• Deep learning
• DeepSurv
• Hepatocellular carcinoma
• Liver transplantation
• Recurrence predictive models

• Humans
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/surgery
• Liver Neoplasms/pathology
• Liver Neoplasms/mortality
• Liver Transplantation/adverse effects
• Male
• Female
• Middle Aged
• Neoplasm Recurrence, Local
• Deep Learning
• Retrospective Studies
• China/epidemiology
• Adult

• Acute liver rejection
• Atezolizumab
• Bevacizumab
• HCC
• HCC recurrence
• Immune checkpoint inhibitors
• Liver transplantation
• Pembrolizumab
• TKIs

• Humans
• Liver Transplantation/adverse effects
• Liver Neoplasms/therapy
• Liver Neoplasms/surgery
• Liver Neoplasms/etiology
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/surgery
• Neoplasm Recurrence, Local/therapy
• Neoplasm Recurrence, Local/prevention & control
• Immunotherapy/methods
• Immunosuppressive Agents/therapeutic use
• Graft Rejection/prevention & control
• Graft Rejection/etiology

• Hepatocellular carcinoma
• Liver transplantation
• Recurrence
• Survival

• comorbidities
• frailty
• hepatocellular carcinoma
• immunosuppression management
• immunotherapy
• liver transplantation
• multidisciplinary care
• recurrence surveillance

• Humans
• Carcinoma, Hepatocellular/surgery
• Liver Neoplasms/surgery
• Liver Transplantation
• Lumbar Vertebrae/surgery
• Neoplasm Recurrence, Local
• Spinal Neoplasms/surgery
• Spinal Neoplasms/secondary

• hepatocellular carcinoma
• immunosuppression
• liver transplantation
• tyrosine kinase inhibitor

• Everolimus
• Immunosuppression
• Liver transplantation
• Recommendations
• Transplant oncology

• Liver Transplantation
• Humans
• Liver Neoplasms/surgery
• Immunosuppression Therapy/methods
• Italy
• Immunosuppressive Agents/therapeutic use
• Carcinoma, Hepatocellular/surgery
• Neoplasm Recurrence, Local

• HCC recurrence
• checkpoint inhibitors
• liver transplantation
• mTOR inhibitors
• vascular invasion

• allograft rejection
• biliary complications
• immunosuppression
• liver transplant
• post-transplant infection
• post-transplant malignancy
• post-transplant metabolic syndrome

• Humans
• Liver Transplantation/adverse effects
• Liver Transplantation/methods
• Long-Term Care
• Organ Transplantation
• Immunosuppression Therapy
• Neoplasms
• Graft Rejection/etiology
• Graft Rejection/prevention & control
• Transplant Recipients

Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2–3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1–2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.

• Liver transplantation
• Hepatocellular carcinoma
• Immunosuppression
• Recurrence
• Surgical treatment
• Locoregional treatment
• Systemic treatment

• Calcineurin Inhibitors
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/surgery
• Humans
• Immune Checkpoint Inhibitors
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery
• Neoplasm Recurrence, Local/therapy
• Retrospective Studies
• Sorafenib/therapeutic use
• TOR Serine-Threonine Kinases

Ischemia reperfusion injury (IRI) is an adverse factor for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Ischemic-free liver transplantation (IFLT) is a novel transplant procedure that can largely reduce or even prevent IRI, but the clinical relevance of IFLT and the recurrence of HCC after liver transplantation are still unknown. This retrospective study compared survival outcomes, HCC recurrence, perioperative data and IRI severity following liver transplantation (LT). 30 patients received IFLT and 196 patients received conventional liver transplantation (CLT) were chosen for the entire cohort between June 2017 and August 2020. A 1:3 propensity score matching was performed, 30 IFLT recipients and 85 matched CLT patients were enrolled in propensity-matched cohorts. An univariate and multivariate Cox regression analysis was performed, and showed surgical procedure (CLT vs IFLT) was an independent prognostic factor (HR 3.728, 95% CI 1.172-11.861, P=0.026) for recurrence free survival (RFS) in HCC patients following liver transplantation. In the Kaplan–Meier analysis, the RFS rates at 1 and 3 years after LT in recipients with HCC in the IFLT group were significantly higher than those in the CLT group both in the entire cohort and propensity-matched cohort (P=0.006 and P=0.048, respectively). In addition, patients in the IFLT group had a lower serum lactate level, lower serum ALT level and serum AST level on postoperative Day 1. LT recipients with HCC in the IFLT group had a lower incidence of early allograft dysfunction than LT recipients with HCC in the CLT group. Histological analysis showed no obvious hepatocyte necrosis or apoptosis in IFLT group. In conclusion, IFLT can significantly reduce IRI damage and has the potential to be a useful strategy to reduce HCC recurrence after liver transplantation.

• hepatocellular carcinoma
• ischemia reperfusion injury
• ischemic-free liver transplantation
• prognosis
• propensity-matched analysis

• Hepatocellular carcinoma
• Liver transplantation
• Management
• Post-recurrence
• Prediction
• Prognosis
• Survival
• Systematic review

The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.

Hepatocellular carcinoma (HCC) is an increasingly important indication for liver transplantation (LT) worldwide. However, LT in the setting of liver cancer is burdened by the risk of tumor recurrence. The prognosis of patients with post-LT HCC recurrence is still very poor and several areas of uncertainty remain in the management of these patients. In this paper, we provide a comprehensive evaluation of available evidence regarding the management of HCC recurrence after LT, starting from the pre- and post-transplant stratification criteria and encompassing post-LT surveillance, preventive strategies and treatment. Much work has been done in the last several years but further effort is still needed in order to improve the outcome of these patients.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10–15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.

• hepatocellular carcinoma
• immunosuppression
• liver transplantation
• recurrence
• surveillance
• treatment

Liver transplantation is a curative treatment option for a subset of patients with hepatocellular carcinoma (HCC). However, about twenty percent of patients develop recurrence in the graft or at extrahepatic sites, which is associated with limited therapeutic options and poor survival. To date, management of the immunosuppressive regimen after recurrence and its impact on survival are unknown. In this retrospective study, we analyzed a cohort of liver recipients with HCC recurrence. Our findings indicate that reduction of immunosuppressive therapy after diagnosis of recurrence has a beneficial impact on patient survival. Therefore, we propose further investigation into the management of immunosuppressive therapy following recurrence.

Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

• immunosuppression
• liver transplantation
• long-term follow-up
• recurrent hepatocellular carcinoma
• surgical tumor resection

• AFP, alpha-fetoprotein
• ALF, acute liver failure
• CA 19-9, carbohydrate antigen 19-9
• CCA, cholangiocarcinoma
• CEA, carcinoembryonic antigen
• DCV, daclatasvir
• EHE, epithelioid hemangioendothelioma
• ESLD, end-stage liver disease
• HBIG, hepatitis B immune globulin
• HBsAg, hepatitis B surface antigen
• HCC, hepatocellular carcinoma
• IS, immunosuppressive therapy
• LT, liver transplantation
• NUCs, nucleos(t)ide analogues
• PSC, primary sclerosing cholangitis
• PTLD, post-transplantation lymphoproliferative disorder
• PegIFN, pegylated interferon
• RBV, ribavirin
• SOF, sofosbuvir
• SVR, sustained viral response
• epithelioid hemangioendothelioma
• hepatocellular carcinoma
• liver transplant
• long-term survival
• surgical resection

• HCC
• RETREAT
• alpha-fetoprotein (AFP)
• immunosuppression
• immunotherapy
• liver transplant
• mammalian target of rapamycin (mTOR)
• transplant oncology

• graft survival
• hepatocellular carcinoma
• ischemic type biliary lesions
• liver resection
• liver transplantation

• cholangiocarcinoma
• colorectal liver metastasis
• hepatocellular carcinoma
• liver transplantation
• neuroendocrine liver metastasis
• transplant oncology

Background: This study investigates the potential predictors of nivolumab plus chemotherapy or multitarget tyrosine kinase inhibitor (TKI) treatment response in patients with recurrent hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).

Methods: Patients with recurrent hepatitis B virus-related HCC who underwent nivolumab plus chemotherapy or TKI treatment between July 2017 and June 2019 at Jinling Hospital in China were retrospectively evaluated and included in this study. These patients also had both complete medical charts and follow-up data available. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of nivolumab initiation. Survival data were compared using log-rank tests, and the associations of patient characteristics with survival were estimated using Cox regression models.

Results: A total of 22 HCC patients were included in this cohort and constituted the basis for this analysis. Twenty progressed cases (91%) and 16 deaths (73%) were identified at a median follow-up of 8.8 months (range 1–25). The median OS from the time of nivolumab initiation was 10.7 months (95% CI, 0.8–20.6 months), with a median PFS of 5.1 months (95% CI, 3.1–7.0 months). The patients were divided into two risk groups according to a nomogram built by age, Eastern Cooperative Oncology Group (ECOG) status, hepatectomy status, and transarterial chemoembolization (TACE) use. The median PFS was 8.2 ± 2.8 months in the low-risk group compared with 1.9 ± 0.4 months in the high-risk group (p = 0.0018). The median OS was estimated as 16.8 ± 4.9 months for low-risk patients vs. 8.6 ± 3.5 months for high-risk patients (p = 0.13).

Conclusion: Nivolumab combined with chemotherapy or TKI treatment is effective in patients with recurrent hepatitis B virus-related HCC. It is observed that previous TACE treatment is associated with a better PFS, and worse PFS in those patients who received hepatectomy. Prospective studies are warranted to evaluate the effects of nivolumab combined chemotherapy or TKI on recurrent hepatitis B virus-related HCC.

• chemotherapy
• hepatitis B virus
• hepatocellular carcinoma
• nivolumab
• programmed cell death protein 1
• tyrosine kinase inhibitor

• AFP, alpha-fetoprotein
• ALP, alkaline phosphatase
• ALT, alanine transaminase
• CNI, calcineurin inhibitor
• CT, computed tomography
• HBV, hepatitis B virus
• HCC, hepatocellular carcinoma
• HCV, hepatitis C virus
• INR, international normalized ratio
• LT, Liver transplantation
• MRI, magnetic resonance imaging
• NASH, nonalcoholic steatohepatitis
• RETREAT, Risk Estimation of Tumor Recurrence After Transplant
• RFA, radiofrequency ablation
• TACE, transarterial chemoembolization
• UCSF, University of California San Francisco
• UNOS, United Network for Organ Sharing
• hepatocellular carcinoma
• immunosuppression
• liver transplantation
• mTOR, mammalian target of rapamycin
• recurrence
• survival

• Hepatocellular carcinoma
• liver resection
• liver transplant
• locoregional therapy

The most common sites of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be the liver, lung, bone, and adrenal glands, but there have also been many reports of cases of multiple recurrence. The prognosis after recurrence is poor, with reported median survival after recurrence of HCC ranging from 9 to 19 months. Here, we report a case of long-term survival after recurrence of pharyngeal metastasis following living-donor liver transplantation (LDLT) for HCC within the Milan criteria, by resection of the metastatic region and cervical lymph node dissection.

A 47-year-old man with a Model End-stage Liver Disease (MELD) score of 11 underwent LDLT for HCC within the Milan criteria for liver cirrhosis associated with hepatitis B virus infection, with his 48-year-old elder brother as the living donor. One year and 10 months after liver transplantation, he visited a nearby hospital with a chief complaint of discomfort on swallowing. A pedunculated polyp was found in the hypopharynx, and biopsy revealed HCC metastasis. We performed pharyngeal polypectomy. Two years later, cervical lymph node metastasis appeared, and neck lymph node dissection was performed. Although recurrence subsequently occurred three times in the grafted liver, the patient is still alive 12 years and 10 months after recurrence of pharyngeal metastasis. He is now a tumor-free outpatient taking sorafenib.

It is necessary to recognize that the nasopharyngeal region is a potential site of HCC metastasis. Prognostic improvement can be expected with close follow-up, early detection, and multidisciplinary treatment, including radical resection.

• Hepatocellular carcinoma
• Liver transplantation
• Nasopharynx
• Pharyngeal metastasis
• Vertebral venous plexus

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma (HCC). However, their role in established post-transplant HCC recurrence is uncertain.

To investigate whether mTOR inhibitor offers a survival benefit in post-transplant HCC recurrence.

A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed. They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression. The primary endpoint was post-recurrence survival.

Seventy-nine (55%) patients received an mTOR inhibitor-based immunosuppressive regime, while 64 (45%) patients did not. The mTOR inhibitor group had a lower number of recurrent tumours (2 vs 5, P = 0.02) and received more active treatments including radiotherapy (39 vs 22%, P = 0.03) and targeted therapy (59 vs 23%, P < 0.001). The median post-recurrence survival was 21.0 ± 4.1 mo in the mTOR inhibitor group and 11.2 ± 2.5 mo in the control group. Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival (P = 0.04, OR = 0.482, 95%CI: 0.241-0.966). The number of recurrent tumours and use of other treatment modalities did not affect survival. No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor.

mTOR inhibitors prolonged survival after post-transplant HCC recurrence.

• Mammalian target of rapamycin inhibitor
• Hepatocellular carcinoma
• Recurrence
• Liver transplant
• Survival
• Outcomes

Background and aim: Liver transplantation (LT) is a validated treatment for hepatocellular carcinoma (HCC). HCC recurrence occurred between 8 and 20% of patients and lung is the most frequent site. Pulmonary metastases resection (PMR) prolongs survival, however in LT-setting the impact on survival is unclear. To give new lights on this issue, we report the experience of three Italian LT Centers.

Methods: All consecutive HCC transplanted patients in three Italian LT Centers, who developed pulmonary metastasis from HCC (PM-HCC), as first metastasis, from 2008 to 2018, were included whenever treated with PMR.

Results: Twenty-five patients were enrolled (median age 58 yrs, 84% male, 3% cirrhotics). HCC recurred after 34 months (9–306) since LT and PMR was performed after 2.4 months (0–43.1). A total of 28 PMR (19 single resections; 9 multiple resections; 16 right; 2 left) have been performed on 24 patients while in one case percutaneous microwave ablation (MWA) was preferred. Four patients have been re-operated due to pulmonary HCC-recurrence after surgery. The majority of surgical resection type was wedge resection (26, 89%). Surgical access was: video-assisted thoracic surgery (VATS) in 17 cases (59%); thoracotomy in 11 (38%); MWA in 1 (3%). The 48% of nodule was in right lower lobe. Perioperative in-hospital mortality and 30 days mortality were nil; median surgical time 90 min (50–365); median post-operative overall stay 5 days (2–11). Post-operative ICU treatment was necessary in 1 case (3%) for 3 days; blood transfusions in 2 cases (7%). Overall, 5 complications (2 bleeding; 1 AKI; 1 major cardiac; 1 wound dehiscence) occurred, with an overall complications rate of 23%. Eight (32%) patients died during a follow-up after HCC recurrence of 32 months (7–213): 7 for HCC progression, 1 for severe liver failure due to chronic rejection. The 1 and 5 year cumulative probability of OS from recurrence were 100 and 43% (95%CI 12–74), respectively, with a median OS of 51 months (95%CI 24–78).

Conclusion: Selected patients with isolated pulmonary HCC-recurrence after LT and with preserved hepatic function showed that a pulmonary metastasectomy could be efficacious in managing a PM-HCC and could give an opportunity for long-term survival.

• hepatocellular carcinoma
• liver transplantation
• pulmonary metastases
• pulmonary resection
• recurrence

• CT scans
• liver transplantation
• lung cancer
• lung surgery
• solitary pulmonary nodule

• cancer
• clinical research
• hepatology
• liver disease: malignant
• liver transplantation
• malignancy
• neoplasia
• practice

• Liver cancer
• hepatocellular carcinoma
• recurrence
• survival
• treatment

• FNA
• fine-needle aspiration
• hepatocellular carcinoma
• liver
• transplant

• Hepatocellular carcinoma
• Liver transplantation
• Recurrence

• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Clinical Protocols
• Combined Modality Therapy/methods
• Humans
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Liver Transplantation
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/therapy
• Patient Care Team/organization & administration
• Survival Rate
• Treatment Outcome

• HCC recurrence
• HCC score
• Liver transplantation

• Adult
• Aged
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Liver Transplantation
• Male
• Middle Aged
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/pathology
• Predictive Value of Tests
• Prognosis
• Retrospective Studies

• Hepatocellular carcinoma
• Living donor liver transplantation
• Milan criteria
• Recurrence
• Survival

• hepatocellular carcinoma
• immunosuppression
• liver transplantation
• mTOR inhibitors

Bridging treatments are employed in liver transplant waitlist patients with hepatocellular carcinoma (HCC) because of the risk of tumor progression during the waiting time. Radioembolization is mostly employed in the control of large or multifocal HCCs when other locoregional treatment modalities cannot be applied because of the number or size of lesions. The purpose of this study was to evaluate our experience with the use of radioembolization as a bridge to transplantation and its effect on tumor recurrence and survival after liver transplantation.

A retrospective review of 40 consecutive patients with HCC who underwent liver transplantation after radioembolization bridging treatment between January 2007 and December 2015 at the University Hospital Essen, Germany, was performed. Patients’ characteristics, alpha-fetoprotein (AFP) levels, pathologic tumor response, tumor recurrence rate, and survival rates were examined through chart review.

Histopathological examination of the explanted liver specimen revealed complete tumor necrosis in 17 specimens, partial necrosis in 18 specimens, and no significant necrosis in five specimens. Median overall survival was 46 months. Nine patients developed recurrent HCC. Median time from liver transplantation to diagnosis of tumor recurrence was 15 months. There was a trend towards a lower risk of tumor recurrence for patients with complete necrosis on explant specimens. Patients with tumor recurrence demonstrated statistically significantly higher pre- and post-treatment AFP levels (p=0.0234 and p=0.0236) and statistically significantly more frequently microvascular invasion (p=0.0163).

Histopathological assessment of explanted livers revealed at least partial necrosis in 87.5% of patients. Patients with successful bridging treatment, i.e. complete necrosis of explant specimens, demonstrate a trend towards a lower risk of tumor recurrence.