World J Surg (2015) 39:471–477 DOI 10.1007/s00268-014-2828-0

ORIGINAL SCIENTIFIC REPORT

Surgical Outcomes in Patients with Hepatocellular Carcinoma Associated with Metabolic Syndrome Naoki Yoshida • Tadatoshi Takayama • Yutaka Midorikawa • Tokio Higaki • Hisashi Nakayama • Masamichi Moriguchi Shingo Tsuji



Published online: 21 October 2014 Ó Socie´te´ Internationale de Chirurgie 2014

Abstract Background Only a few papers have focused on the surgical outcomes of patients with hepatocellular carcinoma (HCC) associated with the metabolic syndrome. We compared the outcomes of patients with metabolic HCC with those of patients with non-B, non-C HCC associated with other etiologies. Methods Metabolic HCC was defined as HCC arising in patients with at least three of the following metabolic disorders: central obesity, dyslipidemia, hypertension, and diabetes mellitus. A total of 246 patients with non-B, nonC HCC were divided into three groups: metabolic HCC (n = 35), alcoholic HCC (n = 114), and cryptogenic HCC (n = 97). Clinical characteristics, surgical data, and survival were compared among the three groups. Results Metabolic HCC was diagnosed at a significantly higher age than alcoholic (75 vs. 68 years, P = 0.004) and cryptogenic HCCs (75 vs. 71 years, P = 0.027). Postoperative complications occurred significantly higher in patients with metabolic HCC compared with those with cryptogenic HCC (40.0 vs. 22.7 %, P = 0.049). Especially, pulmonary complications were significant in metabolic HCC compared with cryptogenic HCC (22.9 vs. 8.2 %, P = 0.023). The overall survival rates in the metabolic, alcoholic, and cryptogenic HCC groups were 96.7 % (95 % CI, 90.5–100), 96.3 % (95 % CI, 92.8–99.9), and 95.6 % (95 % CI, 91.5–99.9) at 1 year, respectively, and 87.2 % (95 % CI, 74.5–100), 82.9 % (95 % CI, 74.6–92.2), and 84.5 % (95 % CI, 75.7–94.3) at 3 years, respectively (P = 0.84). The disease-free survival rates in each group were 74.4 % (95 % CI, 60.5–91.5), 76.9 % (95 % CI, 69.2–85.5), and 74.3 % (95 % CI, 65.0–84.8) at 1 year, respectively, and 29.3 % (95 % CI, 16.6–51.8), 39.0 % (95 % CI, 29.7–51.2), and 41.1 % (95 % CI, 29.7–56.8) at 3 years, respectively, (P = 0.90). Conclusions Metabolic HCC patients have specific risks of postoperative complication related to the metabolic syndrome.

N. Yoshida (&)  T. Takayama  Y. Midorikawa  T. Higaki  H. Nakayama  M. Moriguchi Department of Digestive Surgery, Nihon University School of Medicine, 30-1 Oyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan e-mail: [email protected] T. Takayama e-mail: [email protected] S. Tsuji Genome Science Division, Research Center for Advanced Science and Technologies, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan

Introduction Non-B, non-C hepatocellular carcinoma (HCC) is defined as HCC that is negative for both hepatitis B surface antigen (HBs-Ag) and hepatitis C virus antibody (HCV-Ab). Because of the close association of HCC with insulin resistance and obesity, the proportion of patients with HCC developing as a consequence of metabolic syndrome (‘‘metabolic HCC’’) has increased in recent years [1–3]. Only a few non-comparative studies have focused on the surgical outcomes of patients with metabolic HCC [4–6].

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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. NAFLD ranges from isolated steatosis to non-alcoholic steatohepatitis (NASH) and can progress to cirrhosis or HCC, with or without clinically significant fibrosis [7, 8]. As compared with HCC associated with chronic diseases caused by different factors, the risk of surgery for metabolic HCC is not negligible, even in patients with good preoperative liver function and no fibrosis [4, 6]. Especially in major liver resection, hepatic steatosis is one of the important risk factors for postoperative complications, and metabolic disorders should be carefully evaluated [5, 6, 9]. In addition to liver resection, metabolic syndrome itself harbors high operative risks, even in liver transplantation [10–12]. Severely obese patients have poorer overall survival after operation, with an approximately twofold higher postoperative mortality rate as compared with non-obese patients [12]. Moreover, NASH is associated with a longer operation time and higher operative blood loss [10]. The aim of this study was to clarify the surgical outcomes of liver resection in patients with metabolic HCC as compared with those with non-B, non-C HCC caused by different etiologies.

Patients and methods Patients Among 773 patients with HCC who presented between 2001 and 2013, we studied 246 patients with non-B, non-C HCC who underwent a curative liver resection at Nihon University Itabashi Hospital. We compared clinical characteristics and outcomes among patients with metabolic, alcoholic, and cryptogenic HCCs. Liver function at diagnosis (including the indocyanine green clearance rate at 15 min, ICGR15’), the features of HCC, and survival were ascertained by reviewing the patients’ clinical records. Surgical procedure We performed open liver resections in all patients. Transection of the liver was guided ultrasonographically and performed by the clamp-crushing method with the inflow-blood-occlusion technique. Closed irrigation drains were placed in each cut surface of the liver. Minor liver resection was defined as limited resection or resection of less than two segments, and major liver resection was defined as resection of two or more segments, left or right hepatectomy, or extended hemihepatectomy [13].

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Metabolic syndrome The metabolic syndrome was diagnosed in the presence of at least three of the following metabolic disorders as proposed by Eckel et al. [14]: central obesity (waist circumference C90 cm in men and C80 cm in women, a body mass index (BMI) of greater than 28 kg/m2 was used as an indicator of obesity [4, 15]), dyslipidemia (triglycerides C150 mg/dL or high-density lipoprotein cholesterol \40 mg/dL in men, \50 mg/dL in women), hypertension (blood pressure C130/85 mmHg), and diabetes mellitus (fasting glucose [100 mg/dL). Metabolic HCC was defined as HCC associated with metabolic syndrome without alcohol abuse [4] in patients who were negative for both serum HBs-Ag and HCV-Ab. Alcoholic HCC was defined as HCC arising in patients with a daily alcohol intake exceeding 60 g [16]. Cryptogenic HCC was defined as non-B, non-C HCC in patients without metabolic syndrome or a history of alcohol abuse. Background liver Significant steatosis was histologically defined as the intracytoplasmic accumulation of more than 30 % fat in the liver, with or without fibrosis. Significant steatosis is corresponding to moderate steatosis in the NAFLD Activity Score as defined by Kleiner et al. [7]. Steatohepatitis was histologically defined as the presence of fat accompanied by inflammation and damage of hepatic cells and was characterized by evidence of lobular hepatitis with focal necrosis, mixed inflammatory infiltrates, or ballooning degeneration or fibrosis (or both) [17]. Chronic hepatitis is characterized by varying degrees of hepatocellular necrosis and inflammation and continuing disease without improvement for at least 6 months [18]. Postoperative complications Postoperative complications were stratified according to the Clavien–Dindo classification [19], which defines morbidities as complications with a score of three or higher. Complications specific to liver resection were defined as described elsewhere [20]. Follow-up after operation All patients were followed up for postoperative recurrence, as described previously [21]. Briefly, tumor marker levels were measured and imaging studies, including computed tomography and ultrasonography, were performed every 3 months in all patients. Recurrence of HCC was managed aggressively by liver resection, transcatheter arterial

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Table 1 Patient’s background

Age (year)

Metabolic (M) (n = 35)

Alcoholic (A) (n = 114)

Cryptogenic (C) (n = 97)

M vs. A

M vs. C

A vs. C

75 (53–84)

68 (46–83)

71 (36–85)

0.004

0.027

0.511

0.044

\0.001

Gender (man/woman)

30/5

112/2

66/31

0.002

BMI (kg/m2)

25.7 (20.2–32.8)

24.8 (15.1–36.9)

23.8 (16.8–33.0)

0.02

\0.001

0.045

Dyslipidemia (%)

28 (80.0)

25 (21.9)

16 (16.5)

\0.001

\0.001

0.32

Diabetes mellitus (%)

31 (88.5)

51 (44.7)

31 (32.0)

\0.001

\0.001

0.058

Hypertension (%)

33 (94.2)

70 (61.4)

32 (33.0)

\0.001

\0.001

\0.001

BMI body mass index

Table 2 Preoperative data Metabolic (M) (n = 35)

Alcoholic (A) (n = 114)

Cryptogenic (C) (n = 97)

M vs. A

M vs. C

A vs. C

Albumin (g/dL)

4.0 (3.2–4.9)

4.0 (2.6–4.9)

4.1 (2.3–4.9)

0.64

0.763

0.289

Prothrombin time (%)

95 (36–100)

98 (67-100)

100 (66–100)

0.516

0.217

0.226

Platelet (9104/mm3)

17.6 (8.0–44.3)

16.5 (4.0–35.7)

18.6 (5.6–49.8)

0.326

0.414

0.016

AST (U/L)

28 (13–69)

34 (12–136)

34 (14–172)

0.004

0.007

0.876

ALT (U/L)

22 (10–61)

31 (5–139)

28 (9–172)

0.001

0.023

0.406

Total bilirubin (mg/dL)

0.61 (0.26–1.28)

0.66 (0.21–2.4)

0.66 (0.19–5.2)

0.284

0.107

0.341

ICGR15 (%) a-fetoprotein (ng/mL)

10.5 (1.34–82.3) 5.1 (0.8–5055)

12.1 (4.2–56.0) 8.1 (0.8–143200)

10.3 (2.31–48.1) 7.3 (0.6–111450)

0.99 0.191

0.481 0.043

0.131 0.61

Child-Pugh (A/B)

30/5

101/13

86/11

0.647

0.647

0.989

AST aspartate aminotransferase, ALT Alanine aminotransferase, ICGR15 indocyanine green clearance rate at 15 min

chemoembolization, and chemotherapy according to the status of HCC and liver function at the time of recurrence. Statistical analysis Data collected from each HCC group were statistically analyzed with the v2 test and the Wilcoxon rank-sum test. Survival curves were generated using the Kaplan–Meier method and were compared by the log-rank test. P values of less than 0.05 were considered to indicate statistical significance.

Results Patients’ characteristics Among 246 patients with non-B, non-C HCC, metabolic HCC was diagnosed in 35 patients (14.2 %), alcoholic HCC in 114 (46.3 %), and cryptogenic HCC in 97 (39.4 %) (Table 1). HCC was diagnosed at a significantly higher age in patients with metabolic HCC (metabolic, 75 vs. alcoholic, 68 years, P = 0.004; metabolic, 75 vs. cryptogenic, 71 years, P = 0.027; alcoholic, 68 vs. cryptogenic, 71 years, P = 0.511). The proportion of men was

higher among patients with alcoholic HCC (86 vs. 98 %, P = 0.002; 86 vs. 68 %, P = 0.044; 98 vs. 68 %, P \ 0.001). Patients with metabolic HCC had higher rates of all metabolic disorders, including obesity (25.7 vs. 24.8 kg/m2, P = 0.02; 25.7 vs. 23.8 kg/m2, P \ 0.001; 24.8 vs. 23.8 kg/m2, P = 0.045), dyslipidemia (80.0 vs. 21.9 % P \ 0.001; 80.0 vs. 16.5 %, P \ 0.001; 21.9 vs. 16.5 %, P = 0.32), diabetes mellitus (88.5 vs. 44.7 %, P \ 0.001; 88.5 vs. 32.0 %, P \ 0.001; 44.7 vs. 32.0 %, P = 0.058), and hypertension (94.2 vs. 61.4 %, P \ 0.001; 94.2 vs. 33.0 %, P \ 0.001; 61.4 vs. 33.0 %; P \ 0.001), as compared with the other HCC groups. Despite the presence of significant differences in some laboratory variables, including the aspartate aminotransferase level (28 vs. 34 U/L, P = 0.049; 28 vs. 34 U/L, P = 0.063; 34 vs. 34 U/L, P = 0.876) and alanine aminotransferase level (21.5 vs. 30 U/L, P = 0.012; 21.5 vs. 27.5 U/L, P = 0.038; 31 vs. 28 U/L, P = 0.406), the preoperative data were within the normal range in each group (Table 2). Surgical procedure The proportion of major resection was not significantly different (8.5 vs. 7.0 %, P = 0.759; 8.5 vs. 15.4 %, P = 0.308; 7.0 vs. 15.4 %, P = 0.05). Intraoperative blood

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loss was not significantly different in three groups (537 vs. 385 mL, P = 0.261; 537 vs. 250 mL, P = 0.09; 385 vs. 250 mL; P = 0.289). Postoperative complications occurred significantly higher in patients with alcoholic HCC compared with those with cryptogenic HCC (40.0 vs. 41.2 %, P = 0.897; 40.0 vs. 22.7 %, P = 0.049; 41.2 vs. 22.7 %, P = 0.004). Especially, bile leakage and pulmonary complications were significantly more often in alcoholic and metabolic HCCs (14.3 vs. 14.9 %, P = 0.927; 14.3 vs. 5.2 %, P = 0.08; 14.9 vs. 5.2 %, P = 0.021) (22.9 vs. 13.2 %, P = 0.168; 22.9 vs. 8.2 %, P = 0.023; 13.2 vs. 8.2 %, P = 0.254). However, the rates of morbidity, defined as CGrade 3 complications according to Clavien–Dindo classification, were comparable in each group (22.9 vs. 22.8 %, P = 0.995; 22.9 vs. 13.4 %, P = 0.19; 22.8 vs. 13.4 %, P = 0.079). One patient of cryptogenic HCC died of hepatic insufficiency postoperatively in this series (Table 3). Pathological characteristics Histological examination of the underlying liver revealed that the proportion of fatty changes (8.6 vs. 7.0 %, P = 0.759; 8.6 vs. 8.2 %, P = 0.953; 7.0 vs. 8.2 %, P = 0.737) and steatohepatitis (2.9 vs. 0 %, P = 0.07; 2.9 vs. 3.1 %, P = 0.944; 0 vs. 3.1 %, P = 0.059) was not significantly different in the three groups. Tumor size did not also differ significantly among the three groups (55 vs.

40 mm, P = 0.290; 55 vs. 43 mm, P = 0.641; 40 vs. 43 mm, P = 0.405). The rate of vascular invasion of metabolic HCC was less than the rate of cryptogenic HCC group (7 vs. 34 %, P = 0.255; 7 vs. 39 %, P = 0.032; 34 vs. 39 %, P = 0.114) (Table 4). Survival After a median follow-up of 2.3 years (range, 0.1–12.9 years), a total of 127 patients (51.6 %) had recurrence: 112 patients (88.2 %) in the remnant liver, 11 patients (8.7 %) in distant sites, and four patients (3.1 %) in both sites. Thirty patients (12.2 %) died of cancer recurrence, and two (0.8 %) died of acute myocardial infarction. The median disease-free survival was 2.0 years (95 % confidence interval [CI], 1.1–NA) in patients with metabolic HCC, 2.1 years (95 % CI, 1.7–3.2) in those with alcoholic HCC, and 2.4 years (95 % CI, 1.4–3.9) in those with cryptogenic HCC. At 1 year, the overall survival rates were 96.7 % (95 % CI, 90.5–100), 96.3 % (95 % CI, 92.8–99.9), and 95.6 % (95 % CI, 91.5–99.9), and the disease-free survival rates were 74.4 % (95 % CI, 60.5–91.5), 76.9 % (95 % CI, 69.2–85.5), and 74.3 % (95 % CI, 65.0–84.8), respectively. At 3 years, the overall survival rates were 87.2 % (95 % CI, 74.5–100), 82.9 % (95 % CI, 74.6–92.2), and 84.5 % (95 % CI, 75.7–94.3, P = 0.84), and the disease-free survival rates were 29.3 %

Table 3 Operative and postoperative data Metabolic (M) (n = 35)

Alcoholic (A) (n = 114)

Cryptogenic (C) (n = 97)

M vs. A

M vs. C

A vs. C

Types of resection (minor/major)

32/3

106/8

82/15

0.759

0.308

0.05

Operation (min)

365 (158–655)

347 (169–690)

289 (97–855)

0.52

0.085

0.114

Clamping (min)

81 (0–213)

73 (0–299)

62 (13–222)

0.797

0.246

0.213

Blood loss (mL)

537 (10–2065)

385 (23–2231)

250 (20–2398)

0.261

0.09

0.289

Transfusion (%)

5 (14.3)

7 (6.1)

7 (7.2)

0.121

0.212

0.754

Complication (%)

14 (40.0)

47 (41.2)

22 (22.7)

0.897

0.049

0.004

Liver failure (%)

0 (0)

0 (0)

1 (1.0)

1

0.547

0.277

Bleeding (%)

1 (2.9)

1 (0.9)

1 (1.0)

0.373

0.448

0.909

Ascites (%)

2 (5.7)

1 (0.9)

2 (2.0)

0.075

0.28

0.469

Bile leakage (%)

5 (14.3)

17 (14.9)

5 (5.2)

0.927

0.08

0.021

Wound infection (%)

5 (14.3)

18 (15.8)

7 (7.2)

0.83

0.212

0.055

Abscess (%)

0 (0)

2 (1.8)

0 (0)

0.432

1

0.19

Pulmonary (%)

8 (22.9)

15 (13.2)

8 (8.2)

0.168

0.023

0.254

Cardiovascular (%)

1 (2.9)

1 (0.9)

2 (2.0)

0.373

0.787

0.469

Others (%) Clavien–Dindo grade I/II/III/IV/V

0 (0) 21/6/8/0/0

6 (5.3) 67/21/26/0/0

1 (1.0) 76/8/12/0/1

0.166 0.985

0.547 0.15

0.087 0.01

Hospital stays (days)

12 (7–31)

12 (8–47)

12 (7–51)

0.431

0.374

0.837

In-hospital death (%)

0 (0)

0 (0)

1 (1.0)

1

0.547

0.277

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Table 4 Histological findings Metabolic (M) (n = 35)

Alcoholic (A) (n = 114)

Cryptogenic (C) (n = 97)

M vs. A

M vs. C

A vs. C

Histological diagnosis (NL/CH/LC)

2/25/8

Fatty liver (%)

3 (8.6)

4/77/33

15/69/13

0.69

0.188

\0.001

8 (7.0)

8 (8.2)

0.759

0.953

Steatohepatitis (%)

0.737

1 (2.9)

0 (0)

3 (3.1)

0.07

0.944

0.059

Size (mm)

55 (15–145)

40 (10–190)

43 (10–170)

0.29

0.641

0.405

Differentiation grade (well/mod/por) Capsular formation (%)

7/27/1 27 (77.1)

24/72/18 85 (74.6)

15/73/9 67 (69.1)

0.116 0.757

0.421 0.366

0.154 0.376

Liver

Tumor

Vascular invasion (%)

7 (20.0)

34 (29.8)

39 (40.2)

0.255

0.032

0.114

Number

1.3 ± 0.6

1.5 ± 0.8

1.2 ± 0.7

0.253

0.368

0.013

mod moderately, por poorly, NL normal liver, CH chronic hepatitis, LC liver cirrhosis

A

Metabolic HCC (n = 35)

Discussion

100

Overall survival (%)

80 60 Cryptogenic HCC (n = 97)

40

Alcoholic HCC (n = 114) P = 0.84

20 0

0

2

4

8

6

10

Years aer surgery

Recurrence -free survival (%)

B

100 80 Cryptogenic HCC (n = 97)

P = 0.90

60 Alcoholic HCC (n = 114)

40 20 Metabolic HCC (n = 35) 0 0

2

4

6

10

Years aer surgery

Fig. 1 Overall and recurrence-free survival of patients with non-B, non-C HCC. There were no significant differences in overall survival a or recurrence-free survival b after liver resection among patients with metabolic, alcoholic, or cryptogenic HCC

(95 % CI, 16.6–51.8), 39.0 % (95 % CI, 29.7–51.2), and 41.1 % (95 % CI, 29.7–56.8, P = 0.90), respectively (Fig. 1).

Our results showed for the first time to our knowledge that despite the operative risks associated with underlying metabolic disorders, surgical outcomes, including postoperative complications and survival, did not differ significantly between patients with metabolic HCC and those with other types of HCC. Consistent with the results of a previous study [8], age at liver resection was higher in patients with metabolic HCC than in the other groups, most likely because metabolic syndrome is not yet generally recognized as an important risk factor for HCC [1, 2]. As compared with virus-related HCC, preoperative liver function is generally favorable in non-B, non-C HCC [21]. In our study, there were significant differences in aspartate aminotransferase levels, alanine aminotransferase level, and a-fetoprotein among the groups; however, most laboratory values, including these three variables, remained within normal range. Higher blood loss and a higher rate of intraoperative redcell transfusion are characteristics of not only liver resection in patients with hepatic steatosis [5, 6] but also of liver transplantation [10–12]. In our study, there was a large amount of bleeding in the metabolic HCC group, but there was no significant difference among the three groups. And, the red-cell transfusion rate did not differ significantly among the three groups. Given good preoperative liver function, steatosis per se is a risk factor in liver resection and should be carefully assessed on preoperative or intraoperative liver biopsy in patients with metabolic HCC, even in the absence of fibrosis. The presence of underlying metabolic disorders is also an important risk factor in patients undergoing major liver resection, and mortality rates were reported to be 20 % in patients with macrosteatosis and 6.6 % in those with microsteatosis [5, 6]. Our study showed that postoperative complications rates of

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metabolic HCC were worse than its rates of cryptogenic HCC. The fact that metabolic HCC patients experienced significantly more pulmonary complication than cryptogenic HCC patients were probably related to the metabolic syndrome itself rather than the extent of liver resection. The morbidity, mortality, and duration of hospital stay did not differ significantly among the three groups, perhaps because the rate of major liver resection was low in the present series. A larger tumor size is one of the characteristics of metabolic HCC [8], and the larger tumor size is thought to reflect rapid tumor growth due to hyperinsulinemia associated with diabetes mellitus [22]. But there is no significant difference in tumor size among the groups in our study. In contrast, vascular invasion was significantly less frequent in metabolic HCC than in cryptogenic HCC, suggesting that the malignancy grade of metabolic HCC might be lower than that in other types of HCC. Despite the presence of underlying metabolic diseases, including obesity, hyperlipidemia, diabetes mellitus, and hypertension, overall survival and recurrence-free survival did not differ significantly between patients with metabolic HCC and those with other types of non-B, non-C HCC. We previously reported that surgical outcomes were similar in patients with HCC negative for all virus-related markers and those with HCC positive for at least one marker [21]. In addition and similarly to previous findings, NAFLD- and NASH-related HCC and non-B, non-C HCC showed better recurrence-free survival and overall survival after curative resection [9, 23, 24]. Given that liver resection resulted in better outcomes than radiofrequency ablation and transcatheter chemoembolization in a nationwide study of 4,741 patients with non-B, non-C HCC [25], liver resection should be considered the treatment of choice for metabolic HCC. We conclude that metabolic HCC patients have specific risk of postoperative complications related to the metabolic syndrome. So, we should carefully evaluate of underlying liver steatosis as well as the general condition of the patient and the function of the future liver remnant to prevent avoidable morbidity. Acknowledgments We thank Mr. Peter Star of Medical Network K.K. for assistance in writing the manuscript. This work was mainly supported by a Grant-in-Aid for Scientific Research (A) 24249068 (T.T.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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2. 3.

4.

5.

6.

7.

8.

9.

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11.

12.

13.

14. 15.

16.

17.

18.

19.

Conflict of interest We declare that we have no conflicts of interest. 20.

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Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome.

Only a few papers have focused on the surgical outcomes of patients with hepatocellular carcinoma (HCC) associated with the metabolic syndrome. We com...
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