell line (HepG2) stably transfected with the firefly gene. A luciferase assay was used to determine Nrf2 expression. CDDO-Me was used as a positive control, and transfection excluding saRNA (mock transfection) used as a negative control. To ensure specificity of the lead candidates, further mutated versions were designed and tested using a similar method. Endogenous gene expression was measured using quantitative PCR.Identification of a lead mouse specific candidate was completed with a view to in vivo testing. Murine colorectal cancer (CT26) cells were transfected with the mouse specific saRNA. Mutated samples for ideal candidates were designed and tested in a similar fashion. Gene expression was performed by qPCR. Similar controls were used. Continuous data was assessed for normality using a Shapiro-Wilks test, and analysed with ANOVA (analysis of variance) with a Tukey multiple comparisons test for normally distributed data. Skewed data was analysed with a Kruskal-Wallis’ test. A p value of Results Initial screening of 11 unique human specific saRNAs yielded 2 lead candidates, PR91b and PR145, with a 1.8 and 2.4 fold (p Initial screening with qPCR of 11 unique mouse specific saRNAs yielded 1 lead candidate, PR60, with a 3.0- and 2.5-fold increase in genes Nrf2 and NQO1 respectively. Specificity was assessed with mutated saRNAs which showed minimal to no upregulation of the genes Nrf2 or NQO1. Conclusions To date, there is only one Nrf2 activator licensed for use by the Medicines and Healthcare products Regulatory Agency – dimethyl fumarate for relapsing-remitting multiple sclerosis. Ongoing clinical trials exist aiming to utilise Nrf2 activators in liver related diseases as well as other non-hepatic diseases (such as treatment of diabetic nephropathy and COPD, amongst others). However, the inherent problem with such drugs are off-target effects. In this study we demonstrate upregulation of Nrf2 and its downstream targets by a novel and specific therapy – gene activation. Whilst not upregulating Nrf2 to the same degree as CDDO-Me in vitro, saRNA has the benefit of improved specificity, thereby eliminating off target effects.

Background Cholangiocarcinoma (CCA) is an aggressive malignancy with increasing incidence and persistently poor prognosis. None surgical treatment options for these patients are limited and a preponderance to chemoresistance means the benefits from chemotherapy are modest. The development of new targeted therapeutic strategies that prolong survival and reduce the risk of recurrence post-surgery are required. Accurate models that recapitulate tumour biology are essential to test and identify these novel therapies. Precision-cut tissue slices (PCTS) are patient-derived whole tissue explants that can be cultured ex-vivo. By retaining all aspects of the tumour micro-environment they recapitulate critical aspects of cancer biology, a significant advantage over 3D organoid culture. Our aim is to establish the use of the PCTS technique in CCA as the first step towards creating a patient-derived model of cholangiocarcinoma for use as a drug discovery platform. Methods CCA tissue samples and matched healthy liver tissue were collected from the operating theatre during surgical resection from fully consented patients. Multiple tissue slices (250μm, 5mm diameter) were prepared using a Krumdiek tissue slicer. Tissue slices were randomly incubated in triplicate and cultured for 0–15 days in 24 well plates. Tissue perfusion and air-liquid interface was maintained using Millipore well inserts. Tissue viability was determined at timepoints utilising MTS and ATP viability assays along with histological markers of proliferation (Ki-67) and apoptosis (cleaved-caspase 3). Maintenance of tissue morphology and phenotype during culture was confirmed on histological H&E staining and by staining of tumour specific markers (e.g CK19) on IHC and Western Blot. Results Thus far n=4 patients have had PCTS generated (3=pCCA 1=iCCA) from their tumour along with matched healthy liver. Following optimisation of the experimental protocol viability of the matched normal and tumour tissue slices can be maintained for upto 10 days, as assessed via in-situ MTS assay. Histological assessment of tissue slices harvested at day 0, 1,3,7 of culture shows the morphological and phenotypic structures of the source tumour to be maintained during ex-vivo culture. Viability of the tumour cells was additionally confirmed through the absence of cleave-caspase 3 markers of apoptosis on IHC staining. Conclusions This initial work has shown it is feasible to generate PCTS of CCA from resected surgical specimens with good viability. Further work is still required to ensure that our model retains a robust recapitulation of the in-vivo tumour including examination of the gene-expression profile. However, these initial results provide encouragement for the use of PCTS as a patient-derived model for drug discovery in CCA.

Background Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival but remains a formidable undertaking associated with significant post-operative morbidity and mortality. We aim to share our experience of managing these complex patients within a high-volume UK centre. Methods A retrospective review of a prospectively maintained database was performed on all patients who underwent resection for pCCA at our unit between 2009–2021. Kaplan–Meier analysis was used to estimate overall and disease-free survival (OS/DFS). Post-op complications were graded using the Clavien-dindo classification and reported as minor (Grade1/2) or major complications (Grade3/4). Results 102 patients underwent surgery for pCCA at our unit between 2009–2021. The majority of patients required pre-operative biliary drainage via ERCP and metal stent insertion. Following MDT and CPEX assessment eligible patients underwent an initial staging laparoscopy followed by curative resection. 30% of patients required a PVE to increase the proposed functional liver remnant volume prior to surgery. The majority of patients (76%) had Bismuth-Corlette IIIA/B or IV disease necessitating a major liver resection along with radical bile-duct resection. Post-op morbidity rates were high with 42% experiencing a major (grade3/4) complication. Of these patients 14 individuals subsequently died culminating in a 90-day mortality rate of 13.7%. Median LOS was 11 days (IQR 5–59). Median OS for the entire cohort was 36.3 months (CI:26.7–45.8) with a nominal 5-year survival rate of 34.6%. 40% of patients received adjuvant chemotherapy post-op. During follow up 59% of patients suffered disease recurrence with a median DFS of 20.1 months (CI: 11.5–33.5). The administration of palliative chemotherapy upon recurrence was associated with an improvement in survival of 11 vs 5.3 months (HR 3.5 p 0.01). Conclusions Surgery for pCCA remains a significant undertaking for both patient and clinician with high rates of morbidity and mortality. Long term survival is achievable but recurrence rates remain a challenge. Overall our mortality, morbidity and survival rates are comparable to that reported in other Western centres.

Aims Several putative prognostic models have been developed to stratify patients with peri-hilar cholangiocarcinoma (PHC) by Overall Survival (OS). The objective of this study was to evaluate the utility of these models in determining prognosis for all patients presenting to a tertiary referral centre with PHC. Methods Three hundred and two patients diagnosed with PHC referred to a regional tertiary referral centre between 2008 and 2019 had their demographic and survival data retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. Univariate and multivariate modelling was utilised to determine significant prognostic variables. Concordance indices were constructed for the prognostic models to determine internal validity within the cohort. Results Multivariate analysis demonstrated that: pre-interventional ECOG status (p 0.02); bilirubin levels (p 0.001); resectional status (p 0.001) and Mayo Clinic (MC) model (p 0.003) were significant predictors of OS. MC staging system demonstrated utility in stratifying patients by OS in pre-interventional patients with peri-hilar cholangiocarcinoma in all comers (p 0.001) and patients who did not progress to resection (p=0.021). There was strongly significant concordance between pre-intervention MC staging and OS in all comers in this cohort (C-index 0.59). Conclusions This study has validated the use of the MC model in a pre-interventional clinic setting. Bilirubin, a standardised easily obtainable serological biomarker, should be considered for incorporation into the MC model to refine patient stratification by OS.

Aims Human equilibriative nucleoside transporter protein 1 (hENT1) facilitates nucleoside transport into the cell. Immunohistochemically-detected hENT1 is increased in cholangiocarcinoma tumour cells and in highly metabolising cells. The Mackey 10D7G2 hybridoma has demonstrated prognostic utility in Pancreatic Ductal Adenocarcinoma. The Proteintech Polyclonal hENT1 antibody's prognostic utility has not been assessed. Cellular Ki67 expression is linked to tumour proliferation. This study aims to assess the antibodies’ prognostic utility for resectable hilar cholangiocarcinoma. Methods Between 2009–2016, 54 patients underwent resection for peri-hilar cholangiocarcinoma. Formalin-Fixed Paraffin Embedded blocks from 44 specimens were retrieved. A Tissue-Matched Array was constructed and stained for each antibody. H-scores were utilised to determine expression intensity. Correlation of expression was determined by Pearson correlation co-efficient and Chi-squared. Silencing RNA for transfected HepG2 cell-lines was used to determine accurate hENT1 staining by the Proteintech antibody. Demographic and survival characteristics were acquired from a prospectively held database, and were calculated with global log-rank calculations. Results There was significant correlation between the Mackey and Proteintech antibodies (p Conclusion While the Proteintech antibody demonstrates concordance with the 10D7G2 antibody in determining hENT1 expression, they didn't demonstrate significant prognostic ability. Standard histopathological co-variates retain prognostic utility within the cohort.

Older age is a risk factor for the development of HCC. However, the treatment options available for older patients with HCC, their safety, efficacy and utility, are poorly understood resulting in challenging decision-making. In this review, we aim to report the best available evidence to facilitate optimal decision making for older patients with HCC. We report that surgical resection for HCC is equally safe (90-day mortality ~3%) and effective (five-year disease free survival ~40%) for older patients as it is for younger patients. Five-year survival after ablation therapy for HCC is in excess of 50% in older patients, whilst morbidity rates are in the region of 3%. Survival rates of 30% after chemoembolisation reflects its role as a non-curative treatment. Transplantation is an option that may be helpful for a minority of patients, but the high risks of in-hospital mortality and lower likelihood of receiving a transplant should be duly considered before committing to this approach. We therefore advocate an individualised assessment for older patients based on these risk profiles and probabilities of optimal outcomes. In patients with a projected life-span ≥ 3 years, and who have sufficient physiological and functional reserve, surgical resection should be the treatment of choice. Patients with a projected life-span3 years are better served with loco-regional therapies, and tumour size, at a threshold of 3 cm, should guide the choice between ablation and chemoembolisation therapies.

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. 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. 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). 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.

Background Several potential prognostic models have been developed to stratify patients with peri-hilar cholangiocarcinoma (PHC) by Overall Survival (OS). The American Joint Committee on Cancer (AJCC) staging system is a post-resectional model utilising tumour-specific pathological parameters to stratify and predict OS. The Mayo Clinical (MC) scoring system has been developed utilising primarily clinical, serological, and radiological variables to predict survival in all patients with a diagnosis of peri-hilar cholangiocarcinoma. The objective of this study was to evaluate the utility of these models in determining prognosis for all patients presenting to a tertiary treatment centre with PHC. Methods Three hundred and two patients diagnosed with PHC referred to a regional tertiary referral centre between 2008 and 2019 had their demographic and survival data retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. One hundred and twenty seven patients were surgically explored. Eight-four patients underwent resection. One-hundred and seventy-four (57.6%) patients underwent palliative endoscopic therapy. Univariate and multivariate modelling was utilised to determine significant prognostic variables. Concordance Indices (C-Indices) were constructed for the prognostic models to determine internal validity within the cohort. Results Multivariate analysis demonstrated that: pre-interventional ECOG status (p Conclusions The predictive performance of the stated prognostic models for OS have poor utility. Simple pre-interventional serological, functional and radiological variables appear to provide better prognostic indication of OS. Variables not incorporated in the AJCC registry have a significant effect upon post-resectional OS and require full incorporation in to model prognostication.

Background Hilar cholangiocarcinoma is an aggressive cancer with poor prognosis. Complex pre-operative workup is required prior to major surgery that frequently involves an extended hepatectomy with biliary reconstruction and is associated with high levels of post-operative morbidity and mortality. Tools to predict overall and disease-specific outcome are required to better tailor pre-habilitation interventions and selection of patients for surgery. Here we investigate whether body morphometrics are associated with disease-free and overall survival. Methods Consecutive patients undergoing resection of hilar cholangiocarcinoma were identified within a prospectively maintained database in a single institution. The CoreSlicer web-based app was used to calculate body morphometrics at the L3 vertebral level (muscle, visceral and subcutaneous fat areas) from portal-phase CT images. Median cut-offs defined patient groups and height-normalised morphometric values were compared at diagnostic and subsequent pre-operative imaging. Multivariate analysis was used to identify relationships between body morphometrics at time of diagnosis, changes in body morphometrics in the pre-operative period and outcome. Results Body morphometrics were assessed in 88 patients at the time of diagnosis. Of these patients, 53 underwent re-staging enabling an assessment of change in body morphometrics during the pre-operative period. Men displayed significantly higher muscle area, visceral fat and lower subcutaneous fat than women. High visceral fat area at diagnosis was an independent predictor of reduced overall survival (HR 1.81, 95% CI 1.1-3.3, P = 0.03), whilst loss of skeletal muscle area during the pre-operative period was an independent predictor of reduced disease-free survival (HR 2.90, 95% CI 1.0-8.8, P = 0.05). Patients with higher visceral fat at diagnosis also appear at increased risk of post-hepatectomy liver failure (PHLF) and experience significantly higher 30-day mortality than those without elevated visceral fat. Conclusions The presented results identify potential value in assessing body morphometrics as a prognostic tool in patients undergoing surgery for hilar cholangiocarcinoma. External validation of these findings in larger patient cohorts will help to determine whether this can be utilised to guide pre-habilitation interventions and appropriately select patients for surgery.

Background Human equilibriative nucleoside transporter protein 1 (hENT1) is a trans-membranous protein which facilitates nucleoside transport in to the cell. Immunohistochemically-detected hENT1 abundance is increased in cholangiocarcinoma tumour cells compared to matched non-tumour cells and increased in highly metabolising cells. The privately-held Mackey 10D7G2 hybridoma has demonstrated prognostic utility in Pancreatic Ductal Adenocarcinoma patients. The commercially available Proteintech Polyclonal hENT1 antibody’s prognostic utility has not been previously assessed. Cellular Ki67 expression has been linked to mitotic indices of tumour proliferation. This proof-of-concept study aims to assess the antibodies prognostic utility for hilar cholangiocarcinoma patients undergoing surgical resection. Methods Between February 2009 and February 2016 54 patients underwent resection for peri-hilar cholangiocarcinoma. Formalin-Fixed Paraffin Embedded (FFPE) blocks from a sub-set of 44 resected specimens were retrieved. Appropriate areas of tumour were sampled from the blocks and a Tissue-Matched Array (TMA) was constructed. The TMA underwent staining for each antibody. H-scores were utilised to determine intensity of expression. Correlation of expression between antibodies was determined by Pearson correlation co-efficient and Chi-squared where appropriate. Silencing RNA transfected HepG2 cell-lines was used to determine hENT1 staining by the Proteintech antibody. Demographic and survival characteristics for the patients were acquired from a prospectively held database linked to Hospital Episode Statistics. Survival characteristics were calculated with global log-rank calculations. Results There was significant correlation between the Mackey 10D7G2 and the Proteintech antibodies (p Conclusions While the Proteintech antibody demonstrates concordance with the 10D7G2 antibody in determining hENT1 expression the antibodies did not demonstrate significant prognostic ability in this proof-of-concept study. Standard histopathological co-variates retain prognostic utility within the cohort.

Background Primary hepatobiliary cancer incidence in the UK is rising and survival rates are low. Surgery is the main curative option for these cancers, but multimodality therapies are expanding. The aim of our original study was to determine trends in survival, over an 8-year period, of patients treated for primary hepatobiliary cancers at our tertiary referral Centre. Method Patients treated for the most common types of primary hepatobiliary cancers, namely Hepatocellular carcinoma (HCC), Cholangiocarcinoma and Gallbladder cancer between January 2009 and December 2016 were retrospectively analysed from a prospective database linked to UK Hospital Episode Statistics data. Results A total of 1536 patients with primary hepatobiliary cancers were assessed and treatment plans formulated at our supra-regional specialist Hepatobiliary MDT. The primary hepatobiliary cancers treated were HCC (n = 836), Cholangiocarcinoma (n = 516), and Gallbladder cancer (n = 184). Survival for all the 3 cancers was significantly better with curative treatment. Overall median survival times were 350, 180, and 150 days respectively for HCC, Cholangiocarcinoma and Gallbladder cancer. Excluding best supportive care patients, the respective survival figures were 900, 600, and 400 days. Survival for HCC patients improved over time and was significantly increased in the final 3 years of the study (p ≤ 0.011 for all). Cholangiocarcinoma and Gallbladder cancer survivals were poor and did not change significantly over time. Conclusion HCC outcome has improved in association with expanded multimodal therapies. Survivals for cholangiocarcinoma and gallbladder cancer remain poor in parallel with limited expansion of multimodal therapies highlighting an unmet therapeutic need for biliary tract cancers.

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.

Aims Cholangiocarcinoma is a rare cancer arising from the biliary tree. Case series indicate that 25–40% of all borderline resectable primary tumours are potentially resectable. The Memorial Sloane Kettering System (MSKCC) stratifies patients for resectability by longitudinal and radial extension of the hilar tumour. The Bismuth-Corlette system describes the longitudinal extension of the tumour within the biliary duct system. We sought to validate and, if possible, augment these two scores within an independent validation cohort. Methods Patients diagnosed with hilar cholangiocarcinoma between January 2009 and December 2016 were analysed from a prospectively held database. Patients with distal cholangiocarcinoma, peripheral cholangiocarcinoma and gallbladder cancer were excluded. Comparison of surgical findings to pre-operative radiological imaging was undertaken at the time of surgery. Results The validation cohort was formed of 198 patients, of which, 55 (27.8%) patients underwent resection. Logistic regression analyses identified that BC score, MSKCC score, age at diagnosis and left artery involvement were all significant independent predictor's univariately. BC score explained 28% of the variability in resectability compared to 26% explained by MSKCC. In combination, the model consisting of BC score, age at diagnosis and left artery involvement explained 39% of variability in resectability compared to the 34% explained same model including MSKCC score instead of BC score. Conclusion In this cohort an augmented BC score, incorporating left hepatic artery involvement, is more discriminative in predicting resectability than the current MSKCC system.

Introduction Cholangiocarcinoma (CCA) are sub-divided into intrahepatic (iCCA) or extrahepatic (eCCA). eCCA are further subdivided into perihilar (pCCA) and distal (dCCA). Current and previous versions of the WHO International Coding of Disease and Oncology classifications (ICD) have separate topography codes for iCCA and eCCA, but none for pCCA. Over recent decades, multiple studies report rising incidence rates of iCCA with declining rates of eCCA, without reference to pCCA. We hypothesised the lack of a specific code for pCCA has led to errors CCA coding, specifically with miscoding of pCCA as iCCA. Methods Clinical notes of cases coded as hepatobiliary carcinoma using ICD-10 criteria (C22.1/Intrahepatic Bile Duct carcinoma, C24.0/Extrahepatic Bile Duct carcinoma, C23X/Malignant Neoplasm Gall Bladder, C22.0/Malignant Neoplasm Liver Cell Carcinoma) over a 2 year period (2015–2017), were reviewed by two independent clinicians at three independent UK regional HepatoPancreatoBiliary centres. The agreed final diagnosis was compared to the originally allocated ICD-10 code. Results Of the 625 CCA cases fully reviewed, 226 were coded as C22.1/iCCA. 98 (43%) of these were true iCCA and coded correctly, while 76 cases (34%) were actually pCCA. 92% all pCCA cases were incorrectly coded as iCCA. Conclusion CCA coding misclassification in UK HPB centres is common, particularly the miscoding of pCCA, which is extrahepatic and the commonest form of CCA, as iCCA. This may be contributing to apparent rising incidence rates of iCCA. Our findings confirm the need to implement distinct topographical codes for iCCA, pCCA and dCCA in future iterations of ICD.

In the original article Moritz Schmelzle’s last name is spelled wrong. It is correct as reflected here.

Background Hilar cholangiocarcinoma is staged using the AJCC staging system. Numerous other prognostically important histopathological and demographic characteristics have been reported. The objective of this meta-analysis was to assess statistically the effect of postresectional tumour characteristics on overall survival of patients undergoing attempted radical curative resection for hilar cholangiocarcinoma. Methods Relevant studies were identified by searching the Ovid MEDLINE and PubMed databases. The search was limited to studies published between 2009 and 2017. Papers referring to intrahepatic or distal cholangiocarcinoma were excluded from review. Data extraction used standard Parmar modifications to determine pooled univariable hazard ratios (HRs). Results Twenty-four articles, containing 4599 patients, were assessed quantitatively. In pooled analyses, age (HR 1·16, 95 per cent c.i. 1·04 to 1·28), T category (HR 1·49, 1·30 to 1·70), lymph node involvement (HR 1·78, 1·65 to 1·93), microvascular invasion (HR 1·49, 1·34 to 1·68), perineural invasion (HR 1·54, 1·40 to 1·68) and tumour differentiation (HR 1·54, 1·38 to 1·72) were significant prognostic factors, with low heterogeneity. Portal vein resection (HR 1·54, 1·15 to 1·70) and resection margin status (HR 1·77, 1·57 to 1·99) had significant effects, but with high heterogeneity. Sex, tumour size and preoperative carbohydrate antigen 19-9 levels did not have a statistically significant effect on postoperative prognosis. Conclusion Several tumour biological variables not included in the seventh edition of the AJCC classification affect overall survival. These require incorporation into prognostic models to ensure a personalized approach to prognostication and treatment.

Clinical decision-making around the management of liver-limited stage IV colorectal cancer involves careful assessment of the potential risks and benefits of surgery. This balance can often be optimised through appropriate patient selection to ensure long-term benefit of any operation, with fastidious perioperative care to minimize risk. We reviewed selected relevant articles from the existing literature. Multi-platform imaging is routinely used to determine distribution of disease and whether lesions are technically resectable, but what remains less clear is how to identify patients in whom resection is likely to deliver long-term benefits. A number of prognostic markers have been identified, with growing interest in direct assessment of tumour biology; genotyping of RAS status is routine in specific situations. Following a multidisciplinary team decision to proceed to surgery, patients undergo perioperative assessment and optimisation. Cardiopulmonary exercise testing helps to stratify perioperative risk: patients with low uptake of oxygen at the anaerobic threshold are known to have worse perioperative outcomes, and prehabilitation may offer the chance to reduce this risk. Intraoperative anaesthetic management is on a patient-by-patient basis but sub-normal hydration, epidural anaesthesia and steroids play a key role. Enhanced recovery after surgery programmes have improved perioperative outcomes while providing a potential economic benefit. Despite very good perioperative results, surgical management is not curative for the majority of patients, highlighting the need to further refine patient selection and definition of treatment aim on a patient-by-patient basis.

Chronic inflammation is an aberrantly prolonged form of a protective response to a loss of tissue homeostasis and it is involved in several steps of the carcinogenesis process. As a result, many cancers are inflammation-related. The systemic inflammatory response is associated with survival in advanced and localized cancers. Two categories of scores have been proposed to monitor the systemic inflammatory response, those derived from protein measurement and those based on counting inflammatory cells. This review aims to provide a critical appraisal of these 2 categories of surrogate markers. The 3 scale modified Glasgow prognostic score (mGPS) is based on the combination of C-reactive protein and albumin and is graded 0 to 2. It has been validated worldwide showing an independent prognostic value in patients with cancer in a variety of tumour types and tumour stages. Leukocytes-based scores are mainly neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR). Elevated NLR and/or PLR and lower LMR seem to be associated with decreased survival, but the studies about these markers are very heterogeneous. The main limit is the variety of thresholds used to dichotomize patients, so that reproducibility and reliability of leukocytes-based scores can be questioned. Hence, there is no sufficient evidence to support their use in clinical practice. Comprehensive management of patients with operable and advanced cancer should integrate the host systemic inflammatory response by calculating the mGPS. It could be a helpful tool to tailor patients' management.

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.

Background The prognosis of patients undergoing liver resection for colorectal liver metastases (CLM) seems to be altered when the primary tumour is right-sided. However, data are lacking and conflicting. We aimed to evaluate the influence of the primary tumour location on oncologic outcomes following such surgery. Methods We retrospectively analysed prospectively collected data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We compared the outcomes of patients with right colon tumours and those with left colorectal tumours. The splenic flexure was used as the cut-off point to determine the anatomic primary site. Results Among the 364 patients eligible, 74 (20.3%) had a right-sided primary tumour. These patients were older, had a poorer American Society of Anaesthesiologists status and had fewer node-positive primary tumours. The CLM characteristics were similar between both groups. Median PFS was not significantly different between the two groups at 9.9 months, as well as the pattern of recurrence. Median OS was shorter for patients with right-sided primary tumour (34.6 versus 45.3 months, p = 0.035). Similar results were observed when patients with rectal tumour were excluded from analysis (34.6 vs. 47.5 months, p = 0.007). Primary tumour site was an independent prognosis factor in multivariate analysis. Conclusion Right-sided location of the primary tumour is associated with worse OS after surgery for CLM, but seems to have no influence on PFS, and on the pattern of recurrence.

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.

Background Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine-based adjuvant chemotherapy. Methods A systematic review was performed, searching databases from January 1997 to January 2016. Articles pertaining to hENT1 immunohistochemical analysis in resected PDAC specimens from patients who subsequently underwent adjuvant gemcitabine-based chemotherapy were identified. Eligible studies were required to contain survival data, reporting specifically overall survival (OS) and disease-free survival (DFS) with associated hazard ratios (HRs) stratified by hENT1 status. Results Of 42 articles reviewed, eight were suitable for review, with seven selected for quantitative meta-analysis. The total number of patients included in the meta-analysis was 770 (405 hENT1-negative, 365 hENT1-positive). Immunohistochemically detected hENT1 expression was significantly associated with both prolonged DFS (HR 0·58, 95 per cent c.i. 0·42 to 0·79) and OS (HR 0·52, 0·38 to 0·72) in patients receiving adjuvant gemcitabine but not those having fluoropyrimidine-based adjuvant therapy. Conclusion Expression of hENT1 is a suitable prognostic biomarker in patients undergoing adjuvant gemcitabine-based chemotherapy.

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. 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. 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. This study showed that inflammatory scores expressed as ratios do not seem to be consistently reliable prognostic markers in patients with resectable CLM.

The challenges of conducting surgical oncology trials have resulted to low quantity and poor quality research [1,2]. Considering the definitive role of surgery to offer cure, immediate response to improve surgical research is needed [3]. The European Organization for Research and Treatment of Cancer (EORTC) and the European Society of Surgical Oncology (ESSO) share the vision to achieve excellent surgical research and care for cancer patients. Building on their complimentary expertise, they embarked on a pilot project to map out challenges and initiate a sustainable collaboration to advance cancer surgery research in Europe. This pilot project is EORTC-ESSO 1409 GITCG/ ESSO-01: A Prospective Colorectal Liver Metastasis Database with an Integrated Quality Assurance Program (CLIMB). This article will describe the challenges, milestones and vision of both organizations in setting up this collaboration.

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 ).

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

BACKGROUND Liver transplantation in patients with unresectable early-stage (

Emergency department thoracotomy (EDT) is a potentially life-saving procedure, performed on patients suffering traumatic cardiac arrest. Multiple indications have been reported, but overall survival remains unclear for each indication. The objective of this systematic review is to determine overall survival, survival stratified by indication, and survival stratified by geographical location for patients undergoing EDT across the world. Articles published between 2000 and 2016 were identified which detailed outcomes from EDT. All articles referring to pre-hospital, delayed, or operating room thoracotomy were excluded. Pooled odds ratios (OR) were calculated comparing differing indications. Thirty-seven articles, containing 3251 patients who underwent EDT, were identified. There were 277 (8.5%) survivors. OR demonstrate improved survival for; penetrating vs blunt trauma (OR 2.10; p 0.0028); stab vs gun-shot (OR 5.45; p

The retroperitoneal tumor (RPT) service in the North West costal region of England was centralized in May 2011 by the merger of the Merseyside, Cheshire and Lancashire, Cumbria sarcoma networks. Our aim was to analyze the impact of centralization of services on patient outcomes.An analysis from 01/12/2004 to 30/11/2017 was undertaken from prospectively maintained database and electronic patient records; follow-up was until 30/04/2018. This time period encompassed 6.5 years before and after centralization of services took place. Survival analysis was done for Retroperitoneal Sarcomas (RPS) and also compared the impact of centralization.72 patients (27 men), median age 69 (21-90) years) underwent 95 operations with an intention to excise RPS. Overall there were 52 (54.7%) multi-visceral resections (MVR). 91/95 (95.8%) patients with primary tumors had surgery with a curative (R0/1) intent. 30-day and 90-day operative mortality was 3.2% (n = 3) and 4.2% (n = 4) respectively. The 5-year survival for patients undergoing resection for RPTs was 51.3%. 79 (83.1%) of the resections in this series occurred in the 6.5-years post-centralization with an increase in MVR between the two time points (p 0.0006). Despite the more radical nature of surgery post-centralization, there was no difference in 5-year survival for RPS patients when compared to pre-centralization, p = 0.575. However the 5-yr survival post-centralization compared favorability to national outcomes.Centralization in the management of RPS has resulted in an increase in resection rates and more complex MVRs, without compromising R0/1 resection rates; peri-operative mortality or overall survival.

Summary Surgical resection remains the only proven curative treatment for peri-hilar cholangiocarcinoma. Despite recent advances in liver surgery techniques and perioperative care, resection for peri-hilar cholangiocarcinoma remains associated with significant morbidity and mortality. Considerable variation in the perioperative management of these patients exists. Optimal perioperative management has the potential to deliver improved outcomes. This article seeks to summarize the evidence underpinning best practice in the perioperative care of patients undergoing resection of peri-hilar cholangiocarcinoma. The authors also seek to identify areas where research efforts and future clinical trials should be targeted.

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.

Liver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases.We retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection.Patient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p 0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p = 0.002).Ablation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.

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 (

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 [ (ml kg−1 min−1)] and ventilatory equivalent of CO2 at the anaerobic threshold (AT) were not associated with complications or length of stay. Greater absolute oxygen uptake at AT [ 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 [ (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. J. Surg. Oncol. 2014; 110:439–444. © 2014 Wiley Periodicals, Inc.

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.

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 χ2 = 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

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 0e80), median necrosis 45% (10e100) and median fibrosis 10% (10e70). 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 4.7e22.5). 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. 2013 Elsevier Ltd. All rights reserved.

Background:Todate,thereislimiteddataontheliver‐firstapproachinthemanagementofcolorectallivermetastases(CRLM).Theaimofthestudy was to assess the outcomes of the liver‐first approach for patients with synchronous CRLM in two tertiary referral centers. Methods: Patients with stage IV colorectal cancer selected for the liver‐first approach from January 2009 to December 2012 in two tertiary referral centers were included. Data collated included demographics, chemotherapy, operative findings, histo‐pathological features, and survival. Results: Thirty‐seven patients with synchronous CRLM were considered for the liver‐first approach. Twenty‐five patients had rectal cancer. All patients underwent induction chemotherapy. Thirty patients underwent hepatic resections with no post‐operative deaths. Following liver resection, five patients failed toproceed tocolorectal resection and one patient had completeresponse tochemo‐radiotherapy. Ofthe25 patientsthat completed the liver‐first approach, 13 patients had recurrent disease, of which 12 patients died. The overall 1‐ and 3‐year survival rates were 65.9% and 30.4%, respectively. Conclusion: The liver‐first approach is a feasible strategy for patients with synchronous CRLM and may improve survival in selected patients. The selection of patients should be incorporated in a multidisciplinary approach to achieve the best possible outcomes. J. Surg. Oncol. 2013;108:444–449. 2013 Wiley Periodicals, Inc.

Background To review the outcomes following cetuximab therapy in patients with metastatic colorectal cancer. Methods Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords "colorectal cancer", "cetuximab", "liver metastases", "liver resection" and "hepatectomy". Results Cetuximab was first used in the palliative setting and an increase in response rates were seen, however with no improvement in overall survival. Published data have observed that cetuximab may be beneficial as part of a down-staging programme. The addition of cetuximab to chemotherapy regimens in patients with KRAS wild-type colorectal cancer has been shown to increase the response rates and the number of patients being down-staged and offered potentially curative resection. The OPUS and CRYSTAL trials observed good response rates following the addition of cetuximab but low resection rates. The CELIM and POCHER studies reported higher resection rates due to better patient selection and study design. However, the majority of published studies tend to report minimal surgical data and lack short- and long-term outcomes. Conclusion The use of cetuximab to conventional chemotherapy regimens may improve the efficacy of down-staging programmes, leading to more patients being offered potentially curative resection.