Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

Rodríguez‐Perálvarez, Manuel; Tsochatzis, Emmanuel; Naveas, M.C.; Pieri, Giulia; García-Caparrós, Carmen; O’Beirne, James; Poyato-González, Antonio; Ferrín, Gustavo; Montero-Álvarez, José Luis; Patch, David; Thorburn, Douglas; Briceño, Javier; Mata, Manuel de la; Burroughs, Andrew K.

doi:10.1016/j.jhep.2013.07.012

Cited by 211 publications

(154 citation statements)

References 25 publications

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“…The following factors contributed to the propensity score: donor/recipient age and sex, (2) ABO blood-type compatibility, graft size/ macrosteatosis/ischemia time, donor bilirubin, (18) body mass index, diabetes, HBV infection status, HBV prophylaxis, operative year, neutrophil-to-lymphocyte ratio (NLR), Model for End-Stage Liver Disease (MELD) score, splenomegaly, operative time, transfusion, tumor locoregional treatment, AFP level, Edmonson grade, viable tumor size/number (the Milan criteria), intrahepatic metastasis, microvascular invasion, bile duct invasion, parenchymal cirrhosis, and immunosuppression. (19) Binary logistic regression was used to estimate propensity score. The caliper width was 0.2 standard deviation of the logit-transformed propensity score.…”

Section: Discussionmentioning

confidence: 99%

“…Preoperative PLT was negatively associated with the amount of transfused platelets during surgery (coefficient -0.49; P < 0.001), during the first week after surgery (coefficient -0.55; P < 0.001), and between 1 and 2 weeks after surgery (coefficient -0.21; P < 0.001). Accordingly, the amount of transfused platelets during surgery, during the first week after surgery, and between 1 and 2 weeks after surgery was 0 (0-6), 9 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and 0 (0-0) units in the low platelet group and 0 (0-0), 0 (0-4), and 0 (0-0) units in the high platelet group, respectively, where 1 unit of apheresis platelets was considered to be equivalent to 6 units of platelets, as described previously. (22) Minimum PLT measured at each postoperative day during the first 2 weeks after transplantation was consistently <30 3 10 9 /L in median within the subgroup of recipients who underwent platelet transfusion on each corresponding day, indicating that platelet transfusion was performed according to our standardized protocol targeting PLT >30 3 10 9 /L (Supporting Fig.…”

Section: Association Between Perioperative Plt and Platelet Transfusionmentioning

confidence: 99%

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Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Han¹,

Lee

Yang

et al. 2017

Liver Transpl

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Platelets interact with tumor cells and promote metastasis. The importance of platelets in posttransplant hepatocellular carcinoma (HCC) recurrence is unclear. Thus, we aimed to evaluate the association between preoperative platelet count (PLT) and HCC recurrence after living donor liver transplantation. Of 359 recipients of livers from living donors for HCC, 209 of 240 patients who had preoperative PLT £ 75 3 10 9 /L were matched with 97 of 119 patients who had preoperative PLT >75 3 10 9 /L using propensity score matching, with an unfixed matching ratio based on factors such as tumor biology. The cutoff value of 75 3 10 9 /L was set based on optimum stratification analysis. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. The median follow-up time was 59 months. Before matching, recurrence probability at 1, 2, and 5 years after transplantation was 4.7%, 9.2%, and 11.3% for the low platelet group and 14.5%, 23.0%, and 30.5% for the high platelet group. Recurrence risk was significantly greater in the high platelet group in both univariate (hazard ratio [HR] 5 3.09; 95% confidence interval [CI], 1.86-5.14; P < 0.001) and multivariate analyses (HR 5 2.10; 95% CI, 1.23-3.60; P 5 0.007). In the matched analysis, recurrence risk was also greater in the high platelet group in both univariate (HR 5 2.33; 95% CI, 1.36-4.01; P 5 0.002) and multivariate analyses (HR 5 1.90; 95% CI, 1.02-3.54; P 5 0.04). Preoperative PLT had no interaction with the Milan criteria, alpha-fetoprotein level, Edmonson grade, microvascular invasion, or intrahepatic metastasis. Incorporation of preoperative PLT into the Milan criteria significantly improved predictive power. Inflammation-based scores including neutrophil-tolymphocyte ratio, platelet-to-lymphocyte ratio, and the inflammation-based index did not show superiority to preoperative PLT in predicting HCC recurrence. In conclusion, preoperative PLT appears to be an important host factor affecting HCC recurrence after living donor liver transplantation.Liver Transplantation 24 44-55 2018 AASLD. Liver transplantation is a well-established therapeutic option for treatment of hepatocellular carcinoma (HCC), addressing both underlying liver disease, which is considered a premalignant lesion, and tumor burden. However, many recipients experience tumor recurrence and recurrent HCC is a major cause of death. Thus, better understanding of the contributing factors for HCC metastasis will help improve liver transplant outcome. (1,2) The platelet is the primary cell for hemostasis and tissue repair, (3) but extensive experimental evidence has also illuminated the involvement of platelets in tumor growth and metastasis. (4)(5)(6) Clinical evidence has demonstrated an association between higher platelet counts (PLTs) and shorter survival time and increased recurrence after treatment in various solid tumors. (7) In terms of HCC, a retrospective analysis using a large database of biopsy-proven HCC patients reported a positive Abbrevi...

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Section: Discussionmentioning

confidence: 99%

Section: Association Between Perioperative Plt and Platelet Transfusionmentioning

confidence: 99%

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Han¹,

Lee

Yang

et al. 2017

Liver Transpl

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“…More recent work from a single institute has corroborated these conclusions, by showing an increased risk of HCC recurrence when there is early exposure to high levels of CNIs. The first month after liver transplant appears to be critical, at a time when high trough levels of CNIs are typically encouraged (>10 ng/mL tacrolimus or >300 ng/mL cyclosporin) and at these levels, the risk of recurrent HCC has been found to be increased, by up to 3 times (29).…”

Section: Calcineurin Inhibitors (Cnis)mentioning

confidence: 99%

“…The threshold of tacrolimus trough concentration (10 ng/mL) has been found to increase the risk of HCC recurrence in two separate studies (27,29). Additionally, tacrolimus trough concentrations of 7-10 ng/mL in the first month after liver transplant produce similar rejection rates, halved the occurrence of renal impairment and were associated with longer graft survival (29,44) when compared to trough concentrations >10 ng/mL.…”

Section: Calcineurin Inhibitors (Cnis)mentioning

confidence: 99%

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

Khorsandi¹,

Heaton²

2016

Transl. Gastroenterol. Hepatol.

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“…(4) Immunosuppression based on mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, for HCC has been proposed in recent years. Everolimus is a derivative of sirolimus with improved bioavailability.…”

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confidence: 99%

Lack of benefits of mammalian target of rapamycin inhibitor in patients transplanted for hepatocellular carcinoma: Is this the end of the story?

2016

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Recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) generally carries a dismal prognosis, with fewer than 10% amenable to resection and a median survival of only a year from diagnosis. (1,2) Despite adherence to the Milan criteria, (3) HCC still recurs in 10%-15% after LT.(1) It has been postulated that calcineurin inhibitors (CNIs) may amplify HCC recurrence risk.(4) Immunosuppression based on mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, for HCC has been proposed in recent years. Everolimus is a derivative of sirolimus with improved bioavailability. The mTOR inhibitors have long been suggested to have antineoplastic properties because mTOR regulates cell growth, proliferation, metabolism, and aging, with the mTOR pathway frequently up-regulated in HCC.(5) Initial reports had suggested that sirolimus use is associated with a reduced risk of HCC recurrence after LT. A systematic review by Cholongitas et al. (6) has demonstrated a significantly decreased rate of HCC recurrence with a mTOR inhibitor when compared to standard CNI-based immunosuppression (8% versus 14%), despite a higher proportion with HCC beyond Milan criteria and microvascular invasion in the mTOR inhibitor group. A major criticism of this analysis is the inclusion of mostly retrospective single-center observational studies that are limited by having a small sample size. There are also safety concerns about the use of sirolimus after LT, particularly a high incidence of hepatic artery thrombosis leading to a "Black Box" warning. Many centers have adopted sirolimus-based immunosuppression for HCC patients after LT, even if there are still uncertainties regarding the drug's safety and efficacy.In this issue of Liver Transplantation, Yanik et al.further explore the impact of mTOR inhibitors using the Scientific Registry of Transplant Recipients (SRTR) in the United States from 2002 to 2012. The authors compared the outcomes of 234 HCC patients who received sirolimus within the first 3 months after LT with 3702 HCC patients never treated with sirolimus. They linked the SRTR database with national pharmacy claims, and those with discrepant sirolimus information between these 2 systems and those who died or experienced HCC recurrence within 3 months of LT were excluded. Sirolimus-treated patients were more likely to have HCC outside of the Milan criteria (11% versus 5%), but alpha-fetoprotein (AFP) levels were similar between the 2 groups. No significant differences between the 2 groups in all-cause mortality, cancer-specific mortality, and HCC recurrence were observed. In the subgroup within Milan criteria, cancer-specific mortality and HCC recurrence rates were nonsignificantly lower among sirolimus users. For LT recipients age 55 years, sirolimus use was associated with a significantly higher all-cause mortality. The older subgroup (>55 years)

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Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

Cited by 211 publications

References 25 publications

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

Lack of benefits of mammalian target of rapamycin inhibitor in patients transplanted for hepatocellular carcinoma: Is this the end of the story?

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