Surgical management, including the role of transplantation, for intrahepatic and peri-hilar cholangiocarcinoma.

Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.

Fibrin-based haemostatic agents for reducing blood loss in adult liver resection.

BACKGROUND: Liver resection is the optimal treatment for selected benign and malignant liver tumours, but it can be associated with significant blood loss. Numerous anaesthetic and surgical techniques have been developed to reduce blood loss and improve perioperative outcomes. One such technique is the application of topical fibrin-based haemostatic agents (FBHAs) to the resection surface. There is no standard practice for FBHA use, and a variety of commercial agents and devices are available, as well as non-FBHAs (e.g. collagen-based agents). The literature is inconclusive on the effectiveness of these methods and on the clinical benefits of their routine use. OBJECTIVES: To evaluate the benefits and harms of fibrin-based haemostatic agents in reducing intraoperative blood loss in adults undergoing liver resection. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group (CHBG) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science up to 20 January 2023. We also searched online trial registries, checked the reference lists of all primary studies, and contacted the authors of included trials for additional published or unpublished trials. SELECTION CRITERIA: We considered for inclusion all randomised clinical trials evaluating FBHAs versus no topical intervention or non-FBHAs, irrespective of publication type, publication status, language of publication, and outcomes reported. Eligible participants could have any liver pathology and be undergoing major or minor liver resections through open or laparoscopic surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the literature search and used data extraction forms to collate the results. We expressed dichotomous outcome results as risk ratios (RRs) and continuous outcome results as mean differences (MDs), each with their corresponding 95% confidence interval (CI). We used a random-effects model for the main analyses. Our primary outcomes were perioperative mortality, serious adverse events, haemostatic efficacy, and health-related quality of life. Our secondary outcomes were efficacy as sealant, adverse events considered non-serious, operating time, and length of hospital stay. We assessed the certainty of the evidence with GRADE and presented results in two summary of findings tables. MAIN RESULTS: We included 22 trials (2945 participants) evaluating FBHAs versus no intervention or non-FBHAs; 19 trials with 2642 participants provided data for the meta-analyses. Twelve trials reported commercial funding, one trial reported no financial support, and nine trials provided no information on funding. Below we present the most clinically relevant outcome results, also displayed in our summary of findings table. Fibrin-based haemostatic agents versus no intervention Six trials (1001 participants) compared FBHAs with no intervention. One trial was at low risk of bias in all five domains, and all other trials were at high or unclear risk of bias in at least one domain. Two trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with no intervention have an effect on perioperative mortality (RR 2.58, 95% CI 0.89 to 7.44; 4 trials, 782 participants), serious adverse events (RR 0.96, 95% CI 0.88 to 1.05; 4 trials, 782 participants), postoperative transfusion (RR 1.04, 95% CI 0.77 to 1.40; 5 trials, 864 participants), reoperation (RR 2.92, 95% CI 0.58 to 14.61; 2 trials, 612 participants), or postoperative bile leak (RR 1.00, 95% CI 0.67 to 1.48; 4 trials, 782 participants), as the certainty of evidence was very low for all these outcomes. Fibrin-based haemostatic agents versus non-fibrin-based haemostatic agents Sixteen trials (1944 participants) compared FBHAs with non-FBHAs. All trials had at least one domain at high or unclear risk of bias. Twelve trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with non-FBHAs have an effect on perioperative mortality (RR 1.03, 95% CI 0.62 to 1.72; 11 trials, 1436 participants), postoperative transfusion (RR 0.92, 95% CI 0.68 to 1.25; 7 trials, 599 participants), reoperation (RR 0.48, 95% CI 0.25 to 0.90; 3 trials, 358 participants), or postoperative bile leak (RR 1.15, 95% CI 0.60 to 2.21; 9 trials, 1115 participants), as the certainty of evidence was very low for all these outcomes. FBHAs compared with non-FBHAs may have little or no effect on the risk of serious adverse events (RR 0.99, 95% CI 0.95 to 1.03; 9 trials, 1176 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence for the outcomes in both comparisons (FBHAs versus no intervention and FBHAs versus non-FBHAs) was of very low certainty (or low certainty in one instance) and cannot justify the routine use of FBHAs to reduce blood loss in adult liver resection. While the meta-analysis showed a reduced risk of reoperation with FBHAs compared with non-FBHAs, the analysis was confounded by the small number of trials reporting the event and the risk of bias in all these trials. Future trials should focus on the use of FBHAs in people undergoing liver resection who are at particularly high risk of bleeding. Investigators should evaluate clinically meaningful and patient-important outcomes and follow the SPIRIT and CONSORT statements.

Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours.

PURPOSE OF REVIEW: This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS: In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Selective internal radiation therapy (SIRT) for hepatocellular carcinoma (HCC): informing clinical practice for multidisciplinary teams in England.

Objective: Hepatocellular carcinoma (HCC) deaths are rising alarmingly. Many patients are unsuitable for available therapies. Poor response rates further hamper outcomes for those that are. Selective internal radiation therapy (SIRT) offers hope, although which patients benefit over standard approaches remains unclear. Design/method: As a quality/service improvement, we audited consecutive patients treated with SIRT (2015-2020) by the Newcastle upon Tyne Hospitals National Health Service Foundation Trust HCC multidisciplinary team. Indications, Barcelona clinic liver cancer (BCLC) stage, treatment response, subsequent therapies and survival at 30 September 2021 were assessed. Results: Fifty-one patients received SIRT. Thirty-day mortality was zero. Three months partial response, stable disease and progressive disease on imaging were 50%, 22% and 28%, respectively. Overall median survival was 21 months. There were four subgroups: (1) BCLC-B: HCC>7 cm too large for transarterial chemoembolisation (TACE) alone (n=21); (2) BCLC-B: HCC progressed post TACE (n=7); (3) BCLC-C: HCC with any combination of large tumour burden, branch portal vein thrombosis, non-hepatitis C virus aetiology (n=16); (4) BCLC-C: sorafenib inappropriate (n=7). In group 1, 5/21 (23.8%) of patients were downstaged to resection, 33% received subsequent medical therapies and median survival was >40 months. In BCLC-B patients treated second line (group 2), median survival was 14.2 months. In BCLC-C, median survival was 20.2 months for group 3 and 4.2 months for group 4. Conclusion: SIRT outcomes for advanced HCC, often bridging patients with adverse predictive factors to subsequent surgery or medical therapies, were encouraging. A role after TACE or for BCLC-C patients requires further assessment.

Risk factors for decompensation and death following umbilical hernia repair in patients with end-stage liver disease.

INTRODUCTION: Symptomatic umbilical hernias are a common cause of morbidity and mortality in patients with cirrhosis and end-stage liver disease (ESLD). This study set out to characterise the factors predicting outcome following repair of symptomatic umbilical hernias in ESLD at a single institution. METHODS: A retrospective review was performed of all patients with ESLD who underwent repair of a symptomatic umbilical hernia between 1998 and 2020. Overall survival was predicted using the Kaplan-Meier method. Logistic regression was used to determine predictors of decompensation and 30-day, 90-day and 1-year mortality. RESULTS: One-hundred-and-eight patients with ESLD underwent umbilical hernia repair (emergency n = 78, 72.2%). Transjugular shunting was performed in 29 patients (26.9%). Decompensation occurred in 44 patients (40.7%) and was predicted by emergency surgery (OR, 13.29; P = 0.001). Length of stay was shorter in elective patients compared to emergency patients (3-days vs. 7-days; P = 0.003). Thirty-day, 90-day and 1-year survival was 95.2, 93.2 and 85.4%, respectively. Model for ESLD score >15 predicted 90-day mortality (OR, 18.48; P = 0.030) and hyponatraemia predicted 1-year mortality (OR, 5.31; P = 0.047). Transjugular shunting predicted survival at 1 year (OR, 0.15; P = 0.038). CONCLUSIONS: Repair of symptomatic umbilical hernias in patients with ESLD can be undertaken with acceptable outcomes in a specialist centre, however, this remains a high-risk intervention. Patients undergoing emergency repair are more likely to decompensate postoperatively, develop wound-related problems and have a longer length of stay. Transjugular shunting may confer a benefit to survival, but further prospective trials are warranted.

COVID-19 and liver cancer: lost patients and larger tumours.

BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Impact of prior biliary stenting on diagnostic performance of endoscopic ultrasound for mesenteric vascular staging in patients with head of pancreas and periampullary malignancy.

OBJECTIVE: The diagnostic performance of endoscopic ultrasound (EUS) for stratification of head of pancreas and periampullary tumours into resectable, borderline resectable and locally advanced tumours is unclear as is the effect of endobiliary stents. The primary aim of the study was to assess the diagnostic performance of EUS for resectability according to stent status. DESIGN: A retrospective study was performed. All patients presenting with a solid head of pancreas mass who underwent EUS and surgery with curative intent during an 8-year period were included. Factors with possible impact on diagnostic performance of EUS were analysed using logistic regression. RESULTS: Ninety patients met inclusion criteria and formed the study group. A total of 49 (54%) patients had an indwelling biliary stent at the time of EUS, of which 36 were plastic and 13 were self-expanding metal stents (SEMS). Twenty patients underwent venous resection and reconstruction (VRR). Staging was successfully performed in 100% unstented cases, 97% plastic stent and 54% SEMS, p<0.0001. In successfully staged patients, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for classification of resectability were 70%, 70%, 70%, 42% and 88%. For vascular involvement (VI), sensitivity, specificity, accuracy, PPV and NPV were 80%, 68%, 69%, 26% and 96%. Increasing tumour size OR 0.53 (95% CI, 0.30 to 0.95) was associated with a decrease in accuracy of VI classification. CONCLUSIONS: EUS has modest diagnostic performance for stratification of staging. Staging was less likely to be completed when a SEMS was in situ. Staging EUS should ideally be performed before endoscopic retrograde cholangiopancreatography and biliary drainage.

Comparative analysis of open, laparoscopic and robotic distal pancreatic resection: The United Kingdom's first single-centre experience.

INTRODUCTION: Laparoscopic distal pancreatectomy (LDP) has potential advantages over its open equivalent open distal pancreatectomy (ODP) for pancreatic disease in the neck, body and tail. Within the United Kingdom (UK), there has been no previous experience describing the role of robotic distal pancreatectomy (RDP). This study evaluated differences between ODP, LDP and RDP. METHODS: Patients undergoing distal pancreatectomy performed in the Department of Hepatobiliary and Pancreatic Surgery at the Freeman Hospital between September 2007 and December 2018 were included from a prospectively maintained database. The primary outcome measure was length of hospital stay, and the secondary outcome measures were complication rates graded according to the Clavien-Dindo classification. RESULTS: Of the 125 patients, the median age was 61 years and 46% were male. Patients undergoing RDP (n = 40) had higher American Society of Anesthesiologists grading III compared to ODP (n = 38) and LDP (n = 47) (57% vs. 37% vs. 38%, P = 0.02). RDP had a slightly lower but not significant conversion rate (10% vs. 13%, P = 0.084), less blood loss (median: 0 vs. 250 ml, P < 0.001) and a higher rate of splenic preservation (30% vs. 2%, P < 0.001) and shorter operative time, once docking time excluded (284 vs. 300 min, P < 0.001) compared to LDP. RDP had a higher R0 resection rate than ODP and LDP (79% vs. 47% vs. 71%, P = 0.078) for neoplasms. RDP was associated with significantly shorter hospital stay than LDP and ODP (8 vs. 9 vs. 10 days, P = 0.001). While there was no significant different in overall complications across the groups, RDP was associated with lower rates of Grade C pancreatic fistula than ODP and LDP (2% vs. 5% vs. 6%, P = 0.194). CONCLUSION: Minimally invasive pancreatic resection offers potential advantages over ODP, with a trend showing RDP to be marginally superior when compared to conventional LDP, but it is accepted that that this is likely to be at greater expense compared to the other current techniques.

Does minimally invasive liver resection improve long-term survival compared to open resection for hepatocellular carcinoma? A systematic review and meta-analysis.

INTRODUCTION: Minimally invasive liver surgery for hepatocellular carcinoma has gained widespread interest as an alternative to conventional open liver surgery. However, long-term survival benefits of this approach seem unclear. This meta-analysis was conducted to investigate long-term survival following minimally invasive liver surgery. METHOD: A systematic review was performed to identify studies comparing long-term survival after minimally invasive liver surgery and open liver surgery until January 2020. The I2 test was used to test for statistical heterogeneity and publication bias was assessed using Egger test. Random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year mortality, and disease-specific 5-year and 3-year mortality. Meta-regression was performed for the 5-year and 3-year survival outcomes with adjustment for study factors (region, design), annual center volume, patient factors (American Society of Anesthesiologists (ASA) grade, gender, age, body mass index, cirrhosis, tumor size, and number), and resection extent. Sensitivity analyses were performed on studies by study year, region, annual center volume, and resection type. RESULT: The review identified 50 relevant studies including 13,731 patients undergoing liver resection for hepatocellular carcinoma of which 4071 (25.8%) underwent minimally invasive liver surgery. Pooled analysis revealed similar all-cause (odds ratio: 0.83, 95% confidence interval: 0.70-1.11, p = 0.3) and disease-specific (odds ratio: 0.93, 95% confidence interval: 0.80-1.09, p = 0.4) 5-year mortality after minimally invasive liver surgery compared with open liver surgery. Sensitivity analysis of published studies from 2010 to 2019 demonstrated a significantly lower disease-specific 3-year mortality (odds ratio: 0.75, 95% confidence interval: 0.59-0.96, p = 0.022) and all-cause 5-year mortality (odds ratio: 0.63, 95% confidence interval: 0.50-0.81, p = 0.002). Meta-regression identified no confounding factors in all analyses. CONCLUSIONS: Improvement in minimally invasive liver surgery techniques over the past decade appears to demonstrate superior disease-specific mortality with minimally invasive liver surgery compared to open liver surgery. Therefore, minimally invasive liver surgery can be recommended as an alternative surgical approach for hepatocellular carcinoma.

Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians.

IMPORTANCE: Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC. OBJECTIVE: To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases. EVIDENCE REVIEW: MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included. FINDINGS: Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. CONCLUSIONS AND RELEVANCE: This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.

Treatment strategies for early stage hepatocellular carcinoma: a systematic review and network meta-analysis of randomised clinical trials.

BACKGROUND: Several treatment strategies for early stage hepatocellular cancers (HCC) have been evaluated in randomised controlled trials (RCTs). This network meta-analysis (NMA) aimed to explore the relative effectiveness of these different approaches on their impact on overall (OS) and recurrence-free survival (RFS). METHODS: A systematic review was conducted to identify RCT's reported up to 23rd January 2020. Indirect comparisons of all regimens were simultaneously compared using random-effects NMA. RESULTS: Twenty-eight RCT's, involving 3,618 patients, reporting 13 different treatment strategies for early stage HCC were identified. Median follow-up, reported in 22 studies, ranged from 12-93 months. In this NMA, RFA in combination with iodine-125 was ranked first for both RFS (HR: 0.50, 95% CI: 0.19-1.31) and OS (HR: 0.41, 95% CI: 0.19-0.94). In subgroup with solitary HCC, lack of studies reporting RFS precluded reliable analysis. However, RFA in combination with iodine-125 was associated with markedly better OS (HR: 0.21, 95% CI: 0.05-0.93). CONCLUSION: This NMA identified RFA in combination with iodine-125 as a treatment delivering better RFS and OS, in patients with early stage HCC, especially for those with solitary HCC. This technique warrants further evaluation in both Asia and Western regions.

c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-ß1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.

Therapeutic Strategies Toward Lactate Dehydrogenase Within the Tumor Microenvironment of Pancreatic Cancer.

OBJECTIVES: Pancreatic stellate cells (PSCs) play a key metabolic role within the tumor microenvironment (stroma) of pancreatic ductal adenocarcinoma (PDAC), being glycolytic and associated with protumorigenic acidification from excess lactate. This study investigates the clinical significance of glycolytic enzyme lactate dehydrogenase (LDH) and determines efficacy of the novel pan-LDH inhibitor Galloflavin. METHODS: An in vitro Transwell system was adopted for coculture of PSCs and 3 PDAC cell lines (MIA PaCa-2, PANC-1, and BxPC-3). Cells were treated with Galloflavin, and outcomes were analyzed regarding proliferation, apoptosis, lactate production, and glycolytic enzyme protein expression. Immunohistochemical staining for lactate dehydrogenase B (LDHB) was performed on 59 resected PDAC tumors annotated for clinical outcome. RESULTS: Galloflavin reduced PDAC proliferation in monoculture (P < 0.01); however, in co-culture with PSCs, an antiproliferative effect was only evident in PANC-1 (P = 0.001). An apoptotic effect was observed in MIA PaCa-2 and BxPC-3 in coculture (P < 0.05). A reduction in media lactate was observed in coculture (P < 0.01) with PSCs. Immunohistochemistry revealed stromal and tumoral LDHB expression had no impact on survival. CONCLUSIONS: Galloflavin has the potential to neutralize the acidic PDAC microenvironment and thereby reduce tumor invasiveness and metastasis. Patients with lower LDHB expression are more likely to be beneficial responders.

Meta-Analysis and Meta-Regression of Risk Factors for Surgical Site Infections in Hepatic and Pancreatic Resection.

BACKGROUND: The risk factors for surgical site infection (SSI) after HPB surgery are poorly defined. This meta-analysis aimed to quantify the SSI rates and risk factors for SSI after pancreas and liver resection. METHODS: The PUBMED, MEDLINE and EMBASE databases were systematically searched using the PRISMA framework. The primary outcome measure was pooled SSI rates. The secondary outcome measure was risk factor profile determination for SSI. RESULTS: The overall rate of SSI after pancreatic and liver resection was 25.1 and 10.4%, respectively (p < 0.001). 32% of pancreaticoduodenectomies developed SSI vs 23% after distal pancreatectomy (p < 0.001). The rate of incisional SSI in the pancreatic group was 9% and organ/space SSI 16.5%. Biliary resection during liver surgery was a risk factor for SSI (25.0 vs 15.7%, p = 0.002). After liver resection, the incisional SSI rate was 7.6% and the organ space SSI rate was 10.2%. Pancreas-specific SSI risk factors were pre-operative biliary drainage (p < 0.001), chemotherapy (p < 0.001) and radiotherapy (p = 0.007). Liver-specific SSI risk factors were smoking (p = 0.046), low albumin (p < 0.001) and significant blood loss (p < 0.001). The rate of organ/space SSI in patients with POPF was 47.7% and in patients without POPF 7.3% (p < 0.001). Organ/space SSI rate was 43% in patients with bile leak and 10% in those without (p < 0.001). CONCLUSIONS: The risk factors for SSI following pancreatic and liver resections are distinct from each other, with higher SSI rates after pancreatic resection. Pancreaticoduodenectomy has increased risk of SSI compared to distal pancreatectomy. Similarly, biliary resections during liver surgery increase the rates of SSI.

A systematic review and network meta-analysis of different surgical approaches for pancreaticoduodenectomy.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) is a demanding surgical procedure, thus explaining its slow expansion and limited popularity amongst Hepato-Pancreatico-Biliary (HPB) surgeons. However, three main advantages of robotic assisted pancreaticoduodenectomy (PD) including improved dexterity, 3D vision less surgical fatigue, may overcome some of the hurdles and ultimately lead to a wider adoption. This systematic review and network meta-analysis aims to evaluate the current literature on open and MIPD. METHODS: A systematic literature search was conducted for studies reporting robotic, laparoscopic and open surgery for PD. Network meta-analysis of intraoperative (operating time, blood loss, transfusion rate), postoperative (overall and major complications, pancreatic fistula, delayed gastric emptying, length of hospital stay) and oncological outcomes (R0 resection, lymphadenectomy) were performed. RESULTS: Sixty-one studies including 62,529 patients were included in the network meta-analysis, of which 3% (n = 2131) were totally robotic (TR) and 10% (n = 6514) were totally laparoscopic (TL). There were no significant differences between surgical techniques for major complications, overall and grade B/C fistula, biliary leak, mortality and R0 resections. Transfusion rates were significantly lower in TR compared to TL and open. Operative time for TR was longer compared with open and TL. Both TL and TR were associated with significantly lower rates of wound infections, pulmonary complications, shorter length of stay and higher lymph nodes examined when compared to open. TR was associated with significantly lower conversion rates than TL. CONCLUSION: In summary, this network meta-analysis highlights the variability in techniques within MIPD and compares other variations to the conventional open PD. Current evidence appears to demonstrate MIPD, both laparoscopic and robotic techniques are associated with improved rates of surgical site infections, pulmonary complications, and a shorter hospital stay, with no compromise in oncological outcomes for cancer resections.

A systematic review and network meta-analysis of parenchymal transection techniques during hepatectomy: an appraisal of current randomised controlled trials.

BACKGROUND: Major liver resection can lead to significant morbidity and mortality. Blood loss is one of the most important factors predicting a good outcome. Although various transection methods have been reported, there is no consensus on the best technique. This systematic review and network meta-analysis aims to characterise and identify the best reported technique for elective parenchymal liver transection based on published randomised controlled trials (RCT's). METHODS: A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Central to identify RCT's up to 5th June 2019 that examined parenchymal transection for liver resection. Data including study characteristics and outcomes including intraoperative (blood loss, operating time) and postoperative measures (overall and major complications, bile leaks) were extracted. Indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analyses (NMA) which maintains randomisation within trials. RESULTS: This study identified 22 RCT's involving 2360 patients reporting ten parenchymal transection techniques. Bipolar cautery has lower blood loss and shorter operating time than stapler (mean difference: 85 mL; 22min) and Tissue Link (mean difference: 66 mL; 29min). Bipolar cautery was ranked first for blood loss and operating time followed by stapler and TissueLink. Harmonic scalpel is associated with lower overall complications than Hydrojet (Odds ratio (OR): 0.48), BiClamp forceps (OR: 0.46) and clamp crushing (OR: 0.41). CONCLUSION: Bipolar cautery techniques appear to best at reducing blood loss and associated with shortest operating time. In contrast, Harmonic scalpel appears best for overall and major complications. Given the paucity of data and selective outcome reporting, it is still hard to identify what is the best technique for liver resection. Therefore, further high-quality large-scale RCT's are still needed.

Preemptive Appendicectomy at the Time of Pancreas Transplantation: Is It Necessary?

OBJECTIVES: Pancreas transplant is a major intraabdominal operation, and in most cases the graft is placed in the rightiliac fossa. At our center, preemptive appendicectomy is performed at the time of pancreas transplant to prevent any future risk in a complex transplant patient. The aim of this study was to review all histology reports from the removed appendices. MATERIALS AND METHODS: The histology reports from all incidental appendicectomies performed at pancreas transplant were reviewed. RESULTS: Between January 2001 and June 2016, 107 pancreas transplants were performed (86 simultaneous pancreas and kidney transplants, 11 pancreas after kidney transplants, and 10 pancreas transplants alone), and 65 appendix histology reports were available from this patient group. All were preemptive appendicectomies as none of the patients had symptoms to suggest acute appendicitis. Of the 65 appendix histologies, 43 (66.2%) were reported as normal. Twenty specimens (30.8%) showed fibrosis consistent with previous inflammation of the appendix, and 12 specimens (18.5%) showed fecal material in the lumen (1 due to an obstructing fecalith and another 2 showing luminal distension with feces). Three specimens (4.6%) showed lymphoid hyperplasia. There were 5 (7.7 %) unexpected findings upon histology. In review of histology reports, 1 patient had a 1.1-mm carcinoid tumor in an otherwise normal appendix, 1 had an Enterobius species worm infestation, 1 had focal endometriosis, 1 had crypt abscesses suggestive of inflammatory bowel disease, 1 had a metaplastic polyp, and 1 had melanosis coli of unknown clinical significance. There were no cases of overt acute appendicitis. No patients experienced a complication as a direct result of their appendicectomy. CONCLUSIONS: A policy ofroutine appendicectomy atthe time of pancreas transplant appears to be justified and safe.

Early Experience of Trans-arterial Chemo-Embolisation for Hepatocellular Carcinoma with a Novel Radiopaque Bead.

AIMS: To evaluate early outcomes of patients with hepatocellular carcinoma (HCC) treated with a novel radiopaque bead, the 75-150 µm DC Bead LUMI™ (Biocompatibles UK Ltd). MATERIALS AND METHODS: This was a retrospective review of the first 40 consecutive patients at a UK tertiary hepato-biliary centre, treated for HCC with TACE using radiopaque beads, between May 2017 and March 2019. Information regarding complications, mortality, lesion response and subsequent ablation procedures was collected from electronic records and case notes. Intra- and post-operative imaging was reviewed for visibility of the embolised territory. RESULTS: Fifty-five TACE procedures were performed in 40 patients, with a median age of 70 years (range 28-88) and median lesion size of 3.8 cm (range 1.5-7.8). The median follow-up period was 30 weeks (range 6-101). Mean post-procedure hospital stay was 1.2 days. Complications of CIRSE Grade II or above occurred after 4/55 procedures (7.3%). Mortality at 30 days was zero. Objective response rates (mRECIST) at 1, 3 and 6 months were 32/35 (91.4%), 21/24 (87.5%) and 12/15 (80%), respectively. Complete response rates at 1, 3 and 6 months were 16/35 (45.7%), 12/24 (50%) and 9/15 (60%). The embolised territory was visible on intra-operative and follow-up CT imaging in all patients. The radiopaque beads were used as a fiducial marker to guide ablation in 5/40 patients (12.5%). CONCLUSION: TACE with radiopaque beads shows promising tolerability and efficacy. The radiopaque beads ensure visualisation of the embolised lesion on intra- and post-operative imaging and, in selected cases, can act as a marker for CT-guided ablation.