How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child-Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study.

BACKGROUND: Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). METHODS: DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). RESULTS: Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. CONCLUSIONS: In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.

A national mandatory-split liver policy: A report from the Italian experience.

To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50 years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially "splittable" donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P = .009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P = .045]). The pediatric (4.5% vs 2.5% [P = .398]) and adult (9.7% to 5.2% [P < .001]) LT-waiting list mortality reduced; SLT outcomes remained stable. Retransplantation (HR = 2.641, P = .035) and recipient weight >20 kg (HR = 5.113, P = .048) in LLS, and ischemic time >8 hours (HR = 2.475, P = .048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.

Our experience of liver Epithelioid Hemangioendothelioma: from a misdiagnosis to liver transplantation with long term follow-up.

Malignant Hepatic Epithelioid hemangioendothelioma (HEHE) is an uncommon vascular tumor of intermediate malignant potential. HEHE is a rare tumor and it is difficult to diagnose for surgeons, hepatologists, radiologists and pathologists. So, misdiagnosis with a delay of the treatment is not uncommon. We describe a case of a young woman with a diagnosis of HEHE made 6 years after the first evidence of liver mass with a very long term follow-up after surgical treatment. She had two diagnoses of Hepatocellurar carcinoma (HCC) and a diagnosis of Cholangiocarcinoma after three different fine needle biopsies. After clinical observation, a new laparoscopic core biopsy was performed. In a first time approach, considering clinical and radiological patterns, a diagnosis of Budd-Chiari Syndrome was finally made. For that the patient underwent an orthotopicliver transplantation (OLTx). The surgical sample histological analysis allowed a definitive diagnosis of HEHE. At last, at follow up 7 years after three OLTx the patient is still alive and in good health with no evidence of recurrence.

Hepaticojejunostomy in the treatment of iatrogenic biliary lesions following laparoscopic cholecystectomy. A retrospective study on 51 cases.

BACKGROUND/AIMS: Laparoscopic cholecystectomy is characterized by a higher incidence of iatrogenic biliary lesions. The Authors evaluate the role of hepaticojejunostomy in the treatment of iatrogenic biliary lesions following laparoscopic cholecystectomy in 51 patients observed in the Campania region, Italy from 1991 to 2003. METHODOLOGY: The Authors report the data of a retrospective multicentric study of 51 patients -39 women (76.47%), 12 men (13.53%)-reoperated on for major biliary lesions following laparoscopic cholecystectomy. Hepaticojejunostomy in 20 cases (39.21%) and T-Tube plasty in 20 cases (39.21%) were performed. RESULTS: The mean follow-up was 25.01 months. The mean hospital stay was 25.7 days. 1/51 patients (1.9%) died from intraoperative incontrollable hemorrhage while cumulative postoperative mortality was 9.8% (5/51 patients). Therapeutic success rate of hepaticojejunostomy was 70% with a T-Tube plasty success rate of 65%. 9/51 patients (17.64%) were reoperated while in 4/51 (7.84%) a biliary stent was positioned. In 1/51 patients (1.9%) a biliary cirrhosis and in 3/51 (5.7%) a bioumoral cholestasis was observed. CONCLUSIONS: Laparoscopic cholecystectomy causes a higher incidence of iatrogenic biliary lesions. Hepaticojejunostomy gives better long-term results and lower morbidity compared to T-Tube plasty. Management of septic complications in patients with iatrogenic biliary lesions represents the first therapeutic step.

[Surgical treatment of iatrogenic bile duct injuries following laparoscopic cholecystectomy: analysis of long-term results. Retrospective clinical study in 51 patients operated in the Campania region from 1991 to 2003]. / Trattamento chirurgico delle lesioni iatrogene della via biliare in seguito a colecistectomia videolaparoscopica: analisi dei risultati a distanza. Studio clinico retrospettivo in 51 pazienti operati nella regione Campania dal 1991 al 2003.

An higher incidence rate of iatrogenic bile duct injuries is reported in cholecystectomy performed with the laparoscopy than with the laparotomy approach. The aim of this study was to provide a multicentre report on surgical treatment and the outcome of biliary complications during and following laparoscopic cholecystectomy. A questionnaire was mailed to all surgeons with experience in laparoscopic cholecystectomy in the Campania region. Data were collected from January 1991 to December 2003. Each patient was requested to indicate age, gender, associated diseases, site and type of lesion, surgical experience, diagnosis, treatment and complications. Twenty-six surgeons answered the questionnaire. Fifty-one patients (36 F/15 M; mean age: 42.5 +/- 11.9, range 13-91 years) with bile duct injuries following laparoscopic cholecystectomy were reported. The most frequent lesions were main bile duct partial or total transection. The intraoperative mortality rate was 1/51 (1.9%) due to a complex biliary and vascular injury. The postoperative mortality rate of revision surgery was 5/50 (10%). T-tube positioning (n = 20) and Roux-en-Y hepato-jejunostomy (n = 20) were the procedures most frequently performed. The complication rate in patients treated with the T-tube was significantly higher than in those treated with hepatico-jejunostomy. Surgical treatment of biliary injuries following laparoscopic cholecystectomy was characterized by unusually high mortality and morbidity for a non-neoplastic disease. Roux-en-Y hepato-jejunostomy remains the procedure of choice for these injuries.