Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2016; 22(9): 2749-2759
Published online Mar 7, 2016. doi: 10.3748/wjg.v22.i9.2749
Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients
Xiang-Qian Gu, Wei-Ping Zheng, Da-Hong Teng, Ji-San Sun, Hong Zheng
Xiang-Qian Gu, Organ Transplant Center, The First Central Clinical College, Tianjin Medical University, Tianjin 300192, China
Wei-Ping Zheng, Da-Hong Teng, Ji-San Sun, Hong Zheng, Organ Transplant Center, Tianjin First Central Hospital, Tianjin 300192, China
Author contributions: Zheng H performed the review; Gu XQ wrote the paper; Zheng WP, Teng DH and Sun JS revised the review.
Supported by National High-Tech R and D Program (863 Program; No. 2012AA021003); and the Tianjin Municipal Health Bureau Key Project, No. 13KG103.
Conflict-of-interest statement: The authors declare no conflicts of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hong Zheng, PhD, MD, Professor, Organ Transplant Center, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin 300192, China. zhenghongxyx@163.com
Telephone: +86-22-23626112 Fax: +86-22-23626112
Received: October 28, 2015
Peer-review started: October 28, 2015
First decision: November 27, 2015
Revised: December 13, 2015
Accepted: December 30, 2015
Article in press: December 30, 2015
Published online: March 7, 2016

Abstract

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., “non-oncological factors”), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.

Key Words: Liver transplantation, Immunosuppressive agents, Hepatocellular carcinoma, Recurrence, Living donor, Deceased donor

Core tip: Liver transplantation (LT) has become one of the best curative therapeutic options for patients with hepatocellular carcinoma (HCC). This review discusses the effects of non-oncological factors on tumor recurrence after LT in patients with HCC. These non-oncological factors include the use of immunosuppressive agents, transplant type, hepatitis virus infection, recipient characteristics, and graft-related factors. Our review provides new research ideas and clinical strategies for the prophylaxis and surveillance of post-LT tumor recurrence, and can help the reader improve their management of, and outcomes among, patients with HCC after LT.



INTRODUCTION

After > 50 years of research, liver transplantation (LT) has been adopted as the final curative option for many kinds of end-stage liver disease. After reviewing the history of LT, we found that its application in hepatocellular carcinoma (HCC) is typically considered in the context of specific disease stages. However, the selection of LT usually takes a tortuous course, which often includes a preliminary attempt with unrealistic expectations, failure to fulfil these expectations, reconsideration of the approach, and ultimately acceptance that the LT had failed. Clinical practice data indicate that tumor recurrence after LT is the leading factor that affects the prognosis of patients with HCC who undergo LT, and standardizing the indication criteria is an effective measure for improving post-LT outcomes. Nevertheless, Western countries that strictly follow these criteria also have an estimated recurrence rate of 15%-20%[1]. Therefore, improving the post-LT prognosis among patients with HCC remains a major challenge.

As both the tumor and the entire liver are removed during LT to minimize the tumor load, this procedure is fundamentally different from hepatectomy. However, LT outcomes are influenced by various “non-oncological” factors, which include long-term immunosuppressive therapy, the degree of graft preservation, and the characteristics of the donor liver. Previous studies regarding the mechanism for recurrence after LT have mainly focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein (AFP), and the tumor stage outside of the Milan criteria[2]. Research regarding these oncological factors has achieved outstanding results, and has demonstrated that postoperative recurrence is independently predicted by the degree of differentiation, the presence of hepatic vascular invasion, and elevated serum AFP levels[3,4]. Therefore, transplant centers use formulated selection criteria to guide clinical practice, such as the Milan criteria[5], the University of California, San Francisco criteria[6], the up-to-seven criteria (the new Milan criteria)[7], and the Hangzhou criteria[8]. Although several of these selection criteria are not evidence-based, they still play an important role in reducing recurrence and improving post-LT survival. However, non-oncological factors can also predict recurrence, and these factors include the tumor’s location and the systemic response to its expansion, although the studies that reported these associations typically lack accurate conclusions and an overall understanding of HCC. Furthermore, non-oncological factors can be classified as either modifiable or non-modifiable, and further studies are needed to examine which non-oncological factors can be modified to delay post-LT tumor recurrence. Therefore, we have reviewed the clinical and experimental evidence regarding the relationships between non-oncological factors and post-LT recurrence among patients with HCC.

ROLE OF IMMUNOSUPPRESSIVE AGENTS AND THE IMMUNOLOGICAL STATE

There is a general consensus that pharmacological immunosuppression or a poor immunological state negatively affects post-LT outcomes of HCC and increases the risk of postoperative recurrence[9]. In this context, the innate immune system normally locates and destroys circulating clusters of tumor cells in the early HCC stages and prevents HCC progression. However, the administration of high-dose post-LT immunosuppressive agents reduces innate immune activity and contributes to tumor recurrence[10], which has been confirmed via clinical, in vitro, and animal data[11]. Studies have also demonstrated that calcineurin inhibitors (CNIs) reduce interleukin (IL)-2 expression and increase transforming growth factor (TGF)-β1 expression, which inhibits IL-2-stimulated T-cell proliferation. In addition, TGF-β1 suppresses the natural killer cell-mediated anti-tumor response and is associated with metastases[12,13]. Several studies have also demonstrated that higher CNI doses are correlated with a higher risk of HCC recurrence and lower post-LT overall or recurrence-free survival rates[10,14,15]. A random and homogeneous cohort study recently reported a reduced HCC recurrence rate after receiving only the minimum CNI dose during the first post-LT month, with or without other immunosuppressive drugs[10]. Furthermore, a 10 ng/mL dose of tacrolimus (TC) increased the risk of HCC recurrence, which confirms the findings of an earlier study[14]. However, the exact mechanism for TC-induced immune system impairment, and its possible relationship with tumor recurrence, remains unclear. The aforementioned study also demonstrated that the concomitant use of steroids (even high-dose boluses) for treating LT rejection did not increase the risk of disease recurrence after LT among patients with HCC[10]. Moreover, Vivarelli et al[16] also reported that HCC recurrence was not related to the cumulative steroid dose, although it was associated with cyclosporin A exposure. Nevertheless, the small sample size and short-term follow-up of that study limits the ability to interpret whether high-dose steroids might affect HCC recurrence after LT, and further studies are needed to clarify this issue.

Inhibition of the mammalian target of rapamycin (m-TOR) protein provides effective anti-tumor activity[17,18], and different mouse models have revealed that rapamycin inhibits cancer by blocking angiogenesis via the impairment of vascular endothelial growth factor (VEGF) production and VEGF-induced vascular endothelial cell stimulation[19,20]. In the clinical setting, m-TOR inhibitors (m-TORis; which include both sirolimus and everolimus) are considered immunosuppressive agents that can reduce tumor recurrence among patients with HCC who are undergoing LT. Menon et al[21] performed a systematic review and meta-analysis and concluded that, compared to CNI-treated patients, sirolimus-treated patients exhibited a lower recurrence rate and longer recurrence-free survival and overall survival (OS). A study by Cholongitas et al[22] in 2014 also demonstrated that patients who were treated using CNIs developed HCC recurrence significantly more frequently than patients who were treated using m-TORis (P < 0.001), although the CNI-treated patients exhibited more frequent recurrence using the Milan criteria (74% vs 69%) and lower rates of microvascular invasion, compared to m-TORi-treated patients (22% vs 44%) (P < 0.05). These studies’ findings indicate that m-TORi is favored over CNI to control HCC recurrence after LT (Table 1). Various trials have confirmed two important conclusions: 1) lower doses and reduced exposure to CNIs (e.g., cyclosporine and TC) after LT prevented HCC recurrence, and 2) m-TORis are a new class of immunosuppressants that provide antineoplastic properties and reduce the post-LT HCC recurrence rate compared to CNIs[21].

Table 1 Studies with different basal immunosuppression schedules for patients with hepatocellular carcinoma after liver transplantationv.
Ref.YearImmunosuppressor typeEvaluated parametersRecurrence rateP value
Rodríguez-Perálvarez et al[10]2013CNILow exposure 1stvs high exposure 1st27.7% vs 14.7% at 5 yr0.007
Vivarelli et al[16]2005CSALow exposure vs high exposure0% vs 33.3%< 0.001
Vivarelli et al[14]2008TACLow exposure vs high exposure9.1% vs 50%0.001
Menon et al[21]2013SRL and CNIsSRL vs CNIs4.9%-12.9% vs 17.3%-38.7%NA
Cholongitas et al[22]2014CNIs and mTORiCNIs vs mTORi22% vs 44%< 0.050

In addition to the effects of immunosuppressants, several studies have reported that poor nutritional status and impaired immune response were associated with HCC recurrence by impairing function of CD4+ T-cells, as measured using adenosine triphosphate levels[11,23,24]. For example, human immunodeficiency virus (HIV)-infected patients have compromised immune responses, due to CD4+ T lymphocyte depletion and a significant reduction in the numbers of peripheral blood lymphocytes, which increase their risks of HCC incidence, progression, and mortality. Several studies have also demonstrated that HIV-infected patients experience a more aggressive course of HCC and a poorer OS compared to HIV-negative patients, which suggests that an HIV-related protein might predispose normal hepatocytes to the oncogenic effects of carcinogens, induce growth signals, and ultimately contribute to the initiation and progression of HCC[25-27]. However, HIV infection has a minimal effect on the risk of tumor recurrence among patients who are undergoing LT for HCC. For example, Di Benedetto et al[28] compared 30 HIV-positive patients who underwent LT for HCC and 125 HIV-negative patients with HCC and found that their HCC recurrence rates were 6.7% and 14.4%, respectively (P = 0.15). Therefore, the authors concluded that HIV infection did not predict recurrence or mortality. Similarly, Vibert et al[29] reported that HIV-positive and HIV-negative patients exhibit similar rates of survival and HCC recurrence. Nevertheless, the value of LT in HIV-positive patients with HCC remains debatable, due to these studies’ limited number of HIV-infected patients who underwent LT and the high dropout rate while the patients waited for surgery.

TRANSPLANT TYPE

The need for LTs exceeds the number of deceased donors, which increases waiting times and contributes to a high drop-out rate among patients who experience tumor progression while awaiting surgery[30,31]. Thus, living donor LT (LDLT) provides patients with HCC better access to timely treatment. However, several recent studies have demonstrated that LDLT is associated with an increased incidence of post-LT HCC recurrence, compared to deceased donor LT (DDLT)[32-34]. Vakili et al[34] also found that LDLT recipients experienced higher HCC recurrence rates than DDLT recipients (28.6% vs 12.1%, P < 0.05), and Park et al[32] reported higher rates of cancer recurrence after LDLT compared to after DDLT (cumulative 5-year recurrence rates, 19.3% vs 6.0%, P < 0.05). Multivariate analyses have revealed that LDLT was an independent risk factor for HCC recurrence, and that smaller LDLT grafts were associated with a higher post-LT recurrence rate. Therefore, in addition to the advanced tumor characteristics of the LDLT recipient[35], there are three suggested mechanisms by which LDLT might increase the risk of HCC recurrence. The first mechanism is the release of growth factors that mediate the regeneration of the hemiliver and increase the vascular inflow during the rapid regeneration of the partial grafts from living donors, which might contribute to tumor progression and recurrence[36-38]. Furthermore, small-sized grafts are more likely to cause acute phase graft injury, which results in cell adhesion, angiogenesis, and migration; all of these factors may promote tumor recurrence[38,39]. The second mechanism is the “fast-tracking effect”, whereby patients who undergo LDLT have a shorter waiting time, which might preclude the detection of an aggressive tumor before surgery[40,41] and increase the risk of recurrence. The third mechanism is the LDLT technique itself might directly contribute to a higher recurrence rate, due to the sparing of the inferior vena cava (which is necessary for complete tumor removal) and more extensive liver manipulation during the LDLT[33,42]. All of these factors might contribute to the high recurrence rates after LDLT compared to after DDLT.

Despite these potential mechanisms by which LDLT might increase HCC recurrence, other studies have reported that LDLT recipients have a similar recurrence rate and comparable recurrence-free survival compared to patients who underwent DDLT[43-45]. In these studies, the authors attributed the inferior outcomes after LDLT for HCC to the tumor’s characteristics and biology. Although there is no clear evidence regarding whether LDLT is associated with a higher recurrence rate, the conflicting data suggest that different indication criteria may be appropriate for LDLT and DDLT.

As an alternative to the conventional LT method, the piggyback technique has become the preferred approach in some centers, as it provides a shorter procedure time, a shorter anhepatic phase and warm ischemia period, fewer blood transfusions, and a shorter stay in the intensive care unit[46,47]. This technique has gained widespread acceptance for many end-stage liver diseases, but not for HCC, because it theoretically carries a higher risk of positive vena cava margins and requires greater manipulation of the diseased liver, which could increase the risk of HCC spread[48]. However, it is debatable whether piggyback transplantation increases HCC recurrence in the transplantation setting. For example, Mangus et al[48] reported no significant difference between the two techniques in terms of their survival and recurrence rates and suggested that the presence of HCC should not preclude the use of piggyback transplantation. In addition, Grąt et al[47] found that piggyback transplantation provided superior long-term survival among patients with HCC and potentially decreased the risk of post-transplant recurrence, as compared to the conventional technique. Therefore, piggyback transplantation might be considered for patients with HCC, although further studies are needed to validate this approach. A summary of the disadvantages and recurrence rates after LDLT and piggyback LT, compared to DDLT and conventional LT, respectively, is listed in Table 2.

Table 2 Disadvantages and rates of tumor recurrence after living donor liver transplantation and piggyback liver transplantation compared to deceased donor liver transplantation and conventional orthotropic liver transplantation, respectively.
Transplant typeDisadvantagesRate of tumor recurrence
LDLT vs DDLTThe small-sized graft, the “fast-tracking effect”, the sparing of the inferior vena cava, and more extensive manipulation28.6% vs 12.1%, P < 0.05[34]; 19.3% vs 6%, P < 0.05 (cumulative 5-yr)[32]
PB-LT vs CON-LTThe positive vena cava margin and greater manipulation of the diseased liver6.3% vs 10.1%, P > 0.05[48]
HEPATITIS VIRUSES

There is growing evidence that the hepatitis B virus (HBV) contributes to hepatocarcinogenesis via direct malignant transformation and other indirect effects[49-51]. Furthermore, persistent HBV infection can increase genetic instability by causing hepatocyte destruction and regeneration[52]. Moreover, HBV load is involved in post-LT HCC recurrence[53,54] and increases the risk of post-LT recurrence through an inflammatory effect after HBV or hepatitis C virus (HCV) allograft re-infection[55]. Li et al[53] retrospectively analyzed 340 HBV-positive patients who underwent orthotropic LT (OLT) and found that HBV relapse was an independent predictor of HCC recurrence (P = 0.03), and that high pre-transplant levels of HBV DNA were associated with HCC recurrence. Wu et al[56] also performed a retrospective study of 78 patients with HBV-related HCC who underwent LT, and found that 13 patients (16.6%) experienced HCC recurrence and 18 patients (23.1%) experienced HBV relapse. Therefore, the authors concluded that HBV relapse was closely related to HCC recurrence (P = 0.004) and led to a shorter OS after LT. Thus, HBV relapse and HCC recurrence may have a reciprocal causative relationship in the post-transplantation setting[53].

Antiviral therapy can reduce the risk of recurrence in patients with HCC, which supports a role for hepatitis virus infection in HCC recurrence after LT. For example, Kohli et al[57] retrospectively compared patients who were and were not receiving post-LT interferon and found that the rates of HCC recurrence in these groups were 4.1% and 27.3%, respectively (P < 0.05). This finding suggests that interferon markedly reduces the risk of HCC recurrence and related mortality among patients who are undergoing LT for HCV-related HCC. Anselmo et al[58] have also reported that combined treatment with hepatitis B immunoglobulin and lamivudine after OLT markedly reduced the HBV relapse rates and significantly improved the 1-year and 3-year recurrence-free survival rates.

RECIPIENT CHARACTERISTICS

Overweight and obese patients who undergo OLT for HCC have a relatively high recurrence rate, and these patients exhibit a significantly shorter time to recurrence compared to non-obese patients[59]. The proposed mechanism for this increased risk of recurrence and shorter OS is the altered expression of adipokines (leptin and adiponectin) in obese patients, as these molecules can increase proliferation and suppress apoptosis in cancer cell lines and can also increase cell invasion and upregulate the expression of VEGF and other angiogenesis-related cytokines in HCC[60-63]. Siegel et al[64] retrospectively analyzed 342 consecutive HCC patients who underwent LT and found that a body mass index (BMI) of > 30 kg/m2 was an independent predictor of poor OS and recurrent disease. In addition, Mathur et al[59] found that the rate of HCC recurrence in overweight (15%) and obese (15%) patients was double that in non-obese patients (7%) (P < 0.05). Therefore, BMI is a potentially significant predictor of post-LT tumor recurrence.

In general, there is an arbitrary age limit for LT, due to the increased incidence of age-related comorbidities among elderly patients with HCC[65,66]. Several studies have reported that elderly patients who underwent LT exhibited a lower survival rate and higher rates of HCC malignancy, which may be associated with their increased risk of adverse outcomes due to chronic comorbidities, immunosuppression, and immunosenescence[66,67]. Age-related immunological changes and immunosenescence can increase the susceptibility of elderly patients to infection, autoimmune disease, and cancer[68]; and long-term immunosuppressive therapy after LT might increase these patients’ risks of morbidity and mortality compared to their younger counterparts[69]. However, other studies have reported that LT is not contraindicated for elderly patients[65,70,71], and Ballarin et al[70] reported similar short- and middle-term survival outcomes and morbidities (e.g., HCC recurrence) among young and elderly patients. Moreover, Kim et al[69] demonstrated that OS was prolonged among younger patients who underwent OLT for HCC, although there were no significant differences in HCC-specific survival among the various age groups. Therefore, these findings suggest that carefully selected elderly patients with HCC could experience a benefit from OLT that is equal to the benefit that is experienced by younger patients.

Several studies have reported sex-specific differences in the incidences of HCC among mice and in the survival of patients with HCC[72,73]. For example, estrogen inhibited the production of IL-6 in Kupffer cells that were exposed to necrotic hepatocytes, and diethylnitrosamine-treated male mice exhibited reduced circulating concentrations of IL-6, which reduced inflammation-induced carcinogenesis[72]. Moreover, Yang et al[73] demonstrated that survival among women was superior to that among men when they evaluated patients with HCC who were 18-44 years old and 45-54 years old, respectively, which suggests that menopausal status might be related to HCC outcomes and that estrogen might protect against hepatocarcinogenesis and promote a more favorable HCC outcome. This difference was especially pronounced among patients who underwent surgical resection, although there was no difference among patients who underwent LT. Therefore, as the mean age at transplantation is increasing, a growing number of elderly women are being considered for LT. However, these women may be menopausal and may not experience estrogen’s protective effect, which might lead to poorer survival and increased HCC recurrence compared to those among younger patients. Nevertheless, only limited data are available to support this hypothesis, and it remains unclear whether sex influences post-LT survival and tumor recurrence; further clinical studies are needed to examine this issue.

GRAFT-RELATED FACTORS

Changes in transplant-related factors, such as the allograft excision, organ allocation, transportation of the liver graft, and timing of the recipient surgery, might lead to prolonged periods of cold and warm ischemia. Furthermore, experimental and clinical evidence indicate that ischemia-reperfusion injury may affect HCC recurrence after LT. Nagai et al[74] retrospectively evaluated 391 patients from two transplant centers who underwent LT for HCC and found that prolonged cold ischemia times (> 10 h, P = 0.03; HR = 1.9) and warm ischemia times (> 50 min; P = 0.003; HR = 2.84) were independent risk factors for HCC recurrence after LT. These relationships were especially pronounced among patients with other risk factors, such as poor differentiation, micro- and macrovascular invasion, HCC exceeding the Milan criteria, and AFP levels > 200 ng/dL. Prolonged ischemia was also significantly associated with recurrence within 1 year. A number of biological mechanisms have been proposed to explain how ischemia-reperfusion injury can affect cancer outcomes, based on in vivo and in vitro experiments[75-77]. For example, the exposure of micrometastases to hypoxia could lead to the activation of several distinct pathways and the abnormal expression of genes and cytokines that contribute to angiogenesis, cellular proliferation, growth, and adhesion[75,78]. Hypoxia also stabilizes and activates the transcription factor for hypoxia-inducible factor, which is a key oxygen response regulator that activates the transcription of genes (e.g., VEGF-A) that stimulate angiogenesis[79-81]. Moreover, as the reperfusion progresses, microcirculatory disturbances might exacerbate intrahepatic hypoxia. Therefore, it has been speculated that recipients who receive allografts from donation after brain death (DBD) might experience a lower recurrence rate compared to patients who receive allografts from donation after cardiac death (DCD). Furthermore, patients with HCC exhibit shorter survival after receiving DCD allografts compared to those receiving DBD allografts, even after adjusting for the inherent inferiority of the DCD allografts and other known risk factors[82]. Thus, the survival difference might reflect an increased rate of HCC recurrence. However, the same researchers subsequently reported conflicting results, which indicated that HCC recurrence occurred at equal rates among patients who received DBD or DCD allografts. With respect to donor sex, experimental and clinical observations indicate that livers from women are more susceptible to hepatic reperfusion injury and have a higher sensitivity to reoxygenation damage after prolonged cold storage[83,84], although, to our knowledge, there are only limited data available regarding the effect of donor sex on tumor recurrence after LT among patients with HCC.

Age is another donor factor that is associated with HCC recurrence[85]. For example, the median donor age for patients with HCC recurrence was older than that for patients who did not experience recurrence (49 years vs 36 years, P = 0.008), which suggests that livers from older donors are poorly preserved and have a greater susceptibility to cold ischemia and age-related immune changes, which can lead to inferior outcomes. However, other studies have reported that recipients of livers from elderly donors experienced excellent outcomes, and that age-matched patients were more likely to exhibit better graft survival[86-88]. The authors attributed these findings to the reduced cold storage times for these organs, although the relationship between donor age and HCC recurrence after LT continues to be debated.

ABO-incompatible (ABO-I) LT is exclusively used when a donor liver is urgently needed in pediatric cases, due to the risk of hyperacute or antibody-mediated humoral graft rejection because of the graft’s ABO blood group and the antibodies in the recipient’s blood[89,90]. B-cells and T-cells play a major role in this process, and various procedures have been proposed to overcome this rejection, such as plasma exchange, splenectomy, local infusion of the grafts, and more aggressive immunosuppression[91,92]. All of these protocols have achieved good outcomes. Furthermore, as new monoclonal antibodies (e.g., rituximab and basiliximab) have been developed, ABO-I LDLT has been widely performed, and good results have been reported[93]. However, Miyagi et al[94] found that strong immunosuppressive therapies, such as steroid pulses and rituximab for ABO-incompatible cases, may have a negative effect on tumor recurrence after LT. In addition, Lee et al[93] retrospectively studied 20 patients who underwent ABO-I LDLT due to HCC or liver cirrhosis, using an ABO-I LDLT protocol that included rituximab, plasma exchange, basiliximab, and intravenous immune globulin. The authors found that the proportion of natural killer (NK) cells decreased with declining absolute peripheral blood counts during the early phase of ABO-I LDLT, which contributed to a weakening of the innate immune response to HCC or the hepatitis virus. In this context, NK cells play a critical role in the immune surveillance of liver tumors, through the expression of FasL, perforin, granzyme B, and functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)[95]. Therefore, these cells play an important role in preventing HCC recurrence, and caution is needed when performing ABO-I LDLT, especially in cases with advanced HCC.

Data from our center suggest that the use of moderate-to-severe fatty liver grafts might be related to the incidence of post-LT liver cancer recurrence[96]. Other studies have reported that ischemia-reperfusion injury was much more severe in moderate-to-severe steatotic grafts, and that steatotic livers exhibited a decreased tolerance to ischemia-reperfusion injury[97-99]. These injuries led to an increased release of lipid peroxides, downregulation of adipokines (e.g., adiponectin and resistin) that can protect the steatotic liver grafts[100], and a series of secondary inflammatory reaction cascades, which in turn led to increased angiogenesis that ultimately promotes tumor recurrence. However, there were no significant differences in patient and graft survivals according to steatosis after LT[101]. The mechanism that underlies this process is similar to those for small-for-size graft injuries and regeneration. Table 3 shows a summary of studies that compared the effects of recipient characteristics and graft-related factors on tumor recurrence after LT among patients with HCC patients.

Table 3 Studies comparing the effects of recipient and donor characteristics on tumor recurrence among patients with hepatocellular carcinoma after liver transplantation.
Ref.YearCharacteristicsEvaluated parameterRecurrence rateP value
Recipient
Mathur et al[59]2014Overweight or obeseOverweight vs obese vs non-obese15% vs 15% vs 7%< 0.050
Ballarin et al[70]2011AgeElderly vs younger7.1% vs 4.8%> 0.050
Yang et al[73]2014GenderMale vs femaleNANA
Donor
Nagai et al[74]2014Ischemia timesCIT >10 h vs < 10 h and WIT > 50 min vs ≤ 50 minNA0.015
Sharma et al[85]2012AgeMedian donor age for patients with HCC recurrence vs without HCC recurrenceNA0.008
Miyagi et al[94]2012ABO-I graftStrong imunosuppressive therapy vs other imunosuppressive therapyNANA
Teng da et al[96]2012Steatosis donor liverGrafts with no steatosis vs mild steatosis vs moderate-to-severe steatosis15.8% vs 8.3% vs 33.3% at 1 yr; 28.7% vs 20.8% vs 50% at 3 yr> 0.050
OTHER FACTORS

One study reported that the extent of intraoperative packed red blood cell transfusion was associated with HCC recurrence after LT[74], and intraoperative blood transfusion was hypothesized to have a negative effect on tumor recurrence among patients with various types of cancers[102-104]. This detrimental effect is thought to be caused by suppression of the host’s immune system (including reduced NK-cell and phagocyte activity), increased suppressor T-cell activity with inhibition of IL-2 secretion, and sFAS ligand and soluble human leukocyte antigen (sHLA) molecule transfusion[102,105-110]. In addition, systemic inflammation and cytokine production that is caused by impaired oxygen delivery to vital organs due to massive hemorrhage can reduce antitumor immunity[111]. However, Kaido et al[112] found that the immunosuppressive effect of homologous blood transfusion in LT was unclear and suggested that any immunosuppression would be minimized by the potent action of immunosuppressive drugs.

CONCLUSION

In conclusion, this review summarized the effects of select non-oncological factors on tumor recurrence after LT, although we did not consider the effects of several non-oncological factors (e.g., diabetes mellitus or smoking), due to a lack of data. Although several studies of non-oncological factors made conclusions that were based on insufficient clinical evidence, these studies have provided new research ideas and clinical strategies for the prophylaxis and surveillance of post-LT tumor recurrence. Furthermore, there is strong evidence for an intricate and close connection between injury, infection, inflammation, regeneration, immune imbalance, and a series of physiological occurrences. Therefore, non-oncological factors might also be intrinsically connected to the deactivation of anti-tumor immunity, tumor recurrence, and tumor progression. Thus, closely considering both oncological factors (“seeds”) and non-oncological factors (“soil and environment”) might help to improve the outcomes after LT for patients with HCC.

Footnotes

P- Reviewer: Grassi G, Mihaila RG, Tsai JF S- Editor: Ma YJ L- Editor: Filipodia E- Editor: Ma S

References
1.  Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation - an emerging clinical challenge. Transpl Int. 2013;26:109-118.  [PubMed]  [DOI]
2.  Sotiropoulos GC, Molmenti EP, Lösch C, Beckebaum S, Broelsch CE, Lang H. Meta-analysis of tumor recurrence after liver transplantation for hepatocellular carcinoma based on 1,198 cases. Eur J Med Res. 2007;12:527-534.  [PubMed]  [DOI]
3.  Piardi T, Gheza F, Ellero B, Woehl-Jaegle ML, Ntourakis D, Cantu M, Marzano E, Audet M, Wolf P, Pessaux P. Number and tumor size are not sufficient criteria to select patients for liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2012;19:2020-2026.  [PubMed]  [DOI]
4.  Dumitra TC, Dumitra S, Metrakos PP, Barkun JS, Chaudhury P, Deschênes M, Paraskevas S, Hassanain M, Tchervenkov JI. Pretransplantation α-fetoprotein slope and milan criteria: strong predictors of hepatocellular carcinoma recurrence after transplantation. Transplantation. 2013;95:228-233.  [PubMed]  [DOI]
5.  Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693-699.  [PubMed]  [DOI]
6.  Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394-1403.  [PubMed]  [DOI]
7.  Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35-43.  [PubMed]  [DOI]
8.  Zheng SS, Xu X, Wu J, Chen J, Wang WL, Zhang M, Liang TB, Wu LM. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation. 2008;85:1726-1732.  [PubMed]  [DOI]
9.  Cescon M, Bertuzzo VR, Ercolani G, Ravaioli M, Odaldi F, Pinna AD. Liver transplantation for hepatocellular carcinoma: role of inflammatory and immunological state on recurrence and prognosis. World J Gastroenterol. 2013;19:9174-9182.  [PubMed]  [DOI]
10.  Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, Pieri G, García-Caparrós C, O’Beirne J, Poyato-González A, Ferrín-Sánchez G, Montero-Álvarez JL, Patch D. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol. 2013;59:1193-1199.  [PubMed]  [DOI]
11.  Yan S, Ding Y, Tian Y, Lu Z, Wang Y, Zhang Q, Ye Y, Zhou L, Xie H, Chen H. MHC-mismatched mice liver transplantation promotes tumor growth in liver graft. Cancer Lett. 2014;351:162-171.  [PubMed]  [DOI]
12.  Yang L. TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. Curr Mol Med. 2010;10:374-380.  [PubMed]  [DOI]
13.  Fung J, Kelly D, Kadry Z, Patel-Tom K, Eghtesad B. Immunosuppression in liver transplantation: beyond calcineurin inhibitors. Liver Transpl. 2005;11:267-280.  [PubMed]  [DOI]
14.  Vivarelli M, Cucchetti A, La Barba G, Ravaioli M, Del Gaudio M, Lauro A, Grazi GL, Pinna AD. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg. 2008;248:857-862.  [PubMed]  [DOI]
15.  Vivarelli M, Bellusci R, Cucchetti A, Cavrini G, De Ruvo N, Aden AA, La Barba G, Brillanti S, Cavallari A. Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation. 2002;74:1746-1751.  [PubMed]  [DOI]
16.  Vivarelli M, Cucchetti A, Piscaglia F, La Barba G, Bolondi L, Cavallari A, Pinna AD. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl. 2005;11:497-503.  [PubMed]  [DOI]
17.  Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, Repasky EA, Ma WW, Qiu J, Adjei AA. Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol. 2012;56:176-183.  [PubMed]  [DOI]
18.  Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972-1983, 1983.e1-11.  [PubMed]  [DOI]
19.  Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128-135.  [PubMed]  [DOI]
20.  Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation. 2004;77:1777-1782.  [PubMed]  [DOI]
21.  Menon KV, Hakeem AR, Heaton ND. Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma. Aliment Pharmacol Ther. 2013;37:411-419.  [PubMed]  [DOI]
22.  Cholongitas E, Mamou C, Rodríguez-Castro KI, Burra P. Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review. Transpl Int. 2014;27:1039-1049.  [PubMed]  [DOI]
23.  Cheng JW, Shi YH, Fan J, Huang XW, Qiu SJ, Xiao YS, Wang Z, Dai Z, Tang ZY, Zhou J. An immune function assay predicts post-transplant recurrence in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2011;137:1445-1453.  [PubMed]  [DOI]
24.  Nagai S, Abouljoud MS, Kazimi M, Brown KA, Moonka D, Yoshida A. Peritransplant lymphopenia is a novel prognostic factor in recurrence of hepatocellular carcinoma after liver transplantation. Transplantation. 2014;97:694-701.  [PubMed]  [DOI]
25.  Serraino D, Boschini A, Carrieri P, Pradier C, Dorrucci M, Dal Maso L, Ballarini P, Pezzotti P, Smacchia C, Pesce A. Cancer risk among men with, or at risk of, HIV infection in southern Europe. AIDS. 2000;14:553-559.  [PubMed]  [DOI]
26.  Altavilla G, Caputo A, Lanfredi M, Piola C, Barbanti-Brodano G, Corallini A. Enhancement of chemical hepatocarcinogenesis by the HIV-1 tat gene. Am J Pathol. 2000;157:1081-1089.  [PubMed]  [DOI]
27.  Berretta M, Garlassi E, Cacopardo B, Cappellani A, Guaraldi G, Cocchi S, De Paoli P, Lleshi A, Izzi I, Torresin A. Hepatocellular carcinoma in HIV-infected patients: check early, treat hard. Oncologist. 2011;16:1258-1269.  [PubMed]  [DOI]
28.  Di Benedetto F, Tarantino G, Ercolani G, Baccarani U, Montalti R, De Ruvo N, Berretta M, Adani GL, Zanello M, Tavio M. Multicenter italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients. Oncologist. 2013;18:592-599.  [PubMed]  [DOI]
29.  Vibert E, Duclos-Vallée JC, Ghigna MR, Hoti E, Salloum C, Guettier C, Castaing D, Samuel D, Adam R. Liver transplantation for hepatocellular carcinoma: the impact of human immunodeficiency virus infection. Hepatology. 2011;53:475-482.  [PubMed]  [DOI]
30.  Park SJ, Freise CE, Hirose R, Kerlan RK, Yao FY, Roberts JP, Vagefi PA. Risk factors for liver transplant waitlist dropout in patients with hepatocellular carcinoma. Clin Transplant. 2012;26:E359-E364.  [PubMed]  [DOI]
31.  Bittermann T, Niu B, Hoteit MA, Goldberg D. Waitlist priority for hepatocellular carcinoma beyond milan criteria: a potentially appropriate decision without a structured approach. Am J Transplant. 2014;14:79-87.  [PubMed]  [DOI]
32.  Park MS, Lee KW, Suh SW, You T, Choi Y, Kim H, Hong G, Yi NJ, Kwon CH, Joh JW. Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than deceased-donor liver transplantation. Transplantation. 2014;97:71-77.  [PubMed]  [DOI]
33.  Grant RC, Sandhu L, Dixon PR, Greig PD, Grant DR, McGilvray ID. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant. 2013;27:140-147.  [PubMed]  [DOI]
34.  Vakili K, Pomposelli JJ, Cheah YL, Akoad M, Lewis WD, Khettry U, Gordon F, Khwaja K, Jenkins R, Pomfret EA. Living donor liver transplantation for hepatocellular carcinoma: Increased recurrence but improved survival. Liver Transpl. 2009;15:1861-1866.  [PubMed]  [DOI]
35.  Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94:78-86.  [PubMed]  [DOI]
36.  Man K, Lo CM, Xiao JW, Ng KT, Sun BS, Ng IO, Cheng Q, Sun CK, Fan ST. The significance of acute phase small-for-size graft injury on tumor growth and invasiveness after liver transplantation. Ann Surg. 2008;247:1049-1057.  [PubMed]  [DOI]
37.  Shi JH, Huitfeldt HS, Suo ZH, Line PD. Growth of hepatocellular carcinoma in the regenerating liver. Liver Transpl. 2011;17:866-874.  [PubMed]  [DOI]
38.  Yang ZF, Poon RT, Luo Y, Cheung CK, Ho DW, Lo CM, Fan ST. Up-regulation of vascular endothelial growth factor (VEGF) in small-for-size liver grafts enhances macrophage activities through VEGF receptor 2-dependent pathway. J Immunol. 2004;173:2507-2515.  [PubMed]  [DOI]
39.  Man K, Fan ST, Lo CM, Liu CL, Fung PC, Liang TB, Lee TK, Tsui SH, Ng IO, Zhang ZW. Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression. Ann Surg. 2003;237:256-264.  [PubMed]  [DOI]
40.  Kulik L, Abecassis M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology. 2004;127:S277-S282.  [PubMed]  [DOI]
41.  Fisher RA, Kulik LM, Freise CE, Lok AS, Shearon TH, Brown RS, Ghobrial RM, Fair JH, Olthoff KM, Kam I. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant. 2007;7:1601-1608.  [PubMed]  [DOI]
42.  Di Sandro S, Slim AO, Giacomoni A, Lauterio A, Mangoni I, Aseni P, Pirotta V, Aldumour A, Mihaylov P, De Carlis L. Living donor liver transplantation for hepatocellular carcinoma: long-term results compared with deceased donor liver transplantation. Transplant Proc. 2009;41:1283-1285.  [PubMed]  [DOI]
43.  Xiao GQ, Song JL, Shen S, Yang JY, Yan LN. Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation. World J Gastroenterol. 2014;20:10953-10959.  [PubMed]  [DOI]
44.  Sandhu L, Sandroussi C, Guba M, Selzner M, Ghanekar A, Cattral MS, McGilvray ID, Levy G, Greig PD, Renner EL. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: comparable survival and recurrence. Liver Transpl. 2012;18:315-322.  [PubMed]  [DOI]
45.  Bhangui P, Vibert E, Majno P, Salloum C, Andreani P, Zocrato J, Ichai P, Saliba F, Adam R, Castaing D. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology. 2011;53:1570-1579.  [PubMed]  [DOI]
46.  Khan S, Silva MA, Tan YM, John A, Gunson B, Buckels JA, David Mayer A, Bramhall SR, Mirza DF. Conventional versus piggyback technique of caval implantation; without extra-corporeal veno-venous bypass. A comparative study. Transpl Int. 2006;19:795-801.  [PubMed]  [DOI]
47.  Grąt M, Kornasiewicz O, Lewandowski Z, Skalski M, Zieniewicz K, Pączek L, Krawczyk M. The impact of surgical technique on the results of liver transplantation in patients with hepatocellular carcinoma. Ann Transplant. 2013;18:448-459.  [PubMed]  [DOI]
48.  Mangus RS, Fridell JA, Vianna RM, Cooper AB, Jones DT, Tector AJ. Use of the piggyback hepatectomy technique in liver transplant recipients with hepatocellular carcinoma. Transplantation. 2008;85:1496-1499.  [PubMed]  [DOI]
49.  Tan YJ. Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol. 2011;17:4853-4857.  [PubMed]  [DOI]
50.  Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 1995;21:313-321.  [PubMed]  [DOI]
51.  Tan ZM, Sun BC. Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence. World J Gastroenterol. 2013;19:8895-8901.  [PubMed]  [DOI]
52.  Ishikawa T. Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 2013;19:8861-8866.  [PubMed]  [DOI]
53.  Li MR, Chen GH, Cai CJ, Wang GY, Zhao H. High hepatitis B virus DNA level in serum before liver transplantation increases the risk of hepatocellular carcinoma recurrence. Digestion. 2011;84:134-141.  [PubMed]  [DOI]
54.  Saab S, Yeganeh M, Nguyen K, Durazo F, Han S, Yersiz H, Farmer DG, Goldstein LI, Tong MJ, Busuttil RW. Recurrence of hepatocellular carcinoma and hepatitis B reinfection in hepatitis B surface antigen-positive patients after liver transplantation. Liver Transpl. 2009;15:1525-1534.  [PubMed]  [DOI]
55.  Lai Q, Avolio AW, Lerut J, Singh G, Chan SC, Berloco PB, Tisone G, Agnes S, Chok KS, Sharr W. Recurrence of hepatocellular cancer after liver transplantation: the role of primary resection and salvage transplantation in East and West. J Hepatol. 2012;57:974-979.  [PubMed]  [DOI]
56.  Wu TJ, Chan KM, Chou HS, Lee CF, Wu TH, Chen TC, Yeh CT, Lee WC. Liver transplantation in patients with hepatitis B virus-related hepatocellular carcinoma: the influence of viral characteristics on clinical outcome. Ann Surg Oncol. 2013;20:3582-3590.  [PubMed]  [DOI]
57.  Kohli V, Singhal A, Elliott L, Jalil S. Antiviral therapy for recurrent hepatitis C reduces recurrence of hepatocellular carcinoma following liver transplantation. Transpl Int. 2012;25:192-200.  [PubMed]  [DOI]
58.  Anselmo DM, Ghobrial RM, Jung LC, Weaver M, Cao C, Saab S, Kunder G, Chen PW, Farmer DG, Yersiz H. New era of liver transplantation for hepatitis B: a 17-year single-center experience. Ann Surg. 2002;235:611-619; discussion 619-620.  [PubMed]  [DOI]
59.  Mathur A, Franco ES, Leone JP, Osman-Mohamed H, Rojas H, Kemmer N, Neff GW, Rosemurgy AS, Alsina AE. Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma. HPB (Oxford). 2013;15:504-510.  [PubMed]  [DOI]
60.  Sweeney G. Leptin signalling. Cell Signal. 2002;14:655-663.  [PubMed]  [DOI]
61.  Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207:12-22.  [PubMed]  [DOI]
62.  Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67:2497-2507.  [PubMed]  [DOI]
63.  Rega G, Kaun C, Demyanets S, Pfaffenberger S, Rychli K, Hohensinner PJ, Kastl SP, Speidl WS, Weiss TW, Breuss JM. Vascular endothelial growth factor is induced by the inflammatory cytokines interleukin-6 and oncostatin m in human adipose tissue in vitro and in murine adipose tissue in vivo. Arterioscler Thromb Vasc Biol. 2007;27:1587-1595.  [PubMed]  [DOI]
64.  Siegel AB, Lim EA, Wang S, Brubaker W, Rodriguez RD, Goyal A, Jacobson JS, Hershman DL, Verna EC, Zaretsky J. Diabetes, body mass index, and outcomes in hepatocellular carcinoma patients undergoing liver transplantation. Transplantation. 2012;94:539-543.  [PubMed]  [DOI]
65.  Taner CB, Ung RL, Rosser BG, Aranda-Michel J. Age is not a contraindication for orthotopic liver transplantation: a single institution experience with recipients older than 75 years. Hepatol Int. 2012;6:403-407.  [PubMed]  [DOI]
66.  Herrero JI, Lucena JF, Quiroga J, Sangro B, Pardo F, Rotellar F, Alvárez-Cienfuegos J, Prieto J. Liver transplant recipients older than 60 years have lower survival and higher incidence of malignancy. Am J Transplant. 2003;3:1407-1412.  [PubMed]  [DOI]
67.  Malinis MF, Chen S, Allore HG, Quagliarello VJ. Outcomes among older adult liver transplantation recipients in the model of end stage liver disease (MELD) era. Ann Transplant. 2014;19:478-487.  [PubMed]  [DOI]
68.  Martins PN, Pratschke J, Pascher A, Fritsche L, Frei U, Neuhaus P, Tullius SG. Age and immune response in organ transplantation. Transplantation. 2005;79:127-132.  [PubMed]  [DOI]
69.  Kim J, Ko ME, Nelson RA, Arrington A, Luu C, Falor AE, Nissen NN, Colquhoun S, Hurria A, Singh G. Increasing age and survival after orthotopic liver transplantation for patients with hepatocellular cancer. J Am Coll Surg. 2014;218:431-438.  [PubMed]  [DOI]
70.  Ballarin R, Montalti R, Spaggiari M, Cautero N, De Ruvo N, Guerrini GP, Rompianesi G, Longo C, Gerunda GE, Di Benedetto F. Liver transplantation in older adults: our point of view. J Am Geriatr Soc. 2011;59:1359-1361.  [PubMed]  [DOI]
71.  Adani GL, Baccarani U, Lorenzin D, Rossetto A, Nicolini D, Vecchi A, De Luca S, Risaliti A, De Anna D, Bresadola F. Elderly versus young liver transplant recipients: patient and graft survival. Transplant Proc. 2009;41:1293-1294.  [PubMed]  [DOI]
72.  Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121-124.  [PubMed]  [DOI]
73.  Yang D, Hanna DL, Usher J, LoCoco J, Chaudhari P, Lenz HJ, Setiawan VW, El-Khoueiry A. Impact of sex on the survival of patients with hepatocellular carcinoma: a Surveillance, Epidemiology, and End Results analysis. Cancer. 2014;120:3707-3716.  [PubMed]  [DOI]
74.  Nagai S, Yoshida A, Facciuto M, Moonka D, Abouljoud MS, Schwartz ME, Florman SS. Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation. Hepatology. 2015;61:895-904.  [PubMed]  [DOI]
75.  van der Bilt JD, Kranenburg O, Nijkamp MW, Smakman N, Veenendaal LM, Te Velde EA, Voest EE, van Diest PJ, Borel Rinkes IH. Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology. 2005;42:165-175.  [PubMed]  [DOI]
76.  Man K, Ng KT, Lo CM, Ho JW, Sun BS, Sun CK, Lee TK, Poon RT, Fan ST. Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways. Liver Transpl. 2007;13:1669-1677.  [PubMed]  [DOI]
77.  Ku Y, Kusunoki N, Shiotani M, Maeda I, Iwasaki T, Tominaga M, Kitagawa T, Fukumoto T, Suzuki Y, Kuroda Y. Stimulation of haematogenous liver metastases by ischaemia-reperfusion in rats. Eur J Surg. 1999;165:801-807.  [PubMed]  [DOI]
78.  Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38-47.  [PubMed]  [DOI]
79.  Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394:485-490.  [PubMed]  [DOI]
80.  Brahimi-Horn C, Pouysségur J. The role of the hypoxia-inducible factor in tumor metabolism growth and invasion. Bull Cancer. 2006;93:E73-E80.  [PubMed]  [DOI]
81.  Axelson H, Fredlund E, Ovenberger M, Landberg G, Påhlman S. Hypoxia-induced dedifferentiation of tumor cells--a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol. 2005;16:554-563.  [PubMed]  [DOI]
82.  Croome KP, Wall W, Chandok N, Beck G, Marotta P, Hernandez-Alejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl. 2013;19:1214-1223.  [PubMed]  [DOI]
83.  Gasbarrini A, Addolorato G, Di Campli C, Simoncini M, Montemagno S, Castagneto M, Padalino C, Pola P, Gasbarrini G. Gender affects reperfusion injury in rat liver. Dig Dis Sci. 2001;46:1305-1312.  [PubMed]  [DOI]
84.  Wittnich C, Belanger MP, Askin N, Boscarino C, Wallen WJ. Lower liver transplant success in females: gender differences in metabolic response to global ischemia. Transplant Proc. 2004;36:1485-1488.  [PubMed]  [DOI]
85.  Sharma P, Welch K, Hussain H, Pelletier SJ, Fontana RJ, Marrero J, Merion RM. Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era. Dig Dis Sci. 2012;57:806-812.  [PubMed]  [DOI]
86.  Cameron AM, Ghobrial RM, Yersiz H, Farmer DG, Lipshutz GS, Gordon SA, Zimmerman M, Hong J, Collins TE, Gornbein J. Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants. Ann Surg. 2006;243:748-753; discussion 753-755.  [PubMed]  [DOI]
87.  Segev DL, Maley WR, Simpkins CE, Locke JE, Nguyen GC, Montgomery RA, Thuluvath PJ. Minimizing risk associated with elderly liver donors by matching to preferred recipients. Hepatology. 2007;46:1907-1918.  [PubMed]  [DOI]
88.  Pagano D, Grosso G, Vizzini G, Spada M, Cintorino D, Malaguarnera M, Donati M, Mistretta A, Gridelli B, Gruttadauria S. Recipient-donor age matching in liver transplantation: a single-center experience. Transplant Proc. 2013;45:2700-2706.  [PubMed]  [DOI]
89.  Lo CM, Shaked A, Busuttil RW. Risk factors for liver transplantation across the ABO barrier. Transplantation. 1994;58:543-547.  [PubMed]  [DOI]
90.  Gugenheim J, Samuel D, Reynes M, Bismuth H. Liver transplantation across ABO blood group barriers. Lancet. 1990;336:519-523.  [PubMed]  [DOI]
91.  Ikegami T, Taketomi A, Soejima Y, Yoshizumi T, Uchiyama H, Harada N, Iguchi T, Hashimoto N, Maehara Y. Rituximab, IVIG, and plasma exchange without graft local infusion treatment: a new protocol in ABO incompatible living donor liver transplantation. Transplantation. 2009;88:303-307.  [PubMed]  [DOI]
92.  Urbani L, Mazzoni A, Bianco I, Grazzini T, De Simone P, Catalano G, Montin U, Petruccelli S, Morelli L, Campani D. The role of immunomodulation in ABO-incompatible adult liver transplant recipients. J Clin Apher. 2008;23:55-62.  [PubMed]  [DOI]
93.  Lee SD, Kim SH, Kong SY, Kim YK, Park SJ. Kinetics of B, T, NK lymphocytes and isoagglutinin titers in ABO incompatible living donor liver transplantation using rituximab and basiliximab. Transpl Immunol. 2015;32:29-34.  [PubMed]  [DOI]
94.  Miyagi S, Kawagishi N, Sekiguchi S, Akamatsu Y, Sato K, Takeda I, Kobayashi Y, Tokodai K, Fujimori K, Satomi S. The relationship between recurrences and immunosuppression on living donor liver transplantation for hepatocellular carcinoma. Transplant Proc. 2012;44:797-801.  [PubMed]  [DOI]
95.  Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E. Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway. J Leukoc Biol. 2002;72:668-676.  [PubMed]  [DOI]
96.  Teng da H, Zhu ZJ, Zheng H, Deng YL, Sun LY, Pan C, Liu YH, Song HL, Shen ZY. Effect of steatosis donor liver transplantation on hepatocellular carcinoma recurrence: experience at a single institution. Hepatogastroenterology. 2012;59:858-862.  [PubMed]  [DOI]
97.  Selzner M, Clavien PA. Fatty liver in liver transplantation and surgery. Semin Liver Dis. 2001;21:105-113.  [PubMed]  [DOI]
98.  Ramachandran S, Liaw JM, Jia J, Glasgow SC, Liu W, Csontos K, Upadhya GA, Mohanakumar T, Chapman WC. Ischemia-reperfusion injury in rat steatotic liver is dependent on NFκB P65 activation. Transpl Immunol. 2012;26:201-206.  [PubMed]  [DOI]
99.  Tashiro H, Kuroda S, Mikuriya Y, Ohdan H. Ischemia-reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery. Surg Today. 2014;44:1611-1625.  [PubMed]  [DOI]
100.  Jiménez-Castro MB, Casillas-Ramírez A, Mendes-Braz M, Massip-Salcedo M, Gracia-Sancho J, Elias-Miró M, Rodés J, Peralta C. Adiponectin and resistin protect steatotic livers undergoing transplantation. J Hepatol. 2013;59:1208-1214.  [PubMed]  [DOI]
101.  Doyle MB, Vachharajani N, Wellen JR, Anderson CD, Lowell JA, Shenoy S, Brunt EM, Chapman WC. Short- and long-term outcomes after steatotic liver transplantation. Arch Surg. 2010;145:653-660.  [PubMed]  [DOI]
102.  Schiergens TS, Rentsch M, Kasparek MS, Frenes K, Jauch KW, Thasler WE. Impact of perioperative allogeneic red blood cell transfusion on recurrence and overall survival after resection of colorectal liver metastases. Dis Colon Rectum. 2015;58:74-82.  [PubMed]  [DOI]
103.  Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg. 2012;256:235-244.  [PubMed]  [DOI]
104.  Dionigi G, Rovera F, Boni L, Carrafiello G, Recaldini C, Mangini M, Laganà D, Bacuzzi A, Dionigi R. The impact of perioperative blood transfusion on clinical outcomes in colorectal surgery. Surg Oncol. 2007;16 Suppl 1:S177-S182.  [PubMed]  [DOI]
105.  Kneuertz PJ, Patel SH, Chu CK, Maithel SK, Sarmiento JM, Delman KA, Staley CA, Kooby DA. Effects of perioperative red blood cell transfusion on disease recurrence and survival after pancreaticoduodenectomy for ductal adenocarcinoma. Ann Surg Oncol. 2011;18:1327-1334.  [PubMed]  [DOI]
106.  Blajchman MA. Immunomodulation and blood transfusion. Am J Ther. 2002;9:389-395.  [PubMed]  [DOI]
107.  Innerhofer P, Tilz G, Fuchs D, Luz G, Hobisch-Hagen P, Schobersberger W, Nussbaumer W, Lochs A, Irschick E. Immunologic changes after transfusion of autologous or allogeneic buffy coat-poor versus WBC-reduced blood transfusions in patients undergoing arthroplasty. II. Activation of T cells, macrophages, and cell-mediated lympholysis. Transfusion. 2000;40:821-827.  [PubMed]  [DOI]
108.  Ghio M, Contini P, Mazzei C, Brenci S, Barberis G, Filaci G, Indiveri F, Puppo F. Soluble HLA class I, HLA class II, and Fas ligand in blood components: a possible key to explain the immunomodulatory effects of allogeneic blood transfusions. Blood. 1999;93:1770-1777.  [PubMed]  [DOI]
109.  Waymack JP, Gallon L, Barcelli U, Trocki O, Alexander JW. Effect of blood transfusions on immune function. III. Alterations in macrophage arachidonic acid metabolism. Arch Surg. 1987;122:56-60.  [PubMed]  [DOI]
110.  Kaplan J, Sarnaik S, Gitlin J, Lusher J. Diminished helper/suppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. Blood. 1984;64:308-310.  [PubMed]  [DOI]
111.  Jubert AV, Lee ET, Hersh EM, McBride CM. Effects of surgery, anesthesia and intraoperative blood loss on immunocompetence. J Surg Res. 1973;15:399-403.  [PubMed]  [DOI]
112.  Kaido T, Takada Y, Egawa H, Uemoto S. The influence of intraoperative homologous blood transfusion on prognosis after liver transplantation for hepatocellular carcinoma. Hepatogastroenterology. 2009;56:808-812.  [PubMed]  [DOI]