Aspartate Aminotransferase to Lymphocyte Ratio Outperforms De Ritis

Ratio in Predicting Survival Outcomes in Patients with Upper Tract

Urothelial Carcinoma after Radical Nephroureterectomy

Hang Xu*, Ping Tan*, Jianzhong Ai*, Xi Jin, Tianhai Lin, Lu Yang† and Qiang

Wei†

Department of Urology, Institute of Urology, West China Hospital, Sichuan

University, No. 37 Guoxue Xiang, Chengdu 610041, China

*Co-first authors and contributed equally to the article.

†Correspondence:

Lu Yang, M.D. Department of Urology, Institute of Urology, West China

Hospital, Sichuan University, Chengdu 610041, China. (Tel: +86-135-4123-

5213; Fax: +86-28-8542-2451; Email: wycleflue@163.com)

Qiang Wei, M.D. Department of Urology, Institute of Urology, West China

Hospital, Sichuan University, Chengdu 610041, China. (Tel: +86-189-8060-

1425; Fax: +86-28-8542-2451; Email: weiqiang933@126.com)

Abstract

Background: Aspartate aminotransferase (AST) is widely expressed in

different tissues and able to facilitate tumor cell growth. We sought to explore

the effect of AST to lymphocyte ratio (ALRI) on survival end points in patients

with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy

(RNU).

Materials and methods: We retrospectively reviewed 683 patients with

1

UTUC between March 2003 and December 2006 at one single tertiary

medical center. The cutoff value of ALRI was decided from receiver operating

characteristic (ROC) curves. Kaplan-Meier analyses and Cox proportional

regression models were used to assess the influence of ALRI on cancer-

specific survival (CSS), disease recurrence-free survival (RFS) and overall

survival (OS).

Results: Median follow-up duration was 42 months (interquartile range [IQR]:

20-75 months) and mean patients’ age was 65.9 ± 11.3 years. Survival curves

showed that patients with an increased ALRI (14 or higher) had shorter CSS

(P = 0.0038), RFS (P = 0.0065) and OS (P = 0.0031). Multivariate analysis

demonstrated that elevated ALRI was independently associated with worse

CSS (hazard ratio [HR]:1.66, 95% confidence interval [CI] 1.24-2.21, P =

0.001), RFS (HR: 1.54, 95%CI 1.21-1.95, P < 0.0001) and OS (HR: 1.61,

95%CI 1.25-2.09, P < 0.0001). While the De Ritis ratio (AST/ALT) was not an

independent predictor for CSS (HR: 1.13, P = 0.4), RFS (HR: 0.98, P = 0.874)

and OS (HR: 1.08, P = 0.55).

Conclusion: Preoperative ALRI rather than De Ritis ratio might be applied as

a predictive index of survival outcomes in UTUC sets after RNU.

Keywords Aspartate aminotransferase to lymphocyte ratio, De Ritis ratio,

upper tract urothelial carcinoma, radical nephroureterectomy, biomarkers.

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Introduction

Urothelial carcinoma (UC) is the fifth most common cancer type worldwide.

Upper tract urothelial carcinoma (UTUC), derived from renal pelvis and ureter,

however, is relatively uncommon and represents roughly 5-10% of UCs[1].

Despite recent advances have been made in chemotherapy and

immunotherapy for cancers, radical nephroureterectomy (RNU) with ipsilateral

bladder cuff resection remains the fundamental therapeutic modality for

UTUC. Nevertheless, recurrence and mortality rates in UTUC sets after

surgical treatment are far from satisfactory, as the 5-yr survival rate do not

exceed 50% in muscle-invasive UTUC[1]. Consequently, searching for

effective biomarkers of UTUC before surgery is crucial so as to improve their

prognosis which may allow for earlier intervention among this population.

Aspartate aminotransferase (AST) is an enzyme which is routinely

assessed in individual’s liver function test. It can be released by normal cells

and tumor cells, playing a critical role in tumor cell turnover and

metabolism[2]. Previous studies have demonstrated that high AST level was

associated with decreased survival in several types of cancers[3-5]. Likewise,

it has been reported that De Ritis ratio, known as AST to ALT ratio, is a

negative preoperative factor for survival outcomes in genitourinary

carcinomas including UTUC[6-8], prostate cancer[9] and renal cell

carcinoma[2]. Moreover, given the pivotal role of lymphocyte in host’s

inflammation and immune response[10] and previous studies having indicated

3

its value in the combination of other biomarkers for the prognosis of UTUC

including neutrophil-to-lymphocyte ratio (NLR)[11], platelet-to-lymphocyte ratio

(PLR)[12] and prognostic nutritional index (PNI)[13], we hypothesized that

aminotransferase to lymphocyte ratio (ALRI) might be a potential novel index

in predicting survival outcomes in UTUC after RNU. To our knowledge, no

prior studies have reported the prognostic role of ALRI in UTUC.

Our primary goal was to investigate the predictive value of ALRI in UTUC

after RNU. We also attempted to validate whether De Ritis ratio would affect

patients’ outcomes by using our data sets.

Materials and methods

Study population

This study was approved by the Ethics Committee of West China Hospital

of Sichuan University. 758 cases in all who were pathologically diagnosed

with UTUC undergoing RNU at our medical center from March 2003 to

December 2016 were initially retrieved from our database. We included

patients with available demographic and laboratory data and at least one

follow-up information. The exclusion criteria were as follows: 1) patients

without available laboratory information especially on AST, ALT or

lymphocytes (n = 17); 2) patients with hepatitis or other hepatic disease (n =

13); 3) pathological reports validated as non-urothelial carcinoma (n = 9); 4)

patients who had lost at the first follow up (n= 36). In addition, neoadjuvant

4

chemotherapies were not performed in any of these patients. Consequently,

the final cohort enrolled 683 cases after the selection of patients. Patients

selection flowchart can be seen in supplementary Fig.1.

Surgical procedure included open and laparoscopic RNU which was

conducted through retroperitoneal approach. Distal ureter was removed

through open bladder cuff excision. Lymph node dissection (LND) was not

regularly performed in our center. Only when there were suspected enlarged

lymph nodes (confirmed through the preoperative CT urography or

intraoperative inspection), LND was conducted.

We extracted the information of clinicopathological characteristics of

included patients from their corresponding medical records. Tumor grade was

assessed using the World Health Organization (WHO)/International Society of

Urologic Pathology classification of 2004. Tumor stage was determined

according to 2009 American Joint Committee on Cancer TNM classification

system. Tumor size was confirmed through preoperative radiology. Tumor

architecture included sessile or papillary growth pattern. Concomitant variant

histology (CVH) was defined as urothelial carcinomas accompanied with

aberrant histological differentiation.

Laboratory examination

Laboratory information including plasma AST, ALT, lymphocyte was

acquired within 2 weeks before surgical intervention. The optimal cutoff value

of ALRI and De Ritis ratio was set as 14 and 1.36 by applying receiver

5

operating characteristic (ROC) analysis. We dichotomized all qualified

patients into two groups according to their ALRI value: low ALRI group (ALRI

< 14) and high ALRI group (ALRI ≥ 14).

Follow-up

Our follow-up contents include laboratory and radiology examination. The

specific follow-up strategy was as follows: Cystoscopy and urinary test was

conducted every 3 months for 1 year postoperatively, then every 6 months for

the coming 2 years, and finally once a year thereafter. Radiology examination

(chest/abdominal CT or magnetic resonance imaging) was done every year.

Cancer-specific survival (CSS), disease recurrence-free survival (RFS, also

refers to extravesical survival) and overall survival (OS) was defined as the

time in months from the date of surgery to the date of cancer-related death,

disease recurrence (intravesical recurrence was not categorized as disease

recurrence) and all-cause mortality.

Statistical analysis

Continuous and dichotomous variables between the two groups were

analyzed using independent t test and Chi-squared test, respectively. The

Kaplan–Meier curves with Log-rank tests were used to estimate probabilities

of CSS, RFS and OS between low and high ALRI groups. Cox proportional

hazard regression models were applied to assess the prognostic significance

of factors on CSS, RFS and OS. Factors with a P value < 0.05 in univariate

analysis were included in the multivariate model. Also, subgroup analyses

6

were performed according to tumor grade, tumor size and tumor architecture.

All tests were two-sided and a P value < 0.05 was considered as statistical

significance. Statistical analyses were conducted using R software (version

3.4.4) and SPSS (version 22.0).

Results

Demographic and clinicopathological characteristics

The cutoff value of ALRI was set as 14 according to ROC curve. The area

under the curve (AUC) was 0.543, with the 58% of sensitivity and 53.8% of

specificity for the estimation of CSS (Fig.1A). The cutoff value for De Ritis

ratio was 1.36, The area under the curve (AUC) was 0.512, with 63.8% of

sensitivity and 43.5% of specificity for CSS (Fig.1B). Table 1 demonstrated the

clinicopathological characteristics of patients included in this study. There

were 332 (47.1%) cases in the low ALRI group and 361 (52.9%) cases in the

high ALRI group. Patients with high ALRI had significantly older age (66.8 yr.

vs 64.9 yr., P = 0.035), higher AST level (25.4 vs 18.5 U/L, P < 0.0001), higher

ALT level (23.7 vs 15.9, P < 0.0001) and lower lymphocyte counts (1.17 vs

1.86, P < 00001), compared with those in the low ALRI group. Whereas there

were no significant differences between the two groups with regard to body

mass index (BMI), gender, hypertension, diabetes mellitus, smoking status,

hydronephrosis, tumor location, multifocality, surgical approach, tumor size,

tumor grade, pathological stage, lymph node status, lymphovascular invasion

7

(LVI), positive surgical margins (PSM), tumor architecture, CVH, adjuvant

chemotherapy and De Ritis ratio (each P > 0.05).

Survival analysis

During the median follow-up time of 42 months (interquartile range [IQR]:

20-75months), disease recurrence was found in 287 (42%) patients, death

occurred in 249 (36.5%) cases and 200 (29.3%) died of UTUC. The 5-yr CSS,

RFS and OS rates were 52.1%, 40.2% and 46.5% in patients with high ALRI,

compared with 68.8%, 56.5% and 62.4% in patients with low ALRI. Kaplan–

Meier curves demonstrated that patients with high ALRI had significant lower

CSS (log-rank P = 0.0038), RFS (P = 0.0065) and OS (0.0031) compared with

patients with low ALRI (Fig.2A-C).

Predictors for CSS, RFS and OS

Univariate analysis was shown in Table 2. The results showed that

preoperative elevated ALRI was associated with worse CSS (HR 1.51, P =

0.004), worse RFS (HR 1.38, P = 0.007) and worse OS (HR 1.46, P = 0.004).

Besides, high De Ritis ratio was associated with worse CSS (HR 1.41, P =

0.016) and worse OS (HR 1.31, P = 0.034), while not for RFS (HR 1.20, P =

0.128). Multivariate cox regression analysis identified tumor size, tumor grade,

tumor stage, lymph node status and ALRI were independent predictors for all

above three survival outcomes (CSS, RFS and OS). Tumor architecture was

an independent factor only for CSS (HR 1.71, P = 0.022), and CVH was

independently associated with decreased CSS (HR 1.49, P = 0.01) and OS

8

(HR = 1.40, P = 0.018). The HR values of ALRI were 1.66, 1.54 and 1.61 for

CSS, RFS and OS, respectively (all P < 0.01). Nevertheless, De Ritis ratio

was not an independent factor for CSS (HR: 1.13, P = 0.4), RFS (HR: 0.98, P

= 0.874) and OS (HR: 1.08, P = 0.55).

Prognostic values of ALRI in various subgroups of UTUC

All patients were further stratified according to tumor grade, tumor size and

tumor architecture in order to compare preoperative ALRI in different UTUC

subgroups. Our results revealed that in those with high-grade disease

(Fig.3A-C), tumor size <3cm (Fig.4A-C) and sessile carcinomas (Fig.5A-C),

patients with high ALRI had decreased CSS, RFS and OS compared to its

counterparts (all log-rank P < 0.05). Whereas in those with low-grade disease

(Fig.3D-F), large tumor size (≥3cm) (Fig.4D-F) and papillary carcinoma

(Fig.5D-F), no marked difference was observed between the two groups (all

log-rank P > 0.05).

Discussion

In our work, we firstly proposed a novel prognostic index ALRI in UTUC

after RNU and our results showed that high ALRI was independently

associated with decreased CSS, RFS and OS, especially in those with high-

grade disease, tumor size <3cm and sessile carcinomas. Moreover, we found

that De Ritis ratio was a significant prognostic but not predictive biomarker in

UTUC, suggesting the potential benefit of utilizing ALRI rather than De Ritis

9

ratio in current risk stratifications of UTUC.

Due to the uncommon presentation of UTUC worldwide, researches

involving the prognosis of UTUC are relatively lacking compared with other

genitourinary cancer (prostate cancer, bladder cancer and renal cell

carcinoma). The current available prediction nomograms[14-17] are mainly

based on pathological features (pT stage, grade, etc.) and most of these

predictive models were used postoperatively. Conversely, preoperative

biomarkers gained their superiority in easily-assessed, cost-effective and non-

invasive nature, and most importantly, it allowed for perioperative intervention

(neoadjuvant/adjuvant therapy) so as to delay disease recurrence and

achieve the optimal treatment outcomes.

In general, AST is an enzyme which was assessed in routine hepatic

function tests. It is widely expressed in various tissues and can be released

also by cancer cells[18]. In a retrospective study of 597 patients with

hepatocellular carcinoma which was conducted by Witjes et al.[4], they

showed that high AST level was an independent predictor for OS. Chen et al.

[3] included 231 cases with non-small cell lung cancer after surgery and they

found high AST (> 19 U) was independently associated with worse RFS and

OS. Additionally, established evidence suggested that inflammation played a

crucial role in promoting cancer cell growth and metastasis[19, 20].

Lymphocyte, as one of the most important inflammatory cells, also

participated in host antitumor immune responses[21]. Previous studies

10

showed that preoperative high ALRI was associated with worse OS in

hepatocellular carcinoma[22, 23] and worse progression-free survival in

colorectal cancer[24]. We investigated ALRI in UTUC using a relatively large

Chinese cohort and further unraveled its predictive significance in UTUC sets.

There were several publications suggested that pretreatment high De Ritis

ratio was an independent indicator of shorter survival in renal cell

carcinoma[2], prostate cancer[9] and UTUC[6-8, 25]. Nevertheless, in our

study though we demonstrated high De Ritis ratio was associated with

decreased CSS (HR 1.41) and OS (HR 1.31) (not for RFS) in univariate

analysis, but when in the multivariate analysis no significance exited. The

inconsistence between ours and previous studies might result from the

different cutoff value of De Ritis ratio and population difference. Our results

were in line with a study conducted by Miyake et al.[26] in which they included

74 metastatic castration-resistant prostate cancer (mCRPC) patients treated

with cabazitaxel. They found that De Ritis ratio was a significant factor but not

an independent factor for OS (also not for RFS). Further multicenter

researches with large sample size are still warranted to unravel the prognostic

role of De Ritis ratio in UTUC.

Moreover, we performed detailed subgroup analyses according to tumor

grade, tumor size and tumor architecture to further identify who with high ALRI

had shorter outcomes. Our multivariate analysis showed that these three

factors were independently associated with decreased CSS. Previous studies

11

showed the same results that patients with large tumor size[27] and sessile

carcinoma[28] had worse survival outcomes. Our study suggested that ANRI

was a sensitive index in predict survival end points of UTUC patients after

RNU, especially in different subgroups of patients with UTUC whose

prognosis might be difficult to predict.

Notwithstanding, the limitation of present study should be noticed as well.

The retrospective design of this study was its main limitation and the selection

bias cannot be avoided. Besides, postoperative chemotherapy was given in

41.4% patients, but we were unable to analyze the specific drugs, doses and

duration, which might affect the survival of patients. In addition, the prognostic

significance of ALRI and De Ritis ratio were not evaluated as continuous

variables in the cox regression models. Although we showed ALRI can predict

survival outcomes in UTUC sets, our results might be interpreted with caution.

Even though we’ve included a relatively large number of patients in our

center, we were unable to conduct external validation of our main findings.

Large, multicenter, prospective cohort were needed to validate the results.

Conclusion

In all, this is the first study exploring the prognostic impact of ALRI in

patients with UTUC after RNU. ALRI but not De Ritis ratio can serve as an

independent predictor for CSS, RFS and OS. This parameter warrants further

validation when applying it in current risk stratification of UTUC.

Ethics approval and consent to participate

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This study was approved by the ethics committee of West China Hospital,

Sichuan University.

Acknowledgements

This study was supported by the National key research and development

program of China (Grant No. SQ2017YFSF090096), the Prostate Cancer

Foundation Young Investigator Award 2013, the National Natural Science

Foundation of China (Grant No. 81300627, 81370855, 81702536, 81770756),

Programs from Science and Technology Department of Sichuan Province

(Grant No. 2018JY0089 and 2017HH0063) and Young Investigator Award of

Sichuan University 2017.

Competing Interests

The authors have declared that no competing interest exists.

Abbreviations

UTUC: upper tract urothelial carcinoma; ROC: receiver operating

characteristic; BMI: body mass index; RNU: radical nephroureterectomy;

CSS: cancer-specific survival; RFS: recurrence-free survival; OS: overall

survival; CVH: concomitant variant histology; AST: aspartate

aminotransferase; ALT: alanine aminotransferase; ALRI: aspartate

aminotransferase to lymphocyte ratio index; HR: hazard ratio; CI: confidence

interval.

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Tables

Table 1 Clinicopathological characteristics in upper tract urothelial carcinoma

Variables Low ALRI (n = 322, 47.1%) High ALRI (n = 361, 52.9%) P

Mean age, years 64.9 66.8 0.035Mean BMI, kg/m2 23.1 22.9 0.294

Gender 0.220Male 175 (54.3) 213 (59.0)

Female 147 (45.7) 148 (41.0)Hypertension 129 (40.1) 149 (41.3) 0.748

Diabetes mellitus 45 (14.0) 35 (9.7) 0.083Smoking (former/current) 86 (26.7) 108 (29.9) 0.353

Hydronephrosis 206 (64.0) 217 (60.1) 0.299Tumor location 0.223

Pelvicalyceal 167 (51.9) 197 (54.6)Ureteric 104 (32.3) 96 (26.6)

Both 51 (15.8) 68 (18.8)Multifocality 56 (17.4) 56 (15.5) 0.508

Surgical approach 0.558Open RNU 209 (64.9) 242 (67.0)

Laparoscopic RNU 113 (35.1) 119 (33.0)Tumor size 0.446

< 3 cm 100 (31.1) 122 (33.8)≥ 3 cm 222 (68.9) 239 (66.2)

Tumor grade 0.112Low 94 (29.2) 86 (23.8)High 228 (70.8) 275 (76.2)

Pathological T stage 0.199pTaTisT1 106 (32.9) 104 (28.8)

pT2 56 (17.4) 82 (22.7)pT3 108 (33.5) 128 (35.5)pT4 52 (16.1) 47 (13.0)

Lymph node status 0.599pN0 37 (11.5) 47 (13.0)pNx 250 (77.6) 282 (78.1)pN+ 35 (10.9) 32 (8.9)

Lymphovascular invasion 45 (14.0) 57 (15.8) 0.507Positive surgical margins 20 (6.2) 34 (9.4) 0.121

Sessile carcinoma 221 (68.6) 248 (68.7) 0.986CVH 76 (23.6) 82 (22.7) 0.784

Adjuvant Chemotherapy 130 (40.4) 153 (42.4) 0.595Mean AST, U/L 18.5 25.4 < 0.0001Mean ALT, U/L 15.9 23.7 < 0.0001

Mean lymphocyte, x109/L 1.86 1.17 < 0.0001De Ritis ratio 0.761

≥ 1.36 123 (38.2) 142 (39.3)< 1.36 199 (61.8) 219 (60.7)

Abbreviations: BMI: body mass index; RNU: radical nephroureterectomy; CVH: concomitant variant histology; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALRI: aspartate aminotransferase to lymphocyte ratio index; HR: hazard ratio.

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Table 2 Univariable Cox regression analyses

VariablesCancer-specific survival Recurrence-free survival Overall survivalHR (95%CI) P HR (95%CI) P HR (95%CI) P

Age, years 0.99 (0.98-1.01) 0.302 1.00 (0.99-1.01) 0.381 1.00 (0.99-1.01) 0.834BMI, kg/m2 0.97 (0.94-1.01) 0.094 0.96 (0.92-1.00) 0.076 0.97 (0.92-1.00) 0.071

Gender (male vs female) 0.84 (0.64-1.11) 0.224 0.89 (0.71-1.13) 0.347 0.92 (0.71-1.18) 0.497Hypertension (yes vs no) 1.09 (0.82-1.43) 0.566 1.02 (0.81-1.29) 0.852 1.08 (0.84-1.39) 0.527

Diabetes mellitus (yes vs no) 0.74 (0.47-1.17) 0.198 0.90 (0.63-1.29) 0.576 0.89 (0.61-1.32) 0.569Smoking (former/current vs never) 0.84 (0.61-1.16) 0.284 0.88 (0.68-1.15) 0.363 0.90 (0.68-1.20) 0.471

Hydronephrosis (yes vs no) 1.26 (0.94-1.68) 0.126 1.40 (1.10-1.80) 0.007 1.34 (1.03-1.74) 0.032Tumor location 0.712 0.654 0.827Pelvicalyceal Ref. Ref. Ref.

Ureteric 1.03 (0.74-1.41) 0.882 0.95 (0.72-1.25) 0.714 0.95 (0.71-1.28) 0.746Both 1.17 (0.80-1.71) 0.413 1.12 (0.82-1.54) 0.481 1.08 (0.76-1.52) 0.681

Multifocality (yes vs no) 1.06 (0.71-1.49) 0.896 0.98 (0.71-1.35) 0.892 0.95 (0.67-1.34) 0.777Tumor size (≥ 3 cm vs < 3 cm)

2.03 (1.47-2.81) < 0.0001 1.86 (1.43-2.43) < 0.0001 1.99 (1.49-2.66)<

0.0001Surgical approach (Laparoscopic vs

Open)0.69 (0.50-0.95) 0.023 0.88 (0.68-1.14) 0.331 0.74 (0.55-0.99) 0.040

Tumor grade (high vs low) 3.50 (2.27-5.41) < 0.0001 2.31 (1.69-3.15) < 0.0001 2.91 (2.02-4.18)<

0.0001

Pathological T stage < 0.0001 < 0.0001<

0.0001TaTisT1 Ref. Ref. Ref.

T2 1.62 (0.94-2.80) 0.081 1.49 (0.99-2.24) 0.056 1.63 (1.02-2.60) 0.040

T3 3.94 (2.52-6.14) < 0.0001 3.06 (2.18-4.29) < 0.0001 3.62 (2.46-5.33)<

0.0001

T4 10.11 (6.33-16.14) < 0.0001 7.49 (5.16-10.88) < 0.0001 8.70 (5.76-13.14)<

0.0001

Lymph node status (pN+ vs pN0/x) 4.07 (2.90-5.71) < 0.0001 3.76 (2.78-5.09) < 0.0001 3.63 (2.64-5.00)<

0.0001

lymphovascular invasion (yes vs no) 2.81 (2.05-3.85) < 0.0001 2.28 (1.72-3.00) < 0.0001 2.60 (1.95-3.47)<

0.0001

Positive surgical margins (yes vs no) 2.59 (1.72-3.89) < 0.0001 2.08 (1.44-3.01) < 0.0001 2.39 (1.64-3.48)<

0.0001Tumor architecture (Sessile vs

Papillary) 3.76 (2.52-5.61) < 0.0001 2.53 (1.89-3.38) < 0.0001 2.99 (2.15-4.16)

< 0.0001

Concomitant variant histology (yes vs no)

2.35 (1.76-3.14) < 0.0001 1.97 (1.54-2.54) < 0.0001 2.15 (1.65-2.80)<

0.0001Adjuvant Chemotherapy (yes vs no) 1.02 (0.88-1.17) 0.827 0.94 (0.84-1.05) 0.287 1.06 (0.93-1.20) 0.387

AST 1.76 (0.93-3.33) 0.081 1.27 (0.70-2.33) 0.433 1.74 (0.97-3.10) 0.062De Ritis ratio (≥ 1.36 vs < 1.36) 1.41 (1.07-1.87) 0.016 1.20 (0.95-1.52) 0.128 1.31 (1.02-1.69) 0.034

ALRI (≥ 14 vs <14) 1.51 (1.14-2.01) 0.004 1.38 (1.09-1.74) 0.007 1.46 (1.13-1.88) 0.004Abbreviations: BMI: body mass index; AST: aspartate aminotransferase; ALRI: aspartate aminotransferase to lymphocyte ratio index; HR: hazard ratio; CI: confidence interval.

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Table 3 Multivariate analyses of clinicopathological factors predicting survival outcomes in upper tract urothelial carcinoma

VariablesCancer-specific survival Recurrence-free survival Overall survivalHR (95%CI) P HR (95%CI) P HR (95%CI) P

Tumor size (> 3 vs ≤ 3 cm) 1.46 (1.04-2.05) 0.029 1.41 (1.07-1.86) 0.015 1.47 (1.08-1.99) 0.013

Hydronephrosis (yes vs no) - - 1.13 (0.88-1.46) 0.346 1.03 (0.78-1.36) 0.822

Surgical approach (Laparoscopic vs Open)

0.95 (0.68-1.33) 0.772 - - 0.99 (0.73-1.34) 0.948

Tumor grade (high vs low) 1.81 (1.13-2.90) 0.013 1.45 (1.03-2.04) 0.032 1.67 (1.12-2.47) 0.011

Pathological T stage < 0.0001 < 0.0001<

0.0001

Tis, Ta, T1 Ref. Ref. Ref.

T2 1.09 (0.62-1.92) 0.768 1.11 (0.72-1.71) 0.632 1.18 (0.73-1.93) 0.498

T3 1.99 (1.20-3.32) 0.008 1.94 (1.31-2.87) 0.001 2.09 (1.34-3.26) 0.001

T4 3.49 (1.92-6.34) < 0.0001 3.69 (2.29-5.96) < 0.0001 3.71 (2.19-6.29)<

0.0001

Lymph node status (pN+ vs pN0/x) 1.69 (1.15-2.50) 0.008 1.79 (1.26-2.55) 0.001 1.57 (1.09-2.26) 0.016

Lymphovascular invasion (yes vs no) 1.08 (0.76-1.54) 0.668 0.92 (0.67-1.26) 0.596 1.06 (0.76-1.47) 0.739

Positive surgical margins (yes vs no) 1.38 (0.90-2.11) 0.135 1.21 (0.82-1.78) 0.343 1.34 (0.90-1.99) 0.146

Tumor architecture (Sessile vs Papillary)

1.71 (1.08-2.70) 0.022 1.35 (0.96-1.90) 0.085 1.44 (0.98-2.11) 0.061

CVH (yes vs no) 1.49 (1.10-2.02) 0.010 1.28 (0.98-1.66) 0.067 1.40 (1.06-1.84) 0.018

De Ritis ratio (≥ 1.36 vs < 1.36) 1.13 (0.85-1.51) 0.400 0.98 (0.77-1.25) 0.874 1.08 (0.84-1.40) 0.550

ALRI (≥ 14 vs <14) 1.66 (1.24-2.21) 0.001 1.54 (1.21-1.95) < 0.0001 1.61 (1.25-2.09)<

0.0001Abbreviations: CVH: concomitant variant histology; AST: aspartate aminotransferase; ALRI: aspartate aminotransferase to lymphocyte ratio index; HR: hazard ratio; CI: confidence interval.

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Figures

Fig. 1. ROC analysis. A, AUC of preoperative ALRI for CSS was 0.543 and B, AUC of preoperative De Ritis ratio for CSS was 0.512.

Fig. 2. Kaplan–Meier curves for survival in all UTUC patients according to ALRI. (A) cancer-specific survival, (B) disease recurrence free

survival and (C) overall survival.

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Fig. 3. Kaplan–Meier curves for cancer-specific survival, disease recurrence free survival and overall survival stratified by ALRI in UTUC

patients with high-grade carcinoma (A-C) and low-grade carcinoma (D-F).

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Fig. 4. Kaplan–Meier curves for cancer-specific survival, disease recurrence free survival and overall survival stratified by ALRI in UTUC

patients with tumor size ≥ 3 cm (A-C) and tumor size < 3 cm (D-F).

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Fig. 5. Kaplan–Meier curves for cancer-specific survival, disease recurrence free survival and overall survival stratified by ALRI in UTUC

patients with sessile carcinoma (A-C) and papillary carcinoma (D-F).

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