Search

Simple Summary: Everolimus is an immunosuppressive drug used to prevent rejection after liver transplantation. It is an attractive alternative to tacrolimus for patients with hepatocellular carcinoma who are undergoing liver transplantation due to its antiproliferative effects. In our study, we investigated whether liver transplant patients who received everolimus after transplantation had a reduced risk of hepatocellular carcinoma recurrence compared to those on tacrolimus. In a group of 511 patients, recipients treated with everolimus exhibited a reduced risk of tumor recurrence after transplantation. This was particularly true for patients with more advanced tumors and who received the drug earlier and for longer periods. We recommend including everolimus in the post-transplant immunosuppressive regimen to optimize outcomes of liver transplantation for hepatocellular carcinoma. To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression. [ABSTRACT FROM AUTHOR]

Background: In Italy, data on long-term survivors after liver transplantation are lacking. Materials and Methods: We conducted a hybrid design study on a cohort of 359 adult recipients who received transplants between 1996 and 2002 to identify predictors of survival and the prevalence of co-morbidities among long-term survivors. Results: The actuarial (95% CI) patient survival was 96% (94.6–98.3%), 69% (64.2–73.6%), 55% (49.8–59.9%), 42.8% (37.6–47.8%), and 34% (29.2–38.9%) at 1, 5, 10, 15, and 20 years, respectively. The leading causes of death were hepatitis C virus recurrence (24.6%), extrahepatic malignancies (16.9%), infection (14.4%), and hepatocellular carcinoma recurrence (14.4%). The factors associated with the survival probability were younger donor and recipient ages (p = 0.001 and 0.004, respectively), female recipient sex (p < 0.001), absence of HCV (p < 0.01), absence of HCC (p = 0.001), and absence of diabetes mellitus at one year (p < 0.01). At the latest follow-up, the leading comorbidities were hypertension (53.6%), obesity (18.7%), diabetes mellitus (17.1%), hyperlipidemia (14.7%), chronic kidney dysfunction (14.7%), and extrahepatic malignancies (13.8%), with 73.9% of patients having more than one complication. Conclusions: Aging with a liver graft is associated with an increased risk of complications and requires ongoing care to reduce the long-term attrition rate resulting from chronic immunosuppression. [ABSTRACT FROM AUTHOR]

Malignancy after solid organ transplantation remains a major cause of posttransplant mortality. The mammalian target of rapamycin (mTOR) inhibitor class of immunosuppressants exerts various antioncogenic effects, and the mTOR inhibitor everolimus is licensed for the treatment of several solid cancers. In kidney transplantation, evidence from registry studies indicates a lower rate of de novo malignancy under mTOR inhibition, with some potentially supportive data from randomized trials of everolimus. Case reports and small single-center series have suggested that switch to everolimus may be beneficial following diagnosis of posttransplant malignancy, particularly for Kaposi’s sarcoma and nonmelanoma skin cancer, but prospective studies are lacking. A systematic review has shown mTOR inhibition to be associated with a significantly lower rate of hepatocellular carcinoma (HCC) recurrence versus standard calcineurin inhibitor therapy. One meta-analysis has concluded that patients with nontransplant HCC experience a low but significant survival benefit under everolimus monotherapy, so far unconfirmed in a transplant population. Data are limited in heart transplantation, although observational data and case reports have indicated that introduction of everolimus is helpful in reducing the recurrence of skin cancers. Overall, it can be concluded that, in certain settings, everolimus appears a promising option to lessen the toll of posttransplant malignancy. [ABSTRACT FROM AUTHOR]

Data from the 24-month randomized, multicenter, open-label H2304 study in 719 de novo liver transplant recipients were analyzed to evaluate the influence of variables potentially affecting immunological or renal response: recipient age, gender, end-stage disease, hepatitis C virus ( HCV) status, and Model for End-stage Liver Disease score and estimated glomerular filtration rate ( eGFR) at randomization (day 30). Treated BPAR was similar between everolimus with reduced tacrolimus ( EVR + Reduced TAC) vs. conventional tacrolimus-based therapy ( TAC Control) in all subpopulations, with a trend to lower risk under everolimus with reduced tacrolimus ( EVR + Reduced TAC) in patients <60 yrs and HCV-negative recipients. Risk of graft loss or death was similar in both treatment groups for all subpopulations. The change in eGFR to month 24 showed a benefit for EVR + Reduced TAC vs. TAC Control in all subpopulations other than those with the lowest baseline eGFR (30 to <55 mL/min/1.73m2), with a significant difference in favor of EVR + Reduced TAC for younger recipients (<60 yr), female patients, HCV-negative patients and those with baseline eGFR of 55 to <70 mL/min/1.73 m2. Everolimus with reduced tacrolimus maintains efficacy to at least two yr after liver transplantation even in patients with risk factors for rejection, with particular renal benefits in specific patient subpopulations. [ABSTRACT FROM AUTHOR]

We present the 12-month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 ± 11 years) patients were enrolled at a mean interval of 45.5 ± 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%-per-week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient- and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus-RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 ± 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl ( P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the practice of laparoscopic appendectomy (LA) in Italy. Methods: On behalf of the Italian Society of Young Surgeons (SPIGC), an audit of LA was carried out through a written questionnaire sent to 800 institutions in Italy. The questions concerned the diffusion of laparoscopic surgery and LA over the period 1990 through 2001, surgery-related morbidity and mortality rates, indications for LA, the diagnostic algorithm adopted prior to surgery, and use of LA among young surgeons (<40 years). Results: A total of 182 institutions (22.7%) participated in the current audit, and accounted for a total number of 26863 LA. Laparoscopic surgery is performed in 173 (95%) institutions, with 144 (83.2%) routinely performing LA. The mean interval from introduction of laparoscopic surgery to inception of LA was 3.4 ± 2.5 years. There was an emergent basis for 8809 (32.8%) LA procedures (<6 hours of admission); 10314 (38.4%) procedures were performed on an urgent basis (<24 hours of admission); while 7740 (28.8%) procedures were elective. The conversion rate was 2.1% (561 cases) and was due to intraoperative complications in 197 cases (35.1%). Intraoperative complications ranged as high as 0.32%, while postoperative complications were reported in 1.2% of successfully completed LA. The mean hospital stay for successfully completed LA was 2.5 ± 1.05 days. The highest rate of intraoperative complications was reported as occurring during the learning curve phase of their experience (in their first 10 procedures) by 39.7% of the surgeons. LA was indicated for every case of suspected acute appendiceal disease by 51.8% of surgeons, and 44.8% order abdominal ultrasound (US) prior to surgery. A gynecologic counseling is deemed necessary only by 34.5% surgeons, while an abdominal CT scan is required only by 1.5%. The procedure is completed laparoscopically in the absence of gross appendiceal inflammation by 83%; 79.8% try to complete the procedure laparoscopically in the presence of concomitant disease; while 10.4% convert to open surgery in cases of suspected malignancy. Of responding surgeons aged under 40, 76.3% can perform LA, compared to 47.3% surgeons of all age categories . Conclusions: The low response rate of the present survey does not allow us to assess the diffusion of LA in Italy, but rather to appraise its practice in centers routinely performing laparoscopic surgery. In the hands of experienced surgeons, LA has morbidity rates comparable to those of international series. The higher diagnostic yield of laparoscopy makes it an invaluable tool in the management algorithm of women of childbearing age; its advantages in the presence of severe peritonitis are less clear-cut. Surgeons remain the main limiting factor preventing a wider diffusion of LA in our country, since only 47.3% of surgeons from the audited institutions can perform LA on a routine basis. [ABSTRACT FROM AUTHOR]

Current organ shortage is estimated to keep outpacing demand for years to come. Among the advocated strategies, artificial and bioartificial devices may prove beneficial to a wide category of patients on transplant waiting lists. Bionic organ science allows to reproduce organ architecture and function through a complex interplay of cellular and mechanical elements. Some bioartificial organs may well be used to replace anatomical defects, while others allow to compensate for failing organ functions and to bridge patients to transplantation. Among these latter, bioartificial liver (BAL) systems bear the highest potential for clinical application, even if their use is raising several controversial issues. These latter regard the identification and stratification of patients fit for transplantation, timing and type of transplantation after recovery, appropriateness of double-blind, randomized clinical trials and safety of animal and/or human cell lines. Nonetheless, bionic organ science needs to be regarded as a useful adjunct in the armamentarium of organ replacement therapies for the third millennium. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to immunosuppression and liver transplantation in the previous issue.

The long pentraxin (PTX) 3 and the neuronal pentraxin (NPTX) 2 has been found to exert pleiotropic roles in cancers due to their action in inflammation. However, the accurate clinical significance of PTX3 and NPTX2 in hepatocellular carcinoma (HCC), one of the commonest cancers in the world has not been well-defined. The aim of the study was to analyze the expression profile of PTX3 and NPTX2 in liver biopsies of HCV-positive HCC patients (liver recipients, LR, n = 14, age 59.4 ± 1.8 years) undergoing liver transplantation and in donors (LD, n = 14, age 62.1 ± 17.3 years), trying both to identify them as predictive biomarkers of clinical liver severity in HCC patients and to understand if they were mutually substitutable. The PTX3 and NPTX2 transcripts were significantly up regulated in HCC tissues (p = 0.004 and p = 0.02 LD vs. LR, respectively). Dividing patients following MELD score, PTX3 expression increased as a function of liver disease severity, while this trend was not observed for NPTX2, which mRNA level increased similarly in both MELD group, reaching the significance only in patients with MELD score < 9 (p = 0.01). A positive correlation was found between PTX3 and NPTX2 expression (p = 0.001; r = 0.69). This is the first study that concerns PTX3 and NPTX2 as a function of clinical severity from which emerged that both of them are unequivocally involved in HCC, but only PTX3 could be considered a staging marker in these HCV-related HCC patients, unlike NPTX2, which could only play a role as an inflammatory marker. [ABSTRACT FROM AUTHOR]

Apelin, a peptide of 77 amino acids, and its endogenous ligand, angiotensin-like-receptor 1 (APJ), play a key role in the development of tumors by enhancing angiogenesis, metastasis, cell proliferation, development of cancer stem cells and drug resistance and inhibiting apoptosis of cancer cells. However, little is known about Apelin/APJ system involvement in hepatocellular carcinoma (HCC). The aim of this study was to evaluate Apelin and APJ expression in liver specimens, obtained from subjects with HCV-positive HCC who underwent liver transplantation, according to liver disease severity (liver recipients, LR, n = 14, age 59.4 ± 1.8) and in donors (liver donors, LD, n = 14, age 62.1 ± 17.3). Apelin/APJ axis, apoptotic and inflammatory markers were evaluated by Real-Time PCR analysis. The Apelin/APJ system expression resulted significantly higher in LR in comparison with LD (p < 0.05), in particular in those with more severe liver disease. The apoptotic (Bcl-2, BAX, NOTCH-1, Casp-3) and inflammatory (IL-6, TNF-α) markers were increased as a function of disease severity (p < 0.05). Multiple significant positive correlations were found between Apelin/APJ axis and the other markers. Although further investigations are needed to better understand the role of Apelin/APJ axis in HCC, our result indicated a potential role of this axis in its development and progression as well as in recognizing novel therapeutic targets opening a new avenue for treatment. [ABSTRACT FROM AUTHOR]

Asbestos is still a common problem in a lot of country in the word. It was widely used during the 20th century thanks to its numerous physical and mechanical characteristics. Both the European and the Italian legislations have banned the manufacture, importation, processing and distribution in commerce of asbestos-containing products and have recommended action plans for the mapping and safe removal of asbestos from public and private buildings. The aims of this paper is to elaborate a specific overwiev on the application of remote sensing for mapping the asbestos cement roofs, reporting the Italian experience as a case study, considering different types of sensors, platforms, processing models used for this application. [ABSTRACT FROM AUTHOR]

Background: The advantages of the robotic approach in minimally invasive liver surgery (MILS) are still debated. This study compares the short-term outcomes between laparoscopic (LLR) and robotic (RLR) liver resections in propensity score matched cohorts. Methods: Data regarding minimally invasive liver resections in two liver surgery units were retrospectively reviewed. A propensity score matched analysis (1:1 ratio) identified two groups of patients with similar characteristics. Intra- and post-operative outcomes were then compared. The difficulty of MILS was based on the IWATE criteria. Results: Two hundred sixty-nine patients underwent MILS between January 2014 and December 2021 (LLR = 192; RLR = 77). Propensity score matching identified 148 cases (LLR = 74; RLR = 74) consisting of compensated cirrhotic patients (100%) underwent non-anatomic resection of IWATE 1–2 class (90.5%) for a solitary tumor < 5 cm in diameter (93.2%). In such patients, RLRs had shorter operative time (227 vs. 250 min, p = 0.002), shorter Pringle's cumulative time (12 vs. 28 min, p < 0.0001), and less blood loss (137 vs. 209 cc, p = 0.006) vs. LLRs. Conversion rate was nihil (both groups). In RLRs compared to LLRs, R0 rate (93 vs. 96%, p > 0.71) and major morbidity (4.1 vs. 5.4%, p > 0.999) were similar, without post-operative mortality. Hospital stay was shorter in the robotic group (6.2 vs. 6.6, p = 0.0001). Conclusion: This study supports the non-inferiority of RLR over LLR. In compensated cirrhotic patients underwent resection of low-to-intermediate difficulty for a solitary nodule < 5 cm, RLR was faster, with less blood loss despite the shorter hilar clamping, and required shorter hospitalization compared to LLR. [ABSTRACT FROM AUTHOR]

Background: Patients' adherence to medical prescription during pre- and post- liver transplant phases is crucial to prevent treatment inefficacy. Literature has highlighted the urge of performing a psychological characterization to prevent post-intervention relapses and to impede treatment non-adherence behavior. The aim of this study is to define an "adherence core" by investigating personality traits, cognitive functions, and affective symptoms of patients waiting for liver transplant to enhance treatment effectiveness. We hypothesize a negative correlation between depressive and anxious symptoms and cognitive abilities and a positive association between some personality traits (Openmindedness, Conscientiousness and Extraversion) and cognitive functions. Materials and methods: Forty-six candidates (23 females, mean age: 56.02±7.81 years, range: 39-76) for liver transplantation were assessed utilizing the following psychometric tools: State-Trait Anxiety Inventory Form Y1 and Form Y2, Big Five Questionnaire and Beck Depression Inventory 2. Cognitive assessment included: Coloured Progressive Matrices, Rey's 15-word list, Semantic Incidental Memory Test for Adults, Attentional Matrices Test and Corsi Block-tapping Test. Results: The findings showed that education level negatively correlated with trait anxiety and positively correlated with Open-mindedness and Emotional Stability. Coloured Progressive Matrices negatively correlated with trait anxiety and depressive symptoms and positively correlated with Emotional Stability and Open-mindedness. Significant correlations were also shown between cognitive tests. Rey Immediate Recall scores showed positive correlation with: Rey Delayed Recall, Semantic Incidental Memory, and Attentional Matrices. Moreover, the findings demonstrated a positive correlation between trait anxiety and depressive symptoms, as well as a negative correlation between trait anxiety and Emotional Stability. Additionally, state anxiety was found to be positively correlated with depressive symptoms and negatively correlated with Energy and Open-mindedness. Discussion: Higher fluid abilities, with lower degree of depression state, less pronounced anxious trait, and more open-minded personality can potentially aid patients in managing the distress associated with pre- and post-transplantation, ultimately resulting in optimal adherence. Furthermore, the positive association observed between the attention and memory domains might suggest their significant involvement in predicting adherence trajectories. In line with literature highlighting the paramount role of psychological factors in recovering from organ transplant, this study paves the road for the potentiation of individual resources and weaknesses identification to reduce relapses and healthcare costs. However, small sample size and lack of causality direction of results prevent robust conclusions. [ABSTRACT FROM AUTHOR]

The transcriptional profile of adrenomedullin (AM), a new metastasis-related factor involved in hepatocellular carcinoma (HCC), and its specific receptors (CLR, RAMP1, RAMP3) were evaluated in liver tissues of HCV-positive HCC subjects undergoing liver transplantation (LR) and in donors (LD). AM and its specific receptor expression were also assessed in extracellular vesicles (EVs) secreted by tumorigenic (HepG2) and non-tumorigenic (WRL68) cells by Real-Time PCR. AM expression resulted significantly elevated in LR concerning LD (p = 0.0038) and, for the first time, significantly higher levels in HCC patients as a function of clinical severity (MELD score), were observed. RAMP3 and CLR expression increased in LR as a function of clinical severity while RAMP1 decreased. Positive correlations were found among AM, its receptors, and apoptotic markers. No AM mRNA expression difference was observed between HepG2 and WRL68 EVs. RAMP1 and RAMP3 resulted lower in HepG2 concerning WRL68 while significantly higher levels were observed for CLR. While results at tissue level characterize AM as a regulator of carcinogenesis-tumor progression, those obtained in EVs do not indicate AM as a target candidate, neither as a pathological biomarker nor as a marker involved in cancer therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, Marti J, Tincani G, Cicorelli A, Cioni R, Filipponi F. Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation. Abstract: This is a single center retrospective review of 19 consecutive liver transplant (LT) patients with hepatitis C virus (HCV)-related graft recurrent hepatitis who underwent transjugular intrahepatic portosystemic shunt (TIPS) at a median interval of 21 months (range: 5-50) from LT. Indications were refractory ascites in 11 patients (57.9%), hydrothorax in six (31.6%), and both in two (10.5%). TIPS was successful in 94.7% of cases (18/19) with only one procedure-related mortality (5.3%) owing to sepsis on day 35. At a median follow-up of 23 months (range: one month-nine yr), TIPS allowed for symptoms resolution in 16 patients (84.2%), with ascites resolving in all cases and hydrothorax persisting in 2. Post-TIPS patient survival at six months, one yr, and three yr was 84.2%, 73.7%, and 56.8%, respectively. We compared these results with a control group of 29 patients with HCV recurrence but without unresponsive ascites or hydrothorax. Patients in the control group had better survival than patients undergoing TIPS placement. However, survival of TIPS patients with a MELD score lower than or equal to 12 was similar to that of the control group. We conclude that TIPS may be used to treat complications secondary to HCV. [ABSTRACT FROM AUTHOR]

We herein describe a new ex‐situ machine perfusion device as a "technology spotlight" using a model of donors after circulatory death liver grafts procured from slaughterhouse pigs. Fourteen pig liver grafts were included. The device allowed stable perfusion in both hypothermic (n = 6) and normothermic (n = 8) conditions and no technical failure was observed. During perfusion, perfusate and bile samples were collected to assess liver metabolism and viability. An integrated adsorption device showed efficient removal of inflammatory cytokines during treatment. This preliminary experience represents the starting point for further investigations on the potential clinical benefits of cytokines and other inflammatory mediators adsorption during machine perfusion. [ABSTRACT FROM AUTHOR]

Background: Organs from donation after circulatory death (DCD) are increasingly used for liver transplantation, due to the persisting organ shortage and waiting list mortality. However, the use of DCD grafts is still limited by the inferior graft survival rate and the increased risk of primary non‐function and biliary complications when compared to brain death donors' grafts. Methods: Abdominal normothermic regional perfusion with extracorporeal membrane oxygenation (ECMO) is an in situ preservation strategy. which may mitigate ischemia–reperfusion injuries. and has been proposed to restore blood perfusion after the determination of death thus optimizing liver function before implantation. Results: In this systematic review, we highlighted the clinical evidence supporting the use of normothermic regional perfusion in DCD liver underlying the pathophysiological mechanisms, and technical, logistic, and regulatory aspects. Conclusions: Despite the lack of properly designed, prospective, randomized trials, the current available data suggest beneficial effects of normothermic regional perfusion on clinical outcomes after liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Preliminary experience in laparoscopic liver surgery is usually suggested prior to implementation of a robotic liver resection program. Methods: This was a retrospective cohort analysis of patients undergoing robotic (RLR) versus laparoscopic liver resection (LLR) for hepatocellular carcinoma at a center with concomitant initiation of robotic and laparoscopic programs Results: A total of 92 consecutive patients operated on between May 2014 and February 2019 were included: 40 RLR versus 52 LLR. Median age (69 vs. 67; p = 0.74), male sex (62.5% vs. 59.6%; p = 0.96), incidence of chronic liver disease (97.5% vs.98.1%; p = 0.85), median model for end-stage liver disease (MELD) score (8 vs. 9; p = 0.92), and median largest nodule size (22 vs. 24 mm) were similar between RLR and LLR. In the LLR group, there was a numerically higher incidence of nodules located in segment 4 (20.0% vs. 16.6%; p = 0.79); a numerically higher use of Pringle's maneuver (32.7% vs. 20%; p = 0.23), and a shorter duration of surgery (median of 165.5 vs. 217.5 min; p = 0.04). Incidence of complications (25% vs.32.7%; p = 0.49), blood transfusions (2.5% vs.9.6%; p = 0.21), and median length of stay (6 vs. 5; p = 0.54) were similar between RLR and LLR. The overall (OS) and recurrence-free (RFS) survival rates at 1 and 5 years were 100 and 79 and 95 and 26% for RLR versus 96.2 and 76.9 and 84.6 and 26.9% for LLR (log-rank p = 0.65 for OS and 0.72 for RFS). Conclusions: Based on our results, concurrent implementation of a robotic and laparoscopic liver resection program appears feasible and safe, and is associated with similar oncologic long-term outcomes. [ABSTRACT FROM AUTHOR]

Loco-regional interventional treatments continue to evolve and to play a major role in the therapeutic management of hepatocellular carcinoma (HCC). Image-guided ablation is established as the treatment of choice for patients with early-stage HCC when transplantation or resection is precluded. Recent refinements in technique have substantially increased the ability of radiofrequency ablation to achieve sustained complete response of target tumors in properly selected patients, and new alternate thermal and nonthermal methods for local tumor treatment are currently under investigation. Transarterial chemoembolization (TACE) is the standard of care for patients with multinodular disease at the intermediate stage. The introduction of drug-eluting beads – that enhance drug delivery to the tumor and reduce systemic exposure – appears to improve anticancer activity and safety profile of TACE compared with conventional regimens. Despite these advances, the long-term outcomes of patients treated with loco-regional therapies remain unsatisfactory because of the high rate of tumor recurrence. The introduction of molecular targeted therapies that inhibit tumor proliferation and angiogenesis has opened new prospects in this regard. Clinical trials focused on combining interventional treatment with systemically active drugs are ongoing. The outcomes of such studies are eagerly awaited, as they have the potential to revolutionize treatment of HCC. [ABSTRACT FROM AUTHOR]

• Liver transplant recipients show a high cardiovascular risk. • No validated guidelines are available for cardiovascular prevention. • Available studies display clear methodological limits. • The present study shows a very long follow-up period. • Pre-transplant diabetes is a strong predictor of cardiovascular events. Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome. Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method. Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p =0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p =0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p =0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060–29.183, p =0.049, and HR 86.097, CI 9.510–779.480, p =0.000, respectively). Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B immunoglobulin (HBIG) therapy is available in intravenous (IV) or intra-muscular (IM) formulations. Recently, a subcutaneous (SC) formulation was introduced. This study evaluated changes in quality of life when liver transplant (LT) recipients were switched from IV or IM HBIG to the SC formulation.Methods: This multicentre, observational study involved adults who had undergone LT at least 1 year prior to study entry. Quality of life was evaluated using the ITaLi-Q questionnaire, assessing the impact of HBIG therapy on daily activities and patient satisfaction, and the SF-36 Health Survey. Patients completed the questionnaires prior to switching from IV or IM HBIG to SC HBIG and 6 months later.Results: Eighty-six patients were enrolled; before the switch, 68.6% were receiving IM HBIG and 31.4% IV HBIG. After 6 months, significant improvements in 7 of the 8 ITaLi-Q domains were found, particularly side effects, need for support to adhere to the therapy and satisfaction with the HBIG therapy. Significant improvements in several SF-36 domains were documented, including physical functioning, physical and emotional role limitations, pain, social functioning, physical and mental summary scores.Conclusions: The SC route of administration reduces side effects and their interference with daily life, ameliorates negative feelings, and increases patient autonomy. [ABSTRACT FROM AUTHOR]

Background: Transplant recipients are chronically ill patients, who require lifelong follow-up to manage co-morbidities and prevent graft loss. This necessitates a system of care that is congruent with the Chronic Care Model. The eleven-item self-report Patient Assessment of Chronic Illness Care (PACIC) scale assesses whether chronic care is congruent with the Chronic Care Model, yet its validity for heart transplant patients has not been tested.Methods: We tested the validity of the English version of the PACIC, and compared the similarity of the internal structure of the PACIC across English-speaking countries (USA, Canada, Australia and United Kingdom) and across six languages (French, German, Dutch, Spanish, Italian and Portuguese). This was done using data from the cross-sectional international BRIGHT study that included 1378 heart transplant patients from eleven countries across 4 continents. To test the validity of the instrument, confirmatory factor analyses to check the expected unidimensional internal structure, and relations to other variables, were performed.Results: Main analyses confirmed the validity of the English PACIC version for heart transplant patients. Exploratory analyses across English-speaking countries and languages also confirmed the single factorial dimension, except in Italian and Spanish.Conclusion: This scale could help healthcare providers monitor level of chronic illness management and improve transplantation care.Trial Registration: Clinicaltrials.gov ID: NCT01608477, first patient enrolled in March 2012, registered retrospectively: May 30, 2012. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We report a case of post‐transplant liver graft infection with Schistosoma spp in a migrant from sub‐Saharan Africa transplanted for HBV‐related cirrhosis and with undiagnosed schistosomiasis pre‐transplantation. The occurrence of tropical diseases in non‐endemic areas warrants screening protocols for organ donors and recipients with a history of exposure in endemic areas. [ABSTRACT FROM AUTHOR]

Summary: Several risk factors for ischaemic‐type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donor's decade (<60 yo; 60–69 yo; 70–79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type‐2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post‐transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • DAAs have dramatically improved the outcome of cirrhotic patients with HCV infection. • Since the advent of DAAs there has been a 50% decline in the number of liver transplants. • At least 600 liver grafts every year can currently be allocated to indications other than HCV. • Survival of LT recipients with HCV or HBV infection is currently comparable, because of DAAs. Background & Aims Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs. Methods This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017). Results Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p < 0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p < 0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p < 0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, −58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, −41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807). Conclusions In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe. Lay summary After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV. [ABSTRACT FROM AUTHOR]

It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-βH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-βH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival. [ABSTRACT FROM AUTHOR]

Light at the end of the tunnel: COVID-19 lockdown has not halted liver transplantation at a high volume center in Italy Although preliminary reports emphasized on an initial decline in organ procurement and liver transplantation (LT) in Italy [1,2], 3 months after enforcement of the coronavirus disease-19 (COVID-19) national lockdown data are better than anticipated. At our center in Tuscany, from February 18 to May 4, 2020 (end of lockdown), a total of 39 procedures were performed, namely 29 deceased donor LTs and 10 more brain dead donor surgeries resulting in liver grafts unsuitable for transplantation. [Extracted from the article]

Summary: Locoregional treatment while on the waiting list for liver transplantation (Ltx) for hepatocellular carcinoma (HCC) has been shown to improve survival. However, the effect of treatment type has not been investigated. We investigate the effect of locoregional treatment type on survival after Ltx for HCC. We investigated patients registered in the European Liver Transplant Registry database using multivariate Cox regression survival analysis. Information on locoregional therapy was registered for 4978 of 23 124 patients and was associated with improved overall survival [hazard ratio (HR) 0.84 (0.73–0.96)] and HCC‐specific survival [HR 0.76 (0.59–0.98)]. Radiofrequency ablation (RFA) was the one monotherapy associated with improved overall survival [HR 0.51 (0.40–0.65)]. In addition, the combination of RFA and transarterial chemoembolization also improved survival [HR 0.74 (0.55–0.99)]. Adjusting for factors related to prognosis, disease severity, and tumor aggressiveness, RFA was highly beneficial for overall and HCC‐specific survival. The effect may represent a selection of patients with favorable tumor biology; however, the treatment may be effective per se by halting tumor progression. Clinicaltrials.gov number: NCT02995096. [ABSTRACT FROM AUTHOR]

Background: As medication non-adherence is a major risk factor for poor post-transplant outcomes, we explored how adherence is assessed, enhanced and integrated across the transplant continuum. Aim: The aim of this study was to study practice patterns regarding pre- and post-transplant medication adherence assessment and interventions in international heart transplant centres. Methods: We used data from the Building Research Initiative Group: chronic illness management and adherence in heart transplantation (BRIGHT) study, a cross-sectional study conducted in 36 heart transplant centres in 11 countries. On a 27-item questionnaire, 100 clinicians (range one to five per centre) reported their practice patterns regarding adherence assessment and intervention strategies pre-transplant, immediately post-transplant, less than one year, and one or more year post-transplant. Educational/cognitive, counselling/behavioural and psychosocial/affective strategies were assessed. Clinicians’ responses (intervention present vs. absent; or incongruence in reporting intervention) were aggregated at the centre level. Results: The adherence assessment method most commonly used along the transplant continuum was questioning patients (range 75–88.9%). Pre-transplant, all three categories of intervention strategy were applied. Providing reading materials (82.9%) or instructions (68.6%), involving family or support persons in education (91.4%), and establishing partnership (91.4%) were used most frequently. Post-transplant, strategies closely resembled those employed pre-transplant. Training patients (during recovery) and cueing were more often applied during hospitalisation (74.3%). After the first year post-transplant, except for motivational interviewing (25.7–28.6%), the number of strategies decreased. Conclusions: Across the transplant continuum, diverse adherence interventions are implemented; however, post-transplant, the frequency of adherence interventions decreases. Therefore, increased investment is necessary in long-term adherence interventions. [ABSTRACT FROM AUTHOR]

Recently osteopontin (OPN), a protein of the extracellular matrix, has generated in hepatocellular carcinoma (HCC) a significant interest as a prognostic factor. Aim of this study was to confirm, in liver tissues of subjects with HCV-positive HCC undergoing liver transplantation (RL, n = 10) and of donors (DL, n = 14), the increase of OPN plasma and tissue concentration, the OPN splicing isoforms expression profiling together with those of thrombin, and to evaluate a possible association between OPN measurements. Their association with Notch-1, IV-Collagen-7s domain, IL-6 and TNF-α were also evaluated. Real-Time PCR experiments and immunometric assay were performed. mRNA expression resulted higher in RL than in DL for all analyzed genes and several correlations were found between them. The more relevant association were between OPN-a and OPN-b (p < 0.0001), between thrombin and OPN-a (p = 0.007), between 7s-collagen and OPN isoforms (p < 0.05) and between Notch-1 with OPN-c (p = 0.004). Both OPN plasma and liver tissue extract concentrations were assessed confirming the trend observed at the mRNA level. An important association was found between OPN plasma and protein (p < 0.0001, r = 0.96) even splitting patients in DL (p < 0.0001, r = 0.93) and RL (p < 0.0001, r = 0.96). A reduction of OPN plasma levels was found at 6 months after transplantation. Considering MELD score as liver disease severity, the mRNA expression of our markers as well as of OPN plasma and tissue concentrations resulted increased as a function of clinical severity. Our results might be considered a useful starting point to validate OPN as a prognostic and diagnostic marker of HCC. [ABSTRACT FROM AUTHOR]

The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy-regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors. Hepatic mRNA expression of FNDC5/Irisin and stearoyl-CoA desaturase (SCD-1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p < 0.0001 and p = 0.015, respectively). The hepatic mRNA expression of the neurogenic locus notch homolog protein 1 (NOTCH1) tended to be higher in HCC patients than in donors (p = 0.06). Only in HCC patients, hepatic FNDC5/Irisin strongly correlated with the transcription factor sterol regulatory element–binding factor 1, SCD-1, NOTCH1, tumor necrosis factor-α and Interleukin-6 mRNA expression. Further, in HCC patients, FNDC5/Irisin mRNA tended to correlate to plasma lipid profile namely triglycerides, palmitic/linoleic acid and polyunsaturated fatty acid/saturated fatty acid ratios. In conclusion, HCC-liver tissue over-expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage. [ABSTRACT FROM AUTHOR]

Objective Production of a new classification of Asbestos Containing Products (ACPs), materials (ACM) and Asbestos Containing Waste (ACW), in addition to a correct identification of landfills where ACW should be disposed of in Europe. Methods Analysis of the European and Italian legislation, study of waste classification and management in the main European countries, data analysis of mapping of Italian landfills and quantification of ACW disposed there. Findings Classification according to unique criteria (physical state, substances with which asbestos minerals have been blended, function of the asbestos, etc.). Highlights of cases of incorrect management of ACW in Europe, specifying the Italian ones. Considering the significant inconsistencies between the European and national regulations and the actual implementation of those regulations, this paper provide some precise indications for the proper assignment to ACW of the European Waste Catalogue (EWC) codes. Lastly, suitable types of landfills at which ACW should be disposed of have been identified, in order to assisting the persons involved in ACW management to avoid undue exposition and their improper disposal. Conclusion This study reports a useful manual for classifying worldwide ACPs based on their physical state and considering the substances with which the asbestos minerals have been blended. Moreover several clear tables allow the asbestos remediation and waste management operators to suitably classify and dispose of ACW. [ABSTRACT FROM AUTHOR]

Liver viability using normothermic regional perfusion in uncontrolled donation after circulatory death deserves a multi-parametric assessment In this regard, the 20-min no-touch period enforced in Italy has spurred national transplant centers to implement NRP followed by ex-situ perfusion of DCD liver grafts. On a different note, AST and ALT have failed to predict clinical outcome in LT as previously described in ex-situ MP trials,6,7 since their levels may be influenced by donor age, liver steatosis, and ischemia time among others. [Extracted from the article]

Background & Aims Four gamma-gultamyltransferases ( GGT) fractions (b-, m-, s-, and f- GGT) have been identified in human plasma and their concentrations and ratios vary in different pathological conditions. To assess the behaviour of fractional GGT in cirrhotic patients evaluated for liver transplantation. Methods This was a single-centre, cross-sectional study; GGT fractions were determined by gel-filtration chromatography. Results 264 cirrhotic patients (215 males; median age 54.5 years) were included and compared against a group of 200 healthy individuals (100 males; median age 41.5). Median (25th-75th percentile) total and fractional GGT were higher in cirrhotics, with s- GGT showing the greatest increase [36.6 U/L (21.0-81.4) vs. 5.6 U/L (3.2-10.2), P < 0.0001], while the median b- GGT/s- GGT ratio was lower in cirrhotics than in healthy controls [0.06 (0.04-0.10)] vs. 0.28 (0.20-0.40), P < 0.0001]. The ratio showed higher diagnostic accuracy ( ROC- AUC, 95% CI: 0.951, 0.927-0.969) then either s- GGT (0.924, 0.897-0.947; P < 0.05) or total GGT (0.900, 0.869-0.925; P < 0.001). The diagnostic accuracy of the ratio was maintained (0.940, 0.907-0.963) in cirrhotic patients ( n = 113) with total GGT values within the reference range. The s- GGT fraction consisted of two components, with one (s2- GGT) showing a significant positive correlation with serum aspartate aminotransferases, alanine aminotransferase, lactate dehydrogenases ( LDH), alkaline phosphatases and bilirubin, and negative with albumin. The b- GGT fraction showed a positive correlation with albumin, fibrinogen, and platelet counts, and negative with international normalized ratio, bilirubin and LDH. Conclusions The ratio performs as a sensitive biomarker of the liver parenchymal rearrangement, irrespective of aetiology of cirrhosis and presence of hepatocellular carcinoma, even in patients with total GGT values within the reference range. [ABSTRACT FROM AUTHOR]

To investigate the hypothesis that intestinal colonization by different types of carbapenemase-resistant Klebsiella pneumoniae (CR-Kp) leads to different risks for bloodstream infections (BSI) caused by the same colonizing organism. Prospective observational study including consecutive CR-Kp rectal carriers admitted to the Pisa University Hospital (December 2018 to December 2019). Patients underwent rectal swabbing with molecular testing for the different carbapenemases at hospital admission and during hospitalization. Rectal carriers were classified as: NDM, KPC, VIM and OXA-48. The primary end point was the rate of BSI by the same colonizing organism in each study group. A multivariate logistic regression analysis was performed to identify factors independently associated with the risk for BSI by the colonizing organism. Of 677 rectal carriers, 382/677 (56.4%) were colonized by NDM, 247/677 (36.5%) by KPC, 39/677 (5.8%) by VIM and 9/677 (1.3%) by OXA-48. Dissemination of NDM-Kp was mostly sustained by ST147, while KPC-Kp belonged to ST512. A higher rate of BSI was documented in NDM rectal carriers compared with KPC rectal carriers (59/382, 15.4% versus 20/247, 8.1%, p 0.004). Incidence rates of BSI per 100 patients/month were significantly higher in the NDM group (22.33, 95% CI 17.26–28.88) than in the KPC group (9.56, 95% CI 6.17–14.82). On multivariate analysis, multi-site extraintestinal colonization, solid organ transplantation, invasive procedures, intravascular device, admission to intensive care unit, cephalosporin, fluoroquinolones and NDM rectal colonization (OR 3.27, 95% CI 1.73–6.18, p < 0.001) were independently associated with BSI. NDM-Kp was associated with increased risk of BSI compared with KPC-Kp. This finding seems to be strongly related to the high-risk clone ST147. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver transplantation is the first-line treatment for patients diagnosed with unresectable early stage hepatocellular carcinoma in the setting of cirrhosis. Patients with tumours beyond this stage may benefit from liver transplantation if their tumours are successfully downstaged. Loco-regional therapies, including ablation, trans-arterial and radiotherapeutical approaches are commonly used to treat patients before transplant, with the aim of reducing the risk of drop off from the waiting list due to tumor progression for patients within transplantation criteria as well as decreasing tumour dimension to meet acceptable criteria. In this review, current evidence on the safety, efficacy and utility of locoregional therapies as neoadjuvant therapies before liver transplantation are summarized. Liver transplantation (LT) is the first-line treatment for patients diagnosed with unresectable early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. It is well known that HCC patients within the Milan criteria (solitary tumour ≤ 5 cm or ≤3 tumours, each <3 cm) could undergo LT with excellent results. However, there is a growing tendency to enlarge inclusion criteria since the Milan criteria are nowadays considered too restrictive and may exclude patients who would benefit from LT. On the other hand, there is a persistent shortage of donor organs. In this scenario, there is consensus about the role of loco-regional therapy (LRT) during the waiting list to select patients who would benefit more from LT, reducing the risk of drop off from the waiting list as well as decreasing tumour dimension to meet acceptable criteria for LT. In this review, current evidence on the safety, efficacy and utility of LRTs as neoadjuvant therapies before LT are summarized. [ABSTRACT FROM AUTHOR]

The aim of the present work was to assess the incidence of neuro-nephrotoxicity after a single-staggered dose of calcineurin inhibitors (CI) with different immunosuppressive approaches. From January to December 2006, all liver transplantation (LT) recipients at risk of renal or neurological complications treated with extracorporeal photopheresis (ECP) + mycophenolate mofetil + steroids and staggered introduction of CI (ECP group) were compared with a historical control group on standard CI-based immunosuppression. The ECP group included 24 patients with a mean model for end-stage liver disease (MELD) score of 19.9 ± 11.1. The control group consisted of 18 patients with a mean MELD score of 12.5 ± 5.2 (p = 0.012). In the ECP group CI were introduced at a mean of 9.2 ± 6.2 d (4–31 d) after LT. Five patients in the ECP group presented acute neuro-nephrotoxicity after the first CI administration on post-transplant d 4, 5, 6, 6, and 14. Overall patient survival at one, six, and 12 months was 100%, 95.8%, and 95.8% in the ECP group vs. 94.4%, 77.7%, and 72.2% in the control group (p < 0.001). In conclusion, we showed that CI toxicity may occur after a single-staggered dose administration, ECP seems to be a valuable tool for managing CI-related morbidity regardless of the concomitant immunosuppressive regimen, being associated with a lower mortality rate in the early post-transplant course. [ABSTRACT FROM AUTHOR]

Background/Aims: Experimental studies have shown synergy between radiofrequency (RF) ablation and adjuvant chemotherapy in animal tumour models. We aimed to assess safety and efficacy of doxorubicin-eluting bead (DEB)-enhanced RF ablation in the treatment of human hepatocellular carcinoma (HCC). Methods: Twenty patients with single HCC ranging 3.3–7.0cm (mean, 5.0cm±1.4) showing evidence of residual viable tumour after standard RF ablation underwent intraarterial DEB administration (50–125mg doxorubicin; mean, 60.2mg±21.8). Follow-up period ranged 6–20 months (mean, 12 months±5). Results: No major complication occurred. No deterioration of liver function was observed. The volume of treatment-induced necrosis – as measured on imaging – increased from 48.1cm3 ±35.7 after RF ablation to 75.5cm3 ±52.4 after DEB administration, with an increase of 60.9%±39.0. The enhanced effect resulted in confirmed complete response (CR) of the target lesion in 12 (60%) of 20 patients. Incomplete response with persistence of <10% of initial tumour volume was observed in 6 (30%) of 20 patients, and local tumour progression in 2 (10%) of 20. Conclusions: Intraarterial DEB administration substantially enhances the effect of RF ablation. DEB-enhanced RF ablation is safe and results in a high rate of CR in patients refractory to standard RF treatment. [Copyright &y& Elsevier]

Abstract: Occupational exposure to respirable crystalline silica is associated with the development of silicosis, lung cancer and airways diseases. In order to assess cytotoxic effects and direct–oxidative DNA damage induced by short-term exposure to different doses of respirable α-quartz (NIST SRM1878a), we conducted a study using A549 cells. The cells were exposed to α-quartz at 25, 50, 100μg/ml for 4h and analysed by scanning electron microscope (SEM) and LDH release assay for cytotoxic effect evaluation. Cells were also exposed to 10, 25, 50, 100μg/ml of α-quartz for 2h and 4h and analysed by Fpg comet test to evaluate direct and oxidative DNA damage. SEM observations of treated cells showed bleb development at lower doses and alterations of microvilli morphology at the highest dose. A slight LDH release was found only at 100μg/ml. Fpg comet test showed a dose-related oxidative DNA damage in cells exposed for 2h to quartz. Cells exposed for 4h at the same concentrations showed a dose-related direct DNA damage and the presence of oxidative DNA damage at lower doses. The bleb induction on cell surface evidenced by SEM at lower doses correlates with the presence of oxidative DNA damage at 4h. The cell surface modifications observed by SEM at 100μg/ml indicate that high doses of quartz induce more evident cytotoxic effects confirmed by LDH analysis and correlate with the genotoxicity showed by comet assay. [Copyright &y& Elsevier]

Simple Summary: Microwave (MW) ablation is increasingly used worldwide as a therapeutic option in very-early- and early-stage hepatocellular carcinoma (HCC). Up to now, there have been few published studied showing the correlation with pathology in ablated nodules. The aim of our study was to retrospectively correlate the necrosis obtained with MW ablation with histological findings in excised livers from the time of liver transplantation to assess the MW ablation effectiveness. We obtained, in a population of 30 patients with 36 nodules, a complete ablation at 1-month imaging in 30/36 nodules (83.3%). At pathology, of the 36 treated nodules, 28 (77.8%) showed complete necrosis, and 8 (22.2%) showed partial necrosis. Good agreement was found between the imaging performed 1-month after treatment and the complete pathological response. These data confirm the effectiveness of MW ablation to percutaneously treat HCC nodules smaller than 3 cm with a high sensitiveness of radiological imaging in detecting a complete response after ablation. Microwave (MW) ablation is a worldwide-diffused technique for the percutaneous ablation of hepatocellular carcinoma (HCC). Nevertheless, the efficacy of this technique still needs to be confirmed in pathological specimens. The purpose of this study was to evaluate the efficacy of MW ablation by correlation with histology in excised liver samples at the time of liver transplantation (LT). All patients with MW-ablated HCC who subsequently underwent LT between 2012 and 2020 were retrospectively evaluated. In the explanted livers, the treated lesions were evaluated at pathology, and the necrosis was classified as complete or partial. Thirty-six HCCs were ablated in 30 patients (20.9 ± 6.1 mm, a range of 10–30 mm). Ablations were performed with a single insertion of a MW antenna under ultrasound or CT guidance. A complete radiological response was demonstrated in 30/36 nodules (83.3%) in 24/30 patients (80%) at imaging performed one-month after MW ablation. At pathology, of the 36 treated nodules, 28 (77.8%) showed a complete necrosis, and 8 (22.2%) showed a pathological partial necrosis. Good agreement was found between the imaging performed one-month after treatment and the complete pathological response (Cohen's k = 0.65). The imaging accuracy in detecting a complete response to treatment was 88.9%. All lesions with complete necrosis did not show recurrence at follow-up imaging until transplantation. The rad-path correlation in the explanted livers showed that MW ablation achieved a high rate of complete necrosis if a macroscopical complete ablation was obtained. [ABSTRACT FROM AUTHOR]