The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.

With the advances in transplant oncology in recent years, the role of liver transplantation has expanded to make curative treatment a possibility for a wider patient population. We highlight strategies in Hong Kong, China that have enabled preoperative prognostication for judicious patient selection, downstaging therapy to definitive treatment, and postoperative therapies that have provided a growing role for liver transplantation in patients with more advanced hepatocellular carcinoma.

The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among recipients following liver transplantation has been reported. This nationwide population-based quasi-cohort study investigated whether combining EVR with calcineurin inhibitor therapy affects the risk of HCC and extrahepatic cancers compared to a time duration-matched cohort of recipients not receiving EVR. Using data covering the entire population from Korea, liver transplant recipients who had initiated immunosuppressants between June 2015 and February 2020 were included, and divided into 2 groups: the EVR combination and noncombination groups. We calculated adjusted hazard ratios (aHRs) and absolute risk reduction for the risk of HCC and extrahepatic cancer with EVR combination therapy using a Cox regression model. A time duration-matched retrospective cohort of 932 recipients in both of the groups was identified. The EVR combination group showed a lower risk of HCC (aHR, 0.53; 95% confidence interval, 0.30-0.94) and extrahepatic cancers (aHR, 0.30; 95% confidence interval, 0.14-0.63) compared to the noncombination group. The absolute risk reduction was 0.004 for HCC and 0.012 for extrahepatic cancer. The findings suggest that adding EVR to calcineurin inhibitor therapy reduces cancer risk in liver transplant recipients, highlighting the importance of considering cancer risk when choosing immunosuppressive therapies.

Gastroenteropancreatic neuroendocrine tumors (NET) often metastasize to the liver. Although curative liver resection provides a favorable prognosis for patients with neuroendocrine liver metastasis (NELM), with a 5-year survival rate of 70-80%, recurrence is almost inevitable, mainly in the remnant liver. In Western countries, liver transplantation (LT) has been performed in patients with NELM, with the objective of complete removal of macro- and micro-NELMs. However, prognosis had been unsatisfactory, with 5-year overall survival and recurrence-free survival rates of approximately 50 and 30%, respectively. In 2007, the Milan criteria were proposed as indications for LT for NELM. The criteria included: (1) confirmed histology of NET-G1 or G2; (2) a primary tumor drained by the portal system and all extrahepatic diseases removed with curative resection before LT; (3) liver involvement ≤50%; (4) good response or stable disease for at least 6 months before LT; (5) age ≤ 55 years. A subsequent report demonstrated outstanding LT outcomes for NELM within the Milan criteria, with 5-year overall survival and recurrence rates of 97 and 13%, respectively. In Japan, living donor LT (LDLT) for NELM has been performed sporadically in only 16 patients by 2021 in Japan; however, no consensus has been reached on the indications or perioperative management of LDLT. This article presents the outcomes of these 16 patients who underwent LDLT in Japan and reviews the literature to clarify optimal indications and perioperative management of LDLT for NELM in the era of novel multimodal treatments.

Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.

This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well.

Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which was the third most common cause of cancer death worldwide in 2020. Transplantation remains the preferred treatment for cure in otherwise unresectable HCC. There are several areas of active research that have led to expansion of eligibility criteria for transplantation including local-regional therapy for downstaging patients presenting outside of the Milan criteria and identification of tumor biomarkers aiding in the early diagnosis, determining prognosis and likelihood of recurrence after transplantation for HCC. New neoadjuvant therapies and post-transplant immunosuppression regimens may also result in expansion of transplant eligibility criteria for HCC.

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

We present a case of sirolimus-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a stem cell transplant patient. Sirolimus is an immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR) pathway. A 24-year-old male with a history of acute lymphoblastic leukemia (ALL) underwent testicular extraction followed by hematopoietic stem cell transplantation (HSCT). He presented with pruritic eczematous lesions, which were initially treated with topical steroids. However, he later developed diffuse xerosis, fever, chills, generalized edema, weight gain, eosinophilia, and leukopenia. Skin biopsy showed spongiotic dermatitis with eosinophils, suggesting a drug or atopic reaction. Investigations ruled out infections, and the RegiSCAR score indicated drug reaction syndrome with eosinophilia and systemic symptoms (DRESS). Sirolimus, an immunosuppressive drug, was suspected as the cause. Sirolimus was discontinued, and oral steroids were initiated. After 3 weeks of therapy, the patient showed improvement with resolution of symptoms. Although no cases of sirolimus-induced DRESS syndrome have been reported, allergic reactions with eosinophilia induced by everolimus have been documented. In our case, the patient's history characterized by stem cell transplantation and multiple immunosuppressive therapies may have contributed to the development of DRESS syndrome after beginning sirolimus therapy. This case may be the first evidence of sirolimus-induced DRESS syndrome in a stem cell transplant patient.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

We aimed to compare the adherence to immunosuppressive medication use in patients who underwent liver transplantation (LT) due to hepatocellular carcinoma (HCC) and non-HCC reasons.

The study population was determined as 242 patients with HCC and 1290 patients with non-HCC who had LT performed in our institute between March 2002 and November 2021; all these patients were contacted by phone in March 2022. The sample size was calculated using the MedCalc software program, and the number of patients required in each group was determined as 111 patients. Furthermore, we used the sample.int function, a random integer generator in the R (version 4.1.2) software program. Whereas demographic and clinical parameters were determined as independent variables, the immunosuppressive medication adherence scale (IMAS) score was determined as a dependent variable. Patients were evaluated by the IMAS. This 11-item IMAS scale evaluates the lowest compliance score as 11 and the highest as 55.

Out of a total number of 221 patients, 161 (72%) were men and 60 (27.1%) were women, with a median age of 58 years (IQR: 14); one patient in the non-HCC group was excluded due to lack of data. Among the HCC and non-HCC groups, significant differences were found in terms of the variables of age (P = .003), IMAS score (P < .001), sex (P = .001), working status (P = .004), chronic diseases (P = .008), tacrolimus alone (P < .001), tacrolimus plus everolimus (P < .001), and often medication changes (P < .001). A statistically significant correlation was found between the IMAS score and whether the patients had HCC (P < .001) and frequently changing immunosuppressive drugs (P = .023).

This study showed that patients with frequent drug changes or non-HCC etiology had better adherence to immunosuppressive drug use.

Machine perfusion may be able to mitigate ischemia-reperfusion injury (IRI), which increases hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). This study aimed to investigate the impact of dual-hypothermic oxygenated machine perfusion (D-HOPE) on HCC recurrence in LT.

A single-center retrospective study was conducted from 2016 to 2020. Pre- and postoperative data of HCC patients undergoing LT were analyzed. Recipients of a D-HOPE-treated graft were compared to those of livers preserved using static cold storage (SCS). The primary endpoint was recurrence-free survival (RFS).

Of 326 patients, 246 received an SCS-preserved liver and 80 received a D-HOPE-treated graft (donation after brain death (DBD), n = 66; donation after circulatory death (DCD), n = 14). Donors of D-HOPE-treated grafts were older and had higher BMI. All DCD donors were treated by normothermic regional perfusion and D-HOPE. The groups were comparable in terms of HCC features and estimated 5-year RFS according to the Metroticket 2.0 model. D-HOPE did not reduce HCC recurrence (D-HOPE 10%; SCS 8.9%; p = 0.95), which was confirmed using Bayesian model averaging and inverse probability of treatment weighting-adjusted RFS analysis. Postoperative outcomes were comparable between groups, except for lower AST and ALT peak in the D-HOPE group.

In this single-center study, D-HOPE did not reduce HCC recurrence but allowed utilizing livers from extended criteria donors with comparable outcomes, improving access to LT for patients suffering from HCC.

Organ transplantation has provided another chance of survival for end-stage organ failure patients. Yet, transplant rejection is still a main challenging factor. Immunosuppressive drugs have been used to avoid rejection and suppress the immune response against allografts. Thus, immunosuppressants increase the risk of infection in immunocompromised organ transplant recipients. The infection risk reflects the relationship between the nature and severity of immunosuppression and infectious diseases. Furthermore, immunosuppressants show an immunological impact on the genetics of innate and adaptive immune responses. This effect usually reactivates the post-transplant infection in the donor and recipient tissues since T-cell activation has a substantial role in allograft rejection. Meanwhile, different infections have been found to activate the T-cells into CD₄⁺ helper T-cell subset and CD₈⁺ cytotoxic T-lymphocyte that affect the infection and the allograft. Therefore, the best management and preventive strategies of immunosuppression, antimicrobial prophylaxis, and intensive medical care are required for successful organ transplantation. This review addresses the activation of immune responses against different infections in immunocompromised individuals after organ transplantation.

Everolimus, a selective inhibitor of mamalian target of rapamycin (mTORi), is considered to be an alternative immunosuppressive regimen in the liver transplantation (LT) setting. However, most of the transplant centers avoid its early use (i.e., during the first month) after LT mainly due to safety issues.

We searched for all articles published between 01/2010 and 7/2022 to evaluate the effectiveness and safety of initial/early administration of everolimus after LT.

Seven studies (three randomized controlled trials and four prospective cohort studies) were included: initial/early everolimus-including therapy (group 1) was used in 512 (51%) and calcineurin inhibitor (CNI) based therapy (group 2) in 494 (49%) patients. No significant difference was found between group 1 and group 2 patients regarding the rates of biopsy-proven acute rejection episodes (Odds Ratio [OR]: 1.27, 95% CI: .67-2.41, p = .465) and hepatic artery thrombosis (OR: .43, 95% CI: .09-2.02, p = .289). Everolimus was associated with higher rates of dyslipidemia (14.2% vs. 6.8%, p = .005) and incisional hernia (29.2% vs. 10.1%, p < .001). Finally, no difference was found between the two groups regarding recurrence of hepatocellular carcinoma (Risk Rates [RR]: 1.22 95%CI: .66-2.29, p = .524) and mortality (RR: .85 95%CI: .48-1.50, p = .570).

Use of initial/early everolimus seems to be effective with a satisfactory safety profile, making its administration a reasonable therapeutic option in the LT setting.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC.

This experimental study in rats aimed to investigate the impact of very early introduction (within 3 h) of everolimus (EVR) + reduced-tacrolimus (TAC) after partial liver transplantation (LT) on liver regeneration, rejection, and survival.

Based on appropriate dose of EVR + reduced-TAC in 70% hepatectomy (Experiment 1), allogeneic 30% partial LT (Experiment 2) and whole LT (Experiment 3) were performed.

After partial LT in EVR + reduced-TAC therapy, restoration of liver graft weight (to that of the whole liver) was delayed compared with standard dose TAC monotherapy (standard-TAC) on day 3 (59.3% vs. 72.9%; p < .001) and 14 (88.1% vs. 95.5%; p = .01). Survival was 75%, which was not as high as the value of 100% observed for standard-TAC, because neither infection nor rejection could be prevented. By contrast, survival after whole LT was 100% as neither infection nor rejection occurred.

The very early introduction of EVR + reduced-TAC after partial LT delayed liver regeneration, and made it difficult to manage the dose required to suppress both infection and rejection. On the other hand, EVR + reduced-TAC could be introduced safely very early after whole LT.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.

The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE.

The E_max model was selected for machine learning, where the evaluation indicator was the change rate of systemic lupus erythematosus disease activity index from baseline value.

A total 103 patients with SLE were included for modelling, where the E_max , ET₅₀ were -53.9%, 1.53 months in the final model respectively, and the evaluation of the final model was good. Further simulation found that the follow-up time to achieve 25%, 50%, 75% and 80% (plateau) E_max of sirolimus effecting on disease activity in patients with SLE were 0.51, 1.53, 4.59 and 6.12 months, respectively. In addition, the sirolimus dosage was flexible and adjusted according to drug concentration, where the intersection of sirolimus concentration range included in this study was about 8-10 ng/ml.

This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8-10 ng/ml sirolimus for at least 6.12 months was necessary.