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World J Gastroenterol. Dec 28, 2013; 19(48): 9174-9182
Published online Dec 28, 2013. doi: 10.3748/wjg.v19.i48.9174
Liver transplantation for hepatocellular carcinoma: Role of inflammatory and immunological state on recurrence and prognosis
Matteo Cescon, Valentina Rosa Bertuzzo, Giorgio Ercolani, Matteo Ravaioli, Federica Odaldi, Antonio Daniele Pinna
Matteo Cescon, Valentina Rosa Bertuzzo, Giorgio Ercolani, Matteo Ravaioli, Federica Odaldi, Antonio Daniele Pinna, General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy
Author contributions: Cescon M and Bertuzzo VR performed the literature search and wrote the paper; Ercolani G, Ravaioli M and Odaldi F provided critical expertise and reviewed the paper; Pinna AD provided critical expertise and helped with focusing the topics.
Correspondence to: Matteo Cescon, MD, PhD, General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Padiglione 25, Policlinico Sant’Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy.
Telephone: +39-51-6364750 Fax: +39-51-304902
Received: September 27, 2013
Revised: October 31, 2013
Accepted: November 12, 2013
Published online: December 28, 2013


Criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC) and post-LT indicators of prognosis are historically based on the measurement of the tumor mass. Recently, high throughput technologies have increased the prediction of recurrence, but these tools are not yet routinely available. The interaction between HCC and the immune system has revealed an imbalance of lymphocyte phenotypes in the peritumoral tissue, and the increase of regulatory T cells with respect to cytotoxic lymphocytes has been linked to a higher rate of post-LT HCC recurrence. Moreover, some inflammatory markers have shown good reliability in predicting cancer reappearance after surgery, as a result of either a systemic inflammatory response or a decreased capacity of the organism to control the tumor growth. Among these markers, the neutrophil-to-lymphocyte ratio appears to be the most promising and easily available serum parameter able to predict HCC recurrence after LT and following other types of treatment, although the exact mechanisms determining its elevation have not been clarified. Post-LT immunosuppression may impact on cancer control, and the exposure to high levels of calcineurin inhibitors or other immunusuppressants has recently emerged as a negative prognostic factor for HCC recurrence and patient survival. Despite the absence of prospective randomized trials, inhibitors of the mammalian target of rapamycin have been shown to be associated with lower rates of tumor recurrence compared to other immunosuppressors, suggesting their use especially in patients with HCC exceeding the conventional indication criteria for LT.

Key Words: Liver transplantation, Hepatocellular carcinoma, Inflammation, Immunosuppression, Recurrence

Core tip: This review focuses on inflammatory markers recently emerged as indicators of tumor biological behavior and on immune state of patients submitted to liver transplantation for hepatocellular carcinoma (HCC), with a particular reference to the role of neutrophil-to-lymphocyte ratio. The impact of post-transplant immunosuppression on HCC recurrence is also analyzed according to the most relevant evidences published so far, which outline the importance of minimization of the use of calcineurin inhibitors and the protective role of inhibitors of the mammalian target of rapamycin.

Citation: 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(48): 9174-9182

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and its incidence is increasing in Western countries[1]. For patients with HCC and cirrhosis, liver transplantation (LT) represents the treatment of choice and provides excellent oncological results and a cure for cirrhosis.

Prognostic factors for tumor recurrence and patient outcome have mainly been recognized as an expression of tumor burden and of its biological aggressiveness. Among these factors, the number and size of HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion and elevated serum levels of alpha-fetoprotein (AFP) are the ones most widely utilized to define the indications for LT and to predict the outcome[2-8]. Since it is often difficult to safely and/or reliably obtain histological parameters before LT[9,10], radiological tumor criteria and AFP levels are the main preoperative indicators of prognosis.

The role of markers of inflammation and of the patient’s immunological state have recently emerged as predictors of outcome, providing information on the environment in which the tumor grows and on the systemic response to its expansion[11-20]. These markers are often correlated with dimensional and histological factors determining a high risk of recurrence, but the mechanisms by which they are expressed are still largely unexplored. While waiting for more precise molecular markers[21-23] to become of routine use in defining the indications for and the prognosis of LT, the above parameters of inflammation may help to predict the biological behavior of HCC.

Since post-LT pharmacological immunosuppression can ideally impact on the ability to control tumor reappearance, the type, duration and total load of immunosuppressors have also been investigated in recent years as predictors of HCC recurrence[7,8,24-33].

The role of inflammatory markers and of post-LT immunosuppression on tumor recurrence and patient prognosis after LT for HCC are the subject of the present review. For this purpose, an extensive review of the English literature using the PubMed database was performed independently by two authors (Cescon M, Bertuzzo VR), separately selecting papers pertinent to the key terms “liver transplantation”, “hepatocellular carcinoma”, “recurrence” and “inflammation” for the investigation of the impact of inflammatory markers, and to the terms “liver transplantation”, “hepatocellular carcinoma”, “recurrence” and “immunosuppression” to assess the post-LT impact of pharmacological immunosuppression.


In the last two decades, Virchow’s hypothesis, which postulates that a relationship exists between inflammation and cancer, has permitted new insights into the phenomenon of carcinogenesis[34]. Given the importance of the peritumoral (micro)-environment, researchers have focused on markers that could be an expression of the relationship between liver cancer and surrounding tissue, with a possible consequent change of systemic inflammatory response.

Infiltration of pro-inflammatory macrophages, cytokines and chemokines in the tumor microenvironment has been shown to enhance tumor growth, invasion and metastases[34-36], allowing the use of inflammation parameters as tumor markers[37,38] and the development of new therapeutic strategies[35,36].

C-reactive protein (CRP)[37-41] and erythrocyte sedimentation rate (ESR)[42-45] were the first serum inflammation indicators used as tumor markers. Elevated pre-operative CRP, an acute-phase reactant synthesized by hepatocytes in response to systemic inflammation, has been recognized as a risk factor for incidental colorectal cancer[39] and as an adverse prognostic factor in patients undergoing hepatectomy for HCC[40], whereas ESR has been identified as an indicator of poor prognosis in patients with clear cell renal cell carcinoma and in children with Hodgkin’s lymphoma[42,45].

Inflammatory cytokines such as interleukin-6 (IL-6) and IL-1b are linked to transcriptional signaling pathways associated with carcinogenesis, tumor growth, and invasion[36,46]. IL-6 is known as one of the main regulators of CRP production.

The neutrophil-to-lymphocyte ratio (NLR) is another inflammation index that has been evaluated as a tumor marker[47-53]. Originally used as a systemic inflammatory response index in critically ill patients, it is obtained by dividing the absolute neutrophil count by the absolute lymphocyte count. According to published literature, an NLR ≥ 5 can be considered a valid cut-off[48,50,51].

Some studies have demonstrated the relationship between NLR and tumor progression in patients with colon cancer, liver metastases from colorectal cancer, pancreatic cancer, breast cancer, esophageal cancer, cholangiocarcinoma, and HCC; in addition, a higher incidence of HCC recurrence has been observed in patients with high NLR and undergoing hepatic resection[47-53].

An elevation of NLR could be related to a relative increase of neutrophils - as a consequence of some sort of inflammatory response - to a decrease of lymphocyte count - reflecting a lower immunological control of tumor growth - or to both phenomena, with several studies supporting each of these hypotheses.

LT for HCC represents a particular field of investigation of inflammatory markers and local immunological activation as possible expressions of tumor invasiveness and biological behavior. Although the visible tumor mass is usually treated preoperatively with neoadjuvant treatments, and then entirely removed with hepatectomy, some parameters detected in the serum may help in recognizing a systemic response to cancer relapse due to viable cancer cells still in the patient’s circulation or in remote organs, at any time during the waiting time to LT, and following the procedure.

The role of CRP has been analyzed for prediction of post-LT outcomes of HCC patients[14]. In a series of 85 patients, those with high CRP levels (≥ 1 mg/dL) at the time of LT had higher total bilirubin levels, Child-Pugh grade, Model for End-Stage Liver Disease score, maximal tumor size, and frequency of intrahepatic metastasis compared to patients with low CRP levels (< 1 mg/dL).

By multivariate analyses, HCC beyond the Milan criteria, a high CRP level, and microvascular invasion were associated with tumor recurrence, while a high CRP level and microvascular invasion were related to lower overall survival. In addition, high CRP level was an independent factor for predicting poor outcomes in patients with HCC beyond the Milan criteria, but not in patients with HCC within the criteria[14]. Taken together, these findings suggest that CRP is related to poor liver function and higher tumor invasiveness, but the precise molecular mechanisms for its increase in such circumstances are not clarified. Moreover, another study[16] failed to detect any relationship between CRP (and ESR) and post-LT HCC recurrence.

Unitt et al[11] studied the tumor CD4+, CD8+, CD25+ and Foxp3+ lymphocyte infiltrate in the explant tissue of 69 patients transplanted due to HCC. On multivariate analysis, CD4:CD8 ratio, vascular invasion, tumor size, and reduced lymphocyte infiltration were significant independent predictors of recurrence. The presence of regulatory T cells (Tregs; CD4+, CD25+, Foxp3+ T-lymphocytes) was not predictive of recurrence, but was associated with tumor vascular invasion. These data suggest that a reduced immunological response against cancer expressed as prevalence of Tregs and a lower expression of cytotoxic lymphocytes is associated with poor prognosis.

The above findings were partly supported by another study by Mathai et al[12], who assessed the phenotype of tumor-infiltrating lymphocytes in 131 histology sections of patients undergoing LT or liver resection for HCC. An increased Foxp3:CD3 ratio was associated with poorly differentiated HCC and higher Edmonson-Steiner nuclear grade. An increased Foxp3:CD8 ratio was also associated with poorer differentiation, higher Edmonson-Steiner nuclear grade, tumor recurrence, decreased overall survival, and decreased disease-free survival.

Although not focused on LT recipients, other studies showed that patients with HCC have increased numbers of CD4+ CD25+ Tregs not only among tumor-infiltrating lymphocytes, but also in the peripheral blood; furthermore, the abundance of this cell population correlated with tumor progression. These cells were anergic toward T-cell receptor stimulation and, when cocultured with activated CD4+ CD25- cells, potently suppressed their proliferation and cytokine secretion. Concomitantly, the expression of granzyme A, granzyme B, and perforin was decreased dramatically in tumor-infiltrating CD8(+) T cells, confirming their inefficacy in controlling tumor expansion[54,55].

In summary, an imbalance between Tregs and CD8 lymphocytes, with a prevalence of the former and a defective function of the latter, does reflect an aggressive behavior of HCC and the inability of the organism to control the disease. While these findings potentially pave the way to new treatments, they cannot be unequivocally correlated with markers easily available by means of common lab tests, such as NLR (see below).

Nevertheless, novel methods for assessing the immune function of transplanted patients could be useful in the future. The Immu-Know assay, which measures the amount of adenosine triphosphate (ATP) produced by activated CD4+ T cells, has been used to evaluate the global immune status, and thus the tendency to develop rejection or, on the contrary, post-LT infections[56].

This tool has also proven to be reliable in predicting post-LT HCC recurrence, with recipients diagnosed with recurrent tumors having significantly lower values of ATP compared to those without recurrence[13]. This refined measurement of the immune state of LT recipients could replace the more indirect evaluation allowed by systemic exposure to immunosuppressive agents.

Several studies have demonstrated that an increased NLR is an independent factor for lower recurrence-free survival and/or overall survival in LT HCC patients[15-20]. These studies are reported in Table 1. A total of 892 patients were included. The chosen cutoff value of NLR ranged from 3 to 5, with most studies using the value of 5[15,16,18], while others identified lower values[17,19,20].

Table 1 Studies reporting the negative impact of increased neutrophil-to-lymphocyte ratio measured at transplant on the outcome of liver transplantation for hepatocellular carcinoma.
Ref.Patients (n)Type of LTNLR cut-off level for poor prognosisOther factors associated with worse outcome5-yr RFS with high vs low NLR5-yr OS with high vs low NLRParameters positively correlated with increased NLR
Halazun et al[15]150NA5Tumor sizeAFP25% vs 75%128% vs 64%None
Bertuzzo et al[16]219DDLT5Microvascular invasion6% vs 89%14% vs 73%Micro/macro vascular invasionTumor gradingAFPCRPOutside MC
Wang et al[17]101DDLT3Tumor numberMacrovascular invasion28% vs 65%119% vs 62%Macrovascular invasionAFPTumor sizeOutside MCOutside UCSF criteriaOutside Hangzhou criteria
Limaye et al[18]160NA5Microvascular invasion AFP27% vs 79%38% vs 68%None
Motomura et al[19]158LDLT4Outside MC30% vs 89%57% vs 84%Serum/peritumoral IL-17Density of peritumoral CD163CRPTacrolimus vs cyclosporine
2Yoshizumi et al[20]104LDLT4Nodule size + number ≥ 8.042% vs 86%Not reportedMicrovascular invasionTumor grading

In the groups of patients with NLR above the selected risk thresholds, overall survival ranged between 14% and 57%, and recurrence-free survival was between 6% and 42%. Only one study reported both the NLR at diagnosis of HCC and NLR at transplant, showing that this variable had a similar negative impact on outcome at the two chosen time points[18].

High NLR was an independent predictor of outcome in all studies, in most cases together with other commonly recognized risk factors. Interestingly, in two studies NLR was not correlated with histological, serological and dimensional features with a recognized, negative impact on recurrence[15,18].

In the above reports, different explanations for the alteration of NLR were provided but, though reasonable, most of them were speculative. Only one group, which produced two different analyses on this topic, investigated the correlation between NLR and the alterations of phenotype/function of leucocytes or other cells in tissues surrounding neoplastic nodules[19]. Interestingly, the Authors found that serum and peritumoral IL-17 levels were significantly higher in patients with high NLR, and that the density of peritumoral CD163-positive tumor associated macrophages (TAM) was both correlated with the density of peritumoral IL-17-producing cells, and significantly higher in subjects with elevated NLR. Conversely, tumor, peritumoral and serum expression of vascular endothelial growth factor (VEGF) and of IL-8, i.e., two recognized angiogenesis and tumor growth factors, was similar between high and low NLR groups. Tumor expression of IL-17, CD68, and CD163 was also comparable in patients with elevated or normal NLR.

A positive correlation between CRP and NLR, the absence of correlation between NLR and tumor markers, number and size of nodules, and microvascular invasion, the association between high NLR and an increased serum neutrophil count, and the absence of correlation between NLR and total serum lymphocytes were other important findings[19].

Consistently with previous studies[57-61], the authors came to the following conclusions: (1) contrary to other investigations, the elevation of NLR seems correlated with an increase of neutrophil number rather than of lymphocytes, suggesting a dependence of tumor relapse on the inflammatory state rather than on an impaired host immune response; (2) elevated neutrophils are thought to be a reservoir of VEGF, but the expression of VEGF and of IL-8 did not have any impact on NLR, suggesting that NLR elevation is not directly responsible for augmented HCC-related neo-angiogenesis; (3) IL-17 is a pro-inflammatory cytokine that promotes HCC growth and neutrophil recruitment, thus it could be a key molecule in the relationship between NLR (which is supposed to increase due to expansion of neutrophils following recruitment) and HCC recurrence; and (4) the authors’ results are consistent with the demonstrated relationship between IL-7-producing T cells and TAMs. IL-7-producing T cells promote the differentiation of tissue macrophages in peritumoral tissue into TAMs, which in turn promote tumor proliferation and angiogenesis. In fact, monocytes are recruited from the circulation into local tissue or malignant sites, where they are recognized by CD68-positive residential macrophages. Under the effect of inflammatory cytokines released by tumors, some of these macrophages differentiate into CD163-positive TAMs that, contrary to CD68+ macrophages, are suppressors of the anti-tumor immune response.

IL-17-producing cells interact with TAMs in patients with HCC, and both IL-17-producing cells and CD163+ TAMs generate the same family of chemokines promoting the recruitment of monocytes and neutrophils[19,57-61].

Finally, it should be considered that in the authors’ series splenectomy was performed during LT in patients with hepatitis C virus-positive or significant portal hypertension, and splenectomy itself could have had a role in the balance between neutrophil and lymphocyte count. Moreover, TAMs have been demonstrated to originate from splenic monocytes. However, splenectomy itself was not associated with HCC recurrence in this study, even though in the group of patients with elevated NLR, splenectomy led to significantly better recurrence-free survival than the abstention from this procedure, suggesting the supply of splenic TAMs with high IL-17 concentrations after LT[19].

The same authors confirmed the relevant role of NLR on HCC recurrence in patients undergoing living donor liver transplantation for tumor recurrence after surgical resection and/or locoregional treatment[20], and in those submitted to liver resection[62].

By evaluating 958 patients who underwent hepatectomy without preoperative therapy for HCC, multivariate analysis showed that NLR was an independent prognostic factor of lower overall and recurrence-free survival, the best cutoff being 2.81. Again, CD163-positive cell counts were significantly higher in tumors of patients with high NLR than in those with low NLR[62].

Finally, one of the advantages of an easily obtainable serum marker is to assess the response to pre-LT treatments of HCC and the probability of dropout from the waiting list. NLR has been shown to be a good predictor of the risk of dropout, while platelet-to-lymphocyte ratio has been related to post-LT HCC recurrence[63]. On the other hand, since multimodal treatments are usually adopted while on the waiting list for LT, it has also been shown that NLR, or NLR postoperative changes, correlate with HCC recurrence and patient outcome after radiofrequency ablation[64,65].


At present, there is a general consensus on the negative impact of pharmacological immunosuppression on the outcome of LT for HCC[7,8,24-33]. Specifically, two clinical pieces of evidence have emerged: (1) the higher the exposure to calcineurin inhibitors (CNI), i.e., cyclosporine and tacrolimus, the higher the risk of post-LT HCC recurrence; and (2) one specific class of immunosuppressors, i.e., inhibitors of the mammalian target of rapamycin (mTORi), have a favorable effect in reducing the incidence of post-LT HCC recurrence compared to standard immunosuppressors (CNI). Everolimus and sirolimus, the two mTORi currently in use in solid organ transplantation, interfere with hepatocarcinogenesis through the inhibition of the PI3K/Akt/mTOR pathway, which is a key regulator of cellular proliferation and angiogenesis[66,67].

Several studies led to the above conclusions[7,8,24-33], although it is of relevance that none of these is a prospective, randomized trial. Table 2 depicts the retrospective clinical studies published so far on this topic, with the exclusion of reports with less than 20 patients and previous reviews or meta-analyses.

Table 2 Studies reporting the effect of different basal immunosuppression schedules on the outcome of liver transplantation for hepatocellular carcinoma.
Ref.EvaluatedimmunosuppressorEvaluated parameterPatients (n)Overall recurrence rateOutcome parametersPvalue
Vivarelli et al[24]CsA cumulative dosage 1st yrLow dosage 1st yr vs high dosage 1st yr39 vs 3012.20%5 yr RFS: 93% vs 5 yr RFS: 76%0.0100
Kneteman et al[25]SRLin MC vs out MC19 vs 2112.50%4 yr RFS: 81.1% vs 4 yr RFS: 76.8%0.4800
Vivarelli et al[26]CsALow exposure vs high exposure49 vs 2110.00%RR: 0% vs RR: 33.3%< 0.0010
Decaens et al[27]CNICsA vs TAC264 vs 11931.80%5 yr RFS: 52.5% vs 5 yr RFS: 70.8%0.0030
Decaens et al[27]ATG/OKT3Not administered vs administered356 vs 5531.80%5 yr RFS: 58.8% vs 5 yr RFS: 45.4%0.0200
Vivarelli et al[7]TACLow exposure vs high exposure44 vs 1620.00%RR: 9.1% vs RR: 50%0.0010
Zhou et al[28]TAC and SRLin patients outMCTAC vs SRL46 vs 2727.40%2 yr OS: 50.9% vs 2 yr OS: 80.6%0.0110
Zimmerman et al[29]TAC and SRLTAC + MMF vs TAC + SRL52 vs 4512.40%5 yr RFS: 54.0% vs 5 yr RFS: 78.8%-
Chinnakotla et al[8]TAC and SRLTAC + MMF vs SRL106 vs 12111.00%5 yr RFS: 60% vs 5 yr RFS: 80%0.0001
Vivarelli et al[30]TAC and SRLTAC vs TAC + SRL31 vs 3125.80%3 yr RFS: 56% vs 3 yr RFS: 86%0.0400
Toso et al[31]SRLNot administered vs administered2382 vs 109-5 yr OS: 68.7% vs 5 yr OS: 83.1% ≤ 0.0500
Xing et al[32]Basiliximab and steroids in patients in MCTAC + MMF + basiliximab vs TAC + MMF + steroids28 vs 36-5 yr OS: 88.9% vs 5 yr OS: 57.4%0.0220
Rodríguez-Perálvarez et al[33]CNILow exposure 1st mo vs high exposure 1st mo171 vs 4816.40%5 yr RR: 14.7% vs 5 yr RR: 27%0.0070

Overall recurrence rates ranged between 12% and 32%. Four out of 13 reported studies showed that among patients immunosuppressed with CNI, those exposed to higher dosages had unfavorable outcomes, with significantly higher HCC recurrence rates or lower recurrence-free survival rates compared to patients receiving lower dosages[7,24,26,33]. One study reported a lower recurrence-free survival in patients treated with cyclosporine vs those treated with tacrolimus[27].

In 5 studies, patients treated with sirolimus (most frequently in combination with low dosages of tacrolimus) showed higher overall or recurrence-free survival rates compared to patients receiving standard CNI-based immunosuppression[8,28-31]. In one study[25], patients treated with sirolimus had similar recurrence-free survival rates, irrespective of fulfillment of the Milan criteria.

One study showed a detrimental effect of the use of monoclonal antibodies (anti-thymocite globulins or OKT3), with a lower recurrence-free survival in patients receiving these drugs compared to those not administered them[27]. Another study revealed that the use of steroids vs basiliximab led to significantly lower overall survival rates[32].

A definitive validation of the benefit of mTORi in LT for HCC is expected to be provided in 2014 by an international multicenter, prospective, randomized trial comparing the outcomes of patients administered or not administered sirolimus following post-LT histological confirmation of HCC[68]. However, at present the use of mTORi in LT for HCC seems justified on the basis of the above reported results and according to a recent metanalysis conducted on 5 studies and 474 patients, which showed a lower recurrence rate, longer recurrence-free survival and overall survival, and lower recurrence-related mortality in sirolimus-treated patients in comparison with CNI-treated patients[69].


Recent insights into the interactions between tumor, peritumoral tissue, and systemic inflammatory and immune response have offered new indicators for prognosis of patients with HCC undergoing various types of treatment, including LT. NLR has proven to be a reliable and easily available inflammatory marker of tumor biological aggressiveness, making its use advisable along with common dimensional indexes in assessing the response to treatments and the indication for LT, and to predict the outcomes. Although recent reports provided a reasonable molecular basis for the alteration of NLR and, more in general, for the tumor-related imbalance between immune cells in terms of number and function, much remains to be explored to expand targeted diagnostic and therapeutic tools. On the other hand, despite the lack of prospective, randomized studies, there is sufficient evidence for the minimization of immunosuppression and for the use of mTORi in LT for HCC, especially in the case of extended indications for transplant.


P- Reviewers: Aydin U, Barauskas G, Lai Q S- Editor: Gou SX L- Editor: A E- Editor: Wu HL

1.   Available from: http // Accessed July 20, 2013.  [PubMed]  [DOI]
2.  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]
3.  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]
4.  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]
5.  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]
6.  DuBay D, Sandroussi C, Sandhu L, Cleary S, Guba M, Cattral MS, McGilvray I, Ghanekar A, Selzner M, Greig PD. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg. 2011;253:166-172.  [PubMed]  [DOI]
7.  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]
8.  Chinnakotla S, Davis GL, Vasani S, Kim P, Tomiyama K, Sanchez E, Onaca N, Goldstein R, Levy M, Klintmalm GB. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 2009;15:1834-1842.  [PubMed]  [DOI]
9.  Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57:1592-1596.  [PubMed]  [DOI]
10.  van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, Lee AU. Twenty-year audit of percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J. 2006;36:692-699.  [PubMed]  [DOI]
11.  Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, Morris LS, Coleman N, Alexander GJ. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol. 2006;45:246-253.  [PubMed]  [DOI]
12.  Mathai AM, Kapadia MJ, Alexander J, Kernochan LE, Swanson PE, Yeh MM. Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic features and clinical outcomes of hepatocellular carcinoma. Am J Surg Pathol. 2012;36:980-986.  [PubMed]  [DOI]
13.  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]
14.  An HJ, Jang JW, Bae SH, Choi JY, Yoon SK, Lee MA, You YK, Kim DG, Jung ES. Serum C-reactive protein is a useful biomarker for predicting outcomes after liver transplantation in patients with hepatocellular carcinoma. Liver Transpl. 2012;18:1406-1414.  [PubMed]  [DOI]
15.  Halazun KJ, Hardy MA, Rana AA, Woodland DC, Luyten EJ, Mahadev S, Witkowski P, Siegel AB, Brown RS, Emond JC. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg. 2009;250:141-151.  [PubMed]  [DOI]
16.  Bertuzzo VR, Cescon M, Ravaioli M, Grazi GL, Ercolani G, Del Gaudio M, Cucchetti A, D’Errico-Grigioni A, Golfieri R, Pinna AD. Analysis of factors affecting recurrence of hepatocellular carcinoma after liver transplantation with a special focus on inflammation markers. Transplantation. 2011;91:1279-1285.  [PubMed]  [DOI]
17.  Wang GY, Yang Y, Li H, Zhang J, Jiang N, Li MR, Zhu HB, Zhang Q, Chen GH. A scoring model based on neutrophil to lymphocyte ratio predicts recurrence of HBV-associated hepatocellular carcinoma after liver transplantation. PLoS One. 2011;6:e25295.  [PubMed]  [DOI]
18.  Limaye AR, Clark V, Soldevila-Pico C, Morelli G, Suman A, Firpi R, Nelson DR, Cabrera R. Neutrophil-lymphocyte ratio predicts overall and recurrence-free survival after liver transplantation for hepatocellular carcinoma. Hepatol Res. 2013;43:757-764.  [PubMed]  [DOI]
19.  Motomura T, Shirabe K, Mano Y, Muto J, Toshima T, Umemoto Y, Fukuhara T, Uchiyama H, Ikegami T, Yoshizumi T. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58:58-64.  [PubMed]  [DOI]
20.  Yoshizumi T, Ikegami T, Yoshiya S, Motomura T, Mano Y, Muto J, Ikeda T, Soejima Y, Shirabe K, Maehara Y. Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma. Hepatol Res. 2013;43:709-716.  [PubMed]  [DOI]
21.  Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995-2004.  [PubMed]  [DOI]
22.  Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology. 2011;140:1618-1628.e16.  [PubMed]  [DOI]
23.  Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology. 2011;140:1501-12.e2.  [PubMed]  [DOI]
24.  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]
25.  Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewell LD. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 2004;10:1301-1311.  [PubMed]  [DOI]
26.  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]
27.  Decaens T, Roudot-Thoraval F, Bresson-Hadni S, Meyer C, Gugenheim J, Durand F, Bernard PH, Boillot O, Compagnon P, Calmus Y. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: a multicenter study of 412 patients. World J Gastroenterol. 2006;12:7319-7325.  [PubMed]  [DOI]
28.  Zhou J, Wang Z, Wu ZQ, Qiu SJ, Yu Y, Huang XW, Tang ZY, Fan J. Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transplant Proc. 2008;40:3548-3553.  [PubMed]  [DOI]
29.  Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, Kam I. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2008;14:633-638.  [PubMed]  [DOI]
30.  Vivarelli M, Dazzi A, Zanello M, Cucchetti A, Cescon M, Ravaioli M, Del Gaudio M, Lauro A, Grazi GL, Pinna AD. Effect of different immunosuppressive schedules on recurrence-free survival after liver transplantation for hepatocellular carcinoma. Transplantation. 2010;89:227-231.  [PubMed]  [DOI]
31.  Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology. 2010;51:1237-1243.  [PubMed]  [DOI]
32.  Xing T, Huang L, Yu Z, Zhong L, Wang S, Peng Z. Comparison of steroid-free immunosuppression and standard immunosuppression for liver transplant patients with hepatocellular carcinoma. PLoS One. 2013;8:e71251.  [PubMed]  [DOI]
33.  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]
34.  Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539-545.  [PubMed]  [DOI]
35.  Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860-867.  [PubMed]  [DOI]
36.  Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-444.  [PubMed]  [DOI]
37.  McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg. 2003;90:215-219.  [PubMed]  [DOI]
38.  Il’yasova D, Colbert LH, Harris TB, Newman AB, Bauer DC, Satterfield S, Kritchevsky SB. Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev. 2005;14:2413-2418.  [PubMed]  [DOI]
39.  Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA. 2004;291:585-590.  [PubMed]  [DOI]
40.  Hashimoto K, Ikeda Y, Korenaga D, Tanoue K, Hamatake M, Kawasaki K, Yamaoka T, Iwatani Y, Akazawa K, Takenaka K. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer. 2005;103:1856-1864.  [PubMed]  [DOI]
41.  Castell JV, Gómez-Lechón MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology. 1990;12:1179-1186.  [PubMed]  [DOI]
42.  Kawai Y, Matsuyama H, Korenaga Y, Misumi T, Eguchi S, Hara T, Nagao K, Ohmi C, Sakano S, Naito K. Preoperative erythrocyte sedimentation rate is an independent prognostic factor in Japanese patients with localized clear cell renal cell carcinoma. Urol Int. 2009;83:306-310.  [PubMed]  [DOI]
43.  Lehmann J, Retz M, Nürnberg N, Schnöckel U, Raffenberg U, Krams M, Kellner U, Siemer S, Weichert-Jacobsen K, Stöckle M. The superior prognostic value of humoral factors compared with molecular proliferation markers in renal cell carcinoma. Cancer. 2004;101:1552-1562.  [PubMed]  [DOI]
44.  Forslund A, Engarås B, Lönnroth C, Lundholm K. Prediction of postoperative survival by preoperative serum concentrations of anti-p53 compared to CEA, CA 50, CA 242 and conventional blood tests in patients with colorectal carcinoma. Int J Oncol. 2002;20:1013-1018.  [PubMed]  [DOI]
45.  Bien E, Balcerska A. Serum soluble interleukin-2 receptor, beta2-microglobulin, lactate dehydrogenase and erythrocyte sedimentation rate in children with Hodgkin’s lymphoma. Scand J Immunol. 2009;70:490-500.  [PubMed]  [DOI]
46.  Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004;4:97-105.  [PubMed]  [DOI]
47.  Sharaiha RZ, Halazun KJ, Mirza F, Port JL, Lee PC, Neugut AI, Altorki NK, Abrams JA. Elevated preoperative neutrophil: lymphocyte ratio as a predictor of postoperative disease recurrence in esophageal cancer. Ann Surg Oncol. 2011;18:3362-3369.  [PubMed]  [DOI]
48.  Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91:181-184.  [PubMed]  [DOI]
49.  Malik HZ, Prasad KR, Halazun KJ, Aldoori A, Al-Mukhtar A, Gomez D, Lodge JP, Toogood GJ. Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases. Ann Surg. 2007;246:806-814.  [PubMed]  [DOI]
50.  Halazun KJ, Aldoori A, Malik HZ, Al-Mukhtar A, Prasad KR, Toogood GJ, Lodge JP. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol. 2008;34:55-60.  [PubMed]  [DOI]
51.  Gomez D, Farid S, Malik HZ, Young AL, Toogood GJ, Lodge JP, Prasad KR. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg. 2008;32:1757-1762.  [PubMed]  [DOI]
52.  Gomez D, Morris-Stiff G, Toogood GJ, Lodge JP, Prasad KR. Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol. 2008;97:513-518.  [PubMed]  [DOI]
53.  Bhatti I, Peacock O, Lloyd G, Larvin M, Hall RI. Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil-lymphocyte versus platelet-lymphocyte ratio. Am J Surg. 2010;200:197-203.  [PubMed]  [DOI]
54.  Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65:2457-2464.  [PubMed]  [DOI]
55.  Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328-2339.  [PubMed]  [DOI]
56.  Kowalski R, Post D, Schneider MC, Britz J, Thomas J, Deierhoi M, Lobashevsky A, Redfield R, Schweitzer E, Heredia A. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant. 2003;17:77-88.  [PubMed]  [DOI]
57.  Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8:639-646.  [PubMed]  [DOI]
58.  Kuang DM, Peng C, Zhao Q, Wu Y, Zhu LY, Wang J, Yin XY, Li L, Zheng L. Tumor-activated monocytes promote expansion of IL-17-producing CD8+ T cells in hepatocellular carcinoma patients. J Immunol. 2010;185:1544-1549.  [PubMed]  [DOI]
59.  Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin XY, Zheng L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54:948-955.  [PubMed]  [DOI]
60.  Kono H, Fujii H, Ogiku M, Hosomura N, Amemiya H, Tsuchiya M, Hara M. Role of IL-17A in neutrophil recruitment and hepatic injury after warm ischemia-reperfusion mice. J Immunol. 2011;187:4818-4825.  [PubMed]  [DOI]
61.  Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71-78.  [PubMed]  [DOI]
62.  Mano Y, Shirabe K, Yamashita Y, Harimoto N, Tsujita E, Takeishi K, Aishima S, Ikegami T, Yoshizumi T, Yamanaka T. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 2013;258:301-305.  [PubMed]  [DOI]
63.  Lai Q, Castro Santa E, Rico Juri JM, Pinheiro RS, Lerut J. Neutrophil and platelet-to-lymphocyte ratio as new predictors of dropout and recurrence after liver transplantation for hepatocellular cancer. Transpl Int. 2013;Sep 6; Epub ahead of print.  [PubMed]  [DOI]
64.  Chen TM, Lin CC, Huang PT, Wen CF. Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation. J Gastroenterol Hepatol. 2012;27:553-561.  [PubMed]  [DOI]
65.  Dan J, Zhang Y, Peng Z, Huang J, Gao H, Xu L, Chen M. Postoperative neutrophil-to-lymphocyte ratio change predicts survival of patients with small hepatocellular carcinoma undergoing radiofrequency ablation. PLoS One. 2013;8:e58184.  [PubMed]  [DOI]
66.  Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004;10:8421-8425.  [PubMed]  [DOI]
67.  Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, Hérault A, Saric J, Belghiti J, Franco D. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42-52.  [PubMed]  [DOI]
68.  Schnitzbauer AA, Zuelke C, Graeb C, Rochon J, Bilbao I, Burra P, de Jong KP, Duvoux C, Kneteman NM, Adam R. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer. 2010;10:190.  [PubMed]  [DOI]
69.  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]