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

• Gastrointestinal tumors
• Post-transplant malignancy
• Transplantation
• Treatment
• Tumor microenvironment

• Humans
• Gastrointestinal Neoplasms/etiology
• Gastrointestinal Neoplasms/therapy
• Gastrointestinal Neoplasms/pathology
• Organ Transplantation/adverse effects
• Prognosis
• Immunosuppression Therapy/adverse effects
• Graft Rejection/prevention & control

• 82072662 National Natural Science Foundation of China
• 82173163 National Natural Science Foundation of China

• Humans
• Liver Transplantation
• Immunosuppressive Agents/adverse effects
• Neoplasms
• Surveys and Questionnaires

• Addiction monitoring
• Alcohol relapse
• Liver transplantation
• Survival

• Cancer
• Immunotherapy
• Lymphocytes
• Macrophages
• Tumor microenvironment
• Tumor-associated macrophages

• antineoplastic chemotherapy
• cancer
• immunosuppression
• liver transplantation
• survival

• Aging
• Cancer
• Diabetes
• Liver transplant
• Metabolic syndrome

• Diabetes Mellitus/etiology
• Follow-Up Studies
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/surgery
• Liver Transplantation/adverse effects
• Retrospective Studies
• Risk Factors
• Treatment Outcome

Tobacco use is a modifiable risk factor for cardiovascular events (CVEs) in liver transplant recipients (LTRs), but there is a paucity of data about practitioner adherence to tobacco cessation guidelines for LTRs. We sought to assess adherence to these guidelines as a predictor of CVEs after liver transplant.

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

• De novo malignancy
• Duodenopancreatectomy
• Liver transplantation
• Vena cava leiomyosarcoma
• Vena cava resection

• Adult
• Female
• Humans
• Immunocompromised Host
• Incidence
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Neoplasms/epidemiology
• Neoplasms/etiology
• Neoplasms/immunology
• Postoperative Complications/epidemiology
• Postoperative Complications/etiology
• Postoperative Complications/immunology
• Retrospective Studies
• Risk Factors
• Survival Rate

• ALD, Alcoholic-related liver disease
• CI, confidence interval
• HRAR, High-Risk Alcoholism Relapse
• LT, Liver transplantation
• OR, odds ratio
• RP, Relapse prevention
• SALT, Sustained Alcohol Use PostLT
• addiction
• cancer
• recidivism
• smoking
• survival

Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.

• Germany
• aftercare structures
• liver transplantation
• liver transplantation center
• long-term outcome
• post-liver transplantation management

• Alcoholic cirrhosis
• cancer
• de novo malignancy
• hepatic transplantation

• Aged
• Female
• Humans
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Incidence
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Male
• Middle Aged
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Neoplasms/mortality
• Neoplasms/therapy
• Retrospective Studies
• Risk Factors
• Time Factors
• Treatment Outcome
• Turkey/epidemiology

• Italy
• immunosuppression
• liver transplant
• malignancy
• nested case-control study
• survival

• Adult
• Aged
• Case-Control Studies
• Female
• Humans
• Incidence
• Italy
• Kaplan-Meier Estimate
• Liver Transplantation
• Male
• Middle Aged
• Neoplasms/epidemiology
• Risk Factors
• Transplant Recipients

Unconjugated bilirubin is considered a potent antioxidant when present at moderate levels. However, at high concentrations, it produces severe neurological damage and death associated with kernicterus due to oxidative stress and other mechanisms. While it is widely recognized that oxidative stress by different toxic insults results in severe damage to cellular macromolecules, especially to DNA, no data are available either on DNA damage in the brain triggered by hyperbilirubinemia during the neonatal period or on the activation of DNA repair mechanisms. Here, using a mouse model of neonatal hyperbilirubinemia, we demonstrated that DNA damage occurs in vivo in the cerebellum, the brain region most affected by bilirubin toxicity. We studied the mechanisms associated with potential toxic action of bilirubin on DNA in in vitro models, which showed significant increases in DNA damage when neuronal and nonneuronal cells were treated with 140 nM of free bilirubin (Bf), as determined by γH2AX Western blot and immunofluorescence analyses. Cotreatment of cells with N-acetyl-cysteine, a potent oxidative-stress inhibitor, prevented DNA damage by bilirubin, supporting the concept that DNA damage was caused by bilirubin-induced oxidative stress. Bilirubin treatment also activated the main DNA repair pathways through homologous recombination (HR) and nonhomologous end joining (NHEJ), which may be adaptive responses to repair bilirubin-induced DNA damage. Since DNA damage may be another important factor contributing to neuronal death and bilirubin encephalopathy, these results contribute to the understanding of the mechanisms associated with bilirubin toxicity and may be of relevance in neonates affected with severe hyperbilirubinemia.

• Adult
• Aged
• Female
• Humans
• Immunocompromised Host
• Liver Transplantation/methods
• Living Donors
• Lymphoproliferative Disorders/epidemiology
• Lymphoproliferative Disorders/immunology
• Male
• Middle Aged
• Neoplasms/epidemiology
• Neoplasms/immunology
• Retrospective Studies
• Young Adult

• guidelines
• health services and outcomes research
• liver transplantation/hepatology
• liver transplantation: living donor

• Adult
• Female
• Humans
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Smoking/adverse effects
• Nicotiana

• The Ministry of Education Innovation Team Development Program of China
• A research fund for Young Talent Recruiting Plans of Xi’an Jiaotong University

• Addiction specialist
• Alcohol relapse
• Liver transplantation
• Post-transplant malignancy
• Smoking

• de novo malignancy
• liver transplantation
• pediatric
• preexisting extrahepatic malignancy
• recurrence
• yolk sac tumor

• Incidence
• Mortality
• Posttransplant lymphoproliferative disorder
• Risk factors
• Skin cancer
• Solid organ tumors
• Surveillance

• Cause of Death
• Humans
• Immunosuppression Therapy/adverse effects
• Kidney Transplantation/mortality
• Liver Transplantation/mortality
• Neoplasms/diagnosis
• Neoplasms/etiology
• Neoplasms/mortality
• Neoplasms/therapy
• Population Surveillance
• Postoperative Complications/diagnosis
• Postoperative Complications/etiology
• Postoperative Complications/mortality
• Postoperative Complications/therapy
• Risk Factors
• Survival Rate

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

• Carcinoma, Hepatocellular/surgery
• Female
• Gastrectomy
• Humans
• Liver Neoplasms/surgery
• Liver Transplantation/statistics & numerical data
• Lymph Node Excision
• Male
• Middle Aged
• Neoplasm Staging
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/surgery

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983. Cancer has emerged as a major long-term cause of death for liver transplant recipients. Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers post-liver transplantation; some have also studied risk factors. Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers. Risk of head and neck, lung, esophageal, cervical cancers and Kaposi’s sarcoma is high, but risk of colorectal cancer is not clearly demonstrated. There appears to be no excess risk of developing breast or prostate cancer. Environmental risk factors such as viral infection and tobacco consumption, and personal risk factors such as obesity play a key role, but recent data also implicate the role of calcineurin inhibitors, whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis. In this paper, we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and, ultimately, discuss how to prevent these cancers. Immunosuppressive protocol changes, including a calcineurin inhibitor-free regimen, combined with dietary guidelines and smoking cessation, are theoretically the best preventive measures.

• Liver transplantation
• Tumors
• Calcineurin inhibitors
• Immunosuppression
• Risk factors
• Tacrolimus
• Review
• Incidence

• Alcohol Drinking/adverse effects
• Calcineurin Inhibitors/adverse effects
• Colorectal Neoplasms/etiology
• Female
• Humans
• Immunosuppression Therapy/adverse effects
• Immunosuppression Therapy/methods
• Immunosuppressive Agents/adverse effects
• Life Style
• Liver Transplantation/adverse effects
• Male
• Neoplasms/epidemiology
• Neoplasms/etiology
• Obesity/complications
• Risk Factors
• Smoking/adverse effects
• Tumor Virus Infections/etiology

Smoking is associated with a higher incidence of post-lung transplantation complications and mortality. Prior to inclusion on the lung transplant waiting list in the Czech Republic, patients are supposed to be tobacco free for at least 6 months. Our aim was to determine the prevalence of smoking, validated by urinary cotinine, among patients post lung transplantation and prior to inclusion on the transplant waiting list.

Between 2009 and 2012, we conducted a cross-sectional survey of urinary cotinine to assess tobacco exposure in 203 patients in the Lung Transplant Program in the Czech Republic. We measured urinary cotinine in 163 patients prior to inclusion on the transplantation waiting list, and 53 patients post bilateral lung transplantation.

15.1% (95% CI 0.078 to 0.269) of all lung transplant recipients had urinary cotinine levels corresponding to active smoking; and a further 3.8% (95% CI 0.007 to 0.116) had borderline results. Compared to patients with other diagnoses, patients with COPD were 35 times more likely to resume smoking post- transplantation (95% CI 1.92 to 637.37, p-value 0.016). All patients who tested positive for urinary cotinine levels were offered smoking cessation support. Only one Tx patient sought treatment for tobacco dependence, but was unsuccessful.

Smoking resumption may be an underrecognized risk for lung transplantation recipients, particularly among patients with chronic obstructive pulmonary disease. More rigorous screening, as well as support and treatment to stop smoking among these patients are needed.

• lung
• smoking
• transplantation

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

Cystic lesions of the pancreas resembling intraductal papillary mucinous neoplasms (IPMN) have been reported to develop in an increased rate following liver transplantation and immunosuppression. The cause for this possible association is thus far elusive.

We report on a 60-year-old male patient who developed an extensive multicystic change of the entire pancreas, suspicious for IPMN, under follow-up after liver transplantation for secondary sclerosing cholangitis. A total pancreaduodenectomy with splenectomy was performed. The postoperative histopathological assessment revealed a multifocal branch duct IPMN of the gastric subtype showing low-grade dysplasia.

In the absence of evidence-based guidelines for the management of suspected IPMNs in liver transplant recipients, each patient’s management should be discussed in detail.

Prospective studies may help to understand the disease and identify risk factors for malignant transformation in IPMNs after liver transplantation for treatment optimization.

• Clinical characteristics
• Incidence
• Liver transplantation
• Lung cancer
• Survival

• Adult
• Alcoholism
• Female
• Humans
• Liver Transplantation
• Male
• Middle Aged
• Retrospective Studies

Glycogen storage disease type Ia (GSD-Ia; also termed von Gierke disease) is an inherited metabolic disorder resulting from a glucose-6-phosphatase deficiency. Liver transplantation is considered to be the most effective treatment for GSD-Ia patients. In the present study, the case of a patient with GSD-Ia who received a liver transplantation at 17 years of age is presented. During the 12 years following transplantation, the patient’s quality of life markedly improved. However, recently, the patient was diagnosed with de novo gastric cancer following a biopsy. Thus, a total gastrectomy with lymph node dissection was performed and the tumor was histologically determined to be a poorly differentiated adenocarcinoma (histopathological stage, pT4N1M0). The patient recovered well and was discharged on postoperative day 10 without any complications. To the best of our knowledge, this is the first case of de novo gastric cancer in a patient with GSD-Ia to be reported.

• de novo gastric cancer
• glycogen storage disease
• liver transplantation

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

• 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

• Adult
• China/epidemiology
• Databases, Factual
• Female
• Humans
• Incidence
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Male
• Middle Aged
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Neoplasms/etiology
• Neoplasms/therapy
• Prevalence
• Retrospective Studies
• Risk Factors

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

• de novo
• liver transplantation
• malignancy
• population control study
• standardized incidence ratio