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.

A coordinated national UK liver transplant program response, prioritizing waitlist recipients with the highest need, provided excellent outcomes during the first wave of the COVID-19 pandemic.

INTRODUCTION: Healthcare provision has been severely affected by COVID-19, with specific challenges in organ transplantation. Here, we describe the coordinated response to, and outcomes during the first wave, across all UK liver transplant (LT) centers. METHODS: Several policy changes affecting the liver transplant processes were agreed upon. These included donor age restrictions and changes to offering. A "high-urgency" (HU) category was established, prioritizing only those with UKELD > 60, HCC reaching transplant criteria, and others likely to die within 90 days. Outcomes were compared with the same period in 2018 and 2019. RESULTS: The retrieval rate for deceased donor livers (71% vs. 54%; P < .0001) and conversion from offer to completed transplant (63% vs. 48%; P < .0001) was significantly higher. Pediatric LT activity was maintained; there was a significant reduction in adult (42%) and total (36%) LT. Almost all adult LT were super-urgent (n = 15) or HU (n = 133). We successfully prioritized those with highest illness severity with no reduction in 90-day patient (P = .89) or graft survival (P = .98). There was a small (5% compared with 3%; P = .0015) increase in deaths or removals from the waitlist, mainly amongst HU cohort. CONCLUSIONS: We successfully prioritized LT recipients in highest need, maintaining excellent outcomes, and waitlist mortality was only marginally increased.

Acinar Melanosis of the Bartholin Gland: A Report of 3 Cases.

Melanocytic pigmentation occurs in multiple sites in the lower female genital tract, but is rare within benign cysts of the vulva. We report 3 patients with multiloculated cystic lesions of the vulvar vestibule exhibiting prominent melanocytic pigmentation. The current cases differ from a previous report of melanosis in a Bartholin gland cyst in that the population of melanocytes occupies the acinar structures of the gland, rather than a squamous-lined surface. A similar cell population is demonstrated by immunoperoxidase methods in a fourth patient's nonpigmented gland, suggesting that melanin production may arise in a native, rather than metaplastic, cell population.

Heterogeneity of management practices surrounding operable gallbladder cancer - results of the OMEGA-S international HPB surgical survey.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive, uncommon malignancy, with variation in operative approaches adopted across centres and few large-scale studies to guide practice. We aimed to identify the extent of heterogeneity in GBC internationally to better inform the need for future multicentre studies. METHODS: A 34-question online survey was disseminated to members of the European-African Hepatopancreatobiliary Association (EAHPBA), American Hepatopancreatobiliary Association (AHPBA) and Asia-Pacific Hepatopancreatobiliary Association (A-PHPBA) regarding practices around diagnostic workup, operative approach, utilization of neoadjuvant and adjuvant therapies and surveillance strategies. RESULTS: Two hundred and three surgeons responded from 51 countries. High liver resection volume units (>50 resections/year) organised HPB multidisciplinary team discussion of GBCs more commonly than those with low volumes (p < 0.0001). Management practices exhibited areas of heterogeneity, particularly around operative extent. Contrary to consensus guidelines, anatomical liver resections were favoured over non-anatomical resections for T3 tumours and above, lymphadenectomy extent was lower than recommended, and a minority of respondents still routinely excised the common bile duct or port sites. CONCLUSION: Our findings suggest some similarities in the management of GBC internationally, but also specific areas of practice which differed from published guidelines. Transcontinental collaborative studies on GBC are necessary to establish evidence-based practice to minimise variation and optimise outcomes.

Significance of Biogenic Amines in Cold-Smoked Fish and Their Relation to Microbiological Characteristics of Products Available in Portuguese Retail Markets.

Studies on microbial characterization of cold-smoked salmon and salmon trout during cold storage were performed on samples available in the Portuguese market. Samples were also classified microbiologically according to guidelines for ready-to-eat (RTE) products. Further investigations on sample variability and microbial abilities to produce tyramine and histamine were also performed. The coefficient of variation for viable counts of different groups of microorganisms of samples collected at retail market point was high in the first 2 wk of storage, mainly in the Enterobacteriaceae group and aerobic plate count (APC), suggesting that microbiological characteristics of samples were different in numbers, even within the same batch from the same producer. This variation seemed to be decreased when storage and temperature were controlled under lab conditions. The numbers of Enterobacteriaceae were influenced by storage temperature, as indicated by low microbial numbers in samples from controlled refrigeration. Lactic acid bacteria (LAB) and Enterobacteriaceae were predominant in commercial products, a significant percentage of which were tyramine and less histamine producers. These results might be influenced by (1) the technological processes in the early stages of production, (2) contamination during the smoking process, and (3) conditions and temperature fluctuations during cold storage at retail market point of sale.

The discard of deceased donor kidneys in the UK.

It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002-3 to 12% in 2011-12. A national offering system for hard-to-place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31-80) yr. Kidneys had been offered to a median of 3 (1-12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard-to-place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.

The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis.

The role of hepatic venous pressure gradient (HVPG) measurement in risk stratification before liver resection is an ongoing area of debate. This study examines the impact of preoperative HVPG levels on overall survival (OS)/time to recurrence (TTR) and postoperative complications after hepatic resection of hepatocellular carcinoma (HCC). Thirty-eight HCC patients undergoing HVPG measurement before liver resection at Cambridge University Hospitals NHS Foundation Trust between January 2014 and April 2022 were retrospectively analysed. Statistical analysis comprised univariable/multivariable Cox/logistic regression to identify risk factors of reduced OS/TTR or 90-day post-resection complications and Kaplan-Meier estimator, log-rank, chi-squared, Fisher's exact, and Mann-Whitney U test, or Student's t-test for survival/subgroup analysis. The median HPVG was 6 (range: 0-14) mmHg. The HVPG was an independent risk factor for poorer TTR in the overall cohort (cut-off: ≥7.5 mmHg (17.18/43.81 months; P = 0.009)). In the subgroup analysis of cirrhotic patients (N = 29 (76%)), HVPG was additionally an independent risk factor for lower OS (cut-off: ≥8.5 mmHg [44.39/76.84 months; P = 0.012]). The HVPG had no impact on OS/TTR in non-cirrhotic patients (N = 9 (24%)), nor was it associated with postoperative complications in any cohort. In conclusion, preoperative HVPG levels are useful predictors for TTR and OS in cirrhotic HCC patients undergoing hepatic resection.

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study.

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding: Cambridge Hepatopancreatobiliary Department Research Fund.

Study protocol of a prospective single-arm multicenter clinical study to assess the safety and performance of the aXess hemodialysis graft: The pivotal study.

BACKGROUND: Arteriovenous grafts (AVGs) are used for patients deemed unsuitable for the creation of an autogenous arteriovenous fistula (AVF) or unable to await maturation of the AVF before starting hemodialysis. However, AVGs are prone to infection and thrombosis resulting in low long-term patency rates. The novel aXess Hemodialysis Graft consists of porous polymeric biomaterial allowing the infiltration by cells and the growth of neotissue, while the graft itself is gradually absorbed, ultimately resulting in a fully functional natural blood vessel. The Pivotal Study will examine the long-term effectiveness and safety of the aXess Hemodialysis Graft. METHODS: The Pivotal Study is a prospective, single-arm, multicenter study that will be conducted in 110 subjects with end-stage renal disease who are not deemed suitable for the creation of an autogenous vascular access. The primary efficacy endpoint will be the primary patency rate at 6 months. The primary safety endpoint will be the freedom from device-related serious adverse events at 6 months. The secondary endpoints will include the procedural success rate, time to first cannulation, patency rates, the rate of access-related interventions to maintain patency, the freedom from device-related serious adverse events and the rate of access site infections. Patients will be followed for 60 months. An exploratory Health Economic and Outcomes Research sub-study will determine potential additional benefits of the aXess graft to patients, health care institutions, and reimbursement programs. DISCUSSION: The Pivotal study will examine the long-term performance and safety of the aXess Hemodialysis Graft and compare the outcome measures with historical data obtained with other graft types and autogenous AVFs. Potential advantages may include superior long-term patency rates and lower infection rates versus currently available AVGs and a shorter time to first cannulation compared to an autologous AVF. As such, the aXess Hemodialysis Graft may fulfill an unmet clinical need in the field of hemodialysis access.

Emergency robotic colorectal surgery during COVID-19 pandemic: A retrospective case series study.

Objective: While interest in elective robotic surgery is growing, use in emergency setting remains limited due to challenges posed by sicker patients, advanced pathology and logistical issues. During the COVID-19 pandemic, robotic surgery could provide the benefit of having the surgeon away from the bedside and reducing the number of directly exposed medical staff. The objective of this study was to report patient outcomes and initial learning experience of emergency robotic colorectal surgery during the COVID-19 pandemic. Methods: A case series study was conducted, including patients undergoing emergency robotic colorectal surgery between February 2020 and February 2021 at Queen Alexandra Hospital in Portsmouth, UK. Patient data were collected from an ethics approved prospective database. Patient demographics, operative time, conversions and postoperative complications were recorded. In addition, readmissions, length of stay and short-term oncological outcomes were analyzed. Results: Ten patients with median age 64 y (range, 36-83 y) were included. Four patients had robotic complete mesocolic resection for obstructing cancers. Six had colorectal resections for benign disease in emergency setting. All were R0 with a mean lymph node harvest of 54 ± 13. Mean operative time was 249 ± 117 min, the median length of stay was 9.4 d (range, 5-22 d). Only one patient was given a temporary diverting ileostomy. There were no grade III/V complications and no 30-day mortality. Conclusions: Provided an experienced team and peri-operative planning, emergency robotic colorectal surgery can achieve favorable outcomes with benefits of radical lymph node dissection in oncological cases and avoidance of diverting stoma.

Malignant Melanoma With Neuroendocrine Differentiation: A Case Report and Literature Review.

BACKGROUND: Melanoma has a wide range of histologic variants and cytomorphologic features that make its diagnosis challenging. Melanoma can also rarely have neuroendocrine markers adding further diagnostic uncertainty particularly given that unrelated tumor types, such as prostate cancer, can also display focal neuroendocrine differentiations. CASE PRESENTATION: Our patient is a 74-year-old Caucasian man found to have a lung mass. Initial biopsy revealed typical microscopic morphology and neuroendocrine differentiation consistent with small cell carcinoma. Despite standard chemoradiation treatment, the patient continued to progress with new metastasis in the brain, liver and bone. Subsequent chest wall biopsy revealed golden-brown pigment associated with melanin. Further tumor immunohistochemistry revealed extensive neuroendocrine differentiation with CD56, synaptophysin, and INSM1, as well as strong immunoreactivity for melanocyte markers including SOX10, S100, PRAME, and MITF, consistent with metastatic melanoma with neuroendocrine differentiation. Genomic testing revealed increased tumor mutational burden and alterations in NF1, BRAF, CDKN2A/B, TERT. The patient was transitioned to checkpoint inhibitor therapy with nivolumab and ipilimumab and had resolution of his intracranial mass and decrease in size of other metastatic lesions. CONCLUSION: Often the combination of anatomic findings such as a lung mass, typical microscopic morphology, and confirmation of neuroendocrine differentiation correctly identifies a patient with small cell carcinoma. However, in a patient who fails to respond to treatment, a broader immunohistochemical workup along with molecular testing with additional tissue may be warranted.

A UK Expert Consensus Approach for Managing Symptomatic Arteriovenous Fistula (AVF) Stenosis in Haemodialysis Patients.

PURPOSE: Stenoses in mature arteriovenous fistulas (AVFs) are common and can negatively impact on the quality of haemodialysis, the longevity of the AVF and lead to debilitating symptoms. Multiple treatment options exist; however, management can vary between different centres. We aimed to establish multidisciplinary consensus on the optimal stepwise application of interventions based on evidence and consensus. METHODS: A modified Delphi process was conducted with 13 participants from hospitals across the UK, all of whom have high-volume dialysis access practice. RESULTS: The usual intervention to rectify de novo stenoses of mature AVFs is fistuloplasty, although surgery for inflow segment stenoses is also clinically acceptable. Appropriate first-line interventions include plain old balloon angioplasty or high-pressure balloon angioplasty; if these fail during the fistuloplasty, consider upsizing the balloon, prolonged balloon inflation or using alternative interventions, such as cutting or scoring balloons and ultra-high-pressure balloons. Alternative or subsequent interventions vary by anatomical site and may require additional multidisciplinary team input. For a stenoses recurring between 3 and 12 months, it is appropriate to consider interventions used de novo, but with a lower threshold for using drug-coated balloons (DCBs) in all regions and for using stent grafts in all regions but inflow segment. Recurrence after 12 months should be treated as a de novo lesion, with DCBs considered if they have been used successfully during previous interventions. CONCLUSIONS: These recommendations aim to provide a practical guide to multidisciplinary teams in order to optimise the use of multiple interventions for rectifying AVF stenoses and provide unified evidence-based practice guidelines.

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.

Assessment of the duration of protection in Campylobacter jejuni experimental infection in humans.

A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and duration of protection. Healthy Campylobacter-seronegative adults received C. jejuni strain 81-176 via oral inoculation of 10(5), 10(7), or 10(9) CFU (5 adults/dose), which was followed by clinical and immunological monitoring. Based on dose range clinical outcomes, the 10(9)-CFU dose (n = 31) was used to assess homologous protection at 28 to 49 days (short-term veterans [STV]; n = 8) or 1 year (long-term veterans [LTV]; n = 7) after primary infection. An illness dose effect was observed for naïve subjects (with lower doses, 40 to 60% of the subjects were ill; with the 10(9)-CFU dose, 92% of the subjects were ill) along with complete protection for the STV group and attenuated illness for the LTV group (57%). Partial resistance to colonization was seen in STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection.

Features of immune senescence in liver transplant recipients with established grafts.

Immune senescence is the normal process whereby the human immune system ages, but becomes less effective. We investigated whether liver transplant recipients have features of immune senescence. Lymphocytes from 97 liver transplant recipients with established grafts and 41 age-matched and sex-matched controls were subjected to an 8-color flow cytometry assay that measured expression of killer cell lectin-like receptor subfamily G member 1, cluster of differentiation 127 (CD127), CD45RO, CD27, CD28, CD4, CD8, and CD57. Lymphocyte telomere length was assessed by flow-fluorescence in situ hybridization. Cases were compared with controls for each marker of immune senescence using a Mann-Whitney U test. For liver transplant recipients, linear regression analyses identified associations between markers of immune senescence and clinical or demographic characteristics. Lymphocytes from liver transplant recipients expressed more phenotypic markers of maturity than did lymphocytes from controls. Lymphocyte telomeres were shorter in liver transplant recipients than in controls. Age, hepatocellular carcinoma at transplantation, and skin malignancy developing after transplantation were associated independently with shortened lymphocyte telomeres. Increasing age and previous cytomegalovirus infection were associated independently with phenotypic markers of lymphocyte maturity. Thus, lymphocytes from liver transplant recipients are older "biologically" than lymphocytes from age-matched and sex-matched controls. Hepatocellular carcinoma at transplantation, subsequent skin malignancy, and previous cytomegalovirus infection are associated with lymphocyte senescence in liver transplant recipients.

Tumor recurrence following liver transplantation for hepatocellular carcinoma: role of tumor proliferation status.

The selection of patients with hepatocellular carcinoma for liver transplantation is currently based on the size and number of tumors to minimize the risk of recurrence. These criteria measure tumor bulk but may not reflect tumor behavior accurately. A biological marker of tumor behavior could aid with patient selection further. The aims of this study were to determine factors associated with a higher risk of tumor recurrence and to assess the role of tumor proliferation status with respect to recurrence following transplantation. Pathological data on 67 patients who underwent transplantation for hepatocellular carcinoma were reviewed, and tumor proliferation was assessed by minichromosome maintenance protein-2 (MCM-2) and cyclin A expression. A Cox regression analysis of factors related to tumor recurrence and overall survival was carried out. Recurrence-free survival was assessed according to compatibility with selection criteria, vascular invasion, and proliferation status. Tumor size, vascular invasion, and highest MCM-2 expression were associated with tumor recurrence by multivariate analysis (P < 0.02). Recurrence-free survival was significantly better for those patients without vascular invasion, those who were within the Milan, University of California San Francisco (UCSF), or Up-to-Seven selection criteria, and those with lower expression of MCM-2. In conclusion, tumors meeting the Milan, UCSF, or Up-to-Seven selection criteria had a lower rate of recurrence following liver transplantation. Vascular invasion and tumor proliferation status were associated with the risk of recurrence independently of tumor size. Biopsy of larger tumors to assess proliferative activity could identify those at lower risk of recurrence who could also benefit from liver transplantation.