Liver transplantation (LT) is the definitive treatment for end-stage liver disease, acute liver failure, and liver cancer. Although advancements in surgical techniques, postoperative care, and immunosuppressive therapies have significantly improved outcomes, the long-term use of immunosuppression has increased the risk of complications, including infections, cardiovascular disease, and cancer. Among these, de novo malignancies (DNMs) are a major concern, accounting for 20%-25% of deaths in LT recipients surviving beyond the early post-transplant period. Non-melanoma skin cancers, particularly squamous cell carcinoma are the most prevalent DNMs. Other significant malignancies include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and various solid organ cancers, including head and neck cancers. Compared to the general population, LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders. Risk factors for DNM include chronic immunosuppression, alcohol or tobacco use, viral infections, and underlying liver disease. Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies, including regular dermatological examinations, targeted screenings for high-risk cancers, and patient education on lifestyle modifications. Early detection through enhanced surveillance protocols has been shown to improve outcomes. Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens, with promising results from the use of mTOR inhibitors in select patients. The review highlights the critical need for ongoing research to refine risk stratification, optimize screening protocols, and improve treatment approaches to mitigate the burden of DNMs in LT recipients. By implementing personalized preventive and therapeutic strategies, we can enhance long-term outcomes and quality of life for this vulnerable population.

• Liver transplant
• De novo malignancy
• Immunosuppression
• Post-transplant lymphoproliferative disorder
• Screening
• Squamous cell cancer

• Deceased donor liver transplantation
• Grade
• Living donor liver transplantation
• Multidisciplinary

• Humans
• Asia
• Liver
• Liver Transplantation/methods
• Living Donors
• Tissue and Organ Procurement

• NAFLD
• de novo malignancies
• liver transplantation
• metabolic syndrome
• post-transplant diabetes mellitus

• Barrett’s esophagus
• Esophageal adenocarcinoma
• Immunosuppression
• Solid organ transplant

• Humans
• Barrett Esophagus/complications
• Retrospective Studies
• Disease Progression
• Esophageal Neoplasms/complications
• Organ Transplantation/adverse effects
• Precancerous Conditions/pathology

Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.

• Alcohol
• Liver transplantation
• Long term survival
• Metabolic syndrome
• Renal dysfunction
• Therapy adherence

• Sirolimus
• adverse effects
• everolimus
• hepatocellular carcinoma
• liver transplantation
• mTORi

• Humans
• Melanoma/drug therapy
• Skin Neoplasms/drug therapy
• Skin Neoplasms/diagnosis
• Tumor Necrosis Factor-alpha
• Etanercept
• Infliximab

• Humans
• Immunosuppression Therapy/adverse effects
• Incidence
• Liver Transplantation/adverse effects
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Neoplasms/etiology
• Risk Assessment
• Risk Factors

It is estimated that 50% of patients with colorectal cancer will develop liver metastasis. Surgical resection significantly improves survival and provides a chance of cure for patients with colorectal cancer liver metastasis (CRLM). Increasing the resectability of primary unresectable liver metastasis provides more survival benefit for those patients. Considerable surgical innovations have been made to increase the resection rate and decrease the potential risk of hepatic failure postoperation. Liver transplantation (LT) has been explored as a potential curative treatment for unresectable CRLM. However, candidate selection criteria, chemotherapy strategies, refined immunity regimens and resolution for the shortage of grafts are lacking. This manuscript discusses views on surgical indication, peritransplantation anti-tumor and anti-immunity therapy and updated advances in LT for unresectable CRLM. A literature review of published articles and registered clinical trials in PubMed, Google Scholar, and Clinicaltrials.gov was performed to identify studies related to LT for CRLM. Some research topics were identified, including indications for LT for CRLM, oncological risk, antitumor regimens, graft loss, administration of anti-immunity drugs and solutions for graft deficiency. The main candidate selection criteria are good patient performance, good tumor biological behavior and chemosensitivity. Chemotherapy should be administered before transplantation but is not commonly administered posttransplantation for preventive purposes. Mammalian target of rapamycin regimens are recommended for their potential oncological benefit, although there are limited cases. In addition to extended criterion grafts, living donor grafts and small grafts combined with two-stage hepatectomy are efficient means to resolve organ deficiency. LT has been proven to be an effective treatment for selected patients with liver-only CRLM. Due to limited donor grafts, high cost and poorly clarified oncological risks, LT for unresectable CRLM should be strictly performed under a well-organized study plan in selected patients. Some vital factors, like LT indication and anti-tumor and anti-immune treatment, remain to be confirmed. Ongoing clinical trials are expected to delineate these topics.

• Liver transplantation
• Colon cancer
• Colorectal cancer liver metastasis
• Transplant oncology

• Cancer
• Complication
• Liver transplant
• Neoplasms

• Adolescent
• Adult
• Aged
• Female
• Humans
• Incidence
• Italy
• Kaplan-Meier Estimate
• Liver Diseases/etiology
• Liver Diseases/pathology
• Liver Diseases/surgery
• Liver Transplantation
• Male
• Middle Aged
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Postoperative Complications/diagnosis
• Postoperative Complications/epidemiology
• Proportional Hazards Models
• Retrospective Studies
• Young Adult

Patients receiving a solid organ transplantation, such as a kidney, liver, or lung transplantation, inevitably have to take drugs to suppress the immune system in order to prevent rejection of the transplanted organ. However, these drugs are known to cause malignancies in the long term. This study focuses specifically on newly developed carcinomas in patients who use those drugs after a solid organ transplantation. This systematic review and meta-analysis of published data show a 20-fold risk to develop a carcinoma after solid organ transplantation compared to the general population, with specifically increased risks in patients who receive cyclosporine or azathioprine. By comparing the different pathways involved in immunosuppression and the occurrence of carcinoma development, new insights can be discovered for future research and understanding of carcinoma development in transplantation patients and the general population as well.

Immunosuppressive therapy after solid organ transplantation leads to the development of cancer in many recipients. Analysis of the occurrence of different types of de novo carcinomas in relation to specific immunosuppressive drugs may give insight into their carcinogenic process and carcinogenesis in general. Therefore, a systematic search was performed in Embase and PubMed. Studies describing over five de novo carcinomas in patients using immunosuppressive drugs after solid organ transplantation were included. Incidence per 1000 person-years was calculated with DerSimonian–Laird random effects model and odds ratio for developing carcinomas with the Mantel–Haenszel test. Following review of 5606 papers by title and abstract, a meta-analysis was conducted of 82 studies. The incidence rate of de novo carcinomas was 8.41. Patients receiving cyclosporine developed more de novo carcinomas compared to tacrolimus (OR1.56, 95%CI 1.00–2.44) and mycophenolate (OR1.26, 95%CI 1.03–1.56). Patients receiving azathioprine had higher odds to develop de novo carcinomas compared to mycophenolate (OR3.34, 95%CI 1.29–8.65) and head and neck carcinoma compared to tacrolimus (OR3.78, 95%CI 1.11–12.83). To conclude, patients receiving immunosuppressive drugs after solid organ transplantation have almost a 20-fold increased likelihood of developing carcinomas, with the highest likelihood for patients receiving cyclosporine A and azathioprine. Looking into altered immune pathways affected by immunosuppressive drugs might lead to better understanding of carcinogenesis in general.

• carcinoma
• epidemiologic studies
• immunosuppression
• organ transplantation

Hepatocyte transplantation (HCTx) has the potential for the treatment of end-stage liver disease. However, failure of engraftment and the long-term acceptance of cellular allografts remain significant challenges for its clinical application. The aim of this study was to investigate the efficacy of the immunosuppressive agents, Cyclosporine, Everolimus, and Belatacept to suppress the alloresponse of primary human hepatocytes in a mixed lymphocyte-hepatocyte culture (MLHC) and their potential hepatotoxicity in vitro.

Primary human hepatocytes were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an MLHC. Proliferative alloresponses were determined by flow cytometry, and cytokine secretion was measured using Luminex-based multiplex technology. Using an MLHC, the alloresponses of primary human hepatocytes were compared in the presence and absence of Cyclosporine, Everolimus, and Belatacept. Cultured primary human hepatocytes were assessed for the production of albumin, urea, aspartate transaminase (AST) and DNA content. Metabolic activity was determined with the MTT assay.

Immune responses induced by primary human hepatocytes were effectively suppressed by Cyclosporine, Everolimus, and Belatacept. Everolimus significantly reduced the metabolic activity of primary human hepatocytes in vitro, suggesting impairment of cell viability. However, further functional analysis showed no significant differences between treated and untreated controls.

Cyclosporine, Everolimus, and Belatacept suppressed the alloresponse of primary human hepatocytes in an MLHC without significant cytotoxicity or functional cell impairment.

De novo malignancies constitute an emerging cause of morbidity after solid organ transplant (SOT), significantly affecting the long-term survival of transplant recipients. Pharmacologic immunosuppression may functionally impair the immunosurveillance in these patients, thereby increasing the risk of cancer development. Nevertheless, the multiplicity and heterogeneity of the immune effects induced by immunosuppressive drugs limit the current possibilities to reliably predict the risk of de novo malignancy in SOT patients. Therefore, there is the pressing need to better characterize the immune dysfunctions induced by the different immunosuppressive regimens administered to prevent allograft rejection to tailor more precisely the therapeutic schedule and decrease the risk of de novo malignancies. We herein highlight the impact exerted by different classes of immunosuppressants on the most relevant immune cells, with a particular focus on the effects on dendritic cells (DCs), the main regulators of the balance between immunosurveillance and tolerance.

• cancer
• dendritic cells
• immune cells
• immunosuppressive drugs
• solid organ transplant

• hepatitis b virus
• liver transplantation
• recurrence

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antiviral Agents/therapeutic use
• Drug Therapy, Combination
• Female
• Follow-Up Studies
• Hepatitis B, Chronic/prevention & control
• Hepatitis B, Chronic/surgery
• Humans
• Immunoglobulins/therapeutic use
• Liver Transplantation
• Male
• Middle Aged
• Nucleosides/therapeutic use
• Recurrence
• Retrospective Studies
• Secondary Prevention/methods
• Treatment Outcome
• Young Adult

• Adult
• Aged
• Biopsy
• Calcineurin Inhibitors/administration & dosage
• Case-Control Studies
• Diabetes Mellitus/epidemiology
• Diabetes Mellitus/etiology
• Drug Therapy, Combination
• Everolimus/administration & dosage
• Feasibility Studies
• Female
• Glomerular Filtration Rate
• Graft Rejection/epidemiology
• Graft Rejection/etiology
• Graft Survival/drug effects
• Humans
• Hypertension/epidemiology
• Hypertension/etiology
• Immunosuppression Therapy/methods
• Immunosuppressive Agents/administration & dosage
• Incidence
• Liver Transplantation/methods
• Male
• Middle Aged
• Postoperative Complications/etiology
• Retrospective Studies
• Tacrolimus/administration & dosage
• Time Factors

To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats.

Allogeneic OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with rapamycin.

An 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8⁺CD45RC^low T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not rejected.

Our results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8⁺CD45RC^low T cells as associated with the state of tolerance.

• Myeloid-derived suppressor cells
• Liver transplantation
• Rapamycin
• Regulatory T cells

• Animals
• Drug Evaluation, Preclinical
• Graft Rejection/prevention & control
• Immune Tolerance/drug effects
• Immune Tolerance/immunology
• Immunosuppressive Agents/administration & dosage
• Liver Transplantation
• Male
• Rats, Inbred Lew
• Sirolimus/administration & dosage
• Transplantation, Homologous

Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies. Comprehensive guidelines on use of everolimus (EVR) in LT are still lacking. In Italy, a project, named Everolimus: the road to long-term functioning, was initiated to collect the experience on EVR after LT with the aim of providing guidance for transplant clinicians. Herein, recommendations by this national consensus group, based on Delphi methodology, are presented. Consensus was reached on 20 of the 23 statements proposed, and their level of evidence, grade of recommendation, and percent of agreement are reported. Statements are grouped into 4 areas: (A) renal function; (B) time of EVR introduction, CNI reduction and elimination, and risk for graft rejection; (C) antiproliferative effects of EVR; and (D) management of EVR-related adverse events. The high level of consensus shows that there is good agreement on the routine use of EVR in predefined clinical scenarios, especially in light of posttransplant nephrotoxicity and other adverse events associated with long-term administration of CNIs.

The authors summarize the recommendations reached by an Italian National Consensus group using the Delphi methodology on the use of everolimus in liver transplantation, particularly its role in renal function, antiproliferative effects, adverse events, timing of introduction, and rejection risk.

• Aftercare/methods
• Aftercare/standards
• Checklist
• Graft Rejection/diagnosis
• Graft Rejection/etiology
• Graft Rejection/mortality
• Graft Rejection/prevention & control
• Graft Survival
• Humans
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/therapeutic use
• Kidney Transplantation/mortality
• Liver Transplantation/mortality
• Medication Adherence
• Opportunistic Infections/etiology
• Opportunistic Infections/prevention & control
• Postoperative Complications/diagnosis
• Postoperative Complications/etiology
• Postoperative Complications/mortality
• Postoperative Complications/prevention & control
• Risk Assessment
• Risk Factors

• Biomarkers
• Dendritic cells
• Liver transplantation
• Operational tolerance
• Regulatory T cells

• Animals
• Biomarkers/metabolism
• Biomarkers, Tumor/immunology
• Dendritic Cells/cytology
• Homeostasis
• Humans
• Immunosuppression Therapy
• Immunosuppressive Agents/therapeutic use
• Killer Cells, Natural/cytology
• Liver Failure/immunology
• Liver Failure/surgery
• Liver Transplantation
• Macrophages/cytology
• Macrophages/immunology
• Sirolimus/therapeutic use
• T-Lymphocytes, Regulatory/cytology
• Transplantation Tolerance

The aim of this study is to identify independent pre-transplant cancer risk factors after kidney transplantation and to assess the utility of G-chart analysis for clinical process control. This may contribute to the improvement of cancer surveillance processes in individual transplant centers.

1655 patients after kidney transplantation at our institution with a total of 9,425 person-years of follow-up were compared retrospectively to the general German population using site-specific standardized-incidence-ratios (SIRs) of observed malignancies. Risk-adjusted multivariable Cox regression was used to identify independent pre-transplant cancer risk factors. G-chart analysis was applied to determine relevant differences in the frequency of cancer occurrences.

Cancer incidence rates were almost three times higher as compared to the matched general population (SIR = 2.75; 95%-CI: 2.33–3.21). Significantly increased SIRs were observed for renal cell carcinoma (SIR = 22.46), post-transplant lymphoproliferative disorder (SIR = 8.36), prostate cancer (SIR = 2.22), bladder cancer (SIR = 3.24), thyroid cancer (SIR = 10.13) and melanoma (SIR = 3.08). Independent pre-transplant risk factors for cancer-free survival were age <52.3 years (p = 0.007, Hazard ratio (HR): 0.82), age >62.6 years (p = 0.001, HR: 1.29), polycystic kidney disease other than autosomal dominant polycystic kidney disease (ADPKD) (p = 0.001, HR: 0.68), high body mass index in kg/m² (p<0.001, HR: 1.04), ADPKD (p = 0.008, HR: 1.26) and diabetic nephropathy (p = 0.004, HR = 1.51). G-chart analysis identified relevant changes in the detection rates of cancer during aftercare with no significant relation to identified risk factors for cancer-free survival (p<0.05).

Risk-adapted cancer surveillance combined with prospective G-chart analysis likely improves cancer surveillance schemes by adapting processes to identified risk factors and by using G-chart alarm signals to trigger Kaizen events and audits for root-cause analysis of relevant detection rate changes. Further, comparative G-chart analysis would enable benchmarking of cancer surveillance processes between centers.

• Adolescent
• Adult
• Aged
• Case-Control Studies
• Child
• Disease-Free Survival
• Epidemiological Monitoring
• Female
• Humans
• Kidney Transplantation
• Male
• Middle Aged
• Neoplasms/epidemiology
• Neoplasms/therapy
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Young Adult

• German Federal Ministry of Education and Research

Liver transplantation (LT) is associated with a 2 to 7 fold higher, age and gender adjusted, risk of de novo malignancy. The overall incidence of de novo malignancy post LT ranges from 2.2% to 26%, and 5 and 10 years incidence rates are estimated at 10% to 14.6% and 20% to 32%, respectively. The main risk factors for de novo malignancy include immunosuppression with impaired immunosurveillance, and a number of patient factors which include; age, latent oncogenic viral infections, tobacco and alcohol use history, and underlying liver disease. The most common cancers after LT are non-melanoma skin cancers, accounting for approximately 37% of de novo malignancies, with a noted increase in the ratio of squamous to basal cell cancers. While these types of skin cancer do not impact patient survival, post-transplant lymphoproliferative disorders and solid organ cancer, accounting for 25% and 48% of malignancies, are associated with increased mortality. Patients developing these types of cancer are diagnosed at more advanced stages, and their cancers behave more aggressively compared with the general population. Patients undergoing LT for primary sclerosing cholangitis (particularly with inflammatory bowel disease) and alcoholic liver disease have high rates of malignancies compared with patients undergoing LT for other indications. These populations are at particular risk for gastrointestinal and aerodigestive cancers respectively. Counseling smoking cessation, skin protection from sun exposure and routine clinical follow-up are the current approach in practice. There are no standardized surveillance protocol, but available data suggests that regimented surveillance strategies are needed and capable of yielding cancer diagnosis at earlier stages with better resulting survival. Evidence-based strategies are needed to guide optimal surveillance and safe minimization of immunosuppression.

• Liver transplant
• Immunosuppression
• Risk
• Outcomes
• Malignancy

Mammalian target of rapamycin, also known as mechanistic target of rapamycin (mTOR) is a protein kinase that belongs to the PI3K/AKT/mTOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of mTOR (mTORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immunological tolerance. In this review, we describe the mechanisms by which inhibitors of mTOR induce suppression by regulation of these pathways at different levels of the immune response. In addition, we particularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of mTOR.

• Everolimus
• Immunosuppression
• Mechanistic target of rapamycin inhibitor
• Rapamycin
• Tolerance

• Contraindications
• End Stage Liver Disease/diagnosis
• End Stage Liver Disease/etiology
• End Stage Liver Disease/surgery
• Europe
• Humans
• Liver Transplantation/methods
• Patient Selection
• Prognosis
• Risk Adjustment/methods

• Hepatocarcinoma
• High-risk receptor
• Immunosuppression
• Inmunosupresión
• Liver transplant
• Receptor de riesgo
• Trasplante hepático

• Carcinoma, Hepatocellular
• Consensus
• Humans
• Liver Neoplasms
• Liver Transplantation
• Waiting Lists

• Europe
• Evidence-Based Medicine
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/pathology
• Inflammatory Bowel Diseases/therapy
• Neoplasms/diagnosis
• Neoplasms/etiology
• Neoplasms/mortality
• Neoplasms/therapy
• Prognosis
• Risk Factors

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.

• Liver transplantation
• De novo neoplasms
• Immunosuppression
• mTOR inhibitors
• Hepatocellular carcinoma

• Donor Selection
• Humans
• Immunocompromised Host
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Neoplasms/diagnosis
• Neoplasms/etiology
• Neoplasms/mortality
• Neoplasms/prevention & control
• Risk Assessment
• Risk Factors
• Time Factors
• Tissue Donors
• Treatment Outcome

Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett’s esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.

• De novo malignancies
• De novo tumors tobacco consumption
• Alcoholic cirrhosis
• De novo cancer
• Liver transplant

• hepatitis B, C - infection
• ischemia reperfusion injury - organ preservation and procurement
• molecular diagnostic
• outcome - liver clinical
• solid tumors - malignancies and long term compliations

• alcoholic liver disease
• de novo carcinoma
• everolimus
• liver transplantation
• prognosis

During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

• efficacy
• everolimus
• liver transplantation
• mTOR inhibitors
• safety

• Carcinoma, Basal Cell/epidemiology
• Carcinoma, Basal Cell/immunology
• Carcinoma, Basal Cell/therapy
• Humans
• Immunocompromised Host
• Immunosuppression Therapy/adverse effects
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Life Style
• Practice Guidelines as Topic
• Prevalence
• Risk Factors
• Skin Neoplasms/epidemiology
• Skin Neoplasms/immunology
• Skin Neoplasms/therapy

• cancer
• hepatocellular carcinoma
• immunosuppression
• liver transplantation
• malignancy

• Antilymphocyte Serum/adverse effects
• Azathioprine/adverse effects
• Calcineurin Inhibitors
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/prevention & control
• Carcinoma, Hepatocellular/surgery
• Humans
• Immunosuppression Therapy
• Immunosuppressive Agents/adverse effects
• Liver Neoplasms/chemically induced
• Liver Neoplasms/prevention & control
• Liver Neoplasms/surgery
• Liver Transplantation
• Neoplasm Recurrence, Local/chemically induced
• Neoplasm Recurrence, Local/prevention & control
• Neoplasm Recurrence, Local/surgery
• Risk Factors

• cyclosporine
• everolimus
• malignancy
• mammalian target of rapamycin
• sirolimus
• tacrolimus
• transplantation

• Animals
• Antineoplastic Agents/immunology
• Antineoplastic Agents/therapeutic use
• Humans
• Immunity, Innate/drug effects
• Immunity, Innate/immunology
• Monitoring, Immunologic/methods
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/pathology
• Outcome Assessment, Health Care/methods

Alcoholic cirrhosis remains the second most common indication for liver transplantation. A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list. Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients. Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation (recidivism). These patients need to be identified and require alcohol rehabilitation treatment before transplantation. Recidivism to the level of harmful drinking is reported in about 15%-20% cases. Although, recurrent cirrhosis and graft loss from recidivism is rare, occurring in less than 5% of all alcoholic cirrhosis-related transplants, harmful drinking in the post-transplant period does impact the long-term outcome. The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease. Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome. The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids. Emerging data from retrospective and prospective studies has challenged the 6 mo rule, and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids.

• Alcoholic liver disease
• Liver transplantation
• Transplant evaluation
• Recidivism
• Six months rule
• Alcoholic hepatitis

• Adrenal Cortex Hormones/therapeutic use
• Alcohol Abstinence/psychology
• Alcoholism/complications
• Alcoholism/mortality
• Alcoholism/psychology
• Alcoholism/rehabilitation
• Humans
• Liver Diseases, Alcoholic/etiology
• Liver Diseases, Alcoholic/mortality
• Liver Diseases, Alcoholic/surgery
• Liver Transplantation/mortality
• Patient Selection
• Recurrence
• Risk Factors
• Time Factors
• Treatment Outcome
• Waiting Lists/mortality

AIM: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model.

METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2’-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.

RESULTS: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.

CONCLUSION: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

• Hepatocyte proliferation
• Autophagy
• Microtubule-associated protein 1 light chain 3
• Partial hepatectomy
• Rapamycin

• calcineurin inhibitor
• cancer development
• immunosuppression
• liver transplantation
• long-term survival
• multivariate analysis
• risk factors