Surgical site infections in liver transplantation in the era of multidrug-resistant bacteria.

BACKGROUND: Surgical site infection (SSI) is the major complication in orthotopic liver transplantation (LT). It is of prime importance to assess the incidence of infections in liver transplants and to analyze the risk factors associated with morbidity and mortality. METHODS: Between 2014 and 2019, we performed a retrospective cohort study at the Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. The liver transplant procedure and its related infections were examined in 4 timepoints, both prior and post-surgery. Multiple random-intercept Poisson regression models with robust variance were fitted to calculate the adjusted risk ratios (RR) and the 95% confidence intervals (CI) according to selected recipient and donor variables. RESULTS: We included in the analysis 249 transplants (in 241 patients). The SSIs (mostly due to S. aureus, E. faecium, and K. pneumoniae) were 7 (2.8%) in the days following LT, increasing to 61 (24.5%) within the first month after LT, and declining to 35 (14.1%) between 31 and 60 days, and to 19 (7.6%) afterwards. The factors associated with increased risk of infection were age (RR=1.17 per 10 years, CI: 0.99-1.38), BMI (RR=1.04 per BMI Unit, CI: 0.99-1.08), donor age (RR=0.88 per 10 years, CI: 0.78-0.98), re-interventions (30 infections, RR=2.02, CI: 1.21-3.38) and the Roux-en-Y approach (25 infections, RR=2.75, CI: 1.47-5.15). CONCLUSIONS: The risk of infection occurred mainly in the first two months after LT. Important determinants were age and BMI, donor age, reinterventions, and Roux-en-Y procedure. Our study suggests that these factors should be assessed when performing LT.

The impact of the COVID-19 outbreak on liver transplantation programs in Northern Italy.

In January 2020, Novel Coronavirus Disease 2019 (COVID-19) resulted in a global pandemic, creating uncertainty toward the management of liver transplantation (LT) programs. Lombardy has been the most affected region in Italy: the current mortality rate of COVID-19 patients is 18.3% (10 022 deaths; April 10th) with hospitals in Lombardy having to expand the total number of ICU beds from 724 to 1381 to accommodate infected patients. There has been a drastic decrease in liver donors. From February 23rd until April 10th, 17 LTs were performed in Lombardy. Mean donor age was 49 years (range 18-74) whereas mean recipient age was 55 (13-69); mean MELD score was 12 (6-24). All donors underwent screening for SARS-CoV-2 prior to LT. Two patients tested positive after LT, and one patient died for COVID on POD 30. Sixteen patients are alive after an average of 30 days post-LT (range 3-46). 10 patients have been discharged. This study has found no specific reason concerning the safety of recipients, to stop LT programs. Several key lessons from our experience are reported. However, due to the complex circumstances which surround the viral outbreak, the cessation or a reduction in LT activity is a pragmatic requirement.

Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation.

BACKGROUND: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. METHODS: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected. RESULTS: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95% CI, 8-27); 5-year OS was 18% (95% CI, 4%-32%). Baseline predictors of OS were SOR+mTORi (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; P = 0.04), previous curative treatments (HR, 0.3; 95% CI, 0.2-0.7; P = 0.003) and alpha-fetoprotein > 100 ng/mL (HR, 2.5; 95% CI, 1.1-5.0, P = 0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR, 0.4; 95% CI 0.2-1.0; P = 0.04). CONCLUSIONS: Early and combined treatment with SOR and mTORi resulted in a favorable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.

Focus on Very Late Hepatocellular Carcinoma Recurring After Liver Transplantation: A Case Report and Literature Review.

Hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) is a major clinical concern, occurring in up to 20% and being the most frequent cause of death in this setting. Usually recurrence occurs within the first 2 years, whereas late and very late recurrences are rare. We report a 71-year-old woman with HCC recurrence after 25 years from LT, an event never reported before. Diagnosis was achieved with a progressive increase of alpha-fetoprotein (AFP) followed by a computed tomography scan, showing a mediastinal, upper diaphragmatic, right paracaval mass of 5 cm in size. The lesion was treated with a surgical approach involving a multidisciplinary team including hepatobiliary, thoracic, and cardiovascular surgeons. A sternotomy and mass removal was performed without the need of an extracorporeal bypass. A complete resection of the tumor was achieved, with a drop in AFP and without signs of recurrence after 1-year follow up. In conclusion, the possibility of late HCC recurrences after LT, despite being rare, underlines the need of a standardized, cost-benefit, optimal strategy of a long-term surveillance. From a surgical point of view, our case is unusual for the site and the character of the lesion, and for the absence of the need of an extracorporeal bypass during the operation.

Biliary Stones After Brain Dead Liver Transplantation Today: Rates, Risk Factors, Treatments, and Outcomes.

AIMS: Our aim was to review the rate of biliary duct stones (BDS) after liver transplantation (LT), risk factors, and treatments, and to identify predictive factors for their onset. METHODS: LTs performed in our center from 2004 to 2014 were studied. Risk factors for the onset of BDS were identified using univariable Cox's proportional hazards models. RESULTS: Three hundred and sixty-four grafts with 317 duct-to-duct end-to-end biliary anastomosis on a T-tube and 47 hepaticojejunal anastomosis (HJ) were analyzed. BDS were identified in 13 of 364 (3.5%) grafts, including 10 duct-to-duct end-to-end biliary anastomosis on a T-tube grafts (3.2%) and 3 HJ grafts (6.4%). Predictive factors for BDS were biliary strictures (hazard ratio [HR] 9.94; 95% confidence interval [95% CI] 3.25-30.4), bilirubin (HR 1.04; 95% CI 1.01-1.06, for 1 unit increase), Model for End-Stage Liver Disease score (HR 1.07; 95% CI 1.01-1.14, for 1 unit increase), surgery time (HR 1.04; 95% CI 1.01-1.08, for 10-minute increase), hepatocellular disease (HR 8.3; 95% CI 1.09-64.0), hepatic artery thrombosis (HR 6.71; 95% CI 1.47-30.6), and retransplantation (HR 3.69; 95% CI 1.02-13.43). Among 51 grafts (14%) with biliary strictures, female sex was identified as a risk factor for BDS (HR 5.19; 95% CI 1.29-20.98). Multimodality treatment of BDS was often successful but open surgery was still needed in 23% of them. One-, 5-, and 10-year graft survival was not influenced by the onset of BDS. CONCLUSION: Main predictive factor for BDS in liver grafts is biliary stricture. Recipient's age and body mass index failed to show any statistical importance. In grafts with biliary strictures, female sex is the main risk factor for BDS. In the absence of biliary strictures, hepatic artery thrombosis lead to an increase in the risk of BDS. Multimodality treatment of BDS is often successful. BDS do not influence outcome.

Unusual oral presentation of HSV-1 lesions in an adult liver transplant recipient.

Herpes Simplex Virus (HSV) hepatitis in liver transplant patients is a rarely reported infective complication of HSV with severe consequences, often leading to fulminant hepatitis if left untreated. The clinical signs are often atypical, leading to under-reporting in the literature and potential delays in treatment. Our case report describes such atypical mucocutaneous lesions in a liver transplant recipient. We highlight the need for further reports, especially those with images, in order to aid the diagnosis of HSV infection, and to allow prompt treatment to prevent complications such as HSV hepatitis.

Endo-therapies for biliary duct-to-duct anastomotic stricture after liver transplantation: Outcomes of a nationwide survey.

BACKGROUND: The most appropriate endo-therapeutic approach to biliary anastomotic strictures is yet to be defined. AIM: To retrospectively report on the endo-therapy of duct-to-duct anastomotic strictures during 2013 in Italy. METHODS: Data were collected from 16 Endoscopy Units at the Italian Liver Transplantation Centers (BASALT study group). RESULTS: Complete endo-therapy and follow-up data are available for 181 patients: 101 treated with plastic multistenting, 26 with fully covered self-expandable metal stenting and 54 with single stenting. Radiological success was achieved for 145 patients (80%), that is, 88% of plastic multistenting, 88% of self-expandable metal stenting and 61% of single stenting (P < 0.001 vs plastic multistenting; P < 0.05 vs self-expandable metal stenting). After first-line endo-therapy failure, the patients underwent a second-line endo-therapy with plastic multistenting for 25%, fully covered self-expandable metal stenting for 53% and single stenting for 22% of cases, and radiological success was achieved for 84%, that is, 100%, 85% and 63% with plastic multistenting, self-expandable metal stenting and single stenting (P < 0.05 vs plastic multistenting or self-expandable metal stenting) respectively. Procedure-related complications occurred in 7.8% of endoscopic retrograde cholangiopancreatographies. Overall, clinical success was achieved in 87% of patients after a median follow-up of 25 months. CONCLUSION: Plastic multistenting is confirmed as the preferred first-line treatment, while fully covered self-expandable metal stenting as rescue option for biliary anastomotic strictures. Single stenting has sub-optimal results and should be abandoned.

Prenatal and accurate perinatal diagnosis of type 2 H or ductular duplicate gallbladder.

BACKGROUND: Double gallbladder is a rare biliary anomaly. Perinatal diagnosis of the disorder has been reported in only 6 cases, and in 5 of them the diagnosis was based on ultrasound imaging only. However, the ultrasound technique alone does not provide a sufficiently precise description of cystic ducts and biliary anatomy, an information that is crucial for a correct classification and for a possible future surgery. CASE PRESENTATION: At 21 weeks of gestational age of an uneventful pregnancy in a 38 year old primipara mother, a routine ultrasound screening detected a biliary anomaly in the fetus suggestive of a double gallbladder. A neonatal abdominal ultrasonography performed on postnatal day 2 confirmed the diagnosis. On day 12 the newborn underwent a Magnetic Resonance Cholangiopancreatography (MRCP) that clearly characterized the anatomy of the anomaly: both gallbladders had their own cystic duct and both had a separate insertion in the main biliary duct. CONCLUSIONS: We report a case of early prenatal suspected duplicate gallbladder that was confirmed by a neonatal precise diagnosis of a Type 2, H or ductular duplicate gallbladder, using for the first time 3D images of Magnetic resonance cholangiopancreatography in a newborn. An accurate anatomical diagnosis is mandatory in patients undergoing a possible future cholecystectomy, to avoid surgical complications or reoperations. Therefore, in case of a perinatal suspicion of a double gallbladder, neonates should undergo a Magnetic resonance cholangiopancreatography. A review of the Literature about this variant is included.

Thrombosis after liver transplantation for hepatocellular carcinoma.

The influence of thrombosis on the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT) and the role of the commonest inherited thrombophilia abnormalities factor V Leiden and prothrombin G20210A in the development of thrombosis are unknown. We investigated a cohort of patients who underwent LT for HCC with the aim to estimate the incidence rate (IR) of thrombosis, its influence on mortality and re-transplantation rates and, in the frame of a nested case-control study, the role of thrombophilia in donors and recipients for the development of thrombosis. Four-hundred and thirty patients underwent LT and were followed for a median of 7.2 years. Twenty-six recipients (6%) developed thrombosis (IR 1.06 [95%CI: 0.71-1.53] per 100 pts-yr). Mortality rate after LT was 3.95 (95%CI: 3.22-4.79) per 100 pts-yr and was not influenced by thrombosis. Re-transplantation was planned for 33 patients and was more common in patients with thrombosis than in those without (HR 2.50 [95%CI: 0.87-7.17]). The risk of thrombosis was 4 times higher in recipients with thrombophilia than in those without (OR 4.23 [95%CI: 0.99-18.04]) and 6 times higher when the analysis was restricted to venous thrombosis (OR 6.26 [95%CI: 1.19-32.85]). The presence of inherited thrombophilia in the donors did not increase the risk of thrombosis of the recipient. In conclusion, thrombosis is a complication of 6% of patients transplanted for HCC and increases the risk of re-transplantation but not of mortality. The risk of thrombosis, particularly venous, is increased in the presence of thrombophilia abnormalities in the recipients.

Hepatectomy for hepatocellular carcinoma larger than 10 cm: preoperative risk stratification to prevent futile surgery.

OBJECTIVES: Appropriate patient selection is important to achieving good outcomes and obviating futile surgery in patients with huge (≥10 cm) hepatocellular carcinoma (HCC). The aim of this study was to identify independent predictors of futile outcomes, defined as death within 3 months of surgery or within 1 year from early recurrence following hepatectomy for huge HCC. METHODS: The outcomes of 149 patients with huge HCCs who underwent resection during 1995-2012 were analysed. Multivariate logistic regression analysis was performed to identify preoperative independent predictors of futility. RESULTS: Independent predictors of 3-month mortality (18.1%) were: total bilirubin level >34 µmol/l [P = 0.0443; odds ratio (OR) 16.470]; platelet count of <150 000 cells/ml (P = 0.0098; OR 5.039), and the presence of portal vein tumour thrombosis (P = 0.0041; OR 5.138). The last of these was the sole independent predictor of 1-year recurrence-related mortality (17.2%). Rates of recurrence-related mortality at 3 months and 1 year were, respectively, 6.3% and 7.1% in patients with Barcelona Clinic Liver Cancer (BCLC) stage A disease, 12.5% and 14% in patients with BCLC stage B disease, and 37.8% (P = 0.0002) and 75% (P = 0.0002) in patients with BCLC stage C disease. CONCLUSIONS: According to the present data, among patients submitted to hepatectomy for huge HCC, those with a high bilirubin level, low platelet count and portal vein thrombosis are at higher risk for futile surgery. The presence of portal vein tumour thrombosis should be regarded as a relative contraindication to surgery.

Fifteen years and 382 extended right grafts from in situ split livers in a multicenter study: Are these still extended criteria liver grafts?

In situ split liver extended right grafts (SL-ERGs) are still considered marginal grafts. Our aim was to verify this statement at the present time. From 1997 to 2011, a multicenter, retrospective study based on a prospective database was performed at 9 liver transplantation (LT) centers in northern Italy; it included 382 in situ SL-ERG transplants in adults. There were 358 primary LTs and 24 retransplantations (RETXs). The 1-, 3-, and 5-year overall graft survival rate for LT with in situ SL-ERGs were 73.5%, 63.3%, and 60.7%, respectively, from 1997 to 2004 and 83.5%, 80.3%, and 80.3%, respectively, thereafter (P=0.0001). A shorter total ischemia time and fewer RETX grafts were the main differences between the characteristics of the 2 periods. From 1997 to 2011, the 1-, 3-, and 5-year graft survival rates showed a significant difference between the 358 primary LT in situ SL-ERGs and the 24 RETX in situ SL-ERGs (P<0.001). In a multivariate analysis, the main prognostic factor for 60-day graft survival was a total ischemia time<8 hours for the 358 primary in situ SL-ERGs. From 2005 to 2011, in 2473 LTs, the 5-year graft survival for 184 in situ SL-ERGs and 2289 whole grafts was 75% and 80% (P=0.3), respectively. Univariate and multivariate studies alike failed to indicate that the type of graft was a prognostic factor for graft survival. A donor age>60 years, RETX grafts, and urgency were the main prognostic factors for failure for all of the grafts. Although caution should be taken regarding the choice of appropriate donors, in situ SL-ERGs should no longer be considered marginal grafts for experienced LT centers. SL-ERGs should not be used in RETX settings, and when SL-ERGs are used as primary grafts, the total ischemia time should be less than 8 hours.

Complex Liver Resection Using Standard Total Vascular Exclusion, Venovenous Bypass, and In Situ Hypothermic Portal Perfusion: An Audit of 77 Consecutive Cases.

OBJECTIVE: To identify independent predictors of 90-day mortality after liver resection for patients undergoing standard total vascular exclusion (TVE) with hypothermic portal perfusion and venovenous bypass. The secondary endpoint was to evaluate the long-term outcomes. BACKGROUND: Tumors invading the vena cava and/or the hepatocaval confluence are indications for standard TVE. The inclusion of liver hypothermic perfusion permits safe TVE. There are a limited number of reports focusing on this complex technique and no relevant analysis of short-term and long-term results. METHODS: Seventy-seven consecutive liver resections performed using standard TVE with hypothermic portal perfusion and venovenous bypass between 1998 and 2010 were analyzed. The independent predictors and rates of 90-day mortality, morbidity, and long-term survival were evaluated. RESULTS: The 90-day mortality rate was 19.5% (15 cases). Three independent predictors of mortality were identified: age-adjusted Charlson Comorbidity Index 3 or more (P = 0.0231; odds ratio = 47.565; 95% confidence interval = 1.701-1330.414), tumor size 10 cm or more (P = 0.0442; odds ratio = 6.374; 95% confidence interval = 1.049-38.734), and the presence of 50/50 criteria (P = 0.0407; odds ratio = 6.217; 95% confidence interval = 1.080-35.782). The overall 5-year survival rate was 30.4%. CONCLUSIONS: Liver resection using standard TVE with hypothermic portal perfusion and venovenous bypass is associated with a high mortality rate. The identification of preoperative predictors of mortality should improve the selection of patients for this aggressive surgery. Compared with nonsurgical management, the long-term results are acceptable and justify this aggressive surgery in selected patients.

Liver resection using total vascular exclusion of the liver preserving the caval flow, in situ hypothermic portal perfusion and temporary porta-caval shunt: a new technique for central tumors.

Standard total vascular exclusion (TVE) of the liver is indicated for resection of tumors involving or adjacent to the vena cava and/or the confluence of the hepatic veins. The duration of liver ischemia can be prolonged by combined portal hypothermic perfusion of the liver (in or ex situ). The use of a venovenous bypass (VVB) during standard TVE maintains stable hemodynamics as well as optimal renal and splanchnic venous drainage. When the hepatic veins can be controlled, TVE preserving the caval flow negates the need for VVB. However this technique remains limited in duration as it is performed under warm ischemia (so-called normothermia) of the liver. To prolong the ischemia time, we have designed a modification of TVE with preservation of the caval flow including the use of temporary porta-caval shunt (PCS) and hypothermic perfusion of the liver. We describe here the first two cases of this new technique. Two patients underwent left hepatectomy extended to segments 5 and 8 (also called extended left hepatectomy) for large centrally located tumors. TVE lasted seventy-two and seventy-nine minutes, respectively. The postoperative course was uneventful and both patients were discharged on day ten and day twenty-five respectively. Both are alive without recurrence at ten and seven months following surgery. Provided the roots of the hepatic veins can be controlled, this technique combines the advantages of standard TVE with in situ hypothermic perfusion and VVB and obviates the need and the subsequent risks of the latter.

Early and late de novo tumors after liver transplantation in adults: the late onset of bladder tumors in men.

BACKGROUND: De novo tumors (DNT) after liver transplantation (LT) represent a growing concern. PATIENTS AND METHODS: We analyzed the incidence of DNT, type, time of onset, risk factors and mortality (as of 2010) in 494 adult patients transplanted in the last 26 years (1983-2009). RESULTS: DNT occurred in 41 (8.3%) of the patients. The Standardized Incidence Ratio (SIR) compared with the Italian population was 1.8. There was a higher incidence in males (SIR 2.0), an expected extremely high rate of Kaposi's sarcoma (SIR 127.95) and unexpected higher rates of tumors of the bladder in males (SIR 3.3). The incidence of DNT was higher within the first two years of LT (SIR 2.7) for Kaposi's sarcoma (SIR 393.3) and after 10 years (SIR 1.7) for bladder tumors (SIR 10.6). Multivariate analysis identified alcoholic cirrhosis (HR = 3.0, 95% CI = 1.2-7.8) and sclerosing cholangitis (HR = 3.5, 95% CI = 1.1-11.3) in the recipient as main risk factors for the occurrence of DNT. CONCLUSIONS: Surveillance protocols for DNT must be specifically oriented to patients transplanted for alcoholic cirrhosis and sclerosing cholangitis. They should focus on early detection of Kaposi's sarcomas, and more remarkably, on late development bladder tumors in men after LT.

Thrombotic storm in a teenager with previously undiagnosed ulcerative colitis.

Venous thrombosis can complicate inflammatory bowel diseases, both in adult and pediatric patients, and a few adult cases of thrombotic storm, ie, thrombosis at multiple sites occurring over a period of a few days to a few weeks, have been described. However, venous thrombosis as the first manifestation of an inflammatory bowel disease is extremely rare. We report the case of a 14-year-old girl presenting with ascites and marked hypertransaminasemia resulting from hepatic vein occlusion (Budd-Chiari syndrome). Despite anticoagulant therapy, in the following days she developed criteria suggestive of thrombotic storm to include cerebral vein, right atrial thrombosis, and bilateral pulmonary embolism. Thrombolytic treatment with recombinant-tissue plasminogen activator was started, with resolution of all venous thromboses and without bleeding complications. Additional examinations revealed a severely active ulcerative pancolitis, which did not respond to medical treatment and required surgery. No thrombophilia abnormality nor other risk factors for thrombosis were detected. We conclude that an underlying inflammatory state, such as ulcerative colitis, should be suspected in pediatric patients with venous thrombosis storm.

Liver retransplantation in adults: the largest multicenter Italian study.

This study is the largest Italian survey on liver retransplantations (RET). Data report on 167 adult patients who received 2 grafts, 16 who received 3 grafts, and one who received 4 grafts over a 11 yr period.There was no statistically significant difference in graft survival after the first or the second RET (52, 40, and 29% vs 44, 36, and 18% at 1,5,and 10 yr, respectively: Log-Rank test, p = 0.30).Survivals at 1, 5, and 10 years of patients who underwent 2 (n = 151) or 3 (n = 15) RETs, were 65, 48,and 39% vs 59, 44, and 30%, respectively (p = 0.59).Multivariate analysis of survival showed that only the type of graft (whole vs reduced) was associated with a statistically significant difference (HR = 3.77, Wald test p = 0. 05); the donor age appeared to be a relevant factor as well, although the difference was not statistically significant (HR = 1.91, Wald test p = 0.08).Though late RETs have better results on long term survival relative to early RETs, no statistically significant difference can be found in early results, till three years after RET.Considering late first RETs (interval>30 days from previous transplantation) with whole grafts the difference in graft survival in RETs due to HCV recurrence (n = 17) was not significantly different from RETs due to other causes (n = 53) (65-58 and 31% vs 66-57 and 28% respectively at 1-5 and 10 years, p = 0.66).

Visceral artery aneurysms in liver transplant candidates and in patients after liver transplantation.

There are only few reviews concerning visceral aneurysms in cirrhotics, and a small number of papers on visceral aneurysms in liver transplant patients. The present paper investigates this condition in both groups of patients in a 10-year-retrospective study.