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This study assessed humoral and T cell-mediated immune responses to the BNT162b2 vaccine in orthotopic liver transplant (OLT) and lung transplant (LUT) recipients who received three doses of the vaccine from March 2021 at our institution. Serum samples were collected 60 days post-second and third dose to quantify antibodies against the spike region of SARS-CoV-2 while whole blood samples were collected to analyze the SARS-CoV-2-specific T-cell response using an IFN-γ ELISpot assay. We enrolled 244 OLT and 120 LUT recipients. The third dose increased antibody titres in OLT recipients (from a median value of 131 after the second dose to 5523 IU/mL, p < 0.001) and LUT recipients (from 14.8 to 1729 IU/mL, p < 0.001). T-cell response also increased in OLT recipients (from 8.5 to 23 IFN-γ SFU per 250,000 PBMC, p < 0.001) and LUT recipients (from 8 to 15 IFN-γ SFU per 250,000 PBMC, p < 0.001). A total of 128 breakthrough infections were observed: two (0.8%) OLT recipients were hospitalized due to COVID-19 and one died (0.4%); among LUT recipients, seven were hospitalized (5.8%) and two patients died (1.7%). In conclusion, the three-dose schedule of the BNT162b2 vaccine elicited both humoral and T cell-mediated responses in solid organ transplant recipients. The risk of severe COVID-19 post-vaccination was low in this population.

Rare liver diseases caused by ductal plate malformation, such as congenital hepatic fibrosis (CHF), Caroli syndrome, and polycystic liver disease, can have clinical manifestations such as recurrent cholangitis—frequently involving multidrug-resistant microorganisms—leading to difficulties in selecting the optimal antimicrobial treatment. Without prompt recognition, these infections severely hamper the patient’s quality of life and can develop into life-threatening complications. We report here the case of a 50-year-old woman with a history of recurring cholangitis with occasional systemic involvement leading to bloodstream infection, who ultimately received a diagnosis of CHF and was put on chronic suppressive antibiotic therapy while on the waiting list for a liver transplant. We also reviewed the literature collecting cases of recurrent infections occurring in patients with ductal plate malformation.

Chronic hepatitis C virus (HCV) infection is associated with numerous extra- hepatic complications, including neurological and renal manifestations. We describe the case of a 67-year-old Caucasian man with HCV-associated cryoglobulinemic glomerulonephritis, cirrhosis, and hepatocellular carcinoma. The early posttransplant course was complicated by fibrosing cholestatic hepatitis due to recurrent HCV in the graft (HCV RNA up to 44,944,438 IU/mL). Proliferative glomerulonephritis (nephritic and nephrotic syndrome) with mixed cryoglobulinemia (purpura) was also recorded. Seventy-two days after surgery, the patient presented with seizures and arterial hypertension; brain magnetic resonance imaging indicated the diagnosis of posterior reversible encephalopathy syndrome (PRES). PRES responded well to medical treatment with complete resolution of neurological changes. Antiviral therapy (sofosbuvir and ribavirin, six months) gave a sustained viral response with the improvement of cryoglobulinemic symptoms (including glomerular disease). Repeat liver biopsy revealed the regression of cholestatic damage and perisinusoidal fibrosis. The current follow-up shows stable chronic renal failure (serum creatinine: 1.4 mg/dL) and mild nephritic syndrome. The impact of extrahepatic manifestations of HCV on patient outcomes is highlighted from novel observational studies reporting a relationshipa diseases are underway

Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18–65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4–11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60–85). 5-year tumour event-free survival was 76·8% (95% CI 60·8–96·9) in the transplantation group versus 18·3% (7·1–47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07–0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9–97·1) in the transplantation group versus 31·2% (16·6–58·5) in the control group (HR 0·32, 95% CI 0·11–0·92; p=0·035). The most common registered grade 3–4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. Italian Ministry of Health.

The exposure of adults of reproductive age as well as pregnant women and children to environmental contaminants is of particular concern, as it can impact fertility, in utero development, pregnancy outcomes and child health. Consequently, the World Health Organisation (WHO) and international societies advocate including Environmental Health (EH) in perinatal care, yet perinatal health professionals (HPs) hardly put these recommendations into practice. In 2017, a cross-sectional study was performed in a large panel of perinatal HPs in south-eastern France with the aim of painting a picture of their current attitudes, representation, knowledge, and training expectations. Quantitative and qualitative information was collected via auto-questionnaire. Questionnaires were completed by 962 participants, mainly midwives (41.1%), physicians (25.6%) and nursery nurses (11%). Indoor/outdoor air quality and endocrine disruptors were the best-mastered topics, whereas electromagnetic fields and diet gave rise to unsure responses. Overall, perinatal HPs were ill-trained and -informed about the reproductive risks linked to daily environmental exposure. HPs reported scarce knowledge, fear of patient reaction and lack of solutions as the main barriers to providing information regarding EH to the public. Our findings highlight the need to set up EH training programmes focused on scientific knowledge and to provide simple messages and tips to help perinatal HPs deliver advice to populations to mitigate exposure to environmental toxicants.

Purpose Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations. Methods The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists’ personal experiences. The panel deliberated on and graded each statement before consensus was reached. Results A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver–kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk. Conclusion The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy. Graphical abstract

Background and aims: Hepatocellular carcinoma (HCC) patients frequently present with comorbidities that limit therapeutic options and increase mortality. This study evaluated the performance of the Charlson Comorbidity Index (CCI) and a modified CCI (mCCI) in stratifying patients with HCC to predict treatment allocation and survival. Methods: A retrospective single-center cohort study analyzed 401 patients with de novo HCC (74% male, median age 68 years, 80% Child–Pugh-Turcotte (CPT) A, 65% viral etiology, 70% Barcelona Clinic Liver Cancer stage (BCLC) 0/A). CCI and mCCI (with points related to HCC and chronic liver disease excluded), were calculated at diagnosis for each patient. The primary endpoint was overall survival (OS) estimated by Kaplan–Meier method and compared across mCCI classes; Cox uni/multivariable models were applied to identify predictors of mortality. The secondary aim was evaluating the association between mCCI and treatment allocation. Results: While CCI classified 94% of patients as “high-risk”, mCCI reclassified patients into “high-risk” (21%), “intermediate-risk” (48%), and “low-risk” (31%), demonstrating better stratification whilst maintaining a strong correlation with CCI (Kendall’s tau-b = 0.57, p < 0.001). BCLC B patients with “high-risk” mCCI exhibited significantly lower access to first-line curative treatment (14% vs. 47%, p = 0.03). Moreover, “high” or “intermediate-risk” patients according to mCCI experienced significantly shorter OS compared to “low-risk” (median OS 36 vs. 49 vs. 74 months, p < 0.001). “High-risk” and “intermediate-risk” mCCI classes were independent predictors of mortality, alongside alpha-fetoprotein, CPT and BCLC stage. Considering the items composing mCCI, age and cardiovascular diseases were independent predictors of mortality. Conclusions: mCCI provides a more accurate assessment of comorbidities than the standard CCI and is associated with survival, hence it can contribute to designing patient-tailored therapeutic strategies.

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.

Cold ischemia is necessary to maintain liver grafts viability during preservation and it is the first step of the so called ischemia-reperfusion injury (IRI). IRI affect post-liver transplant (LT) results. Extended criteria donors, increasingly used to enlarge donor pool, are peculiarly susceptible to IRI. The aim of this study is to evaluate biological markers during cold ischemia and to relate them with graft quality and post-LT outcome.

Background. Machine perfusion is increasingly utilized in liver transplantation to face the detrimental consequences of the use of extended-criteria-donors. Hypothermic oxygenated machine perfusion (HOPE) appears to be more protective relative to static cold storage. Conversely, normothermic machine perfusion (NMP) allows a better graft evaluation. We describe a pilot prospective study on machine perfusion in selected grafts. Methods. HOPE was executed for all the grafts procured from donors-after-cardiac-death (DCD) and for donors-after-brain-death (DBD) livers requiring prolonged preservation time. NMP was used when a more precise evaluation was needed. Both HOPE and NMP were performed trough portal vein and hepatic artery. Results. From July 2016 to November 2017, we performed 7 HOPE procedures: 5 for DCD and 2 for DBD grafts. Two livers presented macrovesicular steatosis >30% (1 DCD and 1 DBD). HOPE lasted 240min (180-320min) with a total-ischemia-time of 575min (410-810min). Six grafts were successfully transplanted. One DCD graft required additional evaluation using NMP. The graft was then discarded due to extensive hepatocellular necrosis. In the post-transplant course, acute and chronic renal failure were the main complications affecting 3 and 2 recipients, respectively. In our series, steatosis was the main risk factor for kidney injury. Patient and graft survival rate was 100% and no ischemic colangiopathies were observed after 635 days (471-945 days). Conclusions. Our study confirms HOPE safety and efficacy for DCD and DBD grafts. These data are particularly significant for DCD management in the Italian setting where the mandatory 20 min-hands-off interval before death declaration further prolongs warm-ischemia-time.