Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT).

Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.

Robotic versus Laparoscopic Liver Resection in Various Settings: An International Multicenter Propensity Score Matched Study of 10.075 Patients.

OBJECTIVE: The aim of this study was to compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. SUMMARY BACKGROUND DATA: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: minor resections in the anterolateral (2, 3, 4b, 5, and 6) or posterosuperior segments (1, 4a, 7, 8), and major resections (≥3 contiguous segments). Propensity score matching (PSM) was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After PSM, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs. 71.8%, P<0.001) and TOLS+ (55% vs. 50.4%, P=0.026), less Pringle usage (39.1% vs. 47.1%, P<0.001), blood loss (100 vs. 200 milliliters, P<0.001), transfusions (4.9% vs. 7.9%, P=0.003), conversions (2.7% vs 8.8%, P<0.001), overall morbidity (19.3% vs. 25.7%, P<0.001) and R0 resection margins (89.8% vs. 86%, P=0.015), but longer operative times (190 vs. 210 min, P=0.015). In the subgroups, RLS tended to have higher TOLS rates, compared to LLS, for minor resections in the posterosuperior segments (n=431 per group, 75.9% vs. 71.2%, P=0.184) and major resections (n=321 per group, 72.9% vs. 67.5%, P=0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both producing excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.

Trends in the characteristics and perioperative outcomes of patients undergoing laparoscopic and open resections for benign liver lesions: An international multicenter retrospective cohort study of 845 patients.

BACKGROUND: Solid benign liver lesions (BLL) are increasingly discovered, but clear indications for surgical treatment are often lacking. Concomitantly, laparoscopic liver surgery is increasingly performed. The aim of this study was to assess if the availability of laparoscopic surgery has had an impact on the characteristics and perioperative outcomes of patients with BLL. METHODS: This is a retrospective international multicenter cohort study, including patients undergoing a laparoscopic or open liver resection for BLL from 19 centers in eight countries. Patients were divided according to the time period in which they underwent surgery (2008-2013, 2014-2016, and 2017-2019). Unadjusted and risk-adjusted (using logistic regression) time-trend analyses were performed. The primary outcome was textbook outcome (TOLS), defined as the absence of intraoperative incidents ≥ grade 2, bile leak ≥ grade B, severe complications, readmission and 90-day or in-hospital mortality, with the absence of a prolonged length of stay added to define TOLS+. RESULTS: In the complete dataset comprised of patients that underwent liver surgery for all indications, the proportion of patients undergoing liver surgery for benign disease remained stable (12.6% in the first time period, 11.9% in the second time period and 12.1% in the last time period, p = 0.454). Overall, 845 patients undergoing a liver resection for BLL in the first (n = 374), second (n = 258) or third time period (n = 213) were included. The rates of ASA-scores≥3 (9.9%-16%,p < 0.001), laparoscopic surgery (57.8%-77%,p < 0.001), and Pringle maneuver use (33.2%-47.2%,p = 0.001) increased, whereas the length of stay decreased (5 to 4 days,p < 0.001). There were no significant changes in the TOLS rate (86.6%-81.3%,p = 0.151), while the TOLS + rate increased from 41.7% to 58.7% (p < 0.001). The latter result was confirmed in the risk-adjusted analyses (aOR 1.849,p = 0.004). CONCLUSION: The surgical treatment of BLL has evolved with an increased implementation of the laparoscopic approach and a decreased length of stay. This evolution was paralleled by stable TOLS rates above 80% and an increase in the TOLS + rate.

Management of Coeliac and Hepatic Artery Aneurysms: An Experience of 84 Cases.

OBJECTIVE: To report outcomes following open or endovascular treatment of true hepatic and coeliac artery aneurysms at a single referral centre. METHODS: This was a retrospective cohort study of consecutive patients treated for true hepatic and coeliac artery aneurysms between May 2002 and December 2021. Outcome measures included complications, graft patency, and survival rate. RESULTS: Overall, 84 patients were included with a median age of 63 years (interquartile range 55, 79). The majority (76%) of the patients were men. Frequent comorbidities included a history of tobacco (69%), hypertension (65%), hyperlipidaemia (32%), and diabetes (15%). Multiple synchronous aneurysms were detected in 22 patients (26%). There were 33 (39%) symptomatic aneurysms (abdominal pain without rupture [n = 18], rupture [n = 10], and sepsis [n = 5]). Seventeen patients (20%) had mycotic aetiology. Fifty patients (60%) underwent endovascular treatment with either covered stent placement (n = 29) or coil embolisation (n = 21), and 34 patients (40%) were treated with open surgery using allogenic iliac artery (n = 15), autologous saphenous vein (n = 15), GoreTex graft (n = 2), or ligation (n = 2). The complication rate was 32% in the open group and 18% in the endovascular group (p = .048). The overall 90 day post-operative mortality rate was 1.2%, five year primary patency was 90.0%, five year survival rate was 81.2%, and mean follow up was 6.9 ± 4.2 years. CONCLUSION: Endovascular treatment is the preferred approach whenever technically possible. Despite higher post-operative morbidity, an open approach with vascular reconstruction using autologous or allogenic vascular grafts yields acceptable long term results.

Simultaneous resection of colorectal cancer and synchronous liver metastases: what determines the risk of unfavorable outcomes? An international multicenter retrospective cohort study.

BACKGROUND: The use of a simultaneous resection (SIMR) in patients with synchronous colorectal liver metastases (sCRLM) has increased over the past decades. However, it remains unclear when a SIMR is beneficial and when it should be avoided. The aim of this retrospective cohort study was therefore to compare the outcomes of a SIMR for sCRLM in different settings, and to assess which factors are independently associated with unfavorable outcomes. METHODS: To perform this retrospective cohort study, patients with sCRLM undergoing SIMR (2004-2019) were extracted from an international multicenter database, and their outcomes were compared after stratification according to the type of liver and colorectal resection performed. Factors associated with unfavorable outcomes were identified through multivariable logistic regression. RESULTS: Overall, 766 patients were included, encompassing colorectal resections combined with a major liver resection (n=122), minor liver resection in the anterolateral (n=407), or posterosuperior segments ('Technically major', n=237). Minor and technically major resections, compared to major resections, were more often combined with a rectal resection (29.2 and 36.7 vs. 20.5%, respectively, both P=0.003) and performed fully laparoscopic (22.9 and 23.2 vs. 6.6%, respectively, both P = 0.003). Major and technically major resections, compared to minor resections, were more often associated with intraoperative transfusions (42.9 and 38.8 vs. 20%, respectively, both P = 0.003) and unfavorable incidents (9.6 and 9.8 vs. 3.3%, respectively, both P≤0.063). Major resections were associated, compared to minor and technically major resections, with a higher overall morbidity rate (64.8 vs. 50.4 and 49.4%, respectively, both P≤0.024) and a longer length of stay (12 vs. 10 days, both P≤0.042). American Society of Anesthesiologists grades ≥3 [adjusted odds ratio (aOR): 1.671, P=0.015] and undergoing a major liver resection (aOR: 1.788, P=0.047) were independently associated with an increased risk of severe morbidity, while undergoing a left-sided colectomy was associated with a decreased risk (aOR: 0.574, P=0.013). CONCLUSIONS: SIMR should primarily be reserved for sCRLM patients in whom a minor or technically major liver resection would suffice and those requiring a left-sided colectomy. These findings should be confirmed by randomized studies comparing SIMR with staged resections.

Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosis.

BACKGROUND & AIMS: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. METHODS: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021. RESULTS: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14-24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all-cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001). CONCLUSIONS: Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed. IMPACT AND IMPLICATIONS: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation. Results of this international, multicenter analysis may be used to guide clinical decisions in transplant candidates with complex PVT. Extra-anatomical portal vein anastomoses that allow for at least some recipient splanchnic blood flow to the transplant allograft offer acceptable results. On the other hand, anastomoses that deliver only systemic blood flow to the allograft fail to resolve portal hypertension and should not be performed.

Textbook Outcome of Laparoscopic Microwave Ablation for Hepatocellular Carcinoma.

In the context of spreading interest in textbook outcome (TO) evaluation in different fields, we aimed to investigate an uncharted procedure, that is, laparoscopic microwave ablation (MWA) for hepatocellular carcinoma (HCC). Absence of post-MWA complications, a hospital stay of three days, no mortality nor readmission within 30 days, and complete response of the target lesion at post-MWA CT scan defined TO achievement. Patients treated between January 2014 and March 2021 were retrospectively reviewed, and of the 521 patients eligible for the study, 337 (64.7%) fulfilled all the quality indicators to achieve the TO. The absence of complications was the main limiting factor for accomplishing TO. At multivariable analysis, Child-Pugh B cirrhosis, age of more than 70 years old, three nodules, and MELD score ≥ 15 were associated with decreased probabilities of TO achievement. A score based on these factors was derived from multivariable analysis, and patients were divided into three risk groups for TO achievement. At survival analysis, overall survival (OS) was significantly (p = 0.001) higher in patients who achieved TO than those who did not. Moreover, OS evaluation in the three risk groups showed a trend coherent with TO achievement probability. The present study, having assessed the first TO for laparoscopic MWA for HCC, encourages further broader consensus on its definition and, on its basis, on the development of clinically relevant tools for managing treatment allocation.

Indications, trends, and perioperative outcomes of minimally invasive and open liver surgery in non-obese and obese patients: An international multicentre propensity score matched retrospective cohort study of 9963 patients.

BACKGROUND: Despite the worldwide increase of both obesity and the use of minimally invasive liver surgery (MILS), evidence regarding the safety and eventual benefits of MILS in obese patients is scarce. The aim of this study was therefore to compare the outcomes of non-obese and obese patients (BMI 18.5-29.9 and BMI≥30, respectively) undergoing MILS and OLS, and to assess trends in MILS use among obese patients. METHODS: In this retrospective cohort study, patients operated at 20 hospitals in eight countries (2009-2019) were included and the characteristics and outcomes of non-obese and obese patients were compared. Thereafter, the outcomes of MILS and OLS were compared in both groups after propensity-score matching (PSM). Changes in the adoption of MILS during the study period were investigated. RESULTS: Overall, 9963 patients were included (MILS: n = 4687; OLS: n = 5276). Compared to non-obese patients (n = 7986), obese patients(n = 1977) were more often comorbid, less often received preoperative chemotherapy or had a history of previous hepatectomy, had longer operation durations and more intraoperative blood loss (IOBL), paralleling significantly higher rates of wound- and respiratory-related complications. After PSM, MILS, compared to OLS, was associated, among both non-obese and obese patients, with less IOBL (200 ml vs 320 ml, 200 ml vs 400 ml, respectively), lower rates of transfusions (6.6% vs 12.8%, 4.7% vs 14.7%), complications (26.1% vs 35%, 24.9% vs 34%), bile leaks(4% vs 7%, 1.8% vs 4.9%), liver failure (0.7% vs 2.3%, 0.2% vs 2.1%), and a shorter length of stay(5 vs 7 and 4 vs 7 days). A cautious implementation of MILS over time in obese patients (42.1%-53%, p < .001) was paralleled by stable severe morbidity (p = .433) and mortality (p = .423) rates, despite an accompanying gradual increase in surgical complexity. CONCLUSIONS: MILS is increasingly adopted and associated with perioperative benefits in both non-obese and obese patients.

Impact of Positive Radial Margin on Recurrence and Survival in Perihilar Cholangiocarcinoma.

In resected perihilar cholangiocarcinoma (PHC), positive ductal margin (DM) is associated with poor survival. There is currently little knowledge about the impact of positive radial margin (RM) when DM is negative. The aim of this study was to evaluate the incidence and the role of positive RM. Patients who underwent surgery between 2005 and 2017 where retrospectively reviewed and stratified according to margin positivity: an isolated RM-positive group and DM ± RM group. Of the 75 patients identified; 34 (45.3%) had R1 resection and 17 had positive RM alone. Survival was poorer in patients with R1 resection compared to R0 (p = 0.019). After stratification according to margin positivity; R0 patients showed better survival than DM ± RM-positive patients (p = 0.004; MST 43.9 vs. 23.6 months), but comparable to RM-positive patients (p = 0.361; MST 43.9 vs. 39.5 months). Recurrence was higher in DM ± RM group compared to R0 (p = 0.0017; median disease-free survival (DFS) 15 vs. 30 months); but comparable between RM and R0 group (p = 0.39; DFS 20 vs. 30 months). In univariate and multivariate analysis, DM positivity resulted as a negative prognostic factor both for survival and recurrence. In conclusion, positive RM resections appear to have different recurrence patterns and survival rates than positive DM resections.

Outcome of major hepatectomy in cirrhotic patients; does surgical approach matter? A propensity score matched analysis.

OBJECTIVE: Major hepatectomy in cirrhotic patients still represents a great challenge for liver surgeons. Hence, the aim in the present study is to investigate the clinical impact of major hepatectomy and to assess whether the surgical approach influences the outcome of cirrhotic patients. METHODS: Multicenter retrospective study including cirrhotic patients undergoing major laparoscopic (mjLLR) and open liver resection (mjOLR) in 14 Western liver centers was performed (2009-2020). Clinical, demographic, and perioperative data were compared using propensity score matching (PSM). Long-term outcome after resection for hepatocellular carcinoma was analyzed. RESULTS: Overall, 352 patients were included; 108 after mjLLR and 244 after mjOLR. After PSM, 88 patients were matched in each group. In the mjLLR group, compared to mjOLR, less blood loss (P = .042), lower overall and severe complication (P < .001, .020), such as surgical site infection, acute kidney injury and liver failure were observed, parallel to a shorter length of hospital stay. Stratifying patients based on the type of resection, less severe complications was observed only after laparoscopic left hepatectomy (P = .044), while the advantages of laparoscopy tend to decrease during right hepatectomy. Subgroup analysis of long-term survivals following liver resection for hepatocellular carcinoma showed no difference between mjLLR and mjOLR. CONCLUSIONS: This multicenter experience suggests potential short-term benefits of mjLLR in cirrhotic patients compared to mjOLR, without compromising long-term outcome. These findings might have interesting clinical implications for the management of patients with chronic liver disease.

Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score.

Liver transplantation (LT) for colorectal liver metastasis (CRLM) may provide excellent survival rates in patients with unresectable disease. High tumor load is a risk factor for recurrence and low overall survival (OS) after liver resection (LR). We tested the hypothesis that LT could offer better survival than LR in patients with high tumor load. LR performed at Padua University Hospital for CRLM was compared with LT for unresectable CRLM performed both at Oslo and Padua. High tumor load was defined as tumor burden score (TBS) ≥ 9, and inclusion criteria were as in the SECA-I transplant study. 184 patients were eligible: 128 LRs and 56 LTs. 5-year OS after LR and LT was 40.5% and 54.7% (P = 0.102). In the high TBS cohort, 5-year OS after LR and LT was 22.7% and 52.2% (P = 0.055). In patients with Oslo score ≤ 2 and TBS ≥ 9 (13 LR; 24 LT) the 5-year OS after LR and LT was 14.6% and 69.1% (P = 0.002). The corresponding disease-free survival (DFS) was 0% and 22.9% (P = 0.005). Selected CRLM patients with low Oslo score and high TBS could benefit from LT with survival outcomes that are far better than what is achieved by LR.

Assessment of Textbook Outcome in Laparoscopic and Open Liver Surgery.

Importance: Textbook outcome (TO) is a composite measure that captures the most desirable surgical outcomes as a single indicator, yet to date TO has not been defined and assessed in the field of laparoscopic liver resection (LLR) and open liver resection (OLR). Objective: To obtain international agreement on the definition of TO in liver surgery (TOLS) and to assess the incidence of TO in LLR and OLR in a large international multicenter database using a propensity-score matched analysis. Design, Setting, and Participants: Patients undergoing LLR or OLR for all liver diseases between January 2011 and October 2019 were analyzed using a large international multicenter liver surgical database. An international survey was conducted among all members of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA) and International Hepato-Pancreato-Biliary Association (IHPBA) to reach agreement on the definition of TOLS. The rate of TOLS was assessed for LLR and OLR before and after propensity-score matching. Factors associated with achieving TOLS were investigated. Main Outcomes and Measures: Textbook outcome, with TOLS defined as the absence of intraoperative incidents of grade 2 or higher, postoperative bile leak grade B or C, severe postoperative complications, readmission within 30 days after discharge, in-hospital mortality, and the presence of R0 resection margin. Results: A total of 8188 patients (4559 LLR; median age, 65 years [interquartile range, 55-73 years]; 2529 were male [55.8%] and 3629 OLR; median age, 64 years [interquartile range, 56-71 years]; 2204 were male [60.7%]) were included in the analysis of whom 69.1% achieved TOLS; 74.8% for LLR and 61.9% for OLR (P < .001). On multivariable analysis, American Society of Anesthesiologists grade III, previous abdominal surgery, histological diagnosis of colorectal liver metastases (odds ratio [OR], 0.656 [95% CI, 0.457-0.940]; P = .02), cholangiocarcinoma, non-CRLM, a tumor size of 30 mm or more, minor resection of posterior/superior segments (OR, 0.716 [95% CI, 0.577-0.887]; P = .002), anatomically major resection (OR, 0.579 [95% CI, 0.418-0.803]; P = .001), and nonanatomical resection (OR, 0.612 [95% CI, 0.476-0.788]; P < .001) were associated with a worse TOLS rate after LLR. For OLR, only histological diagnosis of cholangiocarcinoma (OR, 0.360 [95% CI, 0.214-0.607]; P < .001) and a tumor size of 30 mm or more (30-50 mm = OR, 0.718 [95% CI, 0.565-0.911]; P = .01; 50.1-100 mm = OR, 0.729 [95% CI, 0.554-0.960]; P = .02; >10 cm = OR, 0.550 [95% CI, 0.366-0.826]; P = .004) were associated with a worse TOLS rate. Conclusions and Relevance: In this multicenter study, TOLS was found to be a useful tool for assessing patient-level hospital performance and may have utility in optimizing patient outcomes after LLR and OLR.

Immunological risk factors in biliary strictures after liver transplantation.

BACKGROUND: The purpose of this study was to investigate immunological risk factors associated with BS (Biliary Strictures) after LT (Liver Transplantation). MATERIAL AND METHODS: The study included 192 patients out of 273 adult liver transplantations performed from August 2005 to December 2012, with a radiological or surgically proven biliary stricture. About 35 potential risk factors for biliary strictures were studied. Results A biliary stricture was diagnosed in 22.9% of transplants; the anastomotic type and the non-anastomotic type complicated the transplantation in 18.2% and 7.8% of cases, respectively. Six patients (3.1%) presented both of forms. Univariate analysis using logistic regression showed that preoperative serum bilirubin level >2 mg/dl (P=0.040), donor age >46 years old (P=0.007), positive crossmatch (P=0.007), product of donor age and preoperative Model for End Stage Liver Disease (DMELD) >710 (P=0.011), occurrence of acute or chronic rejection (P=0.004; P=0.003), and biliary leak (P=0.002) were all significantly associated with the development of biliary stricture. At the multivariate analysis, Primary Biliary Cirrhosis (PBC) (P=0.019), donor age >46 years (P=0.008), crossmatch positivity (P=0.001), and acute or chronic rejection (P=0.005; P=0.043) appeared to be the only variables independently associated with the development of a biliary stricture. Conclusions Immunological risk factors (PBC, crossmatch positivity, acute and chronic rejection) emerged as being the most important variables associated to the development of biliary strictures after LT.