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Supplementary Figures 1-6 and Tables 1-7

Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90+ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90+ podoplanin+ CD105+ CD146+ CD271+ VCAM-1+ ICAM-1+ α-SMA+) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90+ CD34+ CD105+ CD271+) represents a novel population of CD34+ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90+ CD146+ CD36+ NG2− pericytes in the walls of high endothelial venules and other small vessels, and CD90+ CD146+ NG2+ CD36− pericytes in the walls of larger vessels. Distinguishing between these CD90+ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.

Background Previous radical prostatectomy (RP) is considered a relative contraindication to the laparoscopic approach for inguinal hernia repair (LIHR). This study aimed to compare feasibility, safety and outcomes for patients undergoing totally extraperitoneal (TEP) LIHR who have previously undergone RP. Methods This single surgeon, case–control study was performed using a prospective database of all patients undergoing TEP LIHR between 1995 and 2020. Patients who underwent previous RP were identified and compared to matched controls. Pre-operative, operative and post-operative data were analysed. The type of RP, open, laparoscopic or robotic, was identified and operative outcomes compared between the three groups. Results 6532 LIHR cases were identified. 165 had previously undergone RP and 6367 had undergone primary LIHR without prior RP. The groups were matched for age, demographics and co-morbidities. All operations were commenced laparoscopically, three converted to open in the LIHR + RP group and none in the LIHR group. Median operative time in patients with previous RP was longer, for unilateral (40 min vs. 21 min, p p p = 0.0658) or bilateral (0/24 vs 3/1490, p ≥ 0.999) LIHR, nor chronic pain as measured by patient awareness or restriction of activity. No differences in operative and post-operative outcomes were identified between the three types of RP, other than difference in operative time (p = 0.0336). Conclusions Previous RP should not be an absolute contraindication for TEP LIHR. Although previous RP adds complexity, in experienced hands TEP LIHR can be done safely, with outcomes equivalent to patients who have not previously undergone RP.

Background and objectivesSARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T cell response to the resolution or progression of disease is still unclear. Optimal protective immunity may require activation of distinct immune pathways. As such, defining the contribution of individual T cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. To address this, we performed immunophenotyping of T cell responses in unvaccinated individuals, representing the full spectrum of COVID-19 clinical presentation.MethodsSpectral cytometry was performed on peripheral blood mononuclear cell samples from patients with PCR-confirmed SARS-CoV-2 infection. Computational and manual analyses were used to identify T cell populations associated with distinct disease states through unbiased clustering, principal component analysis and discriminant analysis.ResultsCritical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+(CTL) cells of a T follicular helper (TFH) or effector memory re-expressing CD45RA (TEMRA) phenotype. These CD4+CTLs were largely absent in those with less severe disease. In contrast, those with asymptomatic or mild disease were associated with high proportions of naïve T cells and reduced expression of activation markers.ConclusionHighly activated and cytotoxic CD4+T cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Potential for induction of these detrimental T cell responses should be considered when developing and implementing effective COVID-19 control strategies.

Background Endovascular aneurysm repair (EVAR) is an established treatment for many patients with infra-renal abdominal aortic aneurysm (AAA). Reporting standards were published in 2002 to ensure consistent measurement and reporting of outcomes following EVAR. We aimed to assess the range of clinical outcomes reported after EVAR and whether recent studies adhere to established reporting standards. Methods We searched MEDLINE and Embase from January 2014 until December 2018, using terms for ‘EVAR’ and ‘AAA’. We included prospective studies and randomised controlled trials which reported clinical outcomes of elective infra-renal AAA repair. Data on clinical outcome reporting were extracted and compared with established reporting standards. Results 84 studies were included. Technical success was reported in 49 (58.3%) studies, but only defined in 40 (47.6%), with 22 distinct definitions. Clinical success was reported and defined in 19 (22.6%) studies. Aneurysm rupture was reported in 27 (32.1%) studies and death from rupture in 11 (13.1%) studies. All-cause and aneurysm-related mortality were reported in 72 (85.7%) and 52 (61.9%) studies, respectively. Endoleak type I (n = 61, 72.6%) and II (n = 52, 61.9%) were more commonly reported than type III (n = 45, 53.6%) or IV (n = 13, 15.5%). Complications and mortality were reported by a mean of 18 (21.4%) and 42 (50%) studies, respectively. Conclusions A wide variety of clinical outcomes were reported following EVAR. Few studies adhered to reporting guidelines. We recommend modification of reporting standards to reflect advances in endovascular technology and creation of a core outcome set for EVAR.

B-cell migration within lymph nodes (LNs) is crucial to adaptive immune responses. Chemotactic gradients are proposed to drive migration of B cells into follicles, followed by their relocation to specific zones of the follicle during activation, and ultimately egress. However, the molecular drivers of these processes and the cells generating chemotactic signals that affect B cells in human LNs are not well understood. We used immunofluorescence microscopy, flow cytometry and functional assays to study molecular mechanisms of B-cell migration within human LNs, and found subtle but important differences to previous murine models. In human LNs we find CXCL13 is prominently expressed at the follicular edge, often associated with fibroblastic reticular cells located in these areas, whereas follicular dendritic cells show minimal contribution to CXCL13 expression. Human B cells rapidly downregulate CXCR5 on encountering CXCL13, but recover CXCR5 expression in the CXCL13-low environment. These data suggest that the CXCL13 gradient in human LNs is likely to be different from that proposed in mice. We also identify CD68+ CD11c+ PU.1+ tingible body macrophages within both primary and secondary follicles as likely drivers of the sphingosine-1-phosphate (S1P) gradient that mediates B-cell egress from LNs, through their expression of the S1P-degrading enzyme, S1P lyase. Based on our findings, we present a model of B-cell migration within human LNs, which has both similarities and interesting differences to that proposed for mice.

Background Acute cholangitis (AC) after liver transplantation occurs in 8-12% patients and remains a significant cause of patients' morbidity and mortality. The 2018 Tokyo guidelines use white blood cell count and C-reactive protein (CRP) as diagnostic criteria in AC. However, these and other common inflammatory markers have not been assessed in immunosuppressed liver transplant (LT) recipients with AC. The aims of this study were to compare the discriminative powers of common inflammatory markers, define the best inflammatory marker and determine the diagnostic cut-off values for the inflammatory markers in LT recipients with AC. Methods This was a retrospective cohort study. Over 16 years 212 LT recipients who underwent endoscopic biliary decompression were identified from hospital records. Thirty LT recipients with AC and 30 LT recipients without AC were randomly drawn in a 1:1 ratio. Results Among inflammatory markers, CRP had the highest discriminative power for diagnosing AC. The areas under the receiver operating characteristics curves for CRP, white blood cell count, lymphocyte count and neutrophil-to-lymphocyte ratio were 95% (95% confidence interval (CI): 91-98), 59% (95% CI: 50-68), 65% (95% CI: 53-77) and 70% (95% CI: 59-80), respectively. The cut-off value of CRP for diagnosing AC was equal to or above 9.5 mg/L. Conclusion CRP has the best discriminative power compared with other commonly used inflammatory markers for diagnosing AC in LT recipients. The optimal cut-off value for CRP concentration in diagnosing AC is equal to or above 9.5 mg/L.

The progresses in fast simulations of the hepatic flow in subject-specific vascular tree have created new toolkits for pre-surgical planning. The aim of this short communication is to intro...

Live donor liver transplantation (LDLT) is an important surgical technique for treating children with end-stage liver diseases. Surgical complications may occur, e.g., due to thrombosis formed in hepatic arteries (HAs) or portal veins (PVs). From the hepatic circulation point of view, a hepatic arterial buffer response (HABR) mechanism, where the HA flow counteracts the changes in the PV flow, could play a role in graft dysfunction, yet this intricate mechanism has not been elucidated in LDLT procedures. In this short communication we simulate the HABR which may occur in an adult-to-child LDLT, where the left lateral lobe of an adult donor is transplanted to a child. Using an electrical analog model we show that the HABR could be triggered in both portal hyper-perfusion and venous obstruction scenarios, and this may be associated with arterial and/or venous thrombosis in the liver graft as reported in clinical studies. In conclusion, HABR could be important in adult-to-child LDLT and it should be considered in pre-surgical planning.

Background Surveillance imaging following liver trauma (LT) in asymptomatic patients is performed in many centers. Recent guidelines recommend follow-up imaging if there is a clinical indication. Aim To compare liver complications detected through surveillance versus selective imaging in patients following known LT. Methods A retrospective review of a prospective trauma registry was undertaken including all patients that presented with LT at a single center. All radiology images and reports of patients with LT were reviewed. The indication for follow-up imaging was ascertained by reviewing the radiology request and the patients’ clinical record. Results During the 14-year study, 450 patients were admitted with LT. Liver complications occurred in 50 patients (11%). Follow-up imaging was performed in 169 patients (38%). Of the patients having follow-up imaging, 92 patients had this for clinical deterioration, 55 had surveillance imaging and 22 had follow-up imaging for a non-liver indication. The majority of patients undergoing surveillance imaging had an AAST grade III-V injury (68%). None of the 55 patients having surveillance imaging had a liver complication. In contrast, 36 out of 92 patients having follow-up imaging for clinical deterioration had a complication within their liver (39%). There was a significantly higher incidence of complication detection for clinical deterioration versus surveillance imaging (p = Conclusions Although complications following high-grade LT are common, they invariably cause clinical deterioration. There is no evidence for surveillance imaging following LT. Follow-up imaging should be guided by the patient's clinical condition.

Background potentially curative treatment options for hepatocellular carcinoma (HCC) include liver transplantation (LT), liver resection (LR) and thermal ablation (TA). Long term intent-to-treat (ITT) analysis from a single-centre using all three modalities contemporaneously has not been published. Methods An ITT analysis was undertaken of all patients with HCC listed for LT, or have undergone LR or TA. Results 444 patients were identified; 145 were listed for LT (121 underwent LT), 190 underwent LR and 109 underwent TA. One and 3-year overall survival (OS) was similar among LT, LR and TA (88/77%, 88/64% and 95/72%) whereas 5-year OS was higher following LT than LR or TA (73% vs. 54% vs. 49%). Disease-free survival at 1- and 5-years was higher for LT (97% and 84%) than LR (66% and 35%) or TA (73%, and 19%). Conclusion LT offered the lowest rate of cancer recurrence and highest chance of long-term survival. Differences in outcome likely reflect a combination of cancer-related factors (AFP, micro- and macrovascular invasion), patient-related factors (performance status, co-morbidities and psychosocial issues) and treatment type. Two thirds of patients treated by LR and three quarters treated by TA had HCC recurrence by 5 years, reinforcing the need for close long-term surveillance.

Background Consistent measurement and reporting of outcomes, including adequately defined complications, is important for the evaluation of surgical care and the appraisal of new surgical techniques. The range of complications reported after LC has not been evaluated. This study aimed to identify the range of complications currently reported for laparoscopic cholecystectomy (LC), and the adequacy of their definitions. Methods MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for prospective studies reporting clinical outcomes of LC, between 2013 and 2016. Results In total 233 studies were included, reporting 967 complications, of which 204 (21%) were defined. One hundred and twenty-two studies (52%) did not provide definitions for any of the complications reported. Conversion to open cholecystectomy was the most commonly reported complication, reported in 135 (58%) studies, followed by bile leak in 89 (38%) and bile duct injury in 75 (32%). Mortality was reported in 89 studies (38%). Conclusion Considerable variation was identified between studies in the choice of measures used to evaluate the complications of LC, and in their definitions. A standardised set of core outcomes of LC should be developed for use in clinical trials and in evaluating the performance of surgical units.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90+ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90+ podoplanin+ CD105+ CD146+ CD271+ VCAM-1+ ICAM-1+ α-SMA+) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90+ CD34+ CD105+ CD271+) represents a novel population of CD34+ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90+ CD146+ CD36+ NG2− pericytes in the walls of high endothelial venules and other small vessels, and CD90+ CD146+ NG2+ CD36− pericytes in the walls of larger vessels. Distinguishing between these CD90+ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.

Liver structures of a healthy subject are digitised and segmented from computed tomography (CT) images, and hepatic perfusion is modelled in the hepatic artery and portal vein of the healthy subject with structured tree-based outflow boundary conditions. This self-similar structured tree is widely used in the literature, eg, blood flow simulation in larger systemic arteries and cerebral circulation, and is used in this study to model the effect of the smaller hepatic arteries and arterioles, as well as the smaller hepatic portal veins and portal venules. Physiologically reasonable results are obtained. Since the structured tree terminates at the size of the microvasculature system in liver lobules, the structured tree boundary condition will enable the proposed organ-level model of hepatic arterial flow to be easily connected to tissue-level models of liver lobules. Blood flow in the hepatic vein is also modelled in this subject with three-element Windkessel model as outflow boundary conditions. The benefit of integrating the perfusion in all hepatic vascular vessels is that it helps us analyse some complicated clinical phenomenon more efficiently, eg, one possible application is to obtain the portal pressure gradient (PPG) to help examine the reliability of hepatic venous pressure gradient (HVPG) as an indirect measure of portal pressure. Moreover, since four to six generations of hepatic vessels, which are sufficient for liver classification analysis, were employed in the model, this study is setting the computational foundation of a potentially handy surgical tool.

Preoperative and postoperative hepatic perfusion is modeled with one-dimensional (1-D) Navier-Stokes equations. Flow rates obtained from ultrasound (US) data and impedance resulted from structured trees are the inflow and outflow boundary condition (BC), respectively. Structured trees terminate at the size of the arterioles, which can enlarge their size after hepatectomy. In clinical studies, the resistance to pulsatile arterial flow caused by the microvascular bed can be reflected by the resistive index (RI), a frequently used index in assessing arterial resistance. This study uses the RI in a novel manner to conveniently obtain the postoperative outflow impedance from the preoperative impedance. The major emphasis of this study is to devise a model to capture the postoperative hepatic hemodynamics after left hepatectomy. To study this, we build a hepatic network model and analyze its behavior under four different outflow impedance: (a) the same as preoperative impedance; (b) evaluated using the RI and preoperative impedance; (c) computed from structured tree BC with increased radius of terminal vessels; and (d) evaluated using structured tree with both increased radius of root vessel, ie, the outlets of the postoperative hepatic artery, and increased radius of terminal vessels. Our results show that both impedance from (b) and (d) give a physiologically reasonable postoperative hepatic pressure range, while the RI in (b) allows for a fast approximation of postoperative impedance. Since hemodynamics after hepatectomy are not fully understood, the methods used in this study to explore postoperative outflow BC are informative for future models exploring hemodynamic effects of partial hepatectomy.

BACKGROUND Preoperative supplementation with immunonutrients, including arginine and n-3 fatty acids, has been shown in a number of systematic reviews to reduce infectious complications in patients who have undergone gastrointestinal surgery. Limited information, however, is available on the benefits of nutritional supplementation enriched with arginine and n-3 fatty acids in patients undergoing liver resection. AIM To evaluate the effects of preoperative nutritional supplementation enriched with arginine and n-3 fatty acids on inflammatory and immunologic markers and clinical outcome in patients undergoing liver resection. METHODS Thirty-four patients undergoing liver resection were randomized to either five days of preoperative Impact® [1020 kcal/d, immunonutrition (IMN) group], or standard care [no supplementation, standard care (STD) group]. Nutritional status was measured at study entry by subjective global assessment (SGA). Functional assessments (grip strength, fatigue and performance status) were carried out at study entry, on the day prior to surgery, and on postoperative day (POD) 7 and 30. Inflammatory and immune markers were measured at study entry, on the day prior to surgery, and POD 1, 3, 5, 7, 10 and 30. Postoperative complications were recorded prospectively until POD30. RESULTS A total of 32 patients (17 IMN and 15 STD) were analysed. All except four patients were SGA class A. The plasma ratio of (eicosapentaenoic acid plus docosahexaenoic acid) to arachidonic acid was higher in IMN patients on the day prior to surgery and POD 1, 3, 5 and 7 (P < 0.05). Plasma interleukin (IL)-6 concentrations were elevated in the IMN group (P = 0.017 for POD7). No treatment effect was detected for functional measures, immune response (white cell count and total lymphocytes) or markers of inflammation (C-reactive protein, tumour necrosis factor-α, IL-8, IL-10). There were 10 patients with infectious complications in the IMN group and 4 in the STD group (P = 0.087). Median hospital stay was 9 (range 4–49) d in the IMN group and 8 (3-34) d in the STD group (P = 0.476). CONCLUSION In well-nourished patients undergoing elective liver resection, this study failed to show any benefit of preoperative immunonutrition.

This meta-analysis aimed to compare perioperative and survival outcomes in patients who underwent hepatectomy with and without Bile Duct Tumour Thrombus (BDTT).A comprehensive search of Cochrane Library, PubMed, MEDLINE and EMBASE was performed to identify relevant articles. The perioperative, postoperative and long term outcomes were compared.Eleven studies including 6051 patients met the inclusion criteria. The perioperative outcomes were comparable between the 2 groups. The BDTT group had higher proportion poorly differentiated tumours (OR = 1.87, X(2) = 10.00, df = 6, p = 0.002, I(2) = 40%), Lymphovascular invasion (LVI) (OR = 4.85, X(2) = 28.21, df = 9, p =0.001, I(2) = 68%) and Macrovascular invasion (MVI) (OR = 5.41, X(2) = 8.73, df = 9, p =0.001, I(2) = 0%). There was no difference in 1 and 3 year survival, however 5-yr survival was poorer in the BDTT group (OR = 0.37, X(2) = 37.04, df = 7, p =0.001, I(2) = 81%). The mean difference (MD) in overall survival in the BDTT group was -20 months [-32.31, -7.06], p = 0.002, I(2) = 95%.Patients with HCC with BDTT had more advanced stage HCC with adverse histological features including higher rates of MVI, LVI and poor differentiation. Hepatectomy in this group of patients offers similar survival at 3 years but inferior long-term survival and should be considered when feasible.

Major liver resection (hepatectomy) is required for patients with liver metastasis (e.g., from colorectal cancer) and hepatocellular carcinoma (e.g., from chronic hepatitis B infection). Hepatectomy is based principally on the segmental anatomy of the liver, which has few reliable external landmarks to orientate the surgeon. Anatomical variations are common and significant flow alterations after surgery are thought to be a cause for liver dysfunction. Live donor liver transplants (LDLT) are becoming more frequent due to the shortage of cadaver liver donors. Success of this operation is critically dependent on detailed intra-hepatic ‘replumbing’ to achieve adequate vascular and bile flows post-operatively. Models of hepatic anatomy are currently being used to aid pre-surgical planning and intra-operative guidance. Moreover, multi-scale, biophysical and physiological models have been developed for the prediction of flow variations and parenchymal regrowth after liver transplantations or major resections. The aim of this paper is to provide a brief review of the state-of-the-art models and new trends.

Earlier diagnosis of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) increases treatment options and survival. The aim of this study is to evaluate which factors are associated with late presentation of HBV-related HCC.This is a retrospective review of all cases of HBV-related HCC diagnosed with late-stage/incurable HCC in New Zealand between 2003 and 2017. Cases were defined as patients with a positive hepatitis B surface antigen (HBsAg), and advanced (not amenable to potentially curable treatments) HCC at initial diagnosis. Patients were categorised into four groups according to potential reasons for late presentation: no previous diagnosis of HBV infection (Group A); known HBV diagnosis but not receiving HCC surveillance (Group B); known HBV diagnosis and receiving suboptimal HCC surveillance (Group C); and known HBV diagnosis and receiving optimised HCC surveillance (Group D).A total of 368 patients were reviewed. The average age at death was 59 years, and the majority of patients were Māori (39%), Pacific (34%) or Asian (20%). The incidence of patients presenting with HBV-related advanced HCC increased from 4.5 cases to 6.3 cases per million people over the review period. Of the cases, 40% were categorised into Group A, 26% into Group B, 12% into Group C and 23% in Group D. Overall, the median survival was 138 days, and this did not change during the study period. Patients receiving optimised surveillance (Group D) survived longer (mean 469 days) than patients in Group A (90 days), Group B (145 days) or Group C (152 days) (p0.05). Patients in Group D were more likely to be treated with transarterial chemoembolisation than patients in other groups (40% vs 15%, p0.05).This study has highlighted the need for improved rates of HBV diagnosis, better follow-up of those infected and the importance of optimal HCC surveillance. In New Zealand, HBV-related HCC disproportionately affects minority ethnic groups, and given the increasing incidence, provides a potential domain to reduce health inequities.

Background & aims Both liver disease (LD) and pancreatitis pose substantial burdens. There have been no general population-based studies on frequency of LD after an episode of pancreatitis. The aim of this study was to investigate the occurrence of LD in a population-based cohort of patients following pancreatitis. Methods Nationwide data on the general population of nearly 3 million people were used to identify retrospectively diagnoses of acute pancreatitis, chronic pancreatitis (CP), LD and cirrhosis from 1998 to 2016. Acute pancreatitis was categorised as first (FAP) or recurrent (RAP) episode. Number of pancreatitis recurrences prior to LD diagnosis was determined. Results A total of 20,931 pancreatitis patients were included, of which 874 developed LD following pancreatitis. The incidence of LD in FAP was 115.59 (95% confidence interval 102.19–128.98), in RAP – 217.63 (95% confidence interval 173.31–261.94), and in CP – 539.43 (95% confidence interval 494.72–584.13) patients per 100,000 pancreatitis patients per year. There was a significant increase in the probability of LD with increasing number of pancreatitis recurrences and, for the same number of pancreatitis recurrences, LD was significantly more frequent after CP than RAP (hazard ratio 1.666 (95% confidence interval 1.322–2.098; p = Conclusions The frequency of LD increases from FAP to RAP to CP. While number of pancreatitis recurrences is a significant risk factor for development of LD, there is a higher probability of LD following CP than RAP even for the same number of recurrences. Interventions preventing pancreatitis and its progression may lower the burden of LD.

Patient-reported outcome (PRO) measures (PROMs) are increasingly used as endpoints in surgical trials. PROs need to be consistently measured and reported to accurately evaluate surgical care. Laparoscopic cholecystectomy (LC) is a commonly performed procedure which may be evaluated by PROs. We aimed to evaluate the frequency and consistency of PRO measurement and reporting after LC. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for prospective studies reporting PROs of LC, between 2013 and 2016. Data on the measurement and reporting of PROs were extracted. A total of 281 studies were evaluated. Forty-five unique multi-item questionnaires were identified, most of which were used in single studies (n = 35). One hundred and ten unique rating scales were used to assess 358 PROs. The visual analogue scale was used to assess 24 different PROs, 17 of which were only reported in single studies. Details about the type of rating scale used were not given for 72 scales. Three hundred and twenty-three PROs were reported in 162 studies without details given about the scale or questionnaire used to evaluate them. Considerable variation was identified in the choice of PROs reported after LC, and in how they were measured. PRO measurement for LC is focused on short-term outcomes, such as post-operative pain, rather than longer-term outcomes. Consideration should be given towards the development of a core outcome set for LC which incorporates PROs.

Background Hepatic venous outflow obstruction (HVOO) is a rare but serious complication in liver transplantation (LT). Methods We conducted a retrospective analysis of HVOO with venography and gradient measurement in consecutive LT from a single centre. Results Five hundred and six LTs were performed in 486 patients with a median age of 49 years (range 3 months to 71 years). Nineteen (3.8%) cases of HVOO were identified. Diagnosis was confirmed at a median of 26 days post-LT (1–2312). The incidence fell from 5.5% in the first 253 LT, to 2.0% in the second 253 (P = 0.03). Seventeen were due to narrowing at the anastomosis and two cases were due to thrombosis. In adult patients, reconstruction of the supra-hepatic donor inferior vena cava (IVC) onto two veins versus modified 2–3 hepatic veins did not alter the likelihood of HVOO. 17/19 cases were managed successfully by stenting or venoplasty. Two paediatric patients with early onset HVOO had attempted surgical thrombectomy, one was successful and the other required retransplantation. Conclusion The incidence of HVOO appears to fall with increasing experience and does not appear to be related to the number of veins the donor IVC is anastomosed to in adult recipients.

To determine MR-imaging features for the differentiation between hepatocellular carcinoma (HCC) and benign hepatocellular tumors in the non-cirrhotic liver.107 consecutive patients without liver cirrhosis (46 male; 45 ± 14 years) who underwent liver resection due to suspicion of HCC were included in this multi-center study. The following imaging features were assessed: lesion diameter and demarcation, satellite-lesions, central-scar, capsule, fat-content, hemorrhage, vein-infiltration and signal-intensity (SI) on native T1-, T2- and dynamic-enhanced T1-weighted images (center versus periphery). In addition, contrast-media (CM) uptake in the liver specific phase was analyzed in a sub-group of 42 patients.Significant differences between HCC (n=55) and benign lesions (n=52) were shown for native T1-, T2- and dynamic-enhanced T1-SI, fat-content, and satellite-lesions (all, P.05). Independent predictors for HCC were T1-hypointensity (odds-ratio, 4.81), T2-hypo-/hyperintensity (5.07), lack of central tumor-enhancement (3.36), and satellite-lesions (5.78; all P0.05). Sensitivity and specificity of HCC was 91% and 75% respectively for two out-of four independent predictors, whereas specificity reached 98% for all four predictors. Sub-analysis, showed significant differences in liver specific CM uptake between HCC (n=18) and benign lesions (n=24; P0.001) and revealed lack of liver specific CM uptake (odds-ratio, 2.7) as additional independent feature for diagnosis of HCC.Independent MRI features indicating HCC are T1-hypointensity, T2-hypo- or hyperintensity, lack of central tumor-enhancement, presence of satellite-lesions and lack of liver specific CM-uptake. These features may have the potential to improve the diagnosis of HCC in the non-cirrhotic liver.

Introduction Delayed gastric emptying (DGE) is a common complication after a pylorus‐preserving pancreatoduodenectomy (PPPD) and is associated with significant morbidity. This study determines whether DGE is affected by antecolic (AC) or retrocolic (RC) reconstruction after a PPPD. Method An electronic search was performed of the MEDLINE, EMBASE and PubMed databases to identify all articles related to this topic. Pooled risk ratios (RR) were calculated for categorical outcomes, and mean differences (MD) for secondary continuous outcomes using the fixed‐effects and random‐effects models for meta‐analysis. Results Nine studies including 878 patients met the inclusion criteria. DGE was lower with an AC reconstruction RR 0.31 [0.12, 0.78] Z = 2.47 (P = 0.010). Length of stay (LOS) MD −4 days [−7.63, −1.14] Z = 2.65 (P = 0.008) and days to commence a solid diet MD −5 days [−6.63, −3.15] Z = 5.50 (P ≤ 0.000) were also significantly in favour of the AC group. There was no difference in the incidence of pancreatic fistula, intra‐abdominal collection/bile leak or mortality between the two groups. Conclusion AC reconstruction after PPPD is associated with a lower incidence of DGE. Time to oral intake was significantly shorter with AC reconstruction, with a reduced hospital stay.

Steatotic livers are susceptible to cold ischemia, which is thought to be secondary to mitochondrial dysfunction. Ischemic preconditioning (IPC) has been reported to improve liver function in the setting of warm ischemia/reperfusion injury, but the effect of IPC on steatotic liver mitochondrial function (MF) with cold ischemia has not been previously evaluated. We aimed to evaluate MF with various severities of hepatic steatosis after various durations of cold ischemia storage with or without IPC. Male Sprague-Dawley rats were fed a normal diet or a high-fat/high-sucrose diet for 1, 2, or 4 weeks to induce mild ( 60%) macrovesicular steatosis, respectively. Liver MF was tested with high-resolution respirometry after 1.5, 4, 8, 12, 18, and 24 hours of cold ischemia. Rats in each group (n = 10) underwent 10 minutes of IPC or no IPC before cold ischemia. The baseline (time 0) respiration was similar for lean and severely steatotic livers despite decreased mitochondrial complex I (C-I) activity in severely steatotic livers. Hepatic steatosis was associated with increased C-I–mediated leaks and decreased respiratory control ratios (RCRs) after cold ischemia. Mildly, moderately, and severely steatotic livers showed significantly lower RCRs after 8, 1.5, and 1.5 hours of cold ischemia, respectively, in comparison with lean livers. IPC restored RCRs in mildly steatotic livers to levels comparable to those in lean livers for up to 24 hours of cold ischemia via the attenuation of C-I–mediated leaks, but it had no beneficial effect on moderately and severely steatotic livers. In conclusion, steatotic livers exhibited apparent mitochondrial dysfunction through an alteration in C-I activity, and this made them more susceptible to prolonged cold ischemia. The clinically based IPC protocol used here restored MF in cases of mild hepatic steatosis by attenuating C-I–mediated leaks after prolonged cold ischemia, but it did work not in livers with moderate or severe steatosis. Liver Transpl 21:396–407, 2015. © 2015 AASLD.

BackgroundSteatotic livers are vulnerable to the deleterious effects of ischaemia–reperfusion injury (IRI) that occur after hepatic surgery. Ischaemic preconditioning (IPC) has been shown to abrogate the effects of IRI in patients undergoing hepatic surgery. Experimental studies have suggested that IPC may be beneficial in steatotic livers subjected to IRI.ObjectiveThe aim of this systematic review was to evaluate the effects of IPC on steatotic livers following hepatic IRI in experimental models.MethodsAn electronic search of the OVID Medline and EMBASE databases was performed to identify studies that reported clinically relevant outcomes in animal models of hepatic steatosis subjected to IPC and IRI.ResultsA total of 1093 articles were identified, of which 18 met the inclusion criteria. There was considerable heterogeneity in the type of animal model, and duration and type of IRI. Increased macrovesicular steatosis (> 30%) was associated with a poor outcome following IRI. Ischaemic preconditioning was found to be beneficial in > 30% steatotic livers and provided for decreased histological damage, improved liver function findings and increased survival.ConclusionsExperimental evidence supports the use of IPC in steatotic livers undergoing IRI. These findings may be applicable to patients undergoing liver surgery. However, clinical studies are required to validate the efficacy of IPC in this setting.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type., Cancer: Frequent chromosome loss in rare pancreatic tumors The loss of entire chromosomes seems to be a fundamental driver of tumors arising from the hormone-producing cells of the pancreas. A team led by Cristin Print and Ben Lawrence from the University of Auckland, New Zealand, performed genomic and pathological analysis of 57 pancreatic neuroendocrine tumors, a rare form of cancer caused by the abnormal growth of hormone-producing islet cells within the pancreas. The researchers observed two distinct patterns of chromosome loss, with 26% of the samples missing one copy of 10 specific chromosomes and another 40% lacking a copy of chromosome 11. In both groups, the abnormal chromosome count prompts abnormal gene activity patterns, with recessive mutations unleashed and expressed unopposed. Single gene mutations seem to play only a minor role, suggesting that single gene-targeted drugs will provide little benefit in this disease setting, with more nuanced approaches required.

As well as systemic vascular endothelial cells, the liver has specialised sinusoidal endothelial cells (LSEC). LSEC dysfunction has been documented in many diseased states yet their phenotype in normal human liver has not been comprehensively assessed. Our aim was to improve characterisation of subsets of endothelial cells and associated pericytes in the human liver. Immunofluorescence microscopy was performed on normal human liver tissue samples to assess endothelial and structural proteins in a minimum of three donors. LSEC are distributed in an acinar pattern and universally express CD36, but two distinctive subsets of LSEC can be identified in different acinar zones. Type 1 LSEC are CD36hiCD32−CD14−LYVE-1− and are located in acinar zone 1 of the lobule, while Type 2 LSEC are LYVE-1+CD32hiCD14+CD54+CD36mid-lo and are located in acinar zones 2 and 3 of the lobule. Portal tracts and central veins can be identified using markers for systemic vascular endothelia and pericytes, none of which are expressed by LSEC. In areas of low hydrostatic pressure LSEC are lined by stellate cells that express the pericyte marker CD146. Our findings identify distinctive populations of LSEC and distinguish these cells from adjacent stellate cells, systemic vasculature and pericytes in different zones of the liver acinus.