Proctitis in patients with monkeypox infection: a single-center analysis of 42 consecutive cases from a multidisciplinary observational study on monkeypox proctitis.

BACKGROUND: The current monkeypox (MP) virus outbreak was declared an international emergency in July 2022. The aim of this report is to describe our initial experience with patients with MP, focusing on proctitis. METHODS: We conducted an observational study between 20 May and 31 July 2022, on patients with MP at a reference tertiary center in Madrid, Spain. A descriptive analysis on MP was performed, focusing on its characteristics, symptoms, diagnosis, and outcomes. RESULTS: A total of 143 positive MP cases were diagnosed in our center; 42 of them [all male, median age 39 years (range: 22-57 years)] had proctitis (29.37%), and 3 patients (2.09%/MP total cases and 7.14%/MP proctitis) required surgical drainage of a perianal abscess. CONCLUSIONS: General and digestive surgeons must be aware of the presence of proctological impairment and complications due to MP virus.

Factors Associated with Prolonged Recipient Hepatectomy Time During Liver Transplantation: A Single-Centre Experience.

BACKGROUND: Recipient hepatectomy during liver transplantation can be a challenging operation and can increase cold ischaemic time. The aim of this study is to assess factors associated with prolonged recipient hepatectomy. METHODS: From 2005 to 2015, 930 patients were submitted to liver transplantation in our hospital. Prolonged hepatectomy time was defined as operative time >180 min (from knife on skin to total hepatectomy). Patients undergoing early liver retransplantation and living donation were excluded. RESULTS: A total of 715 patients were included in our study. Median age at transplantation was 53 (18-70) years, and median BMI was 26.2 (16-40). Median hepatectomy time was 131 min. Prolonged hepatectomy time occurred in 89 (12.4%) patients. At univariate analysis, previous decompensated cirrhosis with variceal bleeding and/or ascites, higher BMI and previous abdominal surgery were associated with prolonged operating time. Higher surgeon experience and acute liver failure were associated with shorter hepatectomy time. At multivariate analysis, previous episodes of variceal bleeding (p = 0.027, OR 1.78), BMI > 27 (p = 0.01, OR 1.75), previous abdominal surgery (p = 0.04, OR 1.68) and surgeon experience (p = 0.007, OR 2.04) were independently associated with operating time. Prolonged hepatectomy time was significantly associated with cold and total ischaemic time and intraoperative bleeding (p < 0.001, p = 0.002 and p = 0.002, respectively). CONCLUSIONS: Recipient BMI, previous episodes of variceal bleeding, previous abdominal surgery and surgeon experience are independently associated with hepatectomy duration. These factors can be helpful to identify those patients with potentially prolonged hepatectomy time, and therefore, strategies can be put in place to optimize outcomes in this group of patients.

Liver Transplant From Unexpected Donation After Circulatory Determination of Death Donors: A Challenge in Perioperative Management.

Unexpected donation after circulatory determination of death (uDCD) liver transplantation is a complex procedure, in particular when it comes to perioperative recipient management. However, very little has been published to date regarding intraoperative and immediate postoperative care in this setting. Herein, we compare perioperative events in uDCD liver recipients with those of a matched group of donation after brain death liver recipients. We demonstrate that the former group of recipients suffers significantly greater hemodynamic instability and derangements in coagulation following graft reperfusion. Based on our experience, we recommend a proactive recipient management strategy in uDCD liver transplantation that involves early use of vasopressor support; maintaining adequate intraoperative levels of red cells, platelets, and fibrinogen; and routinely administering tranexamic acid before graft reperfusion.

Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)µg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF.

Coagulation profiles of unexpected DCDD donors do not indicate a role for exogenous fibrinolysis.

It has been suggested that vascular stasis during cardio-circulatory arrest leads to the formation of microvascular thrombi and the viability of organs arising from donation after circulatory determination of death (DCDD) donors may be improved through the application of fibrinolytic therapy. Our aim was to comprehensively study the coagulation profiles of Maastricht category II DCDD donors in order to determine the presence of coagulation abnormalities that could benefit from fibrinolytic therapy. Whole blood from potential DCDD donors suffering out-of-hospital cardiac arrest was sampled after declaration of death in the emergency department, and rotational thromboelastomeric analysis was performed. Between July 2012 and December 2013, samples from 33 potential DCDD donors were analyzed. All patients demonstrated hyperfibrinolysis (HF), as reflected by maximum clot lysis of 98-100% in all cases, indicating that there is no role for additional fibrinolytic therapy in this setting. As well, we observed correlations between thromboelastomeric lysis parameters and maximum hepatic transaminase levels measured in potential donors and renal artery flows measured during ex situ hypothermic oxygenated machine perfusion, indicating that further studies on the utility of thromboelastometry to evaluate organ injury and perhaps even viability in unexpected DCDD may be warranted.

Somatostatin therapy protects porcine livers in small-for-size liver transplantation.

Small-for-size (SFS) injury occurs in partial liver transplantation due to several factors, including excessive portal inflow and insufficient intragraft responses. We aim to determine the role somatostatin plays in reducing portal hyperperfusion and preventing the cascade of deleterious events produced in small grafts. A porcine model of 20% liver transplantation is performed. Perioperatively treated recipients receive somatostatin and untreated controls standard intravenous fluids. Recipients are followed for up to 5 days. In vitro studies are also performed to determine direct protective effects of somatostatin on hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). At reperfusion, portal vein flow (PVF) per gram of tissue increased fourfold in untreated animals versus approximately threefold among treated recipients (p = 0.033). Postoperatively, markers of hepatocellular, SEC and HSC injury were improved among treated animals. Hepatic regeneration occurred in a slower but more orderly fashion among treated grafts; functional recovery was also significantly better. In vitro studies revealed that somatostatin directly reduces HSC activation, though no direct effect on SEC was found. In SFS transplantation, somatostatin reduces PVF and protects SEC in the critical postreperfusion period. Somatostatin also exerts a direct cytoprotective effect on HSC, independent of changes in PVF.

Fibronectin-α4ß1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway.

Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical settings. The expression of fibronectin (FN) by endothelial cells is a prominent feature of the hepatic response to injury. Here we investigate the effects of the connecting segment-1 (CS-1) peptide therapy, which blocks FN-α4ß1 integrin leukocyte interactions, in a well-established model of 24-h cold liver IRI. CS-1 peptides significantly inhibited leukocyte recruitment and local release of proinflammatory mediators (COX-2, iNOS and TNF-α), ameliorating liver IRI and improving recipient survival rate. CS1 therapy inhibited the phosphorylation of p38 MAPK, a kinase linked to inflammatory processes. Moreover, in addition to downregulating the expression of matrix metalloproteinase-9 (MMP-9) in hepatic IRI, CS-1 peptide therapy depressed the expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) by macrophages, a membrane-tethered MMP important for focal matrix proteolysis. Inhibition of p38 MAPK activity, with its pharmacological antagonist SB203580, downregulated MMP-9 and MT1-MMP/MMP-14 expressions by FN-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls FN-mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of FN in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI.

Applicability and results of Maastricht type 2 donation after cardiac death liver transplantation.

Maastricht type 2 donation after cardiac death (DCD) donors suffer sudden and unexpected cardiac arrest, typically outside the hospital; they have significant potential to expand the donor pool. Herein, we analyze the results of transplanted livers and all potential donors treated under our type 2 DCD protocol. Cardiac arrest was witnessed; potential donors arrived at the hospital after attempts at resuscitation had failed. Death was declared based on the absence of cardiorespiratory activity during a 5-min no-touch period. Femoral vessels were cannulated to establish normothermic extracorporeal membrane oxygenation, which was maintained until organ recovery. From April 2002 to December 2010, there were 400 potential donors; 34 liver transplants were performed (9%). Among recipients, median age, model for end-stage liver disease and cold and reperfusion warm ischemic times were 55 years (49-60), 19 (14-21) and 380 (325-430) and 30 min (26-35), respectively. Overall, 236 (59%) and 130 (32%) livers were turned down due to absolute and relative contraindications to donate, respectively. One-year recipient and graft survivals were 82% and 70%, respectively (median follow-up 24 months). The applicability of type 2 DCD liver transplant was <10%; however, with better preservation technology and expanded transplant criteria, we may be able to improve this figure significantly.

Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

Applicability and results of liver transplant combined with neoadjuvant chemo-radiotherapy in the treatment of unresectable hilar cholangiocarcinoma. / Aplicabilidad y resultados del trasplante hepático combinado con quimiorradioterapia neoadyuvante en el tratamiento del colangiocarcinoma perihiliar irresecable.

BACKGROUND: In 2007, a multicenter protocol was developed in Catalonia, Spain, combining neoadjuvant chemoradiotherapy and liver transplantation (LT) for those patients with unresectable hilar cholangiocarcinoma (hCCA). AIM: To analyse the effectiveness of the neoadjuvant chemoradiotherapy and LT for those patients enrolled in the protocol based on intention-to-treat. METHODS: Observational multicenter study which includes patients ≤ 68 years-old diagnosed with unresectable, solitary tumors ≤ 3 cm in radial diameter, without evidence of lymph node metastases. The protocol was based on a strategy of neoadjuvant therapy with high-dose radiation (45 Gy in total) plus intravenous fluorouracil (5-FU) given as a daily bolus for the first 3 days of radiation follow by oral capecitabine until transplantation. The patient was included in waiting list for LT if no evidence of disseminated disease was found. RESULTS: Between 2007 and 2018, 13 patients were enrolled in the transplant protocol. Of those, 61% (8/13) of the patients were transplanted. The average time spent on the waiting list was 122 days (range 5-192). Intent-to-treat survival was 69% and 39% at one and 5 years. Post-transplantation overall survival was 87% and 62% and 29% recurrence rate at 5 years. CONCLUSION: The suitability of the neoadjuvant chemoradiotherapy and LT protocol was 61% in our series with long-term overall survival and should be considered as an alternative to resection for patients with localized node-negative hCCA.

Liver transplant with controlled donors after circulatory death with normothermic regional perfusion and brain dead donors: A multicenter cohort study of transfusion, one-year graft survival and mortality.

BACKGROUND: Controlled donation after circulatory death (cDCD) has expanded the donor pool for liver transplantation (LT). However, transfusion requirements and perioperative outcomes should be elucidated. The aim of this multicenter study was to assess red blood cell (RBC) transfusions, one-year graft and patient survival after LT after cDCD with normothermic regional perfusion (NRP) compared with donors after brain death (DBD). METHODS: 591 LT carried out in ten centers during 2019 were reviewed. Thromboelastometry was used to manage coagulation and blood product transfusion in all centers. Normothermic regional perfusion was the standard technique for organ recovery. RESULTS: 447 patients received DBD and 144 cDCD with NRP. Baseline MCF Extem was lower in the cDCD group There were no differences in the percentage of patients (63% vs. 61% p = 0.69), nor in the number of RBC units transfused (4.7 (0.2) vs 5.5 (0.4) in DBD vs cDCD, p = 0.11. Twenty-six patients (6%) died during admission for LT in the DBD group compared with 3 patients (2%) in the cDCD group (p = 0.15). To overcome the bias due to a worse coagulation profile in cDCD recipients, matched samples were compared. No differences in baseline laboratory data, or in intraoperative use of RBC or one-year outcome data were observed between DBD and cDCD recipients. CONCLUSIONS: cDCD with NRP is not associated with increased RBC transfusion. No differences in graft and patient survival between cDCD and DBD were found. Donors after controlled circulatory death with NRP can increasingly be utilized with safety, improving the imbalance between organ donors and the ever-growing demand.

90Y-Radioembolization After Failed Portal Vein Embolization for Colorectal Liver Metastases: A Case Report.

The main limiting factor for liver resection is insufficient future liver remnant (FLR). Portal vein embolization (PVE) is a standard of care treatment to induce FLR hypertrophy, but it is not always efficient. Radioembolization (RE) has a potential to induce liver hypertrophy for PVE-refractory patients. However, this was reported only for the patients with hepatocellular carcinoma. We described two cases of lobar RE after PVE failure for the patients with colorectal liver metastases. This enabled to reach sufficient FLR, provide good local disease control and bridge the patients to extended hepatectomy.

Cytoprotective effects of a cyclic RGD peptide in steatotic liver cold ischemia and reperfusion injury.

The serious need for expanding the donor population has attracted attention to the use of steatotic donor livers in orthotopic liver transplantation (OLT). However, steatotic livers are highly susceptible to hepatic ischemia-reperfusion injury (IRI). Expression of fibronectin (FN) by endothelial cells is an important feature of hepatic response to injury. We report the effect of a cyclic RGD peptide with high affinity for the alpha5beta1, the FN integrin receptor, in a rat model of steatotic liver cold ischemia, followed by transplantation. RGD peptide therapy ameliorated steatotic IRI and improved the recipient survival rate. It significantly inhibited the recruitment of monocyte/macrophages and neutrophils, and depressed the expression of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and interferon (IFN)-gamma. Moreover, it resulted in profound inhibition of metalloproteinase-9 (MMP-9) expression, a gelatinase implied in leukocyte migration in damaged livers. Finally, we show that RGD peptide therapy reduced the expression of the 17-kDa active caspase-3 and the number of apoptotic cells in steatotic OLTs. The observed protection against steatotic liver IRI by the cyclic RGD peptides with high affinity for the alpha5beta1 integrin suggests that this integrin is a potential therapeutic target to allow the successful utilization of marginal steatotic livers in transplantation.

Hepatitis C virus compartmentalization and infection recurrence after liver transplantation.

Hepatitis C virus (HCV) compartmentalization may have important implications in the pathogenesis of HCV infection. The aim of this study was to investigate the presence and relevance of HCV compartmentalization in the setting of liver transplantation (LT). We collected samples of serum, peripheral blood mononuclear cells (PBMC), perihepatic lymph nodes (PLN) and liver explant at the time of LT, and serum and PBMC after transplantation from 57 HCV-infected cirrhotic patients undergoing LT: 38 individuals received antiviral treatment before LT and 19 were untreated controls. HCV-RNA levels were determined by real-time PCR and the hypervariable region 1 (HVR-1) was sequenced. HCV-RNA was detected in all samples from control patients. In virological responders, recurrence after LT was associated with residual HCV-RNA in the liver explant. Within the entire cohort, 47% of patients harbored differences in direct sequences from distinct compartments. Quasispecies analysis revealed that in most cases, HVR-1 sequences recovered after infection recurrence were identical or closely related to those isolated from the liver explant and serum at the time of LT. Our study shows that a significant proportion of HCV-infected cirrhotic patients exhibit compartmentalization. Viral variants originating within the liver appear to be the main cause of HCV recurrence after LT.

Role of Adult Living Donor Liver Transplantation in the Treatment of Hepatocellular Carcinoma Within and Beyond Milan Criteria: A Comparative Study.

BACKGROUND AND AIMS: In the context of the shortage of donors, adult living donor liver transplantation (aLDLT) represents a feasible alternative for patients within as well as beyond the Milan criteria. METHODS: From 2001, we performed 42 aLDLTs for hepatocellular carcinoma (HCC). Sixteen of the recipients were within the Milan criteria, whereas 26 fulfilled the Barcelona-Clinic Liver Cancer Group (BCLC) expanded criteria (1 tumor ≤7 cm, 5 tumors ≤3 cm, or tumors 3 ≤5 cm without macrovascular invasion or down-staging to Milan after loco-regional therapies). The objective of the current study was to compare the post-transplantation results of these two groups. RESULTS: Six Milan-in and 16 beyond Milan patients received neo-adjuvant loco-regional therapies. One Milan-in and nine patients from the beyond Milan group presented an explant histological stage beyond Milan. After a median follow-up of 64 months, 5- and 10-year overall survival rates were 60.2% and 51.6% in the Milan-in group and 78% and 65% in the beyond Milan group. Five- and 10-year disease-free survival rates were 64.5% and 55.3% in the Milan-in patients and 67.9% and 56.6% in the beyond Milan patients. Being beyond up-to-seven criteria in the histology of the explant was a significant factor for HCC recurrence. CONCLUSION: The use of aLDLT in patients with HCC within and beyond Milan but within the BCLC expanded criteria offers acceptable survival and recurrence rates. Therefore, we believe that its use in this scenario is justified.

Fibronectin-alpha4beta1 integrin interactions modulate p42/44 MAPK phosphorylation in steatotic liver cold ischemia-reperfusion injury.

We investigated the effects of the connecting segment-1 (CS1) peptide, which blocks fibronectin (FN)-alpha4beta1 integrin interactions upon cell signaling, leukocyte migration, and secretion of proinflammatory cytokines, in a well-established steatotic rat liver model using ex vivo cold ischemia followed by isotransplantation. In this model, CS1 peptides were administered through the portal vein of steatotic Zucker rat livers prior and after cold ischemic storage. Lean Zucker recipients of fatty orthotopic liver transplantation (OLT) received an additional 3-day course of CS1 peptides post-OLT. CS1 peptide-treated steatotic OLTs harvested at 1, 3, and 7 days showed moderated levels of p42/44 mitogen-activated protein kinase (MAPK) phosphorylation, comparable to those observed in steatotic naive livers. In contrast, p42/44 MAPK phosphorylation was found up-regulated in 1- to 3-day damaged control OLTs. However, 7-day control OLTs were characterized by virtually lack of p42/44 MAPK phosphorylation. Lack of p42/44 MAPK phosphorylation in 7-day control OLTs was correlated with massive presence of leukocytes in the grafts and elevated levels of proinflammatory cytokines. CS1 peptide-treated OLTs at 7 days showed a profound decrease in T-cell (10 +/- 3 vs 56 +/- 20, P < .03) and monocyte/macrophage (+/++ vs +++) infiltration and significantly reduced levels of cytokine expression, such as IL-2 (approximately sixfold), and IFN-gamma (approximately three- to fourfold), as compared with controls.

Portal vein thrombosis in liver transplantation.

In the initial experience of liver transplantation, complete thrombosis and portal vein occlusion were considered to be absolute contraindications for liver transplantation. The incidence of portal thrombosis in patients being prepared for transplantation varies between 5% and 15% according to published series. There are 2 surgical techniques to solve absent or low portal vein flow due to thrombosis. The most widely used technique is thrombectomy and the second technique is insertion of a shunt with a venous graft in the permeable portion of the superior mesenteric vein or in a vein in the splanchnic territory. Portal thrombosis recurrence rates vary among series, ranging from 0% to 25% or even 30%, depending on its extension and severity and also on time the transplantation was performed. Although overall survival is somewhat lower, there are no significant differences in most of the series when patients with portal thrombosis who underwent transplantation are compared with those without.

HO-1 upregulation suppresses type 1 IFN pathway in hepatic ischemia/reperfusion injury.

Upregulation of heme oxygenase (HO)-1, a heat shock protein 32, protects against hepatic ischemia/reperfusion (I/R) injury. Activation of "innate" toll-like receptor (TLR) 4 system triggers the I/R injury cascade. This study explores cytoprotective functions of HO-1 overexpression following exogenous administration of cobalt protoporphyrin (CoPP), and its relationship with the TLR4 pathway in a model of mouse partial hepatic warm I/R injury. CoPP treatment markedly improved hepatic function and histology, and suppressed pro-inflammatory cytokine elaboration profile, as compared with untreated controls. Although administration of CoPP did not affect intrahepatic TLR4, it downregulated IFN-inducible protein 10 (IP-10) expression. As IP-10 is the major product of type-1 IFN pathway downstream of TLR4, we then infused recombinant IFN-beta (rIFN-beta) directly into mouse livers. Interestingly, infusion of rIFN-beta upregulated hepatic IP-10 expression. In contrast, adjunctive CoPP treatment decreased IP-10 levels in mouse livers infused with rIFN-beta. Thus, CoPP-induced HO-1 upregulation suppresses type-1 IFN pathway downstream of TLR4 system in hepatic warm I/R injury model.