De Ritis Ratio (Aspartate Transaminase/Alanine Transaminase) as a Significant Prognostic Factor With Upper Urinary Tract Carcinoma Who Underwent Radical Nephroureterectomy and Adjuvant Chemotherapy

Article information

Korean J Urol Oncol. 2022;20(1):34-42
Publication date (electronic) : 2022 February 24
doi : https://doi.org/10.22465/kjuo.2022.20.1.34
1Department of Urology, Seoul National University Hospital, Seoul, Korea
2Department of Urology, Inje University Sanggye Paik Hospital, Seoul, Korea
Corresponding author: Ji Hyeong Yu Email: uroone@paik.ac.kr
Co-corresponding author: Hyeong Dong Yuk Email: armenia8@snu.ac.kr
Received 2021 October 11; Revised 2021 October 28; Accepted 2021 November 09.

Abstract

Purpose

To investigate the correlation between preoperative De Ritis ratio (aspartate transaminase [AST]/alanine transaminase [ALT]) and postoperative clinical outcome in patients with upper urinary tract carcinoma (UTUC) who underwent radical nephroureterectomy (RNU) and adjuvant chemotherapy (ACH).

Materials and Methods

We respectively analyzed the clinical and pathological data of 102 patients who underwent RNU and ACH for UTUC. Patients were divided into 2 groups, according to the optimal value of AST/ALT ratio. The effect of the AST/ALT ratio was analyzed by the Kaplan-Meier method and Cox regression hazard models for patients' cancer-specific survival (CSS) and overall survival (OS).

Results

Mean survival time was 50.5±41.2 months. Mean age was 61.4±9.7years. Forty-one of the patients (46.5%) were in the high AST/ALT group. According to receiver operating characteristic analysis, the optimal AST/ALT ratio was 1.2. In Kaplan-Meier analyses, the high AST/ALT group showed worse outcomes in OS (p=0.007) and CSS (p=0.011). Using Cox regression models of clinical and pathological parameters to predict OS, high AST/ALT ratio (hazard ratio [HR], 5.428; 95% confidence interval [CI]; 1.803–16.334; p=0.002), pathological T3 (pT3) or higher (HR, 1.464; 95% CI; 1.156-1.857; p=0.002), and to predict CSS, high AST/ALT ratio (HR, 4.417; 95% CI; 1.545–12.632; p=0.005), and pT3 or higher (HR, 1.475; 95% CI; 1.172–1.904; p=0.002) were determined as independent prognostic factors.

Conclusions

Pretreatment AST/ALT ratio is a significant independent predictor of CSS and OS in advanced UTUC patients receiving systemic ACH after RNU.

INTRODUCTION

Upper urinary tract carcinoma (UTUC) is a malig- nant tumor of the urothelium of the urinary tract from calyx to distal ureter.1 UTUC is relatively uncommon, and represents only 5%–7% of the tumors that develop in the kidneys.1 UTUC accounts for approximately 5%–10% of all genitourinary malignancies.1 The disease has a multifocal nature and is diagnosed twice as often in the renal pelvis, as in the ureters.2 The standard treatment for localized UTUC is a radical nephroureterectomy (RNU), with bladder cuff excision.3 RNU series studies performed in the last years have shown that the proportion of locally advanced UTUC is about 60%, the proportion of high-grade tumors is about 70%, and that the proportion of aggressive disease is increasing.4 The 5-year survival rate of UTUC is 20%, and the prognosis is relatively poor.5 For these advanced UTUCs, adjuvant chemo- therapy (ACH) is recommended to improve long- term prognosis.6 However, some advanced UTUC patients progress or the disease recurs to a distant metastasis site.7 About 7% of patients experience metastatic disease.8 It is important to accurately predict oncologic outcomes and to properly classify patients at risk for progression or recurrence, to perform additional salvage treatments. For this reason, prognostic factors of survival before treatment are clinically important. We have focused on alanine aminotransferase (ALT) and aspartate aminotransferase (AST), among the many pretreatment predictive factors. ALT and AST are liver enzymes commonly used in different clinical fields, and have been reported in several studies as important biomarkers in various malignant tumors, such as kidney cancer, lung cancer, pan- creatic cancer, and colorectal cancer, as well in as chronic liver disease.912 Recent studies have also shown that UTUC was useful as a preoperative predictor.1315 However, no studies have been reported on the role of AST and ALT as prognostic factors in patients with end-stage UTUC, who received ACH. Therefore, we aimed to identify the prognostic significance of AST and ALT before ACH, in patients with UTUC who underwent RNU and ACH.

MATERIALS AND METHODS

1. Ethics Statement

The study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 2018-11-018). We conducted a retrospective case study and were exempted from obtaining prior consent of the patients. The research protocol was in accordance with the Declaration of Helsinki guidelines.

2. Study Sample

We retrospectively analyzed the medical records of 204 patients with advanced UTUC. (pathologic T3 or T4 or pathologic T1- T2N1-N3 without distant metastasis) who were treated in 2 institutions from January 2000 to December 2017. These patients underwent RNU after being diagnosed with UTUC, followed by first line ACH after diagnosis with advanced-stage disease. Of 204 patients, 16 patients suspected of fatty liver and chronic liver disease, and 8 patients suspected of systemic infection and inflammation, were excluded, and 4 patients with incomplete data were also excluded. A total of 176 patients were included in the analyses.

3. Study Design

We divided the patients into 2 groups, according to the optimal value of the AST/ALT ratio. The optimal AST/ALT ratio was determined to have the highest sensitivity and specificity in the receiver operating characteristic curve. Patients were divided into 2 groups based on an optimal AST/ALT of 1.2.

ACH usually started within 3 months after surgery, depending on the general condition and renal function of the patients. Laboratory tests including AST and ALT were routinely performed the day before the first cycle of ACH.

The clinical and pathological data collected on patients for this study were: patient age, body mass index (BMI), sex; underlying diseases, such as hypertension and diabetes; RNU surgery methods; pathologic T stage and N stage; tumor grade, presence of lymphovascular invasion, presence of concurrent carcinoma in situ, presence of ipsilateral hydronephrosis, presence of multifocality, presence of positive surgical margin, regimen and cycle of ACH, American Society of Anesthesiologists (ASA) physical status classification before ACH, and AST and ALT before ACH. Oncologic outcomes data were also collected for mortality, and mortality due to cancer.

Histopathological evaluation of surgical specimens was examined by pathologists skilled in the genital area. The TNM stage and tumor grade were assessed using the 2010 American Joint Committee on Cancer Tumor, Node, Metastases classification, and the World Health Organization/International Society of Urological Pathology consensus classi- fication.

Follow-up was performed every 3 months for the first 2 years, then every 6 months for 2 to 5 years, and every 1 year thereafter. Physical examination, routine laboratory tests, urine analysis, urine cytology, and cystoscopy were performed at every follow-up. Chest computed tomography (CT), abdominal pelvic CT were performed routinely every year.

4. Statistical Analysis

Clinical and pathological characteristics were analyzed by independent t-tests between groups. The continuous variables were expressed as mean, standard deviation, median and interquartile range, and the nominal variables were expressed as probability through crossover analysis. The oncologic outcome was analyzed by Kaplan- Meier survival analysis and log-rank test. Several pretreatment factors affecting the oncologic outcome were analyzed by multivariate Cox pro- portional hazard regression analysis. A total of 82 patients with high AST/ALT ratios were matched in a 1:1 ratio to 94 patients with low AST/ALT ratios using the nearest neighbor method with 0.02 calibrated. Propensity matching was performed to compensate for the difference between age, sex, BMI, ASA, Tumor location, operative type. The propensity score matching was calibrated and differentiated in most items with a standardized mean difference of less than 0.05. All statistical tests were performed using IBM SPSS Statistics ver. 22.0 (IBM Co., Armonk, NY, USA), and a p-value of <0.05 was considered to indicate statistical significance.

RESULTS

The clinicopathologic characteristics of all patients are shown in Table 1. Patients were divided into 2 groups based on an AST/ALT ratio of 1.2. Mean age was 61.4 years and mean AST/ALT ratio was 1.2. Overall mortality was 47.7%, cancer-specific mortality was 44.3%, and mean survival time was 50.5 months. Twenty-eight percent of patients experienced recurrence within the bladder during follow-up. In the high AST/ALT group, the mean age was 64.1 years (p=0.015), the mean mortality rate was 65.9% and the cancer-specific mortality rate was 61.0% (p=0.003 and p=0.006), higher than the low AST/ALT group. The mean survival time of the high AST/ALT group was 40.4 months (p=0.020), which was shorter than the low AST/ALT group. Overall survival (OS) was poor in the high AST/ALT group compared to the low AST/ALT group (p=0.007), and the cancer-specific survival was also poor in the high AST/ALT group, compared to the low AST/ALT group (p=0.011) (Fig. 1).

Clinicopathological characteristics of patients before and after propensity score matching

Fig. 1.

Overall and cancer-specific survival analyses. Kaplan-Meier survival curves comparing overall and cancer-specific survivals according to the aspartate aminotransferase/alanine aminotransferase (AST/ALT).

In multivariate analysis, age (hazard ratio [HR], 1.041; 95% confidence interval [CI], 1.003–1.074; p=0.039), pT3 or higher (HR, 1.464; 95% CI, 1.156–1.857; p=0.002), LVI (HR, 1.445; 95% CI, 1.153–1.854; p=0.005), pN1-N2 (HR, 1.342; 95% CI, 1.011–1.773), pN3 (HR, 3.893; 95% CI, 2.284–6.648; p<0.001), high AST/ALT ratio (HR, 5.428; 95% CI, 1.803–16.334; p=0.002), were significant predictors of poor OS. And pT3 or higher (HR, 1.475; 95% CI, 1.172–1.904; p=0.002), pN3 (HR, 3.815; 95% CI, 2.235–6.493; p<0.001), high AST/ALT ratio (HR, 4.417; 95% CI, 1.545–12.632; p=0.005) were significant predictors of poor cancer-specific sur- vival (CSS) (Table 2).

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival

After propensity score matching, the overall mortality rate was significantly higher (65.9% vs. 34.1%) in the high AST/ALT group (p=0.008) and the cancer-specific mortality rate were also significantly higher (61.0% vs. 31.7%) in the high AST/ALT group (p=0.015) than in the low AST/ALT group (Table 1). The multivariate Cox analysis showed that a high prechemotherapy AST/ALT ratio was a significant independent predictor of poor prognosis such as OS (HR, 2.095; 95% CI, 1.090–4.024; p=0.026), CSS (HR, 2.074; 95% CI, 1.053–4.086; p=0.035) (Table 3). In addition, pathologic T stage, N stage, positive surgical margin are also associated with poor prognosis (Table 3).

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival after propensity score matching

DISCUSSION

In this study, we evaluated patients with increa- sed AST/ALT. We observed poor survival outcomes after ACH for advanced UTUC. The AST/ALT ratio was a predictor of OS (HR, 5.428; 95% CI, 1.803–16.334; p=0.002) and CSS (HR, 4.417; 95% CI, 1.545–12.632; p=0.005). Previous studies on UTUC have also reported that the AST/ALT ratio is a predictor of oncological prognosis.1315 Lee et al.14 reported that preoperative high AST/ALT ratio was significantly associated with a poor prognosis of progression-free survival (PFS), CSS, and OS (all p<0.001) in 263 UTUC patient who underwent RNU. They also reported that a high preoperative AST/ALT ratio greater than 1.5 was an independent predictor of PFS (HR, 2.335; 95% CI, 1.633–3.340; p=0.001), CSS (HR, 2.550; 1.689–3.851; p=0.001), and OS (HR, 2.069; 95% CI, 1.409–3.038; p<0.001) through Cox multivariate analysis.14 Cho et al.13 reported that a high preoperative AST/ALT ratio was significantly associated with a poor prognosis of CSS and OS (all p=0.001), in a multicenter study of 1,049 patients who underwent RNU. They also reported that a preoperative AST/ALT ratio higher than 1.6 was an independent predictor of CSS (HR, 2.49; 95% CI, 1.70–3.64; p=0.001) and OS (HR, 1.84; 95% CI, 1.34–2.52; p=0.001) through Cox multivariate analysis.13 In Nishikawa's study of 109 patients with localized UTUC who underwent RNU, a high AST/ALT was significantly independent of extravesical recurrence-free survival (HR, 4.21; 95% CI, 1.95–9.08; p<0.001). In a study of 153 patients with urothelial bladder cancer who underwent radical cystectomy, Gorgel et al.16 reported that the preoperative AST/ALT ratio was significantly associated with a poor prognosis of disease- specific survival (DSS) and OS (all p<0.001). They also reported that preoperative AST/ALT ratios higher than 1.3 were independent predictors of DSS (HR, 5.79; 95% CI, 2.25–15.13; p<0.001) and OS (HR, 2.61; 95% CI, 1.49–4.56; p<0.001) through Cox multivariate analysis.16

The exact mechanism of the relationship between elevated AST/ALT and poor prognosis of cancer patients, including those with UTUC is not yet known. But there are several hypotheses that explain the relationship between AST/ALT ratio and cancer. The most prominent of them is the Warburg effect.17 In normal cells, energy is produced by mitochondrial oxidative phosphorylation. However, cancer cells produce energy through lactic acid fermentation glycolysis, rather than oxidative phosphorylation, even under oxygen- rich conditions. This aerobic glycolysis is a less efficient pathway than oxidative phosphorylation, and increases the production of metabolites that can contribute to cancer cell proliferation. These metabolites provides anabolic support essential for cancer cell proliferation and growth.17 Increased lactate has been suggested to play an important role in maintaining glycolysis, affecting lactate dehydrogenase, the Nicotinamide adenine dinucleotide (NADH)/Nicotinamide adenine dinucleotide (NAD)+ratio, and affecting glucose transport materials. AST plays an important role in the process by relocating NADH to the mitochondria.18,19 In addition, increases in glucose metabolites due to increased lactate, affects the microenvironment of the tumor and promotes local invasion, progression, and metastasis of cancer cells.18,19

This study has some limitations. First, since this was a retrospective study of a relatively small number of patients, there may be a recall bias. However, the study population was limited to UTUC patients who underwent RNU and ACH, and that limited the number of patients. Second, we didn't know whether the patient was taking unchecked drugs that would affect AST/ALT.

Despite the limitations, this is the first study to identify the AST/ALT ratio as an important prognostic biomarker of ACH in advanced UTUC. There are many cancer biomarkers, but the AST/ALT ratio has the merit of cost effectiveness, com- pared with other methods, and the advantage that it is a quick method that may predict prognosis before cancer treatment.

CONCLUSIONS

An increased AST/ALT ratio is a significant inde- pendent predictor of CSS and OS in advanced UTUC patients receiving systemic ACH after RNU. We suggest that the AST/ALT ratio is a useful and valuable biomarker for predicting oncological outcomes after systemic ACH, as well as RNU in UTUC. The results presented here provide an important insight into the clinical significance of aminotransferase-based markers in postoperative UTUC patients with progressive stage disease, receiving ACH.

Notes

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Article information Continued

Fig. 1.

Overall and cancer-specific survival analyses. Kaplan-Meier survival curves comparing overall and cancer-specific survivals according to the aspartate aminotransferase/alanine aminotransferase (AST/ALT).

Table 1.

Clinicopathological characteristics of patients before and after propensity score matching

Variable Before propensity score matching
After propensity score matching
Low AST/ALT (N=94) High AST/ALT (N=82) p-value Low AST/ALT (N=82) High AST/ALT (N=82) p-value
Age (yr) 59.1±9.9 64.1±8.9 0.015 60.9±8.7 64.1±8.9 0.109
BMI (kg/m2) 28.8±8.8 24.2±9.3 0.020 28.3±7.9 24.2±9.3 0.037
Male sex 78 (83.0) 54 (65.9) 0.109 68 (82.9) 54 (65.9) 0.129
AST 22.3±10.0 23.2±8.5 0.662 21.4±8.8 23.2±8.5 0.348
ALT 28.4±14.2 15.6±6.8 <0.001 27.2±13.3 15.6±6.8 <0.001
AST/ALT ratio 0.8±0.2 1.6±0.4 <0.001 0.8±0.2 1.6±0.4 <0.001
HTN 28 (29.8) 44 (53.7) 0.058 24 (29.3) 44 (53.7) 0.059
DM 16 (17.0) 16 (19.5) 0.623 16 (19.5) 16 (19.5) 0.602
Operation type     0.380     0.467
  Open 72 (76.6) 54 (65.9)   62 (75.6) 54 (65.9)  
  Laparoscopic 22 (23.4) 28 (34.1)   20 (24.4) 28 (34.1)  
ASA PS classification     0.104     0.061
  I 52 (55.3) 26 (31.7)   46 (56.1) 26 (31.7)  
  II 42 (44.7) 54 (65.9)   36 (43.9) 54 (65.9)  
  ≥III 0 (0) 2 (2.4)   0 (0) 2 (2.4)  
Pathologic T stage     0.490     0.648
  pTa 0 (0) 2 (2.4)   0 (0) 2 (2.4)  
  pT1 2 (2.1) 6 (7.3)   2 (2.4) 6 (7.3)  
  pT2 10 (10.6) 4 (4.9)   6 (7.3) 4 (4.9)  
  pT3 74 (78.7) 62 (75.6)   68 (82.9) 62 (75.6)  
  pT4 8 (8.5) 8 (9.8)   6 (7.3) 8 (9.8)  
Tumor grade     0.802     0.672
  Low 8 (8.5) 4 (4.9)   8 (9.8) 4 (4.9)  
  High 86 (91.5) 78 (95.1)   74 (90.2) 78 (95.1)  
Lymphovascular invasion 36 (38.3) 32 (39.0) 0.956 32 (39.0) 32 (39.0) 1.000
Concurrent CIS 10 (10.6) 10 (12.2) 1.000 8 (9.8) 10 (12.2) 1.000
Ipsilateral hydronephrosis 56 (59.6) 50 (61.0) 0.985 50 (61.0) 50 (61.0) 1.000
Multifocality 16 (17.0) 20 (24.4) 0.555 16 (19.5) 20 (24.4) 0.790
Tumor location     0.664     0.714
Pelvis 38 (40.4) 28 (34.1)   30 (36.6) 28 (34.1)  
  Ureter 40 (42.6) 34 (41.5)   38 (46.3) 34 (41.5)  
  Both 16 (17.0) 20 (24.4)   14 (17.1) 20 (24.4)  
Pathologic N stage     0.674     0.609
  pNx–N0 86 (91.4) 68 (82.9)   74 (90.2) 68 (82.9)  
  pN1–N2 4 (4.3) 8 (9.8)   4 (4.9) 8 (9.8)  
  pN3 4 (4.3) 6 (7.3)   4 (4.9) 6 (7.3)  
Positive surgical margin 8 (8.5) 12 (14.6) 0.571 8 (9.8) 12 (14.6) 0.736
Neoadjuvant chemotherapy 2 (2.1) 1 (1.2) 0.453 1 (1.0) 1 (1.2) 0.521
Adjuvant chemotherapy regimens     0.430     0.415
  Gemcitabine – carboplatin 16 (17.0) 14 (17.1)   12 (14.6) 14 (17.1)  
  Gemcitabine – cisplatin 70 (74.4) 62 (75.6)   62 (73.2) 62 (75.6)  
  G – cisplatin & 2 (2.1) 6 (7.3)   2 (2.4) 6 (7.3)  
  G – carboplatin            
  MVAC 2 (2.1) 0 (0)   2 (2.4) 0 (0)  
  Others 4 (4.3) 0 (0)   4 (4.9) 0 (0)  
Chemotherapy cycle 4.0±1.6 4.3±2.3 0.566 4.0±1.6 4.3±2.3 0.548
Survival duration (mo) 59.4±49.2 40.4±26.7 0.025 61.1±52.1 40.4±26.7 0.027
Overall mortality 30 (31.9) 54 (65.9) 0.003 28 (34.1) 54 (65.9) 0.008
Cancer-specific mortality 28 (29.8) 50 (61.0) 0.006 26 (31.7) 50 (61.0) 0.015

Values are presented as mean±standard deviation or number (%).

ALT: alanine aminotransferase, AST: aspartate aminotransferase, BMI: body mass index, HTN: hypertension, DM, diabetes mellitus, ASA PS: American Society of Anesthesiologists physical status, CIS: carcinoma in situ, MVAC: methotrexate, vinblastine, adriamycin and cisplatin.

Table 2.

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival

Parameter Overall survival
Cancer-specific survival
HR (95% Cl) p-value HR (95% Cl) p-value
Age 1.041 (1.003–1.074) 0.039 1.033 (0.994–1.075) 0.083
BMI 0.994 (0.932–1.061) 0.842 1.011 (0.954–1.085) 0.738
Sex        
  Men Reference   Reference  
  Women 0.423 (0.114–1.582) 0.198 0.482 (0.136–1.738) 0.262
ASA PS classification        
  I Reference   Reference  
  ≥II 1.038 (0.790–1.358) 0.207 1.048 (0.795–1.384) 0.185
Pathologic T stage        
  < pT3 Reference   Reference  
  ≥pT3 1.464 (1.156–1.857) 0.002 1.497 (1.174–1.903) 0.001
Tumor grade        
  Low Reference   Reference  
  High 2.665 (0.368–19.883) 0.340 2.437 (0.323–18.302) 0.386
Lymphovascular invasion 1.445 (1.153–1.854) 0.005 1.475 (1.172–1.904) 0.002
Concurrent CIS 0.709 (0.151–3.347) 0.658 0.877 (0.192–4.003) 0.856
Multifocality 0.662 (0.154–2.946) 0.590 0.759 (0.173–3.194) 0.692
Pathologic N stage   <0.001 3.815 (2.234–6.497) <0.001
  pNx–N0 Reference   Reference  
  pN1–N2 1.342 (1.011–1.773) 0.038 1.304 (0.982–1.735) 0.066
  pN3 3.893 (2.284–6.648) <0.001 3.815 (2.235–6.493) <0.001
Positive surgical margin 2.155 (0.927–5.026) 0.075 2.412 (1.028–5.674) 0.043
AST/ALT ratio        
  Low Reference   Reference  
  High 5.428 (1.803–16.334) 0.002 4.417 (1.545–12.632) 0.005

AST: aspartate aminotransferase, ALT: alanine aminotransferase, HR: hazard ratio, CI: confidence interval, BMI: body mass index, ASA PS: American Society of Anesthesiologists physical status, CIS: carcinoma in situ.

Table 3.

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival after propensity score matching

Parameter Overall survival
Cancer-specific survival
HR (95% Cl) p-value HR (95% Cl) p-value
Age 1.046 (1.005–1.090) 0.029 1.031 (0.992–1.071) 0.119
BMI 0.994 (0.958–1.031) 0.748 1.001 (0.964–1.038) 0.983
Sex        
  Men Reference   Reference  
  Women 0.631 (0.301–1.323) 0.228 0.603 (0.276–1.317) 0.205
ASA PS classification        
  I Reference   Reference  
  ≥II 1.080 (0.601–1.939) 0.797 1.158 (0.630–2.129) 0.636
Pathologic T stage        
  < pT3 Reference   Reference  
  ≥pT3 1.358 (1.059–1.744) 0.018 1.600 (1.251–2.062) 0.002
Tumor grade        
  Low Reference   Reference  
  High 3.321 (0.439–25.128) 0.245 2.500 (0.331–18.907) 0.374
Lymphovascular invasion 1.366 (0.737–2.532) 0.322 1.417 (0.747–2.687) 0.285
Concurrent CIS 0.809 (0.228–2.271) 0.687 0.883 (0.313–2.491) 0.814
Multifocality 0.422 (0.178–1.002) 0.051 0.628 (0.276–1.429) 0.267
Pathologic N stage   <0.001   <0.001
  pNx–N0 Reference   Reference  
  pN1–N2 1.362 (1.051–1.753) 0.018 1.702 (1.132–2.558) 0.010
  pN3 3.301 (1.182–9.215) <0.001 5.364 (2.125–13.512) <0.001
Positive surgical margin 2.398 (1.018–5.651) 0.046 2.882 (1.256–6.612) 0.013
AST/ALT ratio        
  Low Reference   Reference  
  High 2.095 (1.090–4.024) 0.026 2.074 (1.053–4.086) 0.035

AST: aspartate aminotransferase, ALT: alanine aminotransferase, HR: hazard ratio, CI: confidence interval, BMI: body mass index, ASA PS: American Society of Anesthesiologists physical status, CIS: carcinoma in situ.