A narrative review of intrahepatic cholangiocarcinoma: a surgical curative option.

BACKGROUND AND OBJECTIVE: Cholangiocarcinoma (CCA) is the second commonest primary liver malignancy. Nowadays, the only available treatment with curative intent of intrahepatic cholangiocarcinoma (iCCA) is surgical resection, with a 5-year overall survival (OS) of 25-40%. However, recurrence rate remains high. In this comprehensive review, we describe the newest surgical strategies for iCCA management, including vascular resection, the role of mini-invasive surgery, liver transplant, strategies for future liver remnant augmentation, and the role of neoadjuvant therapies. METHODS: A review of medical databases (PubMed, Scopus and Cochrane Database) was conducted selecting most relevant articles in English language without a specific timeframe. KEY CONTENT AND FINDINGS: Multifocal presentation, vascular, perineural invasion, and lymph nodes involvement are associated with poor outcome. Prognostic factors are being investigated to improve therapeutic approach and outcomes. The role of lymph nodes dissection remains debated. Harvesting at least 6 lymph nodes is recommended to ensure accurate nodal staging. Liver transplantation (LT) recently represented a treatment option only in patients with unresectable early disease (≤2 cm). CONCLUSIONS: Surgical resection remains the only potentially curative treatment for patients with CCA, but continue understanding in diagnosis, operative technique and chemotherapies are changing the landscape in the prognosis. Multicentric and randomized studies are necessaries in the future research with the intent to personalize the treatments, improve patient selection for the resection and reduce recurrence rate.

The role of sequential normothermic regional perfusion and end-ischemic normothermic machine perfusion in liver transplantation from very extended uncontrolled donation after cardiocirculatory death.

The use of pre-procurement normothermic regional perfusion (NRP) allowed us to implement controlled DCD liver transplantation with results comparable to brain death donors, but the use of uncontrolled DCD is declining due to logistic challenges and the high incidence of post-transplant complications. In Italy, the mandatory stand-off period of 20 min for DCD donors has driven the combined use of NRP and ex-situ machine perfusion with the intent to counterbalance the negative impact of prolonged warm ischemia. Organ viability during NRP is based on duration of warm ischemia, regional perfusion flow, lactate, transaminases values and histology, and those used in Italy are the widest worldwide. However, this evaluation can be difficult, especially when the acute damage is particularly severe. The use of ex-situ NRP could provide a safe organ evaluation. In the period from 06/2020 to 06/2022, all DCD grafts exceeding NRP viability criteria at a single center were eventually evaluated using ex-situ normothermic machine perfusion. Machine perfusion viability criteria were based on lactate clearance, irrespectively to bile production, unless 1-h transaminases perfusate level were not exceeding 5000 IU/L. Three cases of uncontrolled DCD grafts in excess of NRP viability criteria underwent ex-situ graft evaluation. Two matched ex-situ normothermic machine perfusion viability criteria and were successfully transplanted. Both recipients are doing well after 26 and 5 months after surgery with no signs of ischemic cholangiopathy. This experience suggests that the sequential use of NRP and normothermic machine perfusion may further expand the boundaries of organ viability in uncontrolled DCD liver transplantation.

Use of an intraoperative veno-venous bypass during liver transplantation: an observational, single center, cohort study.

BACKGROUND: As previous studies demonstrated conflicting results, we investigated the hemodynamic and renal outcomes of the intra-operative use of a veno-venous bypass during liver transplantation. METHODS: The intraoperative levels of mean artery pressure, cardiac index, inferior vena cava and renal perfusion pressures were compared in liver transplant patients receiving or not the bypass. RESULTS: We enrolled 38 patients: 20 with the bypass and 18 without. No differences characterized the two groups regarding gender (P=0.95), age (P=0.32), BMI (P=0.09), liver disease indicating LT and preoperative serum creatinine levels. Patients with the bypass received more intraoperative fluids (crystalloids and colloids) but with no difference in terms of intraoperative blood products and vasopressors requirements (P=0.33). After clamping of the inferior vena cava, patients with the bypass showed higher mean artery pressure. Simultaneously, pressure in the inferior vena cava below the clamp level sharply increased vs. baseline (P<0.0001) independently of the use of the bypass and remained high until clamp release. Consequently, renal perfusion pressure dropped abruptly (P<0.0001) after vena cava clamping and returned to baseline only upon clamp removal. Overall, 18 subjects developed postoperative acute kidney injury which was equally distributed between patients with (n=9) or without (N.=8) the bypass. CONCLUSIONS: Our data suggest that the use of a veno-venous bypass fails to release the increased renal venous backflow from inferior vena cava clamping resulting in renal congestion with reduced renal perfusion pressure.

Liver transplantation in Jehovah's witnesses: 13 consecutive cases at a single institution.

BACKGROUND: Jehovah's Witnesses represent a tremendous clinical challenge when indicated to liver transplantation because they refuse blood transfusion on religious grounds and the procedure is historically associated with potential massive peri-operative blood loss. We herein describe a peri-operative management pathway with strategies toward a transfusion-free environment with the aim not only of offering liver transplant to selected Jehovah's Witnesses patients but also, ultimately, of translating this practice to all general surgical procedures. METHODS: This is a retrospective review of prospective medical records of JW patients who underwent LT at our Institution. The peri-operative multimodal strategy to liver transplantation in Jehovah's Witnesses includes a pre-operative red cell mass optimization package and the intra-operative use of normovolemic haemodilution, veno-venous bypass and low central venous pressure. RESULTS: In a 9-year period, 13 Jehovah's Witness patients received liver transplantation at our centre representing the largest liver transplant program from deceased donors in Jehovah's Witnesses patients reported so far. No patient received blood bank products but 3 had fibrinogen concentrate and one tranexamic acid to correct ongoing hyper-fibrinolysis. There were 4 cases of acute kidney injury (one required extracorporeal renal replacement treatment) and one patient needed vasoactive medications to support blood pressure for the first 2 postoperative days. Two patients underwent re-laparotomy. Finally, of the 13 recipients, 12 were alive at the 1 year follow-up interview and 1 died due to septic complications. CONCLUSIONS: Our experience confirms that liver transplantation in selected Jehovah's Witnesses patients can be feasible and safe provided that it is carried out at a very experienced centre and according to a multidisciplinary approach.

Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors.

Ex situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts. In this study, 20 primary liver transplantation recipients of older grafts (≥70 years) were randomized 1:1 to NMP or cold storage (CS) groups. The primary study endpoint was to evaluate graft and patient survival at 6 months posttransplantation. The secondary endpoint was to evaluate liver and bile duct biopsies; IRI by means of peak transaminases within 7 days after surgery; and incidence of biliary complications at month 6. Liver and bile duct biopsies were collected at bench surgery, end of ex situ NMP, and end of transplant surgery. Interleukin (IL) 6, IL10, and tumor necrosis factor α (TNF-α) perfusate concentrations were tested during NMP. All grafts were successfully transplanted. Median (interquartile range) posttransplant aspartate aminotransferase peak was 709 (371-1575) IU/L for NMP and 574 (377-1162) IU/L for CS (P = 0.597). There was 1 hepatic artery thrombosis in the NMP group and 1 death in the CS group. In NMP, we observed high TNF-α perfusate levels, and these were inversely correlated with lactate (P < 0.001). Electron microscopy showed decreased mitochondrial volume density and steatosis and an increased volume density of autophagic vacuoles at the end of transplantation in NMP versus CS patients (P < 0.001). Use of NMP with older liver grafts is associated with histological evidence of reduced IRI, although the clinical benefit remains to be demonstrated.

Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study.

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.

Octogenarian donors in liver transplantation grant an equivalent perioperative course to ideal young donors.

BACKGROUND: Use of grafts from very old donors for liver transplantation is controversial. AIM: To compare the perioperative course of patients receiving liver grafts from young ideal vs octogenarian donors. METHODS: Analysis of the perioperative course of patients receiving liver grafts from young, ideal (18-39 years) vs octogenarian (≥80years) deceased donors between 2001 and 2014. RESULTS: 346 patients were studied: 179 (51.7%) received grafts aged 18-39 years whereas 167 (48.3%) received a graft from a donor aged ≥80years. Intra-operative cardiovascular (p=0.2), coagulopathy (p=0.5) and respiratory (p=1.0) complications and incidence of reperfusion syndrome (p=0.3) were similar. Patients receiving a young graft required more fresh frozen plasma units (p≤0.03) but did not differ for the need of packed red cells (p=0.2) and platelet (p=0.3) transfusions. Median ICU stay was identical (p=0.4). Patients receiving octogenarian vs young grafts did not differ in terms of death or re-transplant (p=1.0) during the ICU stay. Similar cardiovascular, respiratory, renal, infectious and neurological postoperative complication rates were observed in the two groups. CONCLUSIONS: Octogenarian donors in liver transplantation grant an equivalent perioperative course to ideal young donors.

Intravenous fenoldopam for early acute kidney injury after liver transplantation.

PURPOSE: Acute kidney injury remains a serious complication after orthotopic liver transplantation. To date, several 'renal-protective' agents have been explored in this setting but with conflicting and disappointing results. Therefore, our aim is to evaluate the effects of fenoldopam in liver transplant patients with an established renal injury. METHODS: In this prospective study, intravenous fenoldopam 0.1 µg/kg/min was administered to consecutive liver transplant patients with postoperative (within 7 days from surgery) stage 2 acute kidney injury (AKI) according to the Acute Kidney Injury Network classification. Actual glomerular filtration rate (GFR; calculated by the iohexol plasma clearance), serum creatinine (SCr) and cystatin C (SCyC) were used to assess the effect of the medication on the patients. RESULTS: During the study, 295 patients underwent liver transplant. Fifty-one patients (17.6%) met the inclusion criteria and the data from 48 patients were analysed. SCr and SCyC levels decreased (p < 0.001 after 48 h; p < 0.0001 after 72 h) and GFR increased (p < 0.001 after 24 h; p < 0.0001 after 72 h). When compared to a cohort of comparable patients with AKI from our historical series, the patients in the present study showed better SCr and SCyC levels. It was not necessary to discontinue the infusion of fenoldopam in any patient because of the occurrence of adverse events potentially attributable to it. CONCLUSION: We showed that fenoldopam was capable of improving some renal function parameters in postoperative liver transplantation patients with on-going AKI. This preliminary study now sets the stage for a multicenter, randomized, placebo-controlled trial in order to provide definite evidence.

The challenges of diagnosing thrombotic thrombocytopenic purpura in the critically ill. A case report.

Thrombotic thrombocytopenic purpura (TTP) is associated with high mortality rates. TTP may have various and different presentations depending on the organs involved. It is now recognized to be the consequence of reduction of blood levels of the disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13. Prompt diagnosis of TTP is paramount, because plasma exchange is the only treatment capable of improving patient's survival with a dual mechanism: removal of anti-ADAMTS-13 auto-antibodies and infusion of the active protease available in the fresh frozen plasma. We report herein on the challenges in diagnosing TTP-like complications of post-surgical facial surgery in a young male patient.

Fever, mental impairment, acute anemia, and renal failure in patient undergoing orthotopic liver transplantation: posttransplantation malaria.

A case of post-transplant malaria is described. The patient presented fever and severe anemia after orthotopic liver transplantation. Diagnosis was made only after the review of donor characteristics. Although a high parasitemia was found at the moment of diagnosis, the treatment with quinine and doxycycline was successful. Donor epidemiology should always be considered for a prompt diagnosis of rare tropical diseases in the graft recipients.

Early morbidity after pancreas transplantation.

This study aims to evaluate and compare the early outcome of both pancreas-alone transplantation (PTA) and simultaneous kidney-pancreas transplantation (SPKT) focusing on the complications affecting the first month after the procedures. The records of all patients who underwent PTA or SPKT were reviewed. We considered the length of ICU stay, the need for postoperative ventilatory support, hemodynamic and metabolic data (arterial pH, serum glucose, need for exogenous insulin), infectious diseases incidence, microbiological colonization rate and any kind of postoperative complication arising during the first month after the transplantation. PTA recipients underwent a quicker surgery (P < 0.01) with shorter ICU stay (P < 0.05) and a lower need for postoperative mechanical ventilation (P < 0.05). They also had a higher hemodynamic stability (P < 0.05) with less cardiological complications (P < 0.05) in the intra- and postoperative phases; bacterial colonisation was also less frequent in PTA recipients (P < 0.05). On the contrary, no significant difference was noted with regard to postoperative nausea/vomiting, sudden myocardial death, ICU re-admissions, graft function, rate of rejection, grafts explantation and re-transplantation. PTA could be considered as preemptive for severe diabetic complications in patients with long-lasting severe type I diabetes. However, establishing the correct timing of PTA is of paramount importance in order not to expose the patients early to risks arising from a major surgery and heavy immunosuppressive treatments.

Stress-inducing factors in ICUs: what liver transplant recipients experience and what caregivers perceive.

The aim of this study was to compare a number of potentially stress-generating factors related to an intensive care unit (ICU) stay from the points of view of patients undergoing liver transplantation or elective major abdominal surgery and their caregivers in order to identify differences and similarities that may help to optimize patient care. The ICU Environmental Stressor Scale questionnaire was administered to 104 liver transplant recipients, 103 major abdominal surgery patients, 35 nurses and 21 physicians. The ICU staff were asked to complete the questionnaire on the basis of their perception of patient stressors. Both patient groups identified Being unable to sleep, Being in pain, Having tubes in nose/mouth, Missing husband/wife, and Seeing family and friends only a few minutes a day as the major stressors; the healthcare providers correctly identified the most stressing factors for the patients, but gave them higher scores. The mean scores were 71.9 +/- 18.7 for the transplant recipients, 66.3 +/- 20.9 for the patients undergoing elective major abdominal surgery, 99.7 +/- 19.2 for the nurses, and 92.7 +/- 16.1 for the physicians (P < 0.001). The qualitative evaluations of potentially stress-inducing ICU situations were substantially the same in the 2 patient groups, but the transplant recipients seemed to feel them more acutely. Although the caregivers identified the most discomforting situations, they overestimated the degree of stress they cause. The staff of each ICU should therefore seek to understand and reduce (even by means of simple interventions) the particular causes of psychophysical stress felt by their patients.

Postoperative intra-abdominal pressure and renal function after liver transplantation.

HYPOTHESIS: Intra-abdominal hypertension frequently threatens renal function early after orthotopic liver transplantation (OLT). DESIGN: A prospective study of consecutive patients who underwent OLT. SETTING: The intensive care unit of a National Health Service teaching hospital. PATIENTS AND MAIN OUTCOME MEASURES: The intra-abdominal pressure (IAP) of 108 consecutive patients who underwent OLT was postoperatively measured 3 times a day for 72 hours using the urinary bladder technique. Intra-abdominal hypertension was defined as an IAP of 25 mm Hg or higher. RESULTS: Thirty-four patients (31%) had a high IAP. Acute renal failure developed in 17 recipients (16%), 11 (65%) of whom had intra-abdominal hypertension (P<.01), with a mean +/- SD IAP of 27.9 +/- 9.9 mm Hg vs 18.6 +/- 5.2 mm Hg in those without acute renal failure (P<.001). The subjects with a high IAP were more frequently administered loop diuretics to maintain adequate diuresis (P<.001) and had a low mean arterial pressure on the day of surgery (P<.01), despite the fact that they were given more intravenous fluids (P<.01) and did not differ in the need for inotropic drugs. Logistic regression analysis showed that intraoperative transfusions of more than 15 U, respiratory failure, and intra-abdominal hypertension (P<.01) were independent risk factors for renal failure. The length of intensive care unit stay was similar in the patients with a normal and a high IAP, but mortality was higher among the latter (P =.02). CONCLUSIONS: Intra-abdominal hypertension is common after OLT and is significantly associated with renal failure, reduced urinary output, and intensive care unit mortality. It is, therefore, worth monitoring IAP in those undergoing OLT.

Intra-abdominal pressure monitoring in liver transplant recipients: a prospective study.

OBJECTIVE: No data are available on the incidence and clinical relevance of increased intra-abdominal pressure after orthotopic liver transplantation. This study assessed abdominal hypertension in a population of transplanted patients as this may be an important cofactor in early postoperative complications. DESIGN AND SETTING: Prospective clinical study in an intensive care unit of a national health system teaching hospital PATIENTS AND MEASUREMENTS: Abdominal pressure was measured every 6 h using the urinary bladder method and was considered elevated when it was 25 mmHg or higher. Hemodynamic status was evaluated at the same times. Renal function was assessed on the basis of hourly urinary output by calculating serum creatinine on postoperative days 2 and 4 and the filtration gradient; patient outcomes were also considered. RESULTS: Intra-abdominal hypertension was observed in 32% of cases; the subjects with high abdominal pressure had significantly lower mean artery pressure values but did not differ in terms of central venous pressure or cardiac output. High intra-abdominal pressure was more frequently associated with renal failure, a lower filtration gradient, delayed postsurgical weaning from ventilation, and a worse outcome. CONCLUSIONS: Abdominal hypertension is frequent after liver transplantation and may be associated with a complicated post-operative course.

Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study.

The aim of this study was to evaluate the efficacy of two antifungal prophylaxis regimens in liver transplant recipients. One hundred and twenty-nine consecutive recipients were randomized to receive sequential treatment with intravenous liposomal amphotericin B + oral itraconazole, intravenous fluconazole + oral itraconazole, or intravenous and oral placebo. Frequency and incidence of mycotic colonization, local and systemic infection of mycotic origin, causes of death, and possible risk factors for mycotic infection were evaluated. The incidence of mycotic colonization was higher in the placebo group ( P<0.01), but there was no significant difference in the incidence of infection between the three groups. Pre-transplant colonization, severity of liver disease, and graft rejection were all risk factors for the development of fungal infection. The routine use of antifungal prophylaxis for all liver transplant recipients does not seem to be justified.