Synthesis and characterisation of a cancerous liver for presurgical planning and training applications.

OBJECTIVES: Oncology surgeons use animals and cadavers in training because of a lack of alternatives. The aim of this work was to develop a design methodology to create synthetic liver models familiar to surgeons, and to help plan, teach and rehearse patient-specific cancerous liver resection surgery. DESIGN: Synthetic gels were selected and processed to recreate accurate anthropomorphic qualities. Organic and synthetic materials were mechanically tested with the same equipment and standards to determine physical properties like hardness, elastic modulus and viscoelasticity. Collected data were compared with published data on the human liver. Patient-specific CT data were segmented and reconstructed and additive manufactured models were made of the liver vasculature, parenchyma and lesion. Using toolmaking and dissolvable scaffolds, models were transformed into tactile duplicates that could mimic liver tissue behaviour. RESULTS: Porcine liver tissue hardness was found to be 23 H00 (±0.1) and synthetic liver was 10 H00 (±2.3), while human parenchyma was reported as 15.06 H00 (±2.64). Average elastic Young's modulus of human liver was reported as 0.012 MPa, and synthetic liver was 0.012 MPa, but warmed porcine parenchyma was 0.28 MPa. The final liver model demonstrated a time-dependant viscoelastic response to cyclic loading. CONCLUSION: Synthetic liver was better than porcine liver at recreating the mechanical properties of living human liver. Warmed porcine liver was more brittle, less extensible and stiffer than both human and synthetic tissues. Qualitative surgical assessment of the model by a consultant liver surgeon showed vasculature was explorable and that bimanual palpation, organ delivery, transposition and organ slumping were analogous to human liver behaviour.

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. Survival was assessed using Kaplan-Meier analysis. RESULTS: We identified 41 patients (23 F, 18 M); median age 61 (range 27-79) years. Mean tumour size was 10.5 (range 0.5-50) mm; most tumours were located in the appendiceal tip (n = 18, 45%). Appendicectomy was the index surgery in 32 patients, 24 of whom subsequently underwent completion surgery at median 3 (range 1.3-13.3) months later. Histology from completion surgery showed residual disease in 8 patients: nodal disease (n = 2) or residual tumour (n = 6). Index surgery for the rest was either colectomy (n = 7) or cytoreductive surgery plus intraperitoneal chemotherapy (CRS-HIPEC) (n = 1). Index and completion surgery had 0% mortality and 2.5% morbidity. Overall and recurrence-free survival were not significantly affected by tumour grade or completion surgery. Disease recurred in 9 patients after a median follow-up of 57.0 (4.6-114.9) months; 7 of these patients died during follow-up. Recurrences were treated with CRS-HIPEC (n = 1), palliative chemotherapy (n = 3) or supportive care (n = 5). Five- and ten- year overall survival were 85.3% and 62.3% respectively; 5-year and 10-year recurrence-free survival were 73.6% and 50.6%. CONCLUSION: The prognosis of aGCCs remains relatively poor. Completion surgery did not prevent recurrence or improve survival, but this needs to be verified with a larger patient cohort. The high mortality associated with tumour recurrence questions current treatment recommendations.

Systematic Review of Treatments for Colorectal Metastases in Elderly Patients to Guide Surveillance Cessation Following Hepatic Resection for Colorectal Liver Metastases.

BACKGROUND: Although included in surveillance programmes for colorectal cancer (CRC) metastases, elderly patients are susceptible to declines in health and quality of life that may render them unsuitable for further surveillance. Deciding when to cease surveillance is challenging. METHODS: There are no publications focused on surveillance of elderly patients for CRC metastases. A systematic review of studies reporting treatment outcomes for CRC metastases in elderly patients was performed to assess the risk-benefit balance of the key objectives of surveillance; detecting and treating CRC metastases. RESULTS: Sixty-eight eligible studies reported outcomes for surgery and chemotherapy in the elderly. Liver resections and use of chemotherapy, including biologics, are more conservative and have poorer outcomes in the elderly compared with younger patients. Selected studies demonstrated poorer quality-of-life (QoL) following surgery and chemotherapy. Studies of ablation in elderly patients are limited. DISCUSSION: The survival benefit of treating CRC metastases with surgery or chemotherapy decreases with advancing age and QoL may decline in the elderly. The relatively lower efficacy and detrimental QoL impact of multimodal therapy options for detected CRC metastases in the elderly questions the benefit of surveillance in some elderly patients. Care of elderly patients should thus be customized based on their preference, formal geriatric assessment, natural life-expectancy, and the perceived risk-benefit balance of treating recurrent CRC metastases. Clinicians may consider surveillance cessation in patients aged 75 years and above if geriatric assessment is unsatisfactory, patients decline surveillance, or patient fitness deteriorates catastrophically.

ACE Inhibitor Therapy Does Not Influence the Survival Outcomes of Patients with Colorectal Liver Metastases Following Liver Resection.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to possibly influence the survival outcomes in certain cancers. The aim of this study was to evaluate the impact of ACE inhibitors on the outcomes of patients undergoing liver resection for colorectal liver metastases (CRLM). The secondary aim was to determine whether ACE inhibitors influenced histopathological changes in CRLM. METHODS: Patients treated with liver resection for CRLM over a 13-year period were identified from a prospectively maintained database. Data including demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome were collated and analysed. RESULTS: A total of 586 patients underwent primary hepatic resections for CRLM during this period including 100 patients on ACE inhibitors. The median follow-up period was 23 (range: 12-96) months, in which 267 patients developed recurrent disease and 131 patients died. Independent predictors of disease-free survival on multivariate analysis included synchronous presentation, neoadjuvant chemotherapy, major liver resection, tumour size and number, extent of hepatic steatosis, R0 resection and presence of perineural invasion. Poorer overall survival was associated with neoadjuvant treatment, major liver resection, presence of multiple metastases, perineural invasion and positive resection margins on multivariate analysis. ACE inhibitors did not influence the survival outcome or histological presentation in CRLM. CONCLUSION: The use of ACE inhibitors did not affect the survival outcome or tumour biology in patients with CRLM following liver resection.

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. RESULTS: 102 patients (52F, 50 M), median age 39.4 (range 16.3-81.1) years, were diagnosed with aNET. Mean tumour size was 12.7 (range 1-60) mm, most sited in appendiceal tip (63%). Index surgery was appendicectomy in 79% of cases while the remainder underwent colectomy. CRH performed in 30 patients at a median 3.2 (range 1.4-9.8) months post-index surgery yielded residual disease in nine: lymph nodes (n = 8) or residual tumour (n = 1). Univariate logistic regression showed residual disease was significantly predicted by tumour size ≥2 cm (p = 0.020). Four patients declined CRH, but did not suffer relapse or reduced survival. One patient developed recurrence after 16.5 years of follow-up and another patient developed a second neuroendocrine tumour after 18.8 years follow-up. There were 5 deaths; one being aNET-related. 5-year and 10-year overall survival were 99% and 92% respectively; 5-year and 10-year relapse-free survival were 98% and 92% respectively. Only 5-year relapse-free survival was affected by ENETS stage (p = 0.002). CONCLUSION: aNETs are indolent with very high rates of overall and relapse-free survival. Recurrence is rare, and in this series only occurred decades later, making a compelling case for selective surveillance and follow-up. The significance of positive lymph nodes and the necessity for completion right hemicolectomy remain unclear.

Retrospective cohort study of statin therapy effect on resected colorectal liver metastases.

BACKGROUND: Above and beyond their role in cardiovascular risk reduction, statins appear to have a chemopreventive role in some gastro-intestinal cancers. In the quest for new chemopreventive agents, some existing established drugs such as statins have shown potential for re-purposing as chemoprevention. Probing existing drugs, whose pharmacodynamics are familiar, for novel beneficial effects offers a more cost-effective and less time-consuming strategy than establishing brand new drugs whose pharmacodynamic profile is unfamiliar. Observational studies show statins decrease the risk of developing colorectal cancer but there are no published studies exploring the potential impact of statins on carcinogenesis in colorectal liver metastases (CRLM). AIM: To evaluate impact of statins on outcomes of CRLM resection, and secondarily to assess if statins influence CRLM histo-pathology. METHODS: We conducted a retrospective cohort study of patients operated for CRLM over a 13-year period from 2005 to 2017. Patients were identified from a prospective database maintained in our Tertiary care hospital. All 586 patients included the study had undergone resection of CRLM following discussion at multidisclipinary team meeting, some patients requiring neoadjuvant chemotherapy to downstage CRLM prior to surgery. We analysed patient demographics, operative details, CRLM histopathology, Index of Deprivation, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and chemotherapy use in relation to clinical outcome. Statistics were performed using SPSS version 16.0; significance taken at 5%. RESULTS: Liver resection for CRLM was undertaken in 586 patients at a median age of 68 (range 19 to 88) years. Statin therapy was used by 181 patients. Median follow-up time was 23 (range 12-96) mo and further colorectal cancer metastases developed in 267 patients. A total of 131 patients died. Multi-variate analysis identified 6 independent predictors of poorer disease-free survival: Synchronous presentation, multiple tumours, tumour size ≥ 5 cm, moderate-severe steatosis, peri-neural invasion, and R1-resection margin. Poorer overall survival was significantly associated with neo-adjuvant chemotherapy, major hepatectomy, peri-neural invasion and R1-resection margin. Neither histo-pathological nor radiological traits of CRLM were affected by statins, and, there was no demonstrable effect of statin therapy on patient outcomes. CONCLUSION: Statin therapy does not affect patient survival following liver resection for CRLM. We postulate the reason for this key finding is that statins do not modulate tumour biology of CRLM.

Percutaneous transhepatic cholangioscopy and lithotripsy in treating difficult biliary ductal stones: Two case reports.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is preferred for managing biliary obstruction in patients with bilio-enteric anastomotic strictures (BEAS) and calculi. In patients whose duodenal anatomy is altered following upper gastrointestinal (UGI) tract surgery, ERCP is technically challenging because the biliary tree becomes difficult to access by per-oral endoscopy. Advanced endoscopic therapies like balloon-enteroscopy or rendevous-ERCP may be considered but are not always feasible. Biliary sepsis and comorbidities may also make these patients poor candidates for surgical management of their biliary obstruction. CASE SUMMARY: We present two 70-year-old caucasian patients admitted as emergencies with obstructive cholangitis. Both patients had BEAS associated with calculi that were predominantly extrahepatic in Patient 1 and intrahepatic in Patient 2. Both patients were unsuitable for conventional ERCP due to surgically-altered UGl anatomy. Emergency biliary drainage was by percutaneous transhepatic cholangiography (PTC) in both cases and after 6-weeks' maturation, PTC tracts were dilated to perform percutaneous transhepatic cholangioscopy and lithotripsy (PTCSL) for duct clearance. BEAS were firstly dilated fluoroscopically, and then biliary stones were flushed into the small bowel or basket-retrieved under visualization provided by the percutaneously-inserted video cholangioscope. Lithotripsy was used to fragment impacted calculi, also under visualization by video cholangioscopy. Satisfactory duct clearance was achieved in Patient 1 after one PTCSL procedure, but Patient 2 required a further procedure to clear persisting intrahepatic calculi. Ultimately both patients had successful stone clearance confirmed by check cholangiograms. CONCLUSION: PTCSL offers a pragmatic, feasible and safe method for biliary tract clearance when neither ERCP nor surgical exploration is suitable.

Acute parotitis due to MRSA causing Lemierre's syndrome.

We report a case of septic thrombophlebitis of the right internal jugular vein linked with right-sided acute parotitis caused by methicillin-resistant Staphylococcus aureus (MRSA) in a patient who had recently undergone a pylorus-preserving pancreaticoduodenectomy. Our case is unique because acute parotitis is a less-recognized cause of Lemierre's syndrome, never previously linked with MRSA infection in this context. We review the literature on diagnosis and management of Lemierre's syndrome caused by acute parotitis. Prompt diagnosis and aggressive antibiotics ensured a favourable outcome.

Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1.

BACKGROUND: Gastrointestinal stromal tumours (GIST) frequently occur in patients with neurofibromatosis type 1 (NF-1). It has been reported that GIST may co-exist with pancreatic endocrine tumors but this has only been in association with NF-1. CASE PRESENTATION: A 76 year old woman presented with a 12 month history of hypoglycaemia symptoms. Abdominal CT scan demonstrated a 13 mm insulinoma localized in the tail of her pancreas. She was commenced on diazoxide and later underwent surgery for enucleation of insulinoma when a small (< 1 cm) incidental tumour was discovered on her stomach wall which was identified as GIST. CONCLUSION: This is the first case report of a pancreatic insulinoma co-existing with a GIST in a patient without NF-1. In addition, we make the first report of rapidly growing cystic GIST recurrence following resection of a primary GIST tumour.

A re-evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver allografts.

Previously, we have found that the absence of the colon after liver transplantation (LT) protects the patient from recurrent primary sclerosing cholangitis (rPSC). As our previous observation has not been confirmed in other series, we have reviewed our cohort of patients grafted for primary sclerosing cholangitis (PSC) with greater numbers and longer follow-up to reassess the rate, consequences, and risk factors for rPSC. We collected data on patients who underwent LT for PSC between January 1986 and April 2006. Data were collected for cytomegalovirus status, inflammatory bowel disease status, time of colectomy, type of colectomy, donor-recipient gender mismatch, recipient sex, extended donor criteria (EDC), and donor risk index. Accepted criteria were used to diagnose rPSC. Of a total of 230 consecutive adult patients, 61 (27%) underwent colectomy pre-/peri-LT, and 54 (23.5%) developed rPSC at a median of 4.6 (range, 0.5-12.9) years post-LT. A total of 263 deceased donor grafts were used, and 73 were EDC grafts. A diagnosis of rPSC was made in 61 of the 263 grafts (23%). The recurrence-free patient survival was significantly better (P < 0.05) in patients who underwent pre-/peri-LT colectomy and in those with non-EDC grafts. In conclusion, in this larger cohort of 230 patients and with longer follow-up of 82.5 (range, 0.0-238.6) months [in comparison with the previous report of 152 recipients with a follow-up of 52.8 (range, 1-146) months], we have shown that colectomy remains a significant risk factor for rPSC and that colectomy before and during initial LT for PSC confers a protective effect against rPSC in subsequent graft(s). Moreover, we have shown that EDC grafts are also a significant risk factor for rPSC.

Coculture of human liver macrophages and cholangiocytes leads to CD40-dependent apoptosis and cytokine secretion.

UNLABELLED: In the vanishing bile duct syndromes (VBDS), primary biliary cirrhosis and chronic allograft rejection, cholangiocyte apoptosis is associated with sustained macrophage infiltration of the liver, suggesting that these cells may mediate tissue damage and contribute to bile duct destruction. We have previously reported that activation of CD40 on cholangiocytes with either soluble CD154 or cross-linking monoclonal antibody to CD40 induces apoptosis in vitro. We have now developed a novel primary human cell coculture model and used it to investigate (1) how macrophages kill cholangiocytes; (2) how paracrine cell interactions can shape the local cytokine milieu within the liver. We report that lipopolysaccharide (LPS) and interferon (IFN) induce sustained expression of CD154 on liver-derived macrophages (LDM) in vitro. Coculture of activated LDM expressing high levels of CD154 (CD40 ligand) with human cholangiocytes resulted in (1) CD40-dependent secretion of proinflammatory cytokines; (2) apoptosis of cholangiocytes that was abolished by antagonistic antibodies directed against human CD40 or human CD154. CONCLUSION: Macrophages are important effector cells in bile duct destruction in VBDS, and this role is dependent on CD40-mediated mechanisms. Thus activation of CD40 on cholangiocytes by activated macrophages provides a molecular mechanism to amplify chronic inflammation and bile duct destruction in liver disease. These data suggest that effective targeting strategies to antagonize CD40/CD154 may have beneficial effects in patients suffering from the VBDS.

Expression and functional consequences of oestrogen and progesterone receptors in human insulinomas.

The expression of steroid receptors by tumours offers a therapeutic advantage if functionally responsive to exogenous hormones. Insulinomas represent a highly symptomatic group of pancreatic tumours and the steroid receptor status of these tumours is poorly understood. The object of the study was to characterise the sex steroid receptor status of human insulinomas and to investigate whether sex steroids alter insulin expression therein. At our tertiary referral University Hospital, archival and prospective tissues from 25 insulinoma patients collected over 14 years were analysed for oestrogen receptor-alpha (ERalpha), oestrogen receptor beta (ERbeta) and progesterone receptor (PR) expression. Tissue explants of insulinoma and control pancreatic tissue from two new insulinoma patients were cultured and treated with oestrogen and progesterone and insulin expression measured by RT-PCR and ELISA. The main outcome measures were established before data collection and included sex steroid receptor status of tumours and insulin expression in fresh tissue in response to exogenous sex steroids. PR was expressed in 24 out of 25, ERalpha in 10 out of 25 and ERbeta in 21 out of 25 insulinomas. In fresh insulinoma cultures, insulin expression was increased by oestrogen or progesterone, whereas no significant effect was observed in adjacent pancreatic tissue. This study demonstrates widespread expression of sex steroid receptors on human insulinoma tissue and provides in vitro evidence of functionality with increased expression of insulin by insulinoma explants in response to exogenous oestrogen or progesterone. Confirmation of these results may provide a therapeutic mechanism for reducing symptomatic insulin secretion by receptor blockade.

A new approach to isolation and culture of human Kupffer cells.

Macrophages are a diverse population of cells that are able to adapt to specific tissue environments. Kupffer cells are liver resident macrophages and form the largest population of fixed tissue macrophages. Their isolation offers an exciting opportunity to study this subpopulation of uniquely adapted cells. However existing Kupffer cell isolation techniques are tedious and are still largely based on enzymatic digestion to liberate tissue macrophages from the closely associated surrounding tissue. Isolation techniques have continually evolved over the last 3 decades but are neither easily applicable nor user friendly. This is highlighted by a review of current literature which will show that there is a scarcity of published studies employing human Kupffer cells. The other difficulty with Kupffer cells and some other populations of macrophages in culture is the strong tenacity with which they adhere to solid substrate and their resistance to conventional sub-culture dissociation agents. The difficulty with cell dissociation has previously required cells to be grown in suspension culture. This has been achieved by culturing macrophages in Teflon bags but unfortunately this deprives cells of the maturation signals generated by adherence. In this article we have upped the ante by describing a 'user friendly' method for Kupffer cell isolation and new culture techniques that allow Kupffer cells to be grown in adherency whilst at the same time circumventing the difficulties posed by the adherence of these unique cells.

Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function.

BACKGROUND/AIMS: In most cases infection with hepatitis C results in chronic infection as a consequence of viral subversion and failed anti-viral immune responses. The suggestion that dendritic cells are defective in chronic HCV infection led us to investigate the phenotype and function of liver-derived myeloid (mDC) and plasmacytoid (pDC) dendritic cells in patients with chronic HCV infection. METHODS: Liver DCs were isolated without expansion in cytokines from human liver allowing us to study unmanipulated tissue-resident DCs ex vivo. RESULTS: Compared with mDCs isolated from non-infected inflamed liver mDCs from HCV-infected liver (a) demonstrated higher expression of MHC class II, CD86 and CD123, (b) were more efficient stimulators of allogeneic T-cells and (c) secreted less IL-10. Reduced IL-10 secretion may be a factor in the enhanced functional properties of mDCs from HCV infected liver because antibody depletion of IL-10 enhanced the ability of mDCs from non-infected liver to stimulate T-cells. In contrast, pDCs were present at lower frequencies in HCV-infected liver and expressed higher levels of the regulatory receptor BDCA-2. CONCLUSIONS: In HCV-infected liver the combination of enhanced mDC function and a reduced number of pDCs may contribute to viral persistence in the face of persistent inflammation.