Bridge Therapy before Liver Transplant for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be considered. Bridge therapies have been introduced in order to limit this issue. The aim of this study is to evaluate if bridge therapies in advanced hepatocellular carcinoma can improve overall survival and reduce de-listing. We selected 185 articles. The search was limited to English articles involving only adult patients. These were deduplicated and articles with incomplete text or irrelevant conclusions were excluded. Sorafenib is the standard of care for advanced hepatocellular carcinoma and increases overall survival without any significant drug toxicity. However, its survival benefit is limited. The combination of transarterial chemoembolization + sorafenib, instead, delays tumor progression, although its survival benefit is still uncertain. A few studies have shown that patients undergoing transarterial chemoembolization + radiation therapy have similar or even better outcomes than those undergoing transarterial chemoembolization or sorafenib alone for rates of histopathologic complete response (89% had no residual in the explant). Also, the combined therapy of transarterial chemoembolization + radiotherapy + sorafenib was compared to the association of transarterial chemoembolization + radiotherapy and was associated with a better survival rate (24 vs. 17 months). Moreover, immunotherapy revealed new encouraging perspectives. Combination therapies showed the most encouraging results and could become the gold standard as a bridge to transplant for patients with advanced hepatocellular carcinoma.

Age and liver graft: a systematic review with meta-regression.

Increasing organ shortage results in extended criteria donors (ECD) being used to face the growing demand for liver grafts. The demographic change leads to greater use of elderly donors for liver transplantation, historically considered marginal donors. Age is still considered amongst ECD in liver transplantation as it could affect transplant outcomes. However, what is the cutoff for donor age is still unclear and debated. A search of PubMed, Scopus and Cochrane Library was performed. The primary outcome was 1-year graft survival (GS). The secondary outcome was overall biliary complications and 3-5 years of graft and overall survival. A meta-regression model was used to analyse the temporal trend relation in the survival outcome. The meta-analysis included 11 studies. Hazard ratios for 1-year (age cutoff of 70 and 80,) and 5-year GS (I2:0%) were similar irrespectively of the age group. The meta-regression analysis showed a significant correlation between the 1-year graft survival and the year of publication. (coef. 0.00027, 95% CI - 0.0001 to - 0.0003 p = 0.0009). Advanced-age donors showed an increased risk of overall biliary complications with an odd ratio (OR) of 1.89 (95% CI 1-3.65). Liver grafts potentially discharged because of high-risk failure show encouraging results, and GS in ECD has progressively improved with a temporal trend. Currently, the criteria of marginality vary amongst centres. Age alone cannot be considered amongst the extended criteria. First of all, because of the positive results in terms of septuagenarian graft survival. Moreover, the potential elderly donor-related adjunctive risk can be balanced by reducing other risk factors. A prospective multicentre study should investigate a multi-factorial model based on donor criteria, recipient features and new functional biomarkers to predict graft outcome, as proper donor-recipient matching seems to be the critical point for good outcomes.

A "cui prodest" evaluation on the development of a minimally invasive liver surgery program: a differential benefit analysis of open and laparoscopic approach for left and right hemihepatectomies.

BACKGROUND: The correlation between technical feasibility and short-term clinical advantage provided by laparoscopic over open technique for major hepatectomies is unclear. This monocentric retrospective study investigates the possible differences in the benefit provided by minimally invasive approach between left and right hepatectomy, deepening the concept of differential benefit in the setting of anatomical major resections. METHODS: All hemihepatectomies performed from January 2004 to December 2021 were identified in the institutional database. A propensity score method was used to match minimal invasive (MILS) and open pairs in the left hemihepatectomies (LH) and right hemihepatectomies (RH) groups with a 1:1 ratio to adjust any potential selection bias. The differential benefit for left and right hepatectomy provided by laparoscopic over open technique was evaluated in a pure analysis (i.e., including cases converted to open) and a risk-adjusted analysis (i.e., after excluding open conversion from the laparoscopic series). RESULTS: The analysis of the risk-adjusted differential benefit demonstrated better result of the MILS in the RH group than in the LH group, in terms of blood loss (∆ blood loss - 150 and - 350, respectively; differential benefit: 200 mL, p < 0.05), morbidity (∆ rate of morbidity - 11.3% and - 18.1%, respectively; differential benefit: 6.8%, p < 0.05) and length of stay, LOS (∆ LOS - 1 day and - 3 days, respectively; differential benefit: 2 days, p < 0.05). CONCLUSION: While MILS is associated with improved clinical outcomes both in left and right hepatectomy procedures, the greater advantage provided by laparoscopy was documented in patients undergoing right hepatectomy, i.e. for more technically demanding procedures. A MILS program should include the broadest range of liver resections to ensure the full benefits of the laparoscopic technique.

The failure to rescue factor: aftermath analyses on 224 cases of perihilar cholangiocarcinoma.

The term "failure to rescue" (FTR) has been recently introduced in the field of hepato-biliary surgery to label cases in which major postoperative complications lead to postoperative fatality. Perihilar cholangiocarcinoma (PHC) surgery has consistently high postoperative morbidity and mortality rates in which factors associated with FTR are yet to be discovered. The primary endpoint of this study is to compare the Rescue with the FTR cohort referencing patients' characteristics and management protocols applied. A cohort of 224 consecutive patients undergoing surgery for PHC, between 2010 and 2021, was enrolled. Perioperative variables were analyzed according to the severity of major postoperative complications (Clavien ≥ 3a). Kaplan-Meier survival analyses were performed to determine complications' impact on survival. Major complications were reported in 86 cases (38%). Among the major complications' cohort, 72 cases (84%) were graded Clavien 3a-4 (Rescue group), while 14 (16%) cases were graded Clavien 5 (FTR group). Number of lymph-node metastases (OR = 1.33 (1.08-1.63) p = 0.006), poorly differentiated (G3) adenocarcinoma (OR = 7.55 (1.24-45.8) p = 0.028, reintervention (OR = 16.47 (2.76-98.08) p = 0.002), and prognostic nutritional index < 40 (OR = 3.01 (2.265-3.654) p < 0.001) rates were independent predictors of FTR. Right resection side (OR 2.4 (1.33-4.34) p = 0.004) increased the odds of major complications but not of FTR. No difference in overall survival was identified. A distinction of perioperative factors associated with postoperative complications' severity is crucial. Patients developing severe outcomes seem to have different biological and nutritional profiles, showing that efficient preoperative protocols are strategic to identify and avert the risk of FTR.

Current Perspectives in Liver Transplantation for Perihilar Cholangiocarcinoma.

Cholangiocarcinoma (CCA) encompasses all malignant neoplasms arising from the epithelial cells of the biliary tree. About 40% of CCAs are perihilar, involving the bile ducts distal to the second-order biliary branches and proximal to the cystic duct implant. About two-thirds of pCCAs are considered unresectable at the time of diagnosis or exploration. When resective surgery is deemed unfeasible, liver transplantation (LT) could be an effective alternative. The overall survival rates after LT at 1 and 3 years are 91% and 81%, respectively. The overall five-year survival rate after transplantation is 73% (79% for patients with underlying PSC and 63% for de novo pCCA). Multicenter case series reported a 5-year disease-free survival rate of ~65%. However, different protocols, including neoadjuvant therapy, have been proposed. The scarcity of organ availability represents a crucial limiting factor in recommending LT preferentially in treating pCCA. Living donor transplantations and marginal cadaveric allografts have proven to be exciting options to overcome organ shortage. Management of jaundice and cholangitis is still challenging for these patients and could impact LT listing. Whether to adopt surgical resection or LT as standard-of-care in pCCA is still a matter of debate, and more prospective studies are needed.

Safe pregnancy after liver transplantation: Evidence from a multicenter Italian collaborative study.

BACKGROUND: Women who have undergone liver transplantation (LT) enjoy better health, and possibility of childbearing. However, maternal and graft risks, optimal immunosuppression, and fetal outcome is still to clarify. AIM: Aim of the study was to assess outcomes of pregnancy after LT at national level. METHODS: In 2019, under the auspices of the Permanent Transplant Committee of the Italian Association for the Study of the Liver, a multicenter survey including 14 Italian LT-centers was conducted aiming at evaluating the outcomes of recipients and newborns, and graft injury/function parameters during pregnancy in LT-recipients. RESULTS: Sixty-two pregnancies occurred in 60 LT-recipients between 1990 and 2018. Median age at the time of pregnancy was 31-years and median time from transplantation to conception was 8-years. During pregnancy, 4 recipients experienced maternal complications with hospital admission. Live-birth-rate was 100%. Prematurity occurred in 25/62 newborns, and 8/62 newborns had low-birth-weight. Cyclosporine was used in 16 and Tacrolimus in 37 pregnancies, with no different maternal or newborn outcomes. Low-birth-weight was correlated to high values of AST, ALT and GGT. CONCLUSION: Pregnancy after LT has good outcome; however, maternal complications and prematurity may occur. Compliance with the immunosuppression is fundamental to ensure the stability of graft function and prevent graft-deterioration.

Impact of MELD 30-allocation policy on liver transplant outcomes in Italy.

BACKGROUND & AIMS: In Italy, since August 2014, liver transplant (LT) candidates with model for end-stage liver disease (MELD) scores ≥30 receive national allocation priority. This multicenter cohort study aims to evaluate time on the waiting list, dropout rate, and graft survival before and after introducing the macro-area sharing policy. METHODS: A total of 4,238 patients registered from 2010 to 2018 were enrolled and categorized into an ERA-1 Group (n = 2,013; before August 2014) and an ERA-2 Group (n = 2,225; during and after August 2014). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of receiving a LT or death between the two eras. The Fine-Gray model was used to estimate the HR for dropout from the waiting list and graft loss, considering death as a competing risk event. A Fine-Gray model was also used to estimate risk factors of graft loss. RESULTS: Patients with MELD ≥30 had a lower median time on the waiting list (4 vs.12 days, p <0.001) and a higher probability of being transplanted (HR 2.27; 95% CI 1.78-2.90; p = 0.001) in ERA-2 compared to ERA-1. The subgroup analysis on 3,515 LTs confirmed ERA-2 (odds ratio 0.56; 95% CI 0.46-0.68; p = 0.001) as a protective factor for better graft survival rate. The protective variables for lower dropouts on the waiting list were: ERA-2, high-volume centers, no competition centers, male recipients, and hepatocellular carcinoma. The protective variables for graft loss were high-volume center and ERA-2, while MELD ≥30 remained related to a higher risk of graft loss. CONCLUSIONS: The national MELD ≥30 priority allocation was associated with improved patient outcomes, although MELD ≥30 was associated with a higher risk of graft loss. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes. CLINICAL TRIAL NUMBER: NCT04530240 LAY SUMMARY: Italy introduced a new policy in 2014 to give national allocation priority to patients with a model for end-stage liver disease (MELD) score ≥30 (i.e. very sick patients). This policy has led to more liver transplants, fewer dropouts, and shorter waiting times for patients with MELD ≥30. However, a higher risk of graft loss still burdens these cases. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes.

Presepsin as Early Marker of Sepsis in Emergency Department: A Narrative Review.

The diagnosis and treatment of sepsis have always been a challenge for the physician, especially in critical care setting such as emergency department (ED), and currently sepsis remains one of the major causes of mortality. Although the traditional definition of sepsis based on systemic inflammatory response syndrome (SIRS) criteria changed in 2016, replaced by the new criteria of SEPSIS-3 based on organ failure evaluation, early identification and consequent early appropriated therapy remain the primary goal of sepsis treatment. Unfortunately, currently there is a lack of a foolproof system for making early sepsis diagnosis because conventional diagnostic tools like cultures take a long time and are often burdened with false negatives, while molecular techniques require specific equipment and have high costs. In this context, biomarkers, such as C-Reactive Protein (CRP) and Procalcitonin (PCT), are very useful tools to distinguish between normal and pathological conditions, graduate the disease severity, guide treatment, monitor therapeutic responses and predict prognosis. Among the new emerging biomarkers of sepsis, Presepsin (P-SEP) appears to be the most promising. Several studies have shown that P-SEP plasma levels increase during bacterial sepsis and decline in response to appropriate therapy, with sensitivity and specificity values comparable to those of PCT. In neonatal sepsis, P-SEP compared to PCT has been shown to be more effective in diagnosing and guiding therapy. Since in sepsis the P-SEP plasma levels increase before those of PCT and since the current methods available allow measurement of P-SEP plasma levels within 17 min, P-SEP appears a sepsis biomarker particularly suited to the emergency department and critical care.

Does chronic oral anticoagulation reduce in-hospital mortality among COVID-19 older patients?

BACKGROUND: Patients hospitalized with COVID-19 experienced an increased risk of venous thromboembolism. AIMS: To evaluate the effect of chronic oral anticoagulation (OAC) therapy, both with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), on prognosis of COVID-19 older patients. METHODS: Single-center prospective study conducted in the Emergency Department (ED) of a teaching hospital, referral center for COVID-19 in central Italy. We evaluated all the patients ≥ 65 years, consecutively admitted to our ED for confirmed COVID-19. We compared the clinical outcome of those who were on chronic OAC at ED admission with those who did not, using a propensity score matched paired cohort of controls. The primary study endpoint was all-cause in-hospital death. Patients were matched for age, sex, clinical comorbidities, and clinical severity at presentation (based on NEWS ≥ 6). Study parameters were assessed for association to all-cause in-hospital death by a multivariate Cox regression analysis to identify independent risk factor for survival. RESULTS: Although overall mortality was slightly higher for anticoagulated patients compared to controls (63.3% vs 43.5%, p = 0.012), the multivariate adjusted hazard ratio (HR) for death was not significant (HR = 1.56 [0.78-3.12]; p = 0.208). Both DOACs (HR 1.46 [0.73-2.92]; p = 0.283) and VKAs (HR 1.14 [0.48-2.73]; p = 0.761) alone did not affect overall survival in our cohort. CONCLUSIONS: Among older patients hospitalized for COVID-19, chronic OAC therapy was not associated with a reduced risk of in-hospital death. Moreover, our data suggest similar outcome both for patients on VKAs or in patients on DOACs.

Pregnancy After Liver Transplant: Neonatal Outcomes and Long-Term Maternal Follow-up.

BACKGROUND: Today, women who have undergone liver transplantation enjoy better health, so they encounter more frequently the possibility of living pregnancy. Many questions about the safety of pregnancy are pending. This study analyzes pregnancy outcomes in women with a liver transplant managed at Policlinico Universitario "A.Gemelli." RESULTS: We identified 17 childbirths in 13 women who had undergone a liver transplant. Causes of transplant include congenital or acquired disorders. The mean age at transplant was 22 ± 9 years, mean maternal age at delivery was 33 ± 5 years, and transplant-to-pregnancy interval was 12 ± 6 years. The mean gestational week was 36.1 ± 3.5. All women had normal liver function after pregnancy. Immunosuppressive therapy before and during pregnancy included tacrolimus (n = 8), cyclosporine (n = 5) and mycophenolate mofetil (n = 1). No maternal death was registered. Maternal complications included increase of aspartate transaminase and alanine transaminase, graft deterioration requiring liver retransplantation, increase of bile acids (n = 1), itch (n = 1), and anemia (n = 1). Twelve women had a high adherence to an immunosuppressive regimen during pregnancy. A woman with poor compliance continued therapy with mycophenolic acid during pregnancy, showing preterm birth (25th week) with fetal respiratory failure. Another woman continued therapy with tacrolimus during breastfeeding without adverse effects. CONCLUSION: Liver transplant does not influence women's fertility; during pregnancy, we report low rates of minor graft complications and no major issues. There are no adverse effects on babies. An evaluation by a multidisciplinary team is recommended. Compliance to an immunosuppressive regimen is fundamental to ensure the stability of graft function and to prevent graft deterioration in pregnancy. Moreover, it is suggested to avoid teratogenic drugs, such as mycophenolic acid.