The importance of preclinical models in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an adenocarcinoma of the hepatobiliary system with a grim prognosis. Incidence is rising globally and surgery is currently the only curative treatment, but is only available for patients who are fit and diagnosed in an early-stage of disease progression. Great importance has been placed on developing preclinical models to help further our understanding of CCA and potential treatments to improve therapeutic outcomes.

A systems approach reveals species differences in hepatic stress response capacity.

To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical species and humans. Species differences in sensitivity to acetaminophen (APAP) liver injury have been related to differences in the fraction of the drug that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically based pharmacokinetic modeling to identify oral doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult.

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

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K.

Long-term morbidity after surgery for perihilar cholangiocarcinoma: A cohort study.

Background: Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery.

Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers.

Introduction: Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease.

Objective: The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait.

Surgical management of suspected gallbladder cancer: The role of intraoperative frozen section for diagnostic confirmation.

Background: 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).

Methods: MDT patients with complex gallbladder disease were included.

A multi-center post-market clinical study to confirm safety and performance of PuraStat® in the management of bleeding during open liver resection.

Background: PuraStat® is a non-bioactive haemostatic agent that has demonstrated efficacy in a number of different surgical procedures. We performed a prospective multi-centre post-market study to evaluate the efficacy and safety of PuraStat® in liver resections performed for metastatic tumors.

Methods: This was a prospective cohort study.

The Impact of Gallium DOTA PET/CT in Managing Patients With Sporadic and Familial Pancreatic Neuroendocrine Tumours.

Objective: Pancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of Gallium (Ga)-DOTA PET/CT in managing patients with panNETs.

Appendiceal goblet cell carcinomas have poor survival despite completion surgery.

Purpose: Appendiceal goblet cell carcinomas (aGCCs) are rare but aggressive tumours associated with significant mortality. We retrospectively reviewed the outcomes of aGCC patients treated at our tertiary referral centre.

Methods: We analysed aGCC patients, diagnosed between 1990-2016, assessing the impact of completion surgery and tumour factors on survival.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration.

Background And Aims: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration.

Approach And Results: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy.

Robotic Surgery for Malignant Liver Disease: a Systematic Review of Oncological and Surgical Outcomes.

Robot-assisted laparoscopic surgery is yet another modification of minimally invasive liver surgery. It is described as feasible and safe from the surgical point of view; however, oncological outcomes need to be adequately analysed to justify the use of this technique when resecting malignant liver tumours. We reviewed existing English medical literature on robot-assisted laparoscopic liver surgery.

The impact of lymph node metastases and right hemicolectomy on outcomes in appendiceal neuroendocrine tumours (aNETs).

Introduction: European Neuroendocrine Tumour Society (ENETS) recommends managing appendiceal neuroendocrine tumours (aNET) with appendicectomy and possibly completion right hemicolectomy (CRH). However, disease behaviour and survival patterns remain uncertain.

Materials And Methods: We retrospectively assessed the impact of lymph nodes and CRH on outcomes, including survival, in all aNET patients diagnosed between 1990 and 2016.

Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.

Background: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear.

Methods: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern.

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

Background: Several prognostic systems have been proposed to guide management strategies post-resection for patients with hilar cholangiocarcinoma. The objective of this study was to evaluate the efficacy of these conventional prognostic models, with respect to Overall Survival (OS), on patients in a modern single-centre resectional cohort.

Method: Patients diagnosed with hilar cholangiocarcinoma, referred to a supra-regional tertiary referral centre between February 2009 and February 2016, were retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data.

Intra-peritoneal mature benign cystic teratoma deposits: an unusual complication from previous surgical resection of an ovarian mature benign cystic teratoma.

In this case, we describe multiple unusual intra-peritoneal lesions containing fat, soft tissue and calcification. These were found radiologically and histologically to be in keeping with mature benign cystic teratoma intra-peritoneal deposits, also described as dermoid cysts. These were presumed to be due to seeding from surgical resection of ovarian mature benign cystic teratoma 5 years previously.

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

Background: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have been identified as potential prognostic factors for overall survival (OS) in primary colorectal cancer, and there is a growing interest in their use in colorectal liver metastases (CLMs). However, optimal cut-off values for these ratios have not been defined by making comparison between series difficult. This study aimed to confirm the prognostic value of inflammatory scores in patients undergoing resection for CLM.

Changing outlook for colorectal liver metastasis resection in the elderly.

Background: This study sought to evaluate the impact of the advancements in clinical care, obtained over the last 20 years, for patients aged 70 and older undergoing liver resection for colorectal liver metastases (CRLM).

Methods: Consecutive patients age 70 or older who underwent liver resection for CRLM at Aintree University Hospital (Liverpool, UK) between May 2008 and May 2015 were compared to a dataset of consecutive patients, meeting the same criteria, between 1990 and 2007. An enhanced recovery programme after surgery (ERAS) combined with cardiopulmonary exercise testing (CPET) was introduced in January 2008.

Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury.

The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI.

Clinical outcome after resection of early-stage hilar cholangiocarcinoma.

Background: Liver transplantation in patients with unresectable early-stage (<3 cm, node negative) hilar cholangiocarcinoma has been recently reported to be associated with longer survival compared to liver resection and therefore suggested as potential treatment option also in resectable disease. Here, we investigated the outcome of resection in early-stage tumours as the standard of care in an experienced European centre.

Methods: Patients with de novo resectable hilar cholangiocarcinomas who underwent liver resection between mid-2009 and December 2017 were classified as early-stage (<3 cm and node negative) or later-stage tumours (≥3 cm and/or node positive), and were investigated with respect to clinical outcome.

Role of a pre-operative radiological scoring system in determining resectability for potentially resectable hilar cholangiocarcinoma.

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.

Optimal perioperative care in peri-hilar cholangiocarcinoma resection.

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.

Oncosurgical Management of Liver Limited Stage IV Colorectal Cancer: Preliminary Data and Protocol for a Randomized Controlled Trial.

Background: Colorectal cancer is the fourth commonest cancer and second commonest cause of cancer-related death in the United Kingdom. Almost 15% of patients have metastases on presentation. An increasing number of surgical strategies and better neoadjuvant treatment options are responsible for more patients undergoing resection of liver metastases, with prolonged survival in a select group of patients who present with synchronous disease.