Advanced donor age does not increase risk of hepatocellular carcinoma recurrence after liver transplantation: a retrospective two-centre analysis using competing risk analysis.

The impact of donor age on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation is still debated. Between 2002 and 2014, all patients transplanted for HCC in 2 European liver transplantation tertiary centres were retrospectively reviewed. Risk factors for HCC recurrence were assessed using competing risk analysis, and the impact of donor age < or ≥65 years and < or ≥80 years was specifically evaluated after propensity score matching. 728 patients transplanted with a median follow-up of 86 months were analysed. The 1-, 3- and 5-year recurrence rates were 4.9%, 10.7% and 13.9%, respectively. In multivariable analysis, recipient age (sHR: 0.96 [0.93; 0.98], P < 0.01), number of lesions (sHR: 1.05 [1.04; 1.06], P < 0.001), maximum size of the lesions (sHR: 1.37 [1.27; 1.48], P < 0.01), presence of a hepatocholangiocarcinoma (sHR: 6.47 [2.91; 14.38], P < 0.01) and microvascular invasion (sHR: 3.48 [2.42; 5.02], P < 0.01) were significantly associated with HCC recurrence. After propensity score matching, neither donor age ≥65 (P = 0.29) nor donor age ≥80 (P = 0.84) years increased the risk of HCC recurrence. In conclusion, donor age was not found to be a risk factor for HCC recurrence. Patients listed for HCC can receive a graft from an elderly donor without compromising the outcome.

The Role of Salvage Transplantation in Patients Initially Treated With Open Versus Minimally Invasive Liver Surgery: An Intention-to-Treat Analysis.

Despite gaining wide consensus in the management of hepatocellular carcinoma (HCC), minimally invasive liver surgery (MILS) has been poorly investigated for its role in the setting of salvage liver transplantation (SLT). A multicenter retrospective analysis was carried out in 6 Italian centers on 211 patients with HCC who were initially resected with open (n = 167) versus MILS (n = 44) and eventually wait-listed for SLT. The secondary endpoint was identification of risk factors for posttransplant death and tumor recurrence. The enrolled patients included 211 HCC patients resected with open surgery (n = 167) versus MILS (n = 44) and wait-listed for SLT between January 2007 and December 2017. We analyzed the intention-to-treat survival of these patients. MILS was the most important protective factor for the composite risk of delisting, posttransplant patient death, and HCC recurrence (OR, 0.26; 95% confidence interval [CI], 0.11-0.63; P = 0.003). MILS was also the only independent protective factor for the risk of post-SLT patient death (OR, 0.29; 95% CI, 0.09-0.93; P = 0.04). After propensity score matching, MILS was the only independent protective factor against the risk of delisting, posttransplant death, and HCC recurrence (OR, 0.22; 95% CI, 0.07-0.75; P = 0.02). On the basis of the current analysis, MILS seems protective over open surgery for the risk of delisting, posttransplant patient death, and tumor recurrence. Larger prospective studies balancing liver function and tumor stage are strongly favored to better clarify the beneficial effect of MILS for HCC patients eventually referred to SLT.

Machine Perfusions in Liver Transplantation: The Evidence-Based Position Paper of the Italian Society of Organ and Tissue Transplantation.

The use of machine perfusion (MP) in liver transplantation (LT) is spreading worldwide. However, its efficacy has not been demonstrated, and its proper clinical use has far to go to be widely implemented. The Società Italiana Trapianti d'Organo (SITO) promoted the development of an evidence-based position paper. A 3-step approach has been adopted to develop this position paper. First, SITO appointed a chair and a cochair who then assembled a working group with specific experience of MP in LT. The Guideline Development Group framed the clinical questions into a patient, intervention, control, and outcome (PICO) format, extracted and analyzed the available literature, ranked the quality of the evidence, and prepared and graded the recommendations. Recommendations were then discussed by all the members of the SITO and were voted on via the Delphi method by an institutional review board. Finally, they were evaluated and scored by a panel of external reviewers. All available literature was analyzed, and its quality was ranked. A total of 18 recommendations regarding the use and the efficacy of ex situ hypothermic and normothermic machine perfusion and sequential normothermic regional perfusion and ex situ MP were prepared and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. A critical and scientific approach is required for the safe implementation of this new technology.

Sustained virological response with 16-week glecaprevir/pibrentasvir after failure to sofosbuvir/velpatasvir in post-transplant severe HCV recurrence in HIV.

Direct-acting antivirals (DAAs) demonstrated high efficacy and safety even in the post-liver transplant (LT) setting and in HIV-infected patients, but data are very limited in the early post-LT period with the most recently available DAA. Two HIV/HCV-coinfected LT recipients (both grafts from HIV/HCV-negative donors) experienced early HCV recurrence with severe hepatitis and were treated with sofosbuvir/velpatasvir for 12 weeks. Unfortunately, both patients failed: one (genotype 4d) showed virological breakthrough at week 3 with resistance-associated substitutions (RASs) for both NS5A and NS5B, while the other (genotype 1a) experienced virological relapse without RAS. Both progressed to fibrosing cholestatic hepatitis and were successfully retreated with glecaprevir/pibrentasvir for 16 weeks achieving sustained virological response. The higher prevalence of RAS in experienced genotype 4 patients and the long time to viral suppression observed in subjects with fibrosing cholestatic hepatitis should be taken into account, considering longer treatment duration to increase the chances of achieving sustained virological response.

Liver Grafts From Donors After Circulatory Death on Regional Perfusion With Extended Warm Ischemia Compared With Donors After Brain Death.

Donation after circulatory death (DCD) in Italy constitutes a relatively unique population because of the requirement of a no-touch period of 20 minutes. The first aim of this study was to compare liver transplantations from donors who were maintained on normothermic regional perfusion after circulatory death and suffered extended warm ischemia (DCD group, n = 20) with those from donors who were maintained on extracorporeal membrane oxygenation (ECMO) and succumbed to brain death (ECMO group, n = 17) and those from standard donors after brain death (donation after brain death [DBD] group, n = 52). Second, we conducted an explorative analysis on the DCD group to identify relationships between the donor characteristics and the transplant outcomes. The 1-year patient survival for the DCD group (95%) was not significantly different from that of the ECMO group (87%; P = 0.47) or the DBD group (94%; P = 0.94). Graft survival was slightly inferior in the DCD group (85%) because of a high rate of primary nonfunction (10%) and retransplantation (15%) but was not significantly different from the ECMO group (87%; P = 0.76) or the DBD group (91%; P = 0.20). Although ischemic cholangiopathy was more frequent in the DCD group (10%), this issue did not adversely impact graft survival because none of the recipients underwent retransplantation due to biliary complications. Moreover, the DCD recipients were more likely to develop posttransplant renal dysfunction with the need for renal replacement therapy. Further analysis of the DCD group showed that warm ischemia >125 minutes and an Ishak fibrosis score of 1 at liver biopsy negatively impacted serum creatinine and alanine transaminase levels in the first posttransplant week, respectively. In conclusion, our findings encourage the use of liver grafts from DCD donors maintained by regional perfusion after proper selection.

Successful donation after cardiac death liver transplants with prolonged warm ischemia time using normothermic regional perfusion.

The role of donation after cardiac death (DCD) in expanding the donor pool is mainly limited by the incidence of primary nonfunction (PNF) and ischemia-related complications. Even greater concern exists toward uncontrolled DCD, which represents the largest potential pool of DCD donors. We recently started the first Italian series of DCD liver transplantation, using normothermic regional perfusion (NRP) in 6 uncontrolled donors and in 1 controlled case to deal with the legally required no-touch period of 20 minutes. We examined our first 7 cases for the incidence of PNF, early graft dysfunction, and biliary complications. Acceptance of the graft was based on the trend of serum transaminase and lactate during NRP, the macroscopic appearance, and the liver biopsy. Hypothermic machine perfusion (HMP) was associated in selected cases to improve cold storage. Most notably, no cases of PNF were observed. Median posttransplant transaminase peak was 1014 IU/L (range, 393-3268 IU/L). Patient and graft survival were both 100% after a mean follow-up of 6.1 months (range, 3-9 months). No cases of ischemic cholangiopathy occurred during the follow-up. Only 1 anastomotic stricture completely resolved with endoscopic stenting. In conclusion, DCD liver transplantation is feasible in Italy despite the protracted no-touch period. The use of NRP and HMP seems to earn good graft function and proves safe in these organs. Liver Transplantation 23 166-173 2017 AASLD.

Prognostic role of nodal ratio, LODDS, pN in patients with pancreatic cancer with venous involvement.

BACKGROUND: The UICC/AJCC TNM staging system classifies lymph nodes as N0 and N1 in pancreatic cancer. Aim of the study is to determine whether the number of examine nodes, the nodal ratio (NR) and the logarithm odds of positive lymph nodes (LODDS) may better stratify the prognosis of patients undergoing pancreatectomy combined with venous resection for pancreatic cancer with venous involvement. METHODS: A multicenter database of 303 patients undergoing pancreatectomy in 9 Italian referral centers was analyzed. The prognostic impact of number of retrieved and examined nodes, NR, LODDS was analyzed and compared with ROC curves analysis, Pearson test, univariate and multivariate analysis. RESULTS: The number of metastatic nodes, pN, the NR and LODDS was significantly correlated with survival at multivariate analyses. The corresponding AUC for the number of metastatic nodes, pN, the NR and LODDS were 0.66, 0.69, 0.63 and 0.65, respectively. The Pearson test showed a significant correlation between the number of retrieved lymph nodes and number of metastatic nodes, pN and the NR. LODDS had the lower coefficient correlation. Concerning N1 patients, the NR, the LODDS and the number of metastatic nodes were able to significantly further stratify survival (p = 0.040; p = 0.046; p = 0.038, respectively). CONCLUSIONS: The number of examined lymph nodes, the NR and LODDS are useful for further prognostic stratification of N1 patients in the setting of pancreatectomy combined with PV/SMV resection. No superiority of one over the others methods was detected.

The European Policy for Liver Allocation in Patients Affected by Hepatocellular Carcinoma.

The main goal of allocation system is to guarantee an equal access to the limited resource of liver grafts for every class of patients on the waiting list, balancing between the ethical principles of equity, utility, benefit, need, and fairness. The aim of this review was to analyze liver allocation policies among these organizations, focusing on HCC. The European area considered for this analysis included 6 macro-areas or countries, which are congregated from the same policy of liver sharing and allocation. By this definition, the 6 areas identified are: Centro Nazionale Trapianti (CNT) in Italy; Eurotransplant (Germany, the Netherlands, Belgium, Luxembourg, Austria, Hungary, Slovenia, and Croatia); Organizacion Nacional de Transplantes (ONT) in Spain; Etablissement francais des Greffes (EfG) in France; NHS Blood Transplant (NHSBT) in the United Kingdom and Ireland; Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland); Romanian National Policy. Each identified area, as network for organ sharing in Europe, adopts a basic allocation system that consider a policy center oriented or patient oriented. Priorization of patients affected by HCC in the waiting list for deceased donors liver transplant worldwide is dominated by 2 main principles: urgency and utility. The main message of this review is the absence of a common organs allocation policy over the Eurpean countries. Despite that, long-term survival of the community of patients listed for transplant due to HCC results, however, highly acceptable in Europe and comparable to the long-term survial reported in the UNOS register.

Neoadjuvant chemotherapy for resectable colorectal liver metastases: what is the evidence? Results of a systematic review of comparative studies.

BACKGROUND: The role of preoperative chemotherapy for resectable colorectal liver metastases is still highly controversial. The purpose of this systematic review is to summarize the current evidence on this topic. METHODS: A systematic literature search was performed to identify all studies published from January 2003 up to and including January 2014 regarding patients with initially resectable colorectal liver metastases. Data were examined for information about indications, operation, neoadjuvant and adjuvant therapies, perioperative results, and survival. RESULTS: Fourteen retrospective studies published between 2003 and 2014 satisfied the inclusion criteria, including 1607 patients who underwent pre-operative chemotherapy and liver resection (NEO-CHT group), and 1785 patients submitted to hepatectomy with or without post-operative chemotherapy (SURG group). Postoperative mortality rates ranged from 0 to 5% in the NEO-CHT group and from 0 to 4% in SURG group. Complications ranged from 7 to 63% in both groups. Adopted pre-operative chemotherapy protocols were highly heterogeneous. The 5-year overall survival rates ranged from 38.9 to 74% in the NEO-CHT group and from 20.7 to 56% in the SURG group, with no significant difference in seven of eight studies. DISCUSSION: This review shows that there is a lack of clear evidence on the role of neoadjuvant chemotherapy in the treatment of resectable colorectal metastases in the literature. The majority of studies were retrospective and there was high heterogeneity among them in the treatment protocols. The EORTC 40983 trial and the majority of retrospective studies did not find any overall survival advantage in patients treated with neoadjuvant therapy. Additional high-quality studies (randomized) are needed to shed light on this topic.

Pancreatoduodenectomy: Risk Factors of Postoperative Pancreatic Fistula.

BACKGROUND/AIMS: The aim of the present study is the analysis of risk factors of postoperative pancreatic fistula (POPF) and of clinical outcome after pancreatoduodenectomy (PD) in a retrospective multicentric review of the patient cohort. METHODOLOGY: From January 2003 to July 2013 143 patients underwent PD: 138 cases were included and 3 groups were identified according to the different types of anastomosis: Group 1 invaginating end-to-end pancreatojejunostomy, Group 2 end-to-side pancreatojejunostomy with duct-to-mucosa anastomosis, Group 3 end-to-side pancreatogastrostomy. RESULTS: Twenty-one % of patients developed POPF, 16% in Group 1, 27% in Group 2, 12% in Group 3. Forty % grade A, 13% grade B and 47% grade C total POPF. It results that POPF occurred in 16% of hard and in 40% of soft pancreatic texture; in 11.4% of dilated Wirsung versus 30.8% of non dilated (p = 0.007). Overall actuarial 1 and 3 year survival after PD is 69% and 48% respectively. Perioperative mortality is 5.8% overall, 17.85% for grade C. CONCLUSIONS: No differences have been found among surgical anastomosis techniques. Soft tissues seem to increase, while dilated Wirsung seems to decrease POPF rate. The development of POPF increase morbidity but it doesn't affect overall survival, more strictly related to tumour histopathology.

Hilar cholangiocarcinoma: preoperative liver optimization with multidisciplinary approach. Toward a better outcome.

INTRODUCTION: The diagnosis and treatment of hilar tumors requires a multidisciplinary approach based on the synergy of radiologists, surgeons, oncologists, and gastroenterologists. Klatskin tumor is a relatively rare disease with a poor prognosis. Currently, the only possible treatment is represented by the removal of the tumor associated with radical surgery, even though its results are still jeopardized by significant morbidity and mortality. A proper preoperative optimization of the patient, including staging laparoscopy, biliary drainage, and portal vein embolization, may improve short-term outcome. The purpose of this study was to evaluate the short- and long-term impact of preoperative optimization in patients affected by hilar cholangiocarcinoma. METHODS: From January 2004 to May 2012, 94 patients with preoperative diagnosis of Klastkin tumors were candidates for surgery at the Hepatobiliary Surgery Unit of the Hospital San Raffaele in Milan. The data of all patients were prospectively collected and retrospectively reviewed. The outcome was evaluated in terms of perioperative morbidity and mortality and overall and disease-free survival. Short-term outcome of patients undergoing preoperative optimization was compared with outcome of patients who did not undergo it in terms of intraoperative data, morbidity and mortality. RESULTS: Of 94 patients undergoing surgery, 80 underwent hepatic and biliary confluence resection. Fourteen patients were considered unresectable due to the presence of peritoneal carcinomatosis or advanced disease seen during staging laparoscopy or at laparotomy and therefore were excluded from the analysis. Seventy-five (93.7 %) patients underwent major liver resections: in 14 of these, surgery was performed at a distance of 30-40 days from PVE. In 55 patients, biliary drainage was preoperatively placed for palliation of obstructive jaundice. The postoperative morbidity rate was 51.2 % and mortality 6.2 %. The most frequent cause of death was postoperative liver failure. Five-year survival rate was 29 %. Patients undergoing preoperative optimization experienced a significant reduction of postoperative morbidity, especially in terms of infectious related events. CONCLUSIONS: Klatskin tumor remains a disease associated with poor prognosis, but a correct preoperative diagnostic and therapeutic management provides tools to perform this type of surgery with acceptable morbidity and mortality, thus improving long-term results.

Laparoendoscopic single site (LESS) surgery for left-lateral hepatic sectionectomy as an alternative to traditional laparoscopy: case-matched analysis from a single center.

BACKGROUND: Laparoscopy is considered the "gold standard" to perform left-lateral sectionectomy with results identical to those of open surgery, yielding decreased postoperative pain and disability, reduced hospital stay, and shortened patient recovery time. As the emphasis on minimizing the invasiveness of surgical techniques continues, laparoendoscopic single site (LESS) surgery is quickly evolving. The purpose of this study was to compare the results of laparoscopic left-lateral sectionectomy performed using the traditional approach or LESS approach with a case-matched analysis for tumor size, type of resection, and surgical indications. METHODS: Thirteen patients who underwent LESS left-lateral sectionectomy are considered the study group (LESS group) and compared with 13 patients who underwent left-lateral sectionectomy with traditional laparoscopic approach (conventional group). RESULTS: There were no significant differences between groups for length of surgery (165 min in conventional group vs. 195 min in LESS group), blood loss (150 mL in conventional group vs. 175 mL in LESS group), conversion to open surgery, histological tumor exposure, and requirements of postoperative analgesics. One patient in the LESS group died of cardiac failure due to an unknown severe aortic valve stenosis. No differences were recorded for postoperative complications (23.1% in both groups) and median length of postoperative stay (4 days in both groups). CONCLUSIONS: For left-lateral hepatic sectionectomy, LESS surgery is technically feasible and as safe as traditional laparoscopic surgery in terms of intraoperative and postoperative results, even though requiring both hepatobiliary and laparoscopic technique experience.

LESS technique for liver resection: the progress of the mini-invasive approach: a single-centre experience.

INTRODUCTION: During the last years, the safety and efficacy of the laparoscopic approach for liver masses located in the left lobe have been demonstrated, encouraging the mini-invasive approach and, in more recent times, the LESS technique (Laparo Endoscopic Single Site), in an attempt to reduce the biological invasiveness related to surgical trauma. MATERIAL AND METHODS: From January 2009 to December 2010, 39 patients underwent laparoscopic liver resection at our institution. In 14 of these, the LESS technique was used. The aim of our study is to evaluate the short-term outcome of this group of patients. RESULTS: We recorded the following results: Mean operative time of 187 min (range 145-420 min), mean intraoperative blood loss of 214 ml (range 50-700 ml), postoperative morbidity rate of 21.4%, one postoperative death (related to acute heart failure related to severe aortic valve stenosis). Excluding this patient from the statistical analysis, the morbidity rate was 14.3%. The median hospital stay was five days. DISCUSSION: The LESS technique for liver resections is safe and effective in selected patients and in centres with high expertise in laparoscopic liver surgery.

Effects of non-surgical periodontal therapy on the glomerular filtration rate of the kidney: an exploratory trial.

OBJECTIVE: To determine whether non-surgical periodontal treatment (PT) would exert, in subjects with generalized chronic periodontitis (GCP), some beneficial effect on renal function as indicated by surrogate measures of the glomerular filtration rate (GFR). MATERIAL AND METHODS: Twenty GCP systemically healthy subjects were treated with PT. Serum samples were collected at baseline and 1 day, 7, 30, 90 and 180 days after treatment. GFR was evaluated using cystatin C, a serum marker and modification of diet in renal disease (MDRD), an equation involving creatinine, urea and albumin. Serum markers of systemic inflammation such as C-reactive protein (CRP), D-dimer, serum amyloid A (SAA) and fibrinogen were also assessed. RESULTS: The cystatin C level decreased significantly from baseline to the end of the trial (p<0.01). Conversely, MDRD did not vary. A significant inflammatory reaction was produced by PT in the short term. Greater increases were noted for CRP and SAA within 24 h (p<0.001 versus baseline), while D-dimer (p<0.05) and fibrinogen (p<0.01) showed mild variations. The values of inflammatory markers were normalized after 30 days. CONCLUSIONS: GFR, as assessed by cystatin C levels, may be positively affected by PT. Because of the exploratory nature of this trial, further research is needed to investigate this preliminary finding.

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver Retransplant.

Importance: Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. Objective: To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. Design, Setting, and Participants: This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Main Outcomes and Measures: Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. Results: At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. Conclusions and Relevance: This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers.