New Insights into Diagnosis and Treatment of Renal Cell ...downloads.hindawi.com/journals/specialissues/896487.pdfGGG3 16(12.0%) 308(15.2%) 104(13.6%) GGG4 19(14.3%) 320(15.7%) 145(18.9%)

BioMed Research International

New Insights into Diagnosis and Treatment of Renal Cell Carcinoma Bladder Cancer and Prostate Cancer

Guest Editors Piotr L Chlosta Tomasz Golabek and Peacuteter Nyiraacutedy

New Insights into Diagnosis and Treatment ofRenal Cell Carcinoma Bladder Cancerand Prostate Cancer



Guest Editors Piotr L Chlosta Tomasz Golabekand Peacuteter Nyiraacutedy

Copyright copy 2017 Hindawi Publishing Corporation All rights reserved

This is a special issue published in ldquoBioMed Research Internationalrdquo All articles are open access articles distributed under the CreativeCommons Attribution License which permits unrestricted use distribution and reproduction in any medium provided the originalwork is properly cited

Contents

New Insights into Diagnosis and Treatment of Renal Cell Carcinoma Bladder Cancer and ProstateCancerPiotr L Chlosta Tomasz Golabek and Peacuteter NyiraacutedyVolume 2017 Article ID 6467072 1 page

Are the Pathological Characteristics of Prostate Cancer More Aggressive or More Indolent Dependingupon the Patient AgeGuangjie Ji Cong Huang Gang Song Gengyan Xiong Dong Fang HeWang Han Hao Lin Cai Qun HeZhisong He and Liqun ZhouVolume 2017 Article ID 1438027 6 pages

Clinical and Prognostic Effect of Plasma Fibrinogen in Renal Cell Carcinoma A Meta-AnalysisYuejun Tian Mei Hong Suoshi Jing Xingchen Liu Hanzhang Wang Xinping Wang Dharam KaushikRonald Rodriguez and Zhiping WangVolume 2017 Article ID 9591506 8 pages

Baseline Chronic Kidney Disease and Ischemic Method of Partial Nephrectomy Are Important Factorsfor the Short- and Long-TermDeterioration in Renal Function for Renal Cell Carcinoma Staged T1-T2A Retrospective Single Center StudySung Han Kim Jae Young Joung Ho Kyung Seo Kang Hyun Lee and Jinsoo ChungVolume 2016 Article ID 5398381 8 pages

Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Nonmetastatic Renal CellCarcinoma A Large Multicenter Cohort AnalysisSeok-Soo Byun Eu Chang Hwang Seok Ho Kang Sung-Hoo Hong Jinsoo Chung Tae Gyun Kwon HyeonHoe Kim Cheol Kwak Yong-June Kim and Won Ki LeeVolume 2016 Article ID 5634148 8 pages

Pretreatment Neutrophil-to-Lymphocyte Ratio Can Predict the Prognosis in Bladder Cancer PatientsWho Receive Gemcitabine and NedaplatinTherapyShinji Ohtake Takashi Kawahara Ryo Kasahara Hiroki Ito Kimito Osaka Yusuke HattoriJun-ichi Teranishi Kazuhide Makiyama Nobuhiko Mizuno Susumu Umemoto Yasuhide MiyoshiNoboru Nakaigawa Hiroshi Miyamoto Masahiro Yao and Hiroji UemuraVolume 2016 Article ID 9846823 5 pages

EditorialNew Insights into Diagnosis and Treatment of Renal CellCarcinoma Bladder Cancer and Prostate Cancer

Piotr L Chlosta1 Tomasz Golabek1 and Peacuteter Nyiraacutedy2

1Department of Urology Jagiellonian University in Krakow ul Grzegorzecka 18 31-531 Krakow Poland2Department of Urology and Centre for Urooncology Semmelweis University Ulloi ut 78b Budapest 1082 Hungary

Correspondence should be addressed to Tomasz Golabek elementareoppl

Received 22 February 2017 Accepted 22 February 2017 Published 13 March 2017

Copyright copy 2017 Piotr L Chlosta et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

In recent years substantial changes in urological cancer-related mortality have occurred These have resulted fromtherapeutic improvements of prostatic cancer decreasedexposure to tobacco smoking and occupational carcinogensof bladder and possibly kidney cancers Despite improvedprimary prevention detection and treatment the incidenceof age-related cancers of the urinary tract is likely to rise asa result of global population ageing Therefore it is vital toidentify and address themost relevant targets for further earlydetection investigation and therapy of urological malignan-cies

In keeping with this spirit this special issue bringsarticles that investigated clinical and prognostic significanceof several factors in the three most common urologicalcancers renal cell carcinoma prostate cancer and bladdercancer

G Ji et al in their report analysed pathological featuresof 2929 men diagnosed with prostate cancer within differentage groups including patients older than 75 years of ageTheyfound that both patients aged le55 years and gt75 years aremore likely to be diagnosed with more aggressive diseaseThese findings have certain consequences including moreaggressive treatment of the disease also in elderly healthymenand bring us into opposition with supporters of nonradicalmanagement of prostate cancer in older men

Two research articles are dedicated to the prognosticrole of blood-derived factors in patients with renal cellcarcinoma Y Tian et al in their systematic review and meta-analysis provide an evidence for elevated plasma fibrinogento be adversely associated with overall cancer-specific anddisease-free survival S-S Byun et al assessed the prognosticsignificance of preoperative neutrophil-to-lymphocyte ratio

in nonmetastatic renal cell carcinomaTheir findings showedthat the investigated parameter was associated with worseclinical tumour behavior and it was a significant prognosticfactor for both recurrence-free and cancer-specific survival inthat group of patients

Predictors of short- and long-term deterioration inrenal function after partial nephrectomy in patients withrenal cell carcinoma or benign tumour with or withoutpreoperative predisposition to chronic kidney disease werestudied by S H Kim et al Their findings confirmed ourunderstanding that abnormal preoperative renal function isassociated with long-term deterioration of renal functionand also indicated the baseline state of the renal func-tion as the predominant factor affecting the postoperativefunctional outcome more than other determinants includ-ing partial nephrectomy procedure or renal cell carcinomaitself

Urothelial bladder cancer remains a lethal malignancy ina significant proportion of advanced cases thus more usefuland reliable biomarkers that provide additional prognosticinformation are needed In the quest for the better prognos-ticator in that group of patients for the first time S Ohtakeet al evaluated an impact of neutrophil-to-lymphocyte ratioin patients with advanced bladder cancer who receivedgemcitabine and nedaplatin therapy Their findings suggestthat this simple biomarker may serve as a new biomarkerto predict responses to chemotherapy in advanced bladdercancer patients

Piotr L ChlostaTomasz GolabekPeter Nyirady

HindawiBioMed Research InternationalVolume 2017 Article ID 6467072 1 pagehttpdxdoiorg10115520176467072

Research ArticleAre the Pathological Characteristics of Prostate Cancer MoreAggressive or More Indolent Depending upon the Patient Age

Guangjie Ji1 Cong Huang1 Gang Song1 Gengyan Xiong1 Dong Fang2 HeWang3

Han Hao1 Lin Cai1 Qun He1 Zhisong He1 and Liqun Zhou1

1Department of Urology Peking University First Hospital Institute of Urology Peking UniversityNational Urological Cancer Center of China Beijing China2Department of Andrology Peking University First Hospital Institute of Urology Peking UniversityNational Urological Cancer Center of China Beijing China3Department of Radiology Peking University First Hospital Beijing China

Correspondence should be addressed to Gang Song sgbmupaper163com and Liqun Zhou zhoulqmailsinacom

Received 29 October 2016 Revised 7 January 2017 Accepted 12 January 2017 Published 7 February 2017

Academic Editor Tomasz Golabek

Copyright copy 2017 Guangjie Ji et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Purpose To identify pathological characteristics of prostate cancer according to patient age at diagnosisMethods A retrospectivereview of 2929 men diagnosed with prostate cancer was performed Pathological characteristics were compared across age groupsle55 56ndash75 andgt75 yearsResultsThe study cohort included 133 patients (45) 2033 patients (695) and 763 patients (260) inthe three age groups respectively The median pathological Gleason sums in the three age groups were 8 7 and 8 respectively TheGleason sum primary Gleason score and second primary Gleason score were significantly different among the three age groups(119885 = 12975 119901 = 0002 119885 = 9264 119901 = 0010 119885 = 6692 119901 = 0035 resp) The percentages of Gleason pattern 5 tumors forthe three age groups were 444 323 and 368 respectively they were significantly different (1205942 = 11641 119901 = 0003) Thepercentages of tumors with Gleason score grade groups 3ndash5 for the three age groups were 669 605 and 663 respectivelythey were significantly different (1205942 = 9401 119901 = 0009) Conclusions The present study indicated that men aged le55 years or gt75years show higher levels of clinically significant prostate cancer compared to patients between the ages of 55 and 75 years Youngerand more elderly male patients are more likely to have a more aggressive disease

1 Introduction

Prostate cancer is considered a disease of older men and isinfrequently reported in patients aged 55 years or younger[1] However presently over 10 of new cases of prostatecancer in the US occur in men aged 55 years or younger [2]Compared with those in older men the pathological char-acteristics of prostate cancer in patients 55 years or youngerappear to be significantly different [3] However limitedinformation is currently available on the pathological featuresof prostate cancer in younger men Radical prostatectomy isrecommended as the standard treatment modality for earlystage prostate cancer in men aged 75 years or younger with alife expectancy ofmore than 10 years [4 5] However patientsover the age of 75 years with prostate cancer are more likely

to receive treatment recommendations of primary hormonaltherapy [6] In addition the pathological features of prostatecancer in elderly patients are different from those of other agecohorts

It is widely accepted that prostate cancer comprisesaggressive and indolent varieties Indolent prostate cancermay exist for a long period without causing any symptomsor death In contrast aggressive prostate cancer may causesymptoms and lead to cancer-specific mortality Howeverthere is no consensus regarding the indolent or aggressivepathological characteristics of prostate cancer in youngeror elderly patients with prostate cancer To our knowledgethere is a lack of research reports regarding the main clinicaland pathological characteristics of prostate cancer amongdifferent age groupsThus the aim of this retrospective study

Hindawi Publishing CorporationBioMed Research InternationalVolume 2017 Article ID 1438027 6 pageshttpdxdoiorg10115520171438027

2 BioMed Research International

was to ascertain the differences in prostate cancer amongdifferent age groups improve the accuracy of clinical diag-nosis and assist in treatment decisions

2 Materials and Methods

21 Study Population and Design A retrospective review ofthe pathological features of patients diagnosed with prostatecancer in the Department of Urology Peking University FirstHospital (Institute of Urology Peking University NationalUrological Cancer Center of China) from January 2001 toJune 2016 was performed All patients were pathologicallydiagnosed with prostate cancer via prostate biopsy and havenot received any form of hormonal therapy or radiotherapybefore biopsy Accordingly all the Gleason score informationof patients was obtained from biopsy specimen The ethicscommittee of the Peking University First Hospital approvedthis study

Patients were stratified by age at the diagnosis into the fol-lowing groups le55 years (Group 1 young men) 56ndash75 years(Group 2 middle-aged and old men) and gt75 years (Group3 very old men) Pathological characteristics (Gleason sumprimary Gleason score second primary Gleason score andpercent ofGleason pattern 5)were compared among the threegroups A new grading system proposed by the InternationalSociety of Urological Pathology (ISUP) in 2014 has beenincorporated in the new 2016 World Health Organization(WHO) prostate cancer reporting guidelines The pathologi-cal characteristics of prostate biopsy can be classified into fivedistinct grade groups on the basis of the new grading systemas follows grade group 1 = Gleason score le 6 grade group 2 =Gleason score 3 + 4 = 7 grade group 3 = Gleason score 4 + 3= 7 grade group 4 = Gleason score 4 + 4 = 8 and grade group5 = Gleason scores 9 and 10 Clinically significant prostatecancer is defined as grade groups 3ndash5 Comparisons were alsomade in the present study among the three age groups in theproportions of grade group 1-2 and grade group 3ndash5 tumorsaccording to the newest grading system

22 Statistical Analysis All analyses were codified and per-formed using SPSS version 130 (SPSS Inc Chicago ILUSA)Pathological features were compared across age groups usingthe Kruskal-Wallis test and statistical significance was setat a 119901 value lt 005 ANOVA tests were applied to analyzethe difference of median age between each of the Gleasongrade groups Further comparisons (Group 1 versus Group2 Group 2 versus Group 3) were performed using the Mann-Whitney-Wilcoxon test and the significance level was set at119901 lt 0025 Pearsonrsquos chi-square test was applied to comparethe percentage of Gleason pattern 5 and the percentage ofGleason score grade groups 3ndash5 among the age groups A 119901value lt 005 was considered significant

3 Results and Discussion

31 Results A total of 2929 men were pathologically diag-nosedwith prostate cancer in our institution between January2001 and June 2016 Of the 2929 men evaluated 133 (45)were in Group 1 (le55 years young men) 2033 (695) were

43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups

GS grade groups 1 amp 2GS grade groups 3ndash5

0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs

Figure 1 The distribution of Gleason score (GS) in different agegroups

in Group 2 (56ndash75 years middle-aged and old men) and 763(260) were in Group 3 (gt75 years very old men) Moreclinical information of all patients is shown in Table 1

The median pathological Gleason sums were 8 (range6ndash10) 7 (range 3ndash10) and 8 (range 3ndash10) in Groups 1 2and 3 respectively There were significant differences amongthe three age cohorts in pathological characteristics includ-ingGleason sum primaryGleason score and second primaryGleason score (119901 lt 005) After further comparisons per-formed between Groups 1 and 2 and Groups 2 and 3 it wasfound that Gleason sum primary Gleason score and secondprimary Gleason score were significantly higher in Group 3than inGroup 2 (119901 lt 0025) All data are presented in Table 2Meanwhile the median age was 71 years (range 42ndash87) 70years (range 36ndash87) 71 years (range 37ndash89) 72 years (range43ndash91) and 71 years (range 33ndash89) in Gleason grade groups(GGG) 1 2 3 4 and 5 respectively (119865 = 215 119901 = 0072)

The percent of Gleason pattern 5 was significant differentamong the three groups (444 323 and 368 resp 1205942 =11641 119901 = 0003 Table 3) When compared to Group 2 (56ndash75 years) Groups 1 (le55 years) and 3 (gt75 years) showed sig-nificantly higher percentages of Gleason pattern 5 (1205942 =8183 119901 = 0004 1205942 = 5065 119901 = 0024 resp)

The distribution of Gleason scores in different age quar-tiles (le45 46ndash55 56ndash65 66ndash75 76ndash85 and gt85 years) basedon the new grading system proposed by the 2016 WHOprostate cancer reporting guidelines is given in Figure 1When a comparison was performed across the three agegroups (le55 56ndash75 and gt75 years) for all study subjects(Table 4) the percentages of patients assigned to grade groups3ndash5 were higher than those assigned to grade groups 1-2 inall three age groupsThere were statistically significant differ-ences in the percentages of patients from each of the agegroups assigned to Gleason score grade groups 3ndash5 with669 605 and 663 of patients in Groups 1 2 and 3(1205942 = 9401 119901 = 0009) The difference between patients in

BioMed Research International 3

Table 1 Clinical data of all 2929 patients in different age groups

Total (2929) Group 1 (133) Group 2 (2033) Group 3 (763)Median Age (years) 71 (33ndash91) 52 (33ndash55) 69 (56ndash75) 79 (76ndash91)Median tPSA (120583gdL) 190 (17ndashgt1000) 20 (37ndash500) 180 (17ndashgt1000) 207 (17ndashgt1000)Median BMI (kgm2) 242 (151ndash417) 251 (180ndash325) 241 (164ndash401) 237 (151ndash417)T stage

T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

Group 1 age le 55 years (young men)Group 2 age 56ndash75 years (middle-aged and old men)Group 3 age gt 75 years (very old men)tPSA total prostate-specific antigen BMI body mass index

Table 2 Comparisons of pathological characteristics between different groups

Groups 1 2 and 3 Group 1 versus Group 2 Group 2 versus Group 3119885 119901 value 119885 119901 value 119885 119901 value

Gleason sum 12975 0002lowast 2120 0034 3155 0002lowast

Primary Gleason score 9264 0010lowast 1954 0051 2564 0010lowast

Second primary Gleasonscore 6692 0035lowast 1496 0153 2285 0022lowast

Group 1 age le 55 years (young men)Group 2 age 56ndash75 years (middle-aged and old men)Group 3 age gt 75 years (very old men)lowastStatistically significant difference

Table 3 The percentages of Gleason pattern 5 tumors in the three age groups

Group 1 (le55 years) Group 2 (56ndash75 years) Group 3 (gt75 years)Gleason pattern lt 5 74 (556) 1376 (677) 482 (632)Gleason pattern = 5 59 (444) 657 (323) 281 (368)

Table 4 The percentages of Gleason grade groups (GGG) in the three age groups

Group 1 (le55 years) Group 2 (56ndash75 years) Group 3 (gt75 years)GGG 1 21 (158) 305 (150) 95 (125)GGG 2 23 (173) 499 (245) 162 (214)GGG 3 16 (120) 308 (152) 104 (136)GGG 4 19 (143) 320 (157) 145 (189)GGG 5 54 (406) 601 (296) 257 (337)GGG 1-2 44 (331) 804 (395) 257 (336)GGG 3ndash5 89 (669) 1229 (605) 506 (663)SUM 133 (100) 2033 (100) 763 (100)


Groups 2 and 3 was also significant (1205942 = 8103 119901 = 0004)whereas no statistically significant difference was observedbetween Group 1 and Group 2 (1205942 = 2190 119901 = 0139)

32 Discussion Prostate cancer is the most commonly diag-nosed malignant tumor in older men but it is infrequentlyreported in younger men [1] Most previous studies onprostate cancer have led many clinicians to reach a consensusthat elderly men are not good candidates for radical prostate-ctomy and they would present better outcomes in response tohormonal therapy [4 5]However till date there is no specificcriterion for defining the different age groups of prostatecancer [1] An earlier retrospective study conducted on youngpatients discussed the clinicopathological features of prostatecancer in men under 50 years of age [7] however there havealso been several reports classifying adults under 55 or 59years respectively as young patients [1 8] A retrospectivereport focusing on age-related outcomes for elderly men withprostate cancer used a cutoff age of 70 years [9] Moreovera large body of literature on the oncological outcomes ofprostate cancer has suggested that patients aged more than75 years should not be treated with radical prostatectomyowing to their very short life expectancy [10] In the currentstudy we assigned 2929 patients with prostate cancer intothree age groups Group 1 (le55 years young men) Group 2(56ndash75 years middle-aged and old men) and Group 3 (gt75years very old men) The purpose of the present study wasto identify and analyze the pathological characteristics ofprostate cancer in different age groups

Several reports have indicated that older men often har-bor more advanced tumors [11ndash13] Our findings suggesteda significant difference in Gleason sum among the three agegroups (scores of 8 7 and 8 in Groups 1 2 and 3 resp)Therewas also a significant difference when Groups 2 and 3 werecompared in isolation These results indicated that patientsaged more than 75 years are more likely to be diagnosed withhigh-risk prostate cancer However a recent study focusingon Korean patients found that radical therapy might be anappropriate treatment option for selected healthy men aged75 years or more [14] Although the differences between theGleason sum inGroups 1 and 2was not statistically significant(119901 = 0034 [gt0025]) this finding might have been observedbecause of the large imbalance in the patient population inwhich only 133 subjects were le55 years of age and there were2033 patients between the ages of 55 to 75 years The resultsindicated a trend towards the association of patients agedle55 years with higher biopsy Gleason scores compared to themiddle-aged and old patient group

Most researchers have concluded that young patientswithprostate cancer have less aggressive clinicopathological char-acteristics andmore favorable outcomes comparedwith oldermen [15ndash17] The Cancer of the Prostate Risk Assessment(CAPRA) score a widely used predictivemodel for biochem-ical recurrence and survival after radical prostatectomy indi-cates that age under 50 years is one of the independent favor-able risk factors [18] Kinnear et al [16] argued that Australianmen aged le50 years diagnosed with prostate cancer havemore favorable pathological features Similarly two otherstudies reported that early age at diagnosis was associated

with less advanced disease characteristics and improvedoutcomes [9 19] Nevertheless several studies showed com-pletely different perspectives detecting a poor prognosis inyounger patients [7 20]

A recent study conducted to analyze the prognosticsignificance of the percent ofGleason pattern 4 suggested thatan increase in the percent of Gleason pattern 4 correlatedwith adverse risk and poorer outcomes [21] Many clini-cians believe that the Gleason pattern 5 might also predictan adverse prognosis in prostatic neoplasms Our findingsshowed that both the young and the very old group had sig-nificantly higher percentages of Gleason pattern 5 than themiddle-aged and old group which indicated that the patientsyounger than 55 years or older than 75 years in this cohortappeared to have a greater likelihood of tumors with aggres-sive behavior The new grading system adopted by the new2016 WHO prostate cancer reporting guidelines was shownto provide a stratification instrument for tumors that is moreaccurate in predicting progression than the Gleason riskstratification system (le6 7 and 8 to 10) [22] One large multi-institutional study [23] revealed that the patients diagnosedwith grade group 1 tumors (Gleason score le 6) did notappear to experience metastasis to lymph nodes with a morepredictable and favorable prognosis Grade group 2 (Gleasonscore 3 + 4 = 7) also has a relatively favorable prognosis withrare metastases Comparing the percentage of grade groups3ndash5 between all three age groups we found that the percent-age in the very old group was statistically higher than that inthemiddle-aged and old group while there was no significantdifference between the percentage in the young group and themiddle-aged and old groupGiven the higher percent ofGlea-son pattern 5 there might be fewer cases of Gleason scores4 + 3 and 4 + 4 in the young group The results suggestedthat the younger and older age at the time of prostate cancerdiagnosis were associated with aggressive cancer characteris-tics

The results of our research were contrasting to thefindings of most published reports which concluded thatyounger men have better disease-free outcomes comparedto older patients [24] One reason for this finding might bethe different grouping strategy [16] It may also be due to theethnic diversity among the studies The incidence of prostatecancer in younger men had increased remarkably since theinitiation ofwidespread use of serumprostate specific antigen(PSA) screening however the results of PSA screeningwouldbe affected by individual differences in malignant latency [3]The slow-growing or indolent tumors would have a betteropportunity to be identified while missing the timely diag-nosis of early onset prostate cancer (diagnosis at le55 years)because of the very short window for detection before symp-toms appear Consequently it is no accident that youngerpatients diagnosed with early onset prostate cancer wouldtend to have more advanced disease characteristics andhigher cancer-specific mortality than other subgroups Atpresent there remains a lack of large studies on the clinico-pathological features of prostate cancer in Chinese patientswho were diagnosed with the disease at an early age Inaddition a prior report indicated that racemight play a signi-ficant role in the tumor biology of prostate cancer in younger


adults [9] In the present study the existing data suggestedthat early onset prostate cancer occurred in a higher propor-tion in the Chinese younger population

Many studies have demonstrated that men with a familyhistory or genetic mutations were at increased risk of prostatecancer particularly at a young age Edwards et al [25]argued that the risk of prostate cancer was almost 23-foldhigher in BRCA2 mutation carriers compared to those withno mutation Moreover Sigurdsson et al [26] found thatBRCA2 mutation in the Icelandic population might be apossible biomarker for an aggressive form of prostate cancerTwo other reports also confirmed that BRCA2 mutationswere associated with more advanced disease and shorterdisease-specific life expectancy [27 28] Furthermore a novelgene variant named HOXB13 G84E was identified by severalgenetic studies that found a strong relationship betweenthis mutation and susceptibility to prostate cancer Howeverinterestingly patients withHOXB13 G84E germlinemutationappeared to have a more favorable prognosis [29ndash31] Theseobservations might open up a new avenue for the screeningand diagnosis of the selected germline mutations and evenpoint to new targets for cancer therapy

There are two reasons why our study included merelypathological grading of prostate cancer in this cohort withoutinvolving the clinical or pathological stages Firstly the tumorstaging could not characterize the pathological features wellbecause the results might have been affected by the methodor timing of diagnosis Secondly the urologists could onlydetermine exact pathological stages of diseases in the patientswho underwent prostatectomy Thus there were no analysesregarding the tumor stages in this study

The present study has certain limitations and constraintsof which the most obvious is the deficiency of a retrospectiveapproach Another important limitation is that all the gradeinformation of the patients was evaluated via biopsy notsurgical specimens which could be more representative ofprostate cancer progression compared to biopsy tissuesdespite the fact that biopsy outcome may be more clinicalinstructive for urologist at tumor diagnosis moment

4 Conclusions

The results of this single institution retrospective analysisindicated that in relation to differences in Gleason scoresamong various age groups men aged le55 years or gt75 yearsshow significantly higher percentages of Gleason pattern 5compared to patients aged 56ndash75 years Younger and elderlyages in this Chinese cohort are associated with more aggres-sive disease characteristics Further studies that evaluate theclinicopathological features of prostate cancer in different agegroups are warranted

Disclosure

Guangjie Ji and Cong Huang are first authors

Competing Interests

The authors declare that they have no competing interests

Authorsrsquo Contributions

Guangjie Ji andCongHuang contributed equally to thisworkGang Song and Liqun Zhou are senior authors contributeequally

Acknowledgments

This work was supported by grants from Capital ClinicalResearch Project of Beijing Municipal Science and Technol-ogy Commission (Z141107002514089) and Wu Jieping Medi-cal Fund (320675012273) The authors thank the entire staffof Department of Urology Peking University First Hospital

References

[1] C K Zhou D P Check J Lortet-Tieulent et al ldquoProstate can-cer incidence in 43 populations worldwide an analysis of timetrends overall and by age grouprdquo International Journal of Cancervol 138 no 6 pp 1388ndash1400 2016

[2] R Siegel DNaishadham andA Jemal ldquoCancer statistics 2012rdquoCA Cancer Journal for Clinicians vol 62 no 1 pp 10ndash29 2012

[3] C A Salinas A TsodikovM Ishak-Howard andK A CooneyldquoProstate cancer in young men an important clinical entityrdquoNature Reviews Urology vol 11 no 6 pp 317ndash323 2014

[4] A Heidenreich P J Bastian J Bellmunt et al ldquoEAU guidelineson prostate cancer Part 1 screening diagnosis and local treat-ment with curative intentmdashupdate 2013rdquo EuropeanUrology vol65 no 1 pp 124ndash137 2014

[5] J L Mohler P W Kantoff A J Armstrong et al ldquoProstate can-cer version 22014rdquo Journal of the National Comprehensive Can-cer Network vol 12 no 5 pp 686ndash718 2014

[6] S K Bechis P R Carroll andM R Cooperberg ldquoImpact of ageat diagnosis on prostate cancer treatment and survivalrdquo Journalof Clinical Oncology vol 29 no 2 pp 235ndash241 2011

[7] J C Astigueta M A Abad C Morante M R Pow-Sang VDestefano and JMontes ldquoCharacteristics ofmetastatic prostatecancer occurring in patients under 50 years of agerdquo ActasUrologicas Espanolas vol 34 no 4 pp 327ndash332 2010

[8] P DellrsquoOglio R J Karnes S Joniau et al ldquoVery long-termsurvival patterns of young patients treated with radical prosta-tectomy for high-risk prostate cancerrdquo Urologic Oncology Sem-inars and Original Investigations vol 34 no 5 pp 234e13ndash234e19 2016

[9] P M Parker K R Rice J R Sterbis et al ldquoProstate cancer inmen less than the age of 50 a comparison of race and outcomesrdquoUrology vol 78 no 1 pp 110ndash115 2011

[10] O Adejoro A Alishahi and B Konety ldquoAssociation of comor-bidity age and radical surgical therapy for prostate cancerbladder cancer and renal cell carcinomardquo Urology vol 97 pp130e1ndash137e1 2016

[11] N B Delongchamps C Y Wang V Chandan et al ldquoPatholog-ical characteristics of prostate cancer in elderly menrdquo Journal ofUrology vol 182 no 3 pp 927ndash930 2009

[12] S A Brassell K R Rice P M Parker et al ldquoProstate cancer inmen 70 years old or older indolent or aggressive clinicopatho-logical analysis and outcomesrdquo Journal of Urology vol 185 no1 pp 132ndash137 2011

[13] PMandel M C Kriegmair J K Kamphake et al ldquoTumor char-acteristics and oncologic outcome after radical prostatectomy inmen 75 years old or olderrdquo Journal of Urology vol 196 no 1 pp89ndash94 2016


[14] J H Ryu Y B Kim T Y Jung et al ldquoRadical prostatectomy inKorean men aged 75-years or older safety and efficacy in com-parison with patients aged 65-69 yearsrdquo Journal of KoreanMedical Science vol 31 no 6 pp 957ndash962 2016

[15] C V Smith J J Bauer R R Connelly et al ldquoProstate cancerin men age 50 years or younger a review of the department ofdefense center for prostate disease researchmulticenter prostatecancer databaserdquo Journal of Urology vol 164 no 6 pp 1964ndash1967 2000

[16] N J Kinnear G Kichenadasse S Plagakis et al ldquoProstate can-cer in men aged less than 50 years at diagnosisrdquo World Journalof Urology vol 34 no 11 pp 1533ndash1539 2016

[17] M Roupret G Fromont M-O Bitker B Gattegno G Vallan-cien and O Cussenot ldquoOutcome after radical prostatectomy inyoung men with or without a family history of prostate cancerrdquoUrology vol 67 no 5 pp 1028ndash1032 2006

[18] M R Cooperberg S J Freedland D J Pasta et al ldquoMultiin-stitutional validation of the UCSF cancer of the prostate riskassessment for prediction of recurrence after radical prostate-ctomyrdquo Cancer vol 107 no 10 pp 2384ndash2391 2006

[19] A Becker P Tennstedt J Hansen et al ldquoFunctional and oncolo-gical outcomes of patients aged lt50 years treated with radicalprostatectomy for localised prostate cancer in a Europeanpopulationrdquo BJU International vol 114 no 1 pp 38ndash45 2014

[20] A Thorstenson H Garmo J Adolfsson and O Bratt ldquoCancerspecificmortality inmen diagnosed with prostate cancer beforeage 50 years a nationwide population based studyrdquo Journal ofUrology vol 197 no 1 pp 61ndash66 2017

[21] B Choy S M Pearce B B Anderson et al ldquoPrognostic signif-icance of percentage and architectural types of contemporarygleason pattern 4 prostate cancer in radical prostatectomyrdquoAmerican Journal of Surgical Pathology vol 40 no 10 pp 1400ndash1406 2016

[22] J I Epstein L Egevad M B Amin B Delahunt J R Srigleyand P A Humphrey ldquoThe 2014 international society of urologi-cal pathology (ISUP) consensus conference on gleason gradingof prostatic carcinoma definition of grading patterns and pro-posal for a new grading systemrdquo American Journal of SurgicalPathology vol 40 no 2 pp 244ndash252 2016

[23] H M Ross O N Kryvenko J E Cowan J P Simko T MWheeler and J I Epstein ldquoDo adenocarcinomas of the prostatewith gleason score (GS)le6 have the potential to metastasize tolymph nodesrdquo American Journal of Surgical Pathology vol 36no 9 pp 1346ndash1352 2012

[24] J Varkarakis G-M Pinggera P Sebe A Berger G Bartschand W Horninger ldquoRadical retropubic prostatectomy in menyounger than 45 years diagnosed during early prostate cancerdetection programrdquo Urology vol 63 no 2 pp 337ndash341 2004

[25] SM Edwards Z Kote-Jarai JMeitz et al ldquoTwo percent ofmenwith early-onset prostate cancer harbor germline mutations inthe BRCA2 generdquoTheAmerican Journal of HumanGenetics vol72 no 1 pp 1ndash12 2003

[26] S Sigurdsson S Thorlacius J Tomasson et al ldquoBRCA2 muta-tion in Icelandic prostate cancer patientsrdquo Journal of MolecularMedicine vol 75 no 10 pp 758ndash761 1997

[27] E Castro C Goh D Olmos et al ldquoGermline BRCAmutationsare associated with higher risk of nodal involvement distantmetastasis and poor survival outcomes in prostate cancerrdquo Jour-nal of Clinical Oncology vol 31 no 14 pp 1748ndash1757 2013

[28] A Mitra C Fisher C S Foster et al ldquoProstate cancer in maleBRCA1 and BRCA2 mutation carriers has a more aggressive

phenotyperdquo British Journal of Cancer vol 98 no 2 pp 502ndash5072008

[29] S C Smith N Palanisamy K A Zuhlke et al ldquoHOXB13 G84E-related familial prostate cancers a clinical histologic andmole-cular surveyrdquoAmerican Journal of Surgical Pathology vol 38 no5 pp 615ndash626 2014

[30] CM Ewing AM Ray EM Lange et al ldquoGermlinemutationsin HOXB13 and prostate-cancer riskrdquo New England Journal ofMedicine vol 366 no 2 pp 141ndash149 2012

[31] R Karlsson M Aly M Clements et al ldquoA population-basedassessment of germline HOXB13 G84E mutation and prostatecancer riskrdquo European Urology vol 65 no 1 pp 169ndash176 2014

Review ArticleClinical and Prognostic Effect of Plasma Fibrinogen inRenal Cell Carcinoma A Meta-Analysis

Yuejun Tian1 Mei Hong12 Suoshi Jing1 Xingchen Liu1 HanzhangWang3 XinpingWang1

Dharam Kaushik3 Ronald Rodriguez3 and ZhipingWang1

1 Institute of Urology Lanzhou University Second Hospital Key Laboratory of Gansu Province for Urological DiseasesGansu Nephro-Urological Clinical Center Lanzhou 730030 China2Drug Discovery Center School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate SchoolShenzhen 518055 China3Department of Urology University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San AntonioTX 78229-3900 USA

Correspondence should be addressed to Zhiping Wang wangzplzu163com

Received 4 August 2016 Accepted 22 September 2016 Published 5 January 2017

Academic Editor Peter Nyirady

Copyright copy 2017 Yuejun Tian et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Although numerous studies have shown that plasma fibrinogen is linked to renal cell carcinoma (RCC) risk theconsistency and magnitude of the effect of plasma fibrinogen are unclear The aim of the study was to explore the associationbetween plasma fibrinogen and RCC prognosisMethods An electronic search of Embase PubMedMEDLINE and the Cochranedatabases was performed to identify relevant studies published prior to June 1 2016 Results A total of 3744 patients with RCC from7 published studies were included in the meta-analysis The prognostic and clinical relevance of plasma fibrinogen are evaluated inRCC patients Statistical significance of the combined hazard ratio (HR) was detected for overall survival cancer-specific survivaland disease-free survival Our pooled results showed that elevated plasma fibrinogen was significantly associated with clinical stageand Fuhrman grading The level of plasma fibrinogen was not found to be associated with tumor type and gender ConclusionsElevated plasma fibrinogen is a strong indicator of poorer prognosis of patients with RCC whereas the plasma fibrinogen is notsignificantly associated with tumor typeTherefore plasma fibrinogen could be used in patients with RCC for risk stratification anddecision providing a proper therapeutic strategy

1 Introduction

Renal cell carcinoma (RCC) is the third most frequentmalignancy in the urogenital system which represents about2 to 3 of cancers in adults [1] Although the diagnosisand therapeutic modalities of RCC have changed remarkablyrapidly up to one-third of patients present with locallyadvanced or metastatic disease at initial diagnosis and thesubsequent 5-year survival rate of metastatic RCC is only 10[2ndash4] Therefore prognostic predictors of high-risk RCC areurgently needed

Plasma fibrinogen as an acute phase glycoprotein that iscommonly associated with the maintenance of hemostasishas a critical role in both inflammatory responses and cancerprogression A number of studies have shown that plasma

fibrinogen level is upregulated in various cancers and mayaccount for progression andmetastasis [5ndash8] However thereare conflicting findings on the role of plasma fibrinogen andsurvival outcomes in RCC For example Xiao et al [9] foundthat plasma fibrinogen level is an effective tumor markerto evaluate lymph node status clinical stage and distantmetastases Sasaki and Onishi [10] also demonstrated thatplasma fibrinogen was a prognostic factor predicting worseoverall survival (OS) in RCC patients However Erdem etal [11] suggested that preexisting plasma fibrinogen had nosignificant effect on the outcome of localized RCC

The aim of our overarching systematic review was to pro-vide a comprehensive and up-to-date summary for the role offibrinogen in RCC In addition we completed meta-analyses



to quantify the changes in OS cancer-specific survival (CSS)and disease-free survival (DFS)


21 Search Strategy This meta-analysis was conducted inaccordance with the guideline of Preferred Reporting Itemsfor Systematic Reviews and Meta-Analyses [12] Becausethe studies included in this meta-analysis have been pub-lished thus no ethical approval is required A literaturesearch for published original articles was conducted inEmbase PubMedMEDLINE and Cochrane databases Thelast updated search was carried out on June 1 2016 Thekey search items consist of plasma fibrinogen (ldquofibrinogenrdquoOR ldquoplasma fibrinogenrdquo) renal cell carcinoma (ldquorenal cellcancerrdquo OR ldquokidney cancerrdquo OR ldquorenal tumorrdquo OR ldquorenalcell carcinomardquo) and ldquoprognosis or prognostic or survival oroutcomerdquo and relevant variants of these search terms Thesearchwas confined to articles that were published in EnglishIn addition references of relevant articles were manuallysearched for potential eligible trials

22 Selection Criteria and Definition The eligible studieswere included only if they met the following criteria (1)articles were published in English (2) any clinical studycomprising the evaluation of plasma fibrinogen on renalcell cancer prognosis was eligible (3) the authors mustoffer the hazard ratios (HRs) and their 119901 values or theinformation that allowedmanual calculation of 95CI in thepapers Accordingly studies with the following criteria wereexcluded (1) reviews and nonoriginal articles (2) studies notrelated to RCC (3) studies that did not analyze the plasmafibrinogen and the clinical features and survival outcome (4)studies lacking sufficient data to acquire HR and its standarderror (SE)When duplicate articles emerged the one with thelargest data set was adopted Two researchers (MH and SSJ)screened titles and abstracts of all the searched literatures andverified the studies that met the inclusion criteria for nextanalysis

23 Data Extraction and Study Quality The following infor-mation was retrieved independently by 2 reviewers (MH andSSJ) from the final set of literatures publication year nameof the first author number of patients enrolled recruitmentperiod age of patients gender ratio cut-off value follow-uptime adjusted factors and Newcastle-Ottawa Scale (NOS)score The data were extracted from the original articles Ifa study provided the results of both multivariate outcomeand univariate outcome we chose the former There are nostandard quality assessment tools for prognostic studies insystematic reviews Study quality was independently appliedaccording to the ldquoNOS scorerdquo for a cohort study that includes3 domains with 8 items Studies with scores of 6 or higherwere graded as high quality [13]

24 Statistical Analysis The pooled HR and its correspond-ing 95 CI were calculated to assess the association betweenplasmafibrinogen andpatient survivalThepooledORand its

corresponding 95 CI were used to quantitatively determinethe association between plasma fibrinogen and the clinicalparameters of RCC Statistical heterogeneity among studieswas assessed using Cochranrsquos 119876 test and Higgins 1198682 statistic[14] A fixed-effect model (MantelndashHaenszel method) wasused to calculate parameters when no obvious heterogeneityexisted among studies (1198682 gt 50 suggested high heterogene-ity) Sensitivity analysis was performed to test the reliability ofthe total pooled results by sequential omission of individualstudies Publication bias was assessed using funnel plots andEggerrsquos test All statistical manipulations in this meta-analysiswere undertakenusing Stata 140 software (StataCorporationCollege Station TX)with 2-tailed119901 values A119901 value oflt005was considered the significance level

3 Results

31 Study Characteristics The initial search identified 48studies that were considered eligible according to the inclu-sion criteria Eventually 7 studies were included [10 11 15ndash19](Figure 1) Two studies provided original information on therelationships between plasmafibrinogen and clinical parame-ters in RCC patients directly [10 18]Themain characteristicsof the 19 studies included in our meta-analysis are shown inTable 1 Our data has 3744 patients from 6 countries (ChinaAustria Turkey Germany Japan and Korea)

Plasma fibrinogen levels were measured in 4 studiesby a functional method based on the Clauss assay [11 15ndash17] fibrinogen tests were included in the coagulation panelamong the preoperative workups in one study [19] and inthe rest of the two studies no comments were made on thispoint [10 17] Differences in the cut-off value for high plasmafibrinogen were observed among the studies The high levelof the plasma fibrinogen was considered to be positive and alow level was considered to be negative

32 Relationship between PlasmaFibrinogen andRCCProgno-sis The forest plots of the meta-analyses for plasma fibrino-gen are shown in Figure 2 and Table 2 The pooled HRs werestatistically significant for OS (HR 213 95 CI 174ndash261)CSS (HR 312 95 CI 219ndash444) and DFS (HR 167 95CI 130ndash215)

33 Association between Plasma Fibrinogen in RCC and Clin-ical Parameters As shown in Figure 3(a) elevated plasmafibrinogen was significantly higher in advanced RCC (T3-T4)than in early stage RCC (T1-T2) (OR = 369 95 CI 181ndash754 119901 = 00003) The pooled OR from 3 studies including1430 RCC grade G1-G2 and 787 RCC grade G3-G4 patientsis presented in Figure 3(b) (OR = 204 95 CI 168ndash248119901 lt 000001) which indicates that plasma fibrinogen wassignificantly higher in RCC patients of low Fuhrman gradesthan in those of high Fuhrman grades The pooled OR fromthree studies including 1834 ccRCC (clear cell renal cellcarcinoma) and 383 non-ccRCC cases is shown in Figure 3(c)(OR = 079 95 CI 062ndash101 119901 = 006) indicating thatplasma fibrinogen was not strongly associated with tumortype in RCC patients The pooled OR from four studies


Records identified through database searching (n = 48)

Records screened (n = 26)

Full-text articles assessed for eligibility (n = 16)

Records excluded after title andabstract review (n = 10) lettersreviews and meeting abstracts (n = 5)nonprognostic (n = 2) not relatedto this research topic (n = 3)

Full-text articles excluded withreasons (n = 9) non-RCC category(n = 2) no available data(n = 4) with overlappingpatients (n = 3)

Studies included in quantitative synthesis (meta-analysis) (n = 7)

Records after duplicates were removed (n = 26)

Figure 1 Flow chart of study selection

including 1601males and 596 females is shown in Figure 3(d)(OR = 086 95 CI 070ndash105 119901 = 014) indicating thatplasma fibrinogen was not strongly associated with gender inRCC patients (Table 3)

34 Publication Bias The Egger and Begg tests did notindicate any significant publication bias in the analysis ofOS in RCC (119875begg = 0707 119875egger = 0272) No evidence ofasymmetry was found in our funnel plot (Figure 4)

4 Discussion

Numerous researchers have reported various results relatingplasma fibrinogen to RCC However up to now no meta-analysis had been performed for the studies evaluatingplasma fibrinogen as a prognostic marker in RCC

In the current study we enrolled 7 eligible studies com-paring the correlations of RCC according to plasma fibrino-gen The individual data were organised according to OSCSS and DFS and we identified the notion that an elevatedplasma fibrinogen level predicts shorter OS CSS and DFSOur results also indicate that RCC patients with elevatedplasma fibrinogen level are likely to have a higher patho-logical T stage and a lower Fuhrman grade The estimatedpooled HRs of 7 trials for RCC were statistically significantsuggesting that plasma fibrinogen is a strong predictor ofpoor prognosis among patients with RCC Our analysis helpsto elucidate the results of individual studies which are relatedto the hypothesis that plasma fibrinogen is a prognostic factorfor RCC in addition to the identification of the high-risk sub-groups of patients for whom adjuvant therapy may be useful

The biological mechanism of plasma fibrinogen canexplain its prognostic significance in RCC It has been shownthat tumor progression may set up a cascade of events which

includes increased systemic inflammatory response which inturn leads to increased plasma fibrinogen level [20ndash22]

Other studies show that fibrinogen can be endogenouslysynthesised by cancer cells [23 24] Fibrinogen is an extracel-lular matrix element and regulates the growth of cancer cellsby binding to the vascular endothelial growth factor (VEGF)fibroblast growth factor-2 (FGF-2) and platelet-derivedgrowth factor (PDGF) [24ndash26]The binding of growth factorspromotes cellular adhesion proliferation and metastasisduring angiogenesis and tumor cell growth Fibrinogenpromotes platelets to adhere to tumor cells and plateletsalso conversely induce more fibrinogen to aggregate aroundtumor cells by forming thrombin Fibrinogen and plateletsare promoted mutually and protect tumor cells from naturalkiller cytotoxicity [27] Furthermore using cell line modelsit has been shown that highly concentrated fibrinogen caninduce epithelial-mesenchymal transition (EMT) by increas-ing the expression of vimentin and reducing expression of E-cadherin which enhances cancer cell invasion andmetastasis[28] Moreover in vitro studies have shown that one possiblemechanism is the association between tissue factor (TF) andVEGF TF which is expressed on the surface of tumor cells isa key inducer of the coagulation pathway in carcinogenesis[29] VEGF stimulates TF in endothelial cells leading toactivation of the coagulation cascade which includes fibrino-gen [25 30] Therefore in RCC which is characterised asa hypervascular tumor it may be that an elevated plasmafibrinogen level is clearly associated with more aggressivepathological features and subsequent worse survival [16 31]

To our knowledge this meta-analysis is the first studyto systematically evaluate the clinical and prognostic valueof plasma fibrinogen level in RCC The elevated plasmafibrinogen level predicted poorer pathological outcomes andwas a significant risk factor affecting survival

However several limitations of this study need to beacknowledged First the applied methods for detecting


Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD

HlactatedehydrogenaseHbhemoglobin

PSperform

ance

statusN

An

otavailable


Study or subgroup log[hazard ratio] SE Weight Hazard ratioIV fixed 95 CI IV fixed 95 CI

Hazard ratio

Du et al 2013Erdem et al 2014Lee et al 2016Niedworok et al 2015Pichler et al 2013Sasaki and Onishi 2015

06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)

10 200Favours negative

1010005Favours positive

Test for overall effect Z = 730 (p lt 000001)Heterogeneity 1205942

= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042

Erdem et al 2014Lee et al 2016Obata et al 2016Pichler et al 2013

Total (95 CI)

2 5 101Favours negative


Heterogeneity 1205942= 247 df = 3 (p = 048) I2 = 0

Test for overall effect Z = 630 (p lt 000001)

(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123

Du et al 2013Erdem et al 2014Obata et al 2016

Total (95 CI)





(c)

Figure 2 Results of subgroup analysis of the association between plasma fibrinogen and OSCSSDFS of RCC (a) Six studies includedinvestigating the relationship between OS and plasma fibrinogen (b) Four studies included investigating the relationship between CSS andplasma fibrinogen (c)Three studies included investigating the relationship betweenDFS and plasma fibrinogen CI confidence interval CSScancer-specific survival DFS disease-free survival OS overall survival RCC renal cell carcinoma

Table 2 HR values of the OS CSS and DFS of the RCC

Outcome Studies (119899) Patients HR 95 CI 119901 value Model Chi2 1198682 119901 valueOS 6 3143 213 174ndash261 0000 Fixed 526 5 038CSS 4 3234 312 219ndash444 0000 Fixed 247 0 048DFS 3 1015 167 130ndash215 0000 Fixed 387 48 014CI confidence interval CSS cancer-specific survival Fixed fixed inverse variance model HR hazard ratio 1198682 119868-squared OS overall survival Randomrandom IndashV heterogeneity model DFS disease-free survival

plasma fibrinogen and the cut-off values were varied in theeligible studies which could cause heterogeneity among thestudies Second studies in other languages were excludedexcept for English the literatures were not comprehensiveThird other clinical factors such as race age and gender ineach study might lead to bias Fourth subgroup analysis andmetaregression were performed by type of RCC (clear cell

RCC versus non-clear cell RCC) we lumped together thenon-clear cell RCC group but in this group there are a lotof different kinds of malignancies with different biologicalbehaviors and genetic abnormalities which might renderthe results less reliable Finally we could not ascertain arelationship between plasma fibrinogen and tumor type ofRCC patients clear cell RCC is more aggressive than other


Odds ratioM-H random 95 CI

Odds ratioM-H random 95 CIWeight

233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000

TotalEventsTotalEventsT1-T2

6443816

698

130553898

1941

206637

276165

143184

T3-T4Study or subgroup

Total (95 CI) Total events



Heterogeneity 1205912 = 025 1205942= 639 df = 2 (p = 004) I2 = 69

Test for overall effect Z = 359 (p = 00003)

Sasaki and Onishi 2015Obata et al 2016Lee et al 2016

(a)

Odds ratioOdds ratioM-H fixed 95 CIM-H fixed 95 CIWeightTotalEventsTotalEventsStudy or subgroup G3-G4 G1-G2

418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]

204 [168 248]Total (95 CI) Total events




= 391 df = 2 (p = 014) I2 = 49


(b)

Odds ratioOdds ratioM-H fixed 95 CIM-H fixed 95 CIWeightTotalEvents TotalEventsStudy or subgroup Non-ccRCCCcRCC

074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146

159Total (95 CI) Total events

2 5Favours negative


Test for overall effect Z = 185 (p = 006)Heterogeneity 1205942

= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)

Odds ratioOdds ratioM-H fixed 95 CIM-H fixed 95 CIWeightTotalEventsTotalEventsStudy or subgroup Male Female


Sasaki and Onishi 2015Obata et al 2016Lee et al 2016 544

4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)

Figure 3 Results of subgroup analysis of the association between plasma fibrinogen and clinicopathological parameters (a) The pooled ORfrom three studies including 1941 stage T1 and T2 and 276 stage T3 and T4 cases (b) The pooled OR from three studies including 1430 gradeG1 and G2 and 787 grade G3 and G4 cases (c) The pooled OR from three studies including 1834 ccRCC and 383 non-ccRCC cases (d) Atotal of 2277 RCC patients were pooled from three studies to assess whether plasma fibrinogen in RCC was associated with gender ccRCCclear cell renal cell carcinoma RCC renal cell carcinoma


Beggrsquos funnel plot with pseudo 95 confidence limits

1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)

Eggerrsquos publication bias plot

minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)

Figure 4 Funnel plots of Begg and Egger were used to detect publication bias on overall survival (OS) They showed no publication bias onOS in Beggrsquos test (a) and Eggerrsquos test (b)

Table 3 Plasma fibrinogen according to clinicopathological features

Outcome of interest Studies (119899) Patients OR 95 CI 119901 value Model Chi2 1198682 119901 valueT3-T4 versus T1-T2 3 2217 369 181ndash754 00003 Random 639 69 004G3-G4 versus G1-G2 3 2217 204 168ndash248 0000 Fixed 391 49 014CcRCC versus non-ccRCC 3 2217 079 062ndash101 006 Fixed 138 0 006Male versus female 3 2217 086 070ndash105 014 Fixed 283 29 024CcRCC clear cell renal cell carcinoma Fixed fixed inverse variance model 1198682 119868-squared OR odds ratio Random random IndashV heterogeneity model RCCrenal cell carcinoma

subtypes however only one study determined the plasmafibrinogen level differences between clear cell and othertypes and found no statistically significant differences In thisrespect other factors might also play a role in affecting RCCprognosis such as clinical stage and Fuhrman grade

In conclusion this meta-analysis indicates that highplasma fibrinogen level is closely associated with poor sur-vival and aggressive clinical feature in patients with RCCWhile these are hypothesis generating results the excellentaccessibility and low cost of plasma fibrinogen should furtherfacilitate its wider application in patients with RCC for riskstratification and decision-making of individualized treat-ment We require further validation of our study

Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper


Yuejun Tian and Mei Hong contributed equally to this work

Acknowledgments

This paper was supported by the National Natural ScienceFoundation of China (Grant no 81372733H1619) and theNational Science Foundation of China (no 81302240)

References

[1] C EDeSantis C C Lin A BMariotto et al ldquoCancer treatmentand survivorship statistics 2014rdquo CA A Cancer Journal forClinicians vol 64 no 4 pp 252ndash271 2014

[2] S Custodio A Joaquim V Peixoto et al ldquoMetastatic renalcell carcinoma the importance of immunohistochemistry indifferential diagnosisrdquo Case Reports in Oncology vol 5 no 1pp 30ndash34 2012

[3] L J Eisengart G R MacVicar and X J Yang ldquoPredictors ofresponse to targeted therapy in renal cell carcinomardquo Archivesof Pathology and Laboratory Medicine vol 136 no 5 pp 490ndash495 2012

[4] X Yu BWang X Li et al ldquoThe significance of metastasectomyin patients with metastatic renal cell carcinoma in the eraof targeted therapyrdquo BioMed Research International vol 2015Article ID 176373 8 pages 2015

[5] Y Mei S Zhao X Lu H Liu X Li and R Ma ldquoClinical andprognostic significance of preoperative plasma fibrinogen levelsin patients with operable breast cancerrdquo PLoS ONE vol 11 no1 Article ID e0146233 2016

[6] K T Troppan T Melchardt K Wenzl et al ldquoThe clinicalsignificance of fibrinogen plasma levels in patients with diffuselarge B cell lymphomardquo Journal of Clinical Pathology vol 69 no4 pp 326ndash330 2015

[7] D Zhang X Zhou W Bao et al ldquoPlasma fibrinogen levels arecorrelated with postoperative distant metastasis and prognosisin esophageal squamous cell carcinomardquo Oncotarget vol 6 no35 pp 38410ndash38420 2015

[8] L-R Zhu J Li P Chen Q Jiang and X-P Tang ldquoClinicalsignificance of plasma fibrinogen andD-dimer in predicting the


chemotherapy efficacy and prognosis for small cell lung cancerpatientsrdquo Clinical and Translational Oncology vol 18 no 2 pp178ndash188 2016

[9] B Xiao L-LMa S-D Zhang et al ldquoCorrelation between coag-ulation function tumor stage and metastasis in patients withrenal cell carcinoma a retrospective studyrdquo Chinese MedicalJournal vol 124 no 8 pp 1205ndash1208 2011

[10] T Sasaki and T Onishi ldquoPretherapeutic plasma fibrinogen levelis an independent survival predictor in renal cell carcinomardquoOncology Research and Treatment vol 38 no 7-8 pp 374ndash3782015

[11] S Erdem A S Amasyali O Aytac K Onem H Issever andO Sanli ldquoIncreased preoperative levels of plasma fibrinogenand d dimer in patients with renal cell carcinoma is associatedwith poor survival and adverse tumor characteristicsrdquo UrologicOncology Seminars andOriginal Investigations vol 32 no 7 pp1031ndash1040 2014

[12] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses ThePRISMA statementrdquo British Medical Journal vol 339 no 7716pp 332ndash336 2009

[13] A Stang ldquoCritical evaluation of the Newcastle-Ottawa scale forthe assessment of the quality of nonrandomized studies inmeta-analysesrdquo European Journal of Epidemiology vol 25 no 9 pp603ndash605 2010

[14] J P T Higgins S G Thompson J J Deeks and D G AltmanldquoMeasuring inconsistency in meta-analysesrdquo British MedicalJournal vol 327 no 7414 pp 557ndash560 2003

[15] J Du J-H Zheng X-S Chen et al ldquoHigh preoperative plasmafibrinogen is an independent predictor of distantmetastasis andpoor prognosis in renal cell carcinomardquo International Journal ofClinical Oncology vol 18 no 3 pp 517ndash523 2013

[16] M Pichler G CHutterer T Stojakovic SMannweiler K Pum-mer and R Zigeuner ldquoHigh plasma fibrinogen level representsan independent negative prognostic factor regarding cancer-specificmetastasis-free aswell as overall survival in a Europeancohort of non-metastatic renal cell carcinoma patientsrdquo BritishJournal of Cancer vol 109 no 5 pp 1123ndash1129 2013

[17] C Niedworok B Dorrenhaus F Vom Dorp et al ldquoRenal cellcarcinoma and tumour thrombus in the inferior vena cavaclinical outcome of 98 consecutive patients and the prognosticvalue of preoperative parametersrdquoWorld Journal of Urology vol33 no 10 pp 1541ndash1552 2015

[18] J Obata N Tanaka R Mizuno et al ldquoPlasma fibrinogen levelan independent prognostic factor for disease-free survival andcancer-specific survival in patients with localised renal cellcarcinomardquo BJU International vol 118 no 4 pp 598ndash603 2016

[19] H Lee S E Lee S-S Byun H H Kim C Kwak and S KHong ldquoPreoperative plasma fibrinogen level as a significantprognostic factor in patients with localized renal cell carcinomaafter surgical treatmentrdquoMedicine (United States) vol 95 no 4Article ID e2626 2016

[20] G Y Lip B S Chin and A D Blann ldquoCancer and theprothrombotic staterdquoThe Lancet Oncology vol 3 no 1 pp 27ndash34 2002

[21] V Seebacher S Polterauer C Grimm et al ldquoThe prognosticvalue of plasma fibrinogen levels in patients with endometrialcancer a multi-centre trialrdquo British Journal of Cancer vol 102no 6 pp 952ndash956 2010

[22] H-J Son J W Park H J Chang et al ldquoPreoperative plasmahyperfibrinogenemia is predictive of poor prognosis in patients

with nonmetastatic colon cancerrdquo Annals of Surgical Oncologyvol 20 no 9 pp 2908ndash2913 2013

[23] P J Simpson-Haidaris and B Rybarczyk ldquoTumors and fibrino-gen The role of fibrinogen as an extracellular matrix proteinrdquoAnnals of the New York Academy of Sciences vol 936 pp 406ndash425 2001

[24] A Sahni P J Simpson-haidaris S K Sahni G G Vaday and CW Francis ldquoFibrinogen synthesized by cancer cells augmentsthe proliferative effect of fibroblast growth factor-2 (FGF-2)rdquoJournal ofThrombosis andHaemostasis vol 6 no 1 pp 176ndash1832008

[25] A Sahni and CW Francis ldquoVascular endothelial growth factorbinds to fibrinogen and fibrin and stimulates endothelial cellproliferationrdquo Blood vol 96 no 12 pp 3772ndash3778 2000

[26] E Witsch M Sela and Y Yarden ldquoRoles for growth factors incancer progressionrdquo Physiology vol 25 no 2 pp 85ndash101 2010

[27] S Zheng J Shen Y Jiao et al ldquoPlatelets and fibrinogenfacilitate each other in protecting tumor cells fromnatural killercytotoxicityrdquo Cancer Science vol 100 no 5 pp 859ndash865 2009

[28] Y-J Shu H Weng R-F Bao et al ldquoClinical and prognos-tic significance of preoperative plasma hyperfibrinogenemiain gallbladder cancer patients following surgical resection aretrospective and in vitro studyrdquo BMC Cancer vol 14 no 1article 566 2014

[29] F R Rickles S Patierno and P M Fernandez ldquoTissue factorthrombin and cancerrdquo Chest vol 124 no 3 supplement pp58Sndash68S 2003

[30] H M W Verheul K van Erp M Y V Homs et al ldquoThe rela-tionship of vascular endothelial growth factor and coagulationfactor (fibrin and fibrinogen) expression in clear cell renal cellcarcinomardquo Urology vol 75 no 3 pp 608ndash614 2010

[31] I V Tsimafeyeu L V Demidov A V Madzhuga O VSomonova and A L Yelizarova ldquoHypercoagulability as aprognostic factor for survival in patients with metastatic renalcell carcinomardquo Journal of Experimental and Clinical CancerResearch vol 28 no 1 article 30 2009

Research ArticleBaseline Chronic Kidney Disease and Ischemic Method ofPartial Nephrectomy Are Important Factors for the Short- andLong-Term Deterioration in Renal Function for Renal CellCarcinoma Staged T1-T2 A Retrospective Single Center Study

Sung Han Kim Jae Young Joung Ho Kyung Seo Kang Hyun Lee and Jinsoo Chung

Department of Urology Center for Prostate Cancer Research Institute and Hospital of the National Cancer CenterGoyang Republic of Korea

Correspondence should be addressed to Jinsoo Chung cjs5225nccrekr

Received 21 October 2016 Accepted 28 November 2016


Copyright copy 2016 Sung Han Kim et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The renal functions of 215 patients (24with benign renalmass the rest with RCC staged T1-T2) who underwent partial nephrectomy(PN) between 2003 and 2014 were evaluated to identify predictors of short- and long-term deterioration in renal function after PNamong renal cell carcinoma (RCC) patients with or without preoperative predisposition to chronic kidney disease (CKD) andamong patients with benign renal mass The 1- and 5-year predictive factors for de novo CKD were statistically analyzed Theincidence of de novo CKD differed significantly (119901 lt 0001) among patients with benign renal mass those with RCC but nopreoperative CKD predisposition and those with RCC combined with preoperative CKD predisposition Independent predictorsfor de novo CKD at 1 year postoperatively included intraoperative ischemic method ECOG score elevated albumin levels malesex and smoking exposure (in pack-years) Predictors for de novo CKD at 5 years postoperatively included hypertension highpreoperative albumin levels De Ritis ratio (aspartate aminotransferasealanine aminotransferase ratio) smoking exposure andpreoperative predisposition to CKD Preoperative predisposition to CKD and ischemic method applied during PN along withother preoperative parameters were important factors affecting postoperative renal function deterioration in patients with T1-T2RCC

1 Introduction

With the improvement in diagnostic modalities and wide-spread implementation of early screening systems the abilityto detect small early-stage localized renal cell carcinoma(RCC) has increased which has made it possible to initiateoncological treatment with improved safety and efficacyresulting in prolonged survival for patients with RCC [1]Furthermore the standard treatment strategy for RCC stagedT1-T2 has changed from radical nephrectomy to partialnephrectomy (PN) taking into account comorbidities andlife expectancy [2] as a strong association was found betweenrenal function decline and the surgical management of smallrenal masses [2ndash4] PN should also be recommended as thefirst therapeutic option for other types of RCC includingfamilial RCC von Hippel-Lindau RCC or bilateral RCC as

well as in patients with a history of underlying chronic renaldisease

The effect of various aggravating and protective factorswas investigated during the postoperative follow-up of RCCpatients who underwent PN with the aim to identify the keyaspects involved in preserving renal function and preventingor delaying the development of chronic kidney disease (CKD)[5] It was found that the volume of resected renal tissuewhich affects postoperative renal function depends on thelocation and size of the tumor lesions the presence ofperitumoral structures and renal vascular state However itis not easy to predict the postoperative development of CKDin RCC patients because that would require monitoring verymany factors during the follow-upwhose range of actionmayor may not overlap in time (ie some should be monitoredduring the short-term follow-up while others during the



long-term follow-up) Moreover the moment and directionof aggravation of renal function in RCC patients were onlyevaluated in comparison to the evolution of patients whounderwent PN but had normal kidneys

Several groups have attempted to describe the functionaloutcomes after renal surgery in terms of serum creatininelevels as indicative of kidney function [6 7] However theNational Kidney Foundation guidelines assert that the assess-ment of renal function should be based on the estimatedglomerular filtration rate (eGFR) which is a more accuratemeasure of kidney function because it considers serumcreatinine levels in addition to the patientrsquos age sex raceand body mass index A reduced eGFR has been associatedwith increased risk of death cardiovascular events andhospitalization [8] end-stage renal disease characterized bylow eGFR leads to significant morbidity and mortality andrepresents a major burden to any healthcare system

Therefore in the present study we monitored the changein renal function assessed in terms of eGFR in patientswho underwent PN for RCC staged T1-T2 The patientswere stratified into two groups based on their predispositionto CKD and these two groups were compared against acontrol group (which included patients who underwent PNfor benign renal mass) in terms of renal function Thedevelopment of de novo CKD and the predictive factors forrenal deteriorationwere evaluated statistically for the first andfifth year after PN in patients with a predisposition for CKDand in those without such predisposition

2 Patients and Methods

21 Ethical Statement Following approval by the Institu-tional Review Board (IRB) of the Research Institute andHospital of the National Cancer Center (IRB approval num-ber NCC2014-0193) every patient record was anonymizedand deidentified prior to analysis All study protocols wereconducted according to the ethical guidelines of the WorldMedical Association Declaration of Helsinki-Ethical Princi-ples for Medical Research Involving Human Subjects Theneed for written consent was waived by the IRB

22 Patients The Kidney Cancer Database of the NationalCancer Center in Korea was searched for records of RCCpatients who underwent PN between 2003 and 2014 Themedical records of 252 RCC patients who underwent PNin that period were identified in order to retrospectivelyevaluate the development of de novo CKD and its predictivefactors Patients with a single kidney metastatic RCC othermetastases to the kidney or any preoperative histories ofkidney intervention or therapies were excluded resultingin a final enrollment of 215 patients including 24 (112)PN patients with benign renal mass The cases with benignrenal masses diagnosed pathologically after PN included6 renal cysts 1 pyelonephrosis 1 pheochromocytomas 3cystic nephromas 9 angiomyolymphomas 1 hemangioen-dothelioma 1 Castlemanrsquos disease 1 mucinous adenoma and1 case with no tumor All enrolled patients had completefollow-up data regarding renal function for at least one year

postoperatively whereas 124 (577) patients had such datafor five years postoperatively

The clinicopathological parameters including intraoper-ative findings smoking history and laboratory findings wereused for the analysis of predictive factors for renal functionaldeterioration within one year and after five years from PNRenal function was assessed based on serum creatininelevels evaluated at the following points preoperatively andat 1 3 6 9 12 24 36 48 and 60 months postoperativelyPreexisting CKD was defined as a preoperative eGFR lt60mLmin173m2 (stage 3 according to the National KidneyFoundation guidelines) [9] Postoperative CKD acute kidneyinjury and renal functional deterioration were defined eitheras a decline in the renal function using the classification givenin the National Kidney Foundation guidelines from stages 1or 2 to stage 3 or as a decline in the renal condition fromstage 3A (eGFR 45ndash59mLmin173m2) to stage 3B (eGFR30ndash44mLmin173m2) [9]

23 Definition of Groups by Preoperative Condition Twogroups of RCC patients were defined according to thepreoperative state of the renal function the preoperative non-CKD RCC group (non-CKD group) and the preoperativeCKD RCC group (CKD group) A third group was definedincluding the patients with benign renal disease (controlgroup)

24 Definition of Renal Function Aggravation for Each GroupRenal function deterioration was defined differently for eachgroup For the non-CKD and control groups it was definedas having a postoperative eGFR lt 60mLmin173m2 for theCKD group it was defined as a decline in the renal functionfrom CKD stage 3A to 3B or from CKD stage 3B to 4 [9]

25 Statistical Analyses The differences in the occurrenceof postoperative de novo CKD or renal functional deteri-oration at the first year and at the fifth year of follow-upwere statistically evaluated for the three groups Time toprogression either to renal functional deterioration or to denovoCKDdevelopmentwas assessed using theKaplan-Meieranalysis with the log-rank test The predictive risk factors forrenal functional deterioration or de novo CKD developmentwere analyzed using the Cox-regression hazard analysis withbackward selection (alpha = 005) Statistical analyses wereperformed by using Stata software (Release 92 StataCorpCollege Station TX USA) A p value of lt 05 was deemedstatistically significant

3 Results

A total of 145 (674) patients were included in the non-CKD group whereas 46 (214) patients were included inthe CKD group (Table 1) The median follow-up time for allpatients was 43 months (12ndash134 months) All RCC patients(888) had T1 stage RCC and only 05 experienced tumorrecurrence despite the tumor-free resection margin A totalof 846 of the patients underwent open PN with a medianischemic time of 21 minutes warm ischemia was applied in


Table 1 Patient baseline demographics (119873 = 215)

Parameter Median (range) Percentage or SDAge (years) 55 (24ndash78)Gender (malefemale) 15461 716284BMI (kgm2) 247 (166ndash398)Underlying disease

Diabetes 32 149Hypertension 89 414Hypercholesterolemia 9 42Ischemic heart disease 5 23

Anticoagulation therapy history 8 37Aspirin therapy 21 98ASA score 012 112958 52144237ECOG 012 143702 66532609Smoking 121 563Smoking volume (PY) 8 (0ndash87)Follow-up duration (mo) 43 (12ndash134)Preoperative laboratory findings

Hemoglobin 14 (86ndash175)Albumin 46 (36ndash59)Calcium 94 (83ndash109)Total Cholesterol 1855 (97ndash335)De Ritis ratio (ASTAPT) 11 (03ndash31)Creatinine 10 (06ndash18)

Estimated GFR 697 (373ndash1034)Preoperative PADUA score 80 (5ndash12)Tumor number 24 (03ndash16)Lowintermediatehigh 678662 312400288Longitudinal Infinterpolarmedmidsup 604236050 27919514279233RENAL score 7 (3ndash18)

Antpost 107108 498502Disease category

PreoperativeCKD RCC 46 214Non-CKD RCC 145 674Benign renal mass 24 112

Operative methodLaparoscopy 33 154Open 182 846

Pathologic T stageT1 193 898T2 22 102

Fuhrman grade1 20 932 131 6093 43 2004 2 14Unknown 19 88

Margin positive 30 140Safety resection margin (mm) 20 (10ndash90)Ischemic method warmcoldno 1314242 609195195Ischemic time (min) 21 (0ndash70)Number of clamping vessels 2 (1ndash4)Tumor diameter (cm) 20 (05ndash22)


Table 1 Continued

Parameter Median (range) Percentage or SDPostoperative 5-year follow-up

Creatinine 16 (06ndash22)eGFR 781 (29ndash1188)

HistologyClear cell pure 167 777Papillary 16 74Chromophobe 8 37Benign renal mass 24 112

Recurrence 1 05Time to recurrence 521 (48ndash488)SD standard deviation MSKCC Memorial Sloane Kettering Cancer Center LN lymph node FU follow-up PD progressive disease SD stable disease PRpartial response CR complete response RECIST Response Evaluation Criteria In Solid Tumors

Table 2 Creatinine and estimated GFR data at baseline (119873 = 215)and postoperative first (119873 = 215) and last year (119873 = 124)

Median (minndashmaxrange) or119873 (percentage

)Baseline

Baseline sCr 10 (06ndash18)Baseline eGFR 697 (373ndash1034)

First yearChange of sCr at first year 20 (1ndash4)Change of eGFR at first year 695 (256ndash1291)First year CKD 14 (65)Time to CKD at first year (mo) 13 (2ndash16)

Fifth yearLast CKD 32 (149)Time to CKD at fifth year 354 (09ndash1337)Change of sCr at fifth year 10 (06ndash22)Change of eGFR at fifth year 781 (29ndash1188)

most cases (609) Other baseline demographics includingclinicopathological characteristics and intraoperative find-ings are described in Table 1

When comparing the data regarding renal functionchanges from the 5-year follow-up with those from the 1-year follow-up there were higher changes in eGFR after 5-years than after 1 year (5 years 781mLmin173m2 1 year695mLmin173m2) and higher development of de novoCKD after 5 years than the after 1 year (5 years 149 1 year65 Table 2) The incidence of de novo CKD in the controlnon-CKD and CKD groups was respectively 0 28 and52 after 1 year and 0 32 and 65 after 5 years (both119901 lt 0001 Figure 1) However the difference regarding theincidence of de novo CKD between the control and the non-CKD groups was not statistically significant after 1 year (119901 =0648) compared to the control group the non-CKD grouphad a decline in renal function after five years of follow-up(Figure 1(b)) The median time to develop CKD as identified

after 1 and 5 years after PN was 13 (2ndash16) months and 354(09ndash1337) months respectively (p lt 0001 Table 2 Figure 1)

The results of the multivariate analyses of predictivefactors for renal functional deterioration or de novo CKDdevelopment given in terms of hazard ratio (HR) and 95confidence interval (95 CI) for each variable that showedsignificance at 1 year after PN (p lt 005 Table 3) wereas follows cold ischemia HR = 0053 95 CI = 0004ndash0699 no ischemia HR = 0077 95 CI = 0007ndash0827Eastern Cooperative Oncology Group (ECOG) score 1 HR= 00002 95 CI = 00001ndash0077 ECOG score 0 HR =0002 95 CI = 00001ndash0203 preoperative albumin levelsHR = 0010 95 CI = 00001ndash0793 male sex HR = 3140195 CI = 3037ndash324649 and smoking exposure expressedas pack-years HR = 1061 95 CI = 1021ndash11036 For eachvariable that showed significance at 5 years after PN (p lt005 Table 3) the results of the multivariate analyses were asfollows hypertension HR = 16991 95 CI = 2666ndash108298preoperative albumin levels HR = 28172 95 CI = 2177ndash364577 De Retis ratio of aspartate aminotransferasealanineaminotransferase (ASTALT) HR = 13772 95 CI = 1330ndash142550 smoking exposure HR = 1081 95 CI = 1028ndash1137and preoperative CKD HR = 13158 95 CI = 1654ndash104659

4 Discussion

In the present study we evaluated renal functional deteriora-tion and its predictive factors at one and five years after PNin patients with RCC staged T1-T2 The CKD and non-CKDgroups accounted for 214 and 674 of our study samplerespectively which is in agreement with previously reportedrates for CKD (20ndash24) [9]The RCC patients were stratifiedinto CKD or non-CKD groups according to the preoperativestate of their renal function to rule out the oncologic effect ofRCC itself on the change in renal function and to differentiateamong the factors predisposing for CKD in RCC patientswhose renal function is recovering after PN In additionwe also considered a control group which included patientswho underwent PN for removal of benign renal masses Weexamined and compared the postoperative changes in renal


Short-term follow-upCu

mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250

Follow-up time (months)

pre-CKD RCCpre-non-CKD RCCBenign renal mass

pre-CKD RCC-censoredpre-non-CKD RCC-censoredBenign renal mass-censored

(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up

Category diseasepre-CKD RCCpre-non-CKD RCCBenign renal mass


00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)

Figure 1 Incidence curve for chronic kidney disease (CKD) (a) during the short-term (first year postoperatively) and (b) during the long-term (fifth year postoperatively) follow-up in patients with renal cell carcinoma (RCC) staged T1-T2 treated with partial nephrectomy

function for patients of the CKD non-CKD and controlgroups

As expected the changes in renal function indicatedmoredeterioration and higher incidence of de novo CKD within 5years after PN than within the first year (149 versus 65Table 2) The number of patients who developed de novoCKD was almost twice as high (p lt 0001 Figure 1) in theCKD group than in the non-CKD group both during thefirst year (52 versus 28) and during the fifth year (65versus 32) of follow-up whereas none of the patients in thecontrol group showed postoperative development of CKDFurthermore for the first postoperative year there was nostatistically significant difference between the control groupand the non-CKD group regarding the number of patientswith de novo CKD (Figure 1(b)) These results indicate thatin patients with small localized RCC staged T1-T2 the long-term deterioration of renal function is influenced mostly bythe baseline state of the renal function rather than by thePN procedure or by RCC itself Therefore an active closemonitoring of renal function is necessary in such high-riskpatients undergoing PN especially those already predisposedto CKD in the preoperative stage Patients with benigntumors undergoing PN are unlikely to experience deteriora-tion of the renal function merely due to PN itself Howeverthe renal function in RCCpatients with no preoperative CKDshould be monitored for at least 5 years after PN and furtherinvestigation should be performed to identify and monitorpotential aggravating factors

We assessed the differences between short-term- andlong-term-acting risk factors for renal function deteriorationand development of de novo CKD We considered all knownrisk factors reported in previous studies [4 8ndash13] Onlysmoking exposure was found as a significant factor for boththe short-term and long-term deterioration of renal function(p lt 005 Table 3) Smoking is known to have detrimentaleffects on the state of the vessels and kidneys and heaviersmoking may have a more significant effect on renal functionrecovery [1 7]

We found that the intraoperative ischemic method (coldischemia HR = 0053 no ischemia HR = 0077) representeda significant preventive factor for development of de novoCKD in the short term which is similar to what hasbeen reported in previous studies [12 14] The ischemicmethod prevented ischemic changes in the nephrons Theno-clamping technique without ischemia was the best PNprocedure for preservation of renal function where possibleHowever this observation might be affected by the fact thatmost of the renal masses included in our study were stagedT1 (898) and represented small-sized (20 cm) RCC Undersuch circumstances the removal of a small volume of kidneytissue is not expected to critically influence the degree ofpostoperative deterioration in renal function In additionour multivariate analysis did not indicate any significance ofischemic time in terms of CKD prediction (p gt 005) despitethe fact that univariate analysis showed that ischemic timediffered significantly among the groups (295 plusmn 130min for


Table 3 Multivariate analysis of predictive risk factors with backward selection (119901 = 005) for 1-year short-term and 5-year long-term renalfunctional deterioration

119901 value Hazard ratio 950 confidence intervalLower Upper

Significant parameters at 1 yearSex 0004 31401 3037 324649Smoking volume 0003 1061 1021 1103Albumin 0039 010 0001 793Hemoglobin 0077 1619 949 2765Ischemic method

Warm 0076Cold 0026 053 004 699None 0034 077 007 827

ECOGGroup 2 0012Group 1 0004 0002 0001 077Group 0 0009 002 0001 203

Significant parameters at 5 yearsHypertension 0003 16991 2666 108298Preoperative Albumin (mgdl) 0011 28172 2177 364577Calcium level (mgdl) 0132 135 010 1829De Ritis ratio 0028 13772 1330 142550ASA class 1 0001ASA class 2 0317 101 001 8968ASA class 3 0212 16464 202 1343216Smoking volume (PY) 0003 1081 1028 1137Predisposing CKD 0015 13158 1654 104659ECOG Eastern Cooperative Oncology Group score De Ritis ratio ASTAPT ASA American Society of Anesthesiologist Score CKD chronic kidney disease

the CKD RCC group 219 plusmn 21min for the non-CKD RCCgroup and 107 plusmn 161min for the control group 119901 lt 0001data not shown) A recent systematic review showed thatwarm ischemia does not harm long-term renal function aslong as ischemia time is kept between 20 and 25 minutes [15]

We also found that in the short term further significantfactors influencing the postoperative evolution of renal func-tion were male sex (HR 31401) albumin levels (HR 0010)and ECOG score (0 and 1 HR lt 10) which were previouslyreported as factors affecting renal function [16ndash18] Patientswith good nutritional status and general performance inthe preoperative stage are expected to have good baselinerenal function and postoperative recovery after PN [16]Compared to female patients male Korean patients have ahigher tendency of exposing themselves to negative socialfactors that may affect the recovery of renal function likelybecause of their stressful occupational environment and habitof social drinking [17 19 20] Another interesting findingregarding short-term risk factors was that an ECOG scoreof 1 was associated with less deterioration of renal functionthan an ECOG score of 0 probably because patients withECOG score 1 were more likely to visit their physician forhealth issues and have their renal function closely monitored

by clinicians who intervened sufficiently early to prevent ordelay renal function deterioration or detect newly developedsmall renal masses

As for the long-term factors we found no protecting fac-tors but did identify detrimental factors such as hypertension(HR = 16991) high levels of serum albumin (HR = 28172)high De Ritis ratio (HR = 13772) and baseline predispositionto CKD (HR = 13158) in addition to smoking exposure (HR= 1081) These findings are in line with those reported byprevious studies [1 7 9 10 17 20ndash22] In particular hyper-tension and predisposition for CKD represent well-knownaggravating factors in combination with smoking exposurecausing systemic cardiovascular changes and deterioration inrenal function [10 17 20ndash22] Interestingly our multivariateanalysis did not indicate diabetes as a significant predictorof short- or long-term CKD development in spite of thesignificant differences in the incidence of diabetes among thethree groups (37 in the CKD RCC group 98 in the non-CKD RCC group and 14 in the control group 119901 = 0002data not shown) This observation is likely related to the factthat our study sample included patients with RCC staged T1-T2 which required removing only a small volume of tissueduring PN furthermore most patients did not exhibit severe


diabetic state suggesting that this aspect did not significantlyaffect kidney function and consequently was not related tothe development of CKD postoperatively

Abnormalities in albumin levels and De Ritis ratio valuesare factors indicating chronic liver disease [23] It is wellknown that patients with chronic liver disease also had poorrenal function mostly related to the development of acutekidney injury precipitated by either an acute disturbanceof hemodynamics or an acute structural damage to thekidneys [10] The incidence of chronic renal failure has beenrising due to increasing prevalence of conditions such asdiabetes or viral hepatitis which can be associated with renaldamage In addition AST and ALT levels which providethe De Ritis ratio [24] have been previously reported assignificant prognostic biomarkers in several malignanciesincluding kidney diseases [25] The mechanism underlyingthe relationship of AST and RCC is related to the vitalrole of AST in glycolysis by relocation of NADH into themitochondria through the malate-aspartate shuttle pathwayin which clear cell RCC with VHL loss was known to inducethe expression of hypoxia factors known to be connected toextensively increased glycolysis in the mitochondria whichis well-known as the Warburg effect [26 27] No studieshave ever suggested the importance of De Ritis ratio onpostoperative renal functional changes after renal surgeriesfor which the levels of hepatic factors and serum albumin aresignificant

Our study has several limitations related to the smallsample size and retrospective design Not all the patientscompleted at least five years of follow-up and thus the long-term evaluation of renal function and underlying hepaticdiseases was incomplete for such patients However it isclinically relevant to identify significant risk factors (amongwhich those related to hepatic disease) for renal functiondeterioration and our study is the first to identify long-term-acting risk factors related to hepatic function that affectpostoperative renal function in RCC patients who underwentPN Further prospective studies with long-term follow-upare warranted to evaluate the role of hepatic function in therecovery of renal function

5 Conclusion

The study showed the significant predisposal of CKDpatientsfor long-term renal function deterioration and the significantinfluence of intraoperative ischemic method and time forshort-term renal function deterioration in patients with T1-T2 RCC who underwent PN Further parameters includingsmoking exposure hypertension preoperative albumin lev-els and De Ritis ratio values were also significant factors forpostoperative renal functional deterioration Careful patientselection for postoperative general management as well asintraoperative planning may help reduce this unfavorableoutcome in renal function

Competing Interests

The authors declared no competing interests


Sung Han Kim Jae Young Joung Ho Kyung Seo Kang HyunLee and Jinsoo Chung contributed to project developmentdata collection andmanuscript writing Jae Young Joung HoKyung Seo KangHyunLee and JinsooChung assisted in datacollection Sung Han Kim helped in manuscript writing

References

[1] S Weikert and B Ljungberg ldquoContemporary epidemiologyof renal cell carcinoma perspectives of primary preventionrdquoWorld Journal of Urology vol 28 no 3 pp 247ndash252 2010

[2] R H Thompson S A Boorjian C M Lohse et al ldquoRadicalnephrectomy for pT1a renal masses may be associated withdecreased overall survival compared with partial nephrectomyrdquoThe Journal of Urology vol 179 no 2 pp 468ndash472 2008

[3] W C Huang E B Elkin A S Levey T L Jang and P RussoldquoPartial nephrectomy versus radical nephrectomy in patientswith small renal tumorsmdashis there a difference in mortality andcardiovascular outcomesrdquo The Journal of Urology vol 181 no1 pp 55ndash62 2009

[4] L Zini P Perrotte U Capitanio et al ldquoRadical versus partialnephrectomy effect on overall and noncancer mortalityrdquo Can-cer vol 115 no 7 pp 1465ndash1471 2009

[5] B Ljungberg N C Cowan D C Hanbury et al ldquoEAU guide-lines on renal cell carcinoma the 2010 updaterdquo EuropeanUrology vol 58 no 3 pp 398ndash406 2010

[6] W K O Lau M L Blute A L Weaver V E Torres andH Zincke ldquoMatched comparison of radical nephrectomy vsnephron-sparing surgery in patients with unilateral renal cellcarcinoma and a normal contralateral kidneyrdquo Mayo ClinicProceedings vol 75 no 12 pp 1236ndash1242 2000

[7] J McKiernan R Simmons J Katz and P Russo ldquoNaturalhistory of chronic renal insufficiency after partial and radicalnephrectomyrdquo Urology vol 59 no 6 pp 816ndash820 2002

[8] A S Go G M Chertow D Fan C E McCulloch and C-YHsu ldquoChronic kidney disease and the risks of death cardiovas-cular events and hospitalizationrdquo The New England Journal ofMedicine vol 351 no 13 pp 1296ndash1305 2004

[9] L J Barlow R Korets M Laudano M Benson and J McK-iernan ldquoPredicting renal functional outcomes after surgery forrenal cortical tumours a multifactorial analysisrdquo BJU Interna-tional vol 106 no 4 pp 489ndash492 2010

[10] M Hartleb and K Gutkowski ldquoKidneys in chronic liver dis-easesrdquo World Journal of Gastroenterology vol 18 no 24 pp3035ndash3049 2012

[11] A Sharma M J Mucino and C Ronco ldquoRenal functional re-serve and renal recovery after acute kidney injuryrdquo NephronmdashClinical Practice vol 127 no 1ndash4 pp 94ndash100 2014

[12] A Fergany ldquoChronic renal insufficiency after partial nephrec-tomy for T1b tumorsrdquo Current Opinion in Urology vol 23 no5 pp 394ndash398 2013

[13] P Russo ldquoFunctional preservation in patients with renal corticaltumors the rationale for partial nephrectomyrdquo Current UrologyReports vol 9 no 1 pp 15ndash21 2008

[14] A Mukkamala C He A Z Weizer et al ldquoLong-term renalfunctional outcomes ofminimally invasive partial nephrectomyfor renal cell carcinomardquo Urologic Oncology vol 32 no 8 pp1247ndash1251 2014


[15] X Rod B Peyronnet T Seisen et al ldquoImpact of ischaemiatime on renal function after partial nephrectomy a systematicreviewrdquo BJU International vol 118 no 5 pp 692ndash705 2016

[16] S L Hofbauer A J PantuckM deMartino et al ldquoThe preoper-ative prognostic nutritional index is an independent predictorof survival in patients with renal cell carcinomardquo UrologicOncology vol 33 no 2 pp 68e1ndash68e7 2015

[17] S H Kim S E Lee S K Hong et al ldquoIncidence and risk factorsof chronic kidney disease in Korean patients with T1a renalcell carcinoma before and after radical or partial nephrectomyrdquoJapanese Journal of Clinical Oncology vol 43 no 12 pp 1243ndash1248 2013

[18] S Rajan R Babazade S R Govindarajan et al ldquoPeriopera-tive factors associated with acute kidney injury after partialnephrectomyrdquo British Journal of Anaesthesia vol 116 no 1 pp70ndash76 2016

[19] C S E Kim E H U Bae S K W Ma S-S Kweon and SW A Kim ldquoImpact of partial nephrectomy on kidney functionin patients with renal cell carcinomardquo BMC Nephrology vol 15article 181 2014

[20] H J Kong J S Park D Y KimH S Shin andH J Jung ldquoRenalfunction following curative surgery for renal cell carcinomawho is at risk for renal insufficiencyrdquoKorean Journal of Urologyvol 54 no 12 pp 830ndash833 2013

[21] L LiW L Lau CMRhee et al ldquoRisk of chronic kidney diseaseafter cancer nephrectomyrdquo Nature Reviews Nephrology vol 10no 3 pp 135ndash145 2014

[22] P Satasivam F Reeves K Rao et al ldquoPatients with medical riskfactors for chronic kidney disease are at increased risk of renalimpairment despite the use of nephron-sparing surgeryrdquo BJUInternational vol 116 no 4 pp 590ndash595 2015

[23] C Pipili andE Cholongitas ldquoRenal dysfunction in patientswithcirrhosis where do we standrdquoWorld Journal of GastrointestinalPharmacology andTherapeutics vol 5 no 3 pp 156ndash168 2014

[24] F De Ritis M Coltorti and G Giusti ldquoAn enzymic test for thediagnosis of viral hepatitis the transaminase serum activitiesrdquoClinica Chimica Acta vol 369 no 2 pp 148ndash152 2006

[25] A Bezan E Mrsic D Krieger et al ldquoThe preoperative ASTALT (De Ritis) ratio represents a poor prognostic factor in acohort of patients with nonmetastatic renal cell carcinomardquoTheJournal of Urology vol 194 no 1 pp 30ndash35 2015

[26] O Warburg ldquoOn respiratory impairment in cancer cellsrdquo Sci-ence vol 124 no 3215 pp 269ndash270 1956

[27] W V V Greenhouse and A L Lehringer ldquoOccurrence ofthe malate-aspartate shuttle in various tumor typesrdquo CancerResearch vol 36 no 4 pp 1392ndash1396 1976

Research ArticlePrognostic Significance of PreoperativeNeutrophil-to-Lymphocyte Ratio in Nonmetastatic Renal CellCarcinoma A Large Multicenter Cohort Analysis

Seok-Soo Byun1 Eu Chang Hwang2 Seok Ho Kang3 Sung-Hoo Hong4 Jinsoo Chung5

Tae Gyun Kwon6 Hyeon Hoe Kim1 Cheol Kwak1 Yong-June Kim7 andWon Ki Lee8

1Department of Urology College of Medicine Seoul National University Seoul Republic of Korea2Department of Urology College of Medicine Chonnam National University Gwangju Republic of Korea3Department of Urology College of Medicine Korea University Seoul Republic of Korea4Department of Urology College of Medicine Catholic University Seoul Republic of Korea5Department of Urology National Cancer Center Goyang Republic of Korea6Department of Urology College of Medicine Kyungpook National University Daegu Republic of Korea7Department of Urology College of Medicine Chungbuk National University Cheongju Republic of Korea8Department of Urology College of Medicine Hallym University Chuncheon Republic of Korea

Correspondence should be addressed to Won Ki Lee rheewkhanmailnet

Received 18 August 2016 Accepted 12 October 2016


Copyright copy 2016 Seok-Soo Byun et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background The prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in nonmetastatic renal cell carcinoma (non-mRCC) is controversial althoughNLR has been established as a prognostic factor in several cancersThe objective of our study wasto assess the prognostic significance of preoperative NLR in non-mRCC based on a large multicenter cohort analysis MethodsTotally 1284 non-mRCC patients undergoing surgery were enrolled from six institutions between 2000 and 2014 Recurrence-freesurvival (RFS) and cancer-specific survival (CSS) were calculated and the prognostic significance of NLR was evaluated ResultsPatients with higher NLR had larger tumors (119901 lt 0001) higher T stage (119901 lt 0001) worse Eastern Cooperative Oncology Groupperformance status (119901 lt 0001) worse symptoms (119901 = 0003) sarcomatoid differentiation (119901 = 0004) and tumor necrosis(119901 lt 0001)The 5-year RFS and CSS rates were significantly lower in patients with high NLR than in those with lowNLR (each 119901 lt0001) Multivariate analysis identified NLR to be an independent predictor of RFS and CSS (each 119901 lt 005) Moreover predictiveaccuracy ofmultivariatemodels for RFS andCSS increased by 22 and 42 respectively withNLR inclusionConclusions HigherNLRwas associated with worse clinical behavior of non-mRCC Also NLRwas a significant prognostic factor of both RFS and CSS

1 Introduction

Renal cell carcinoma (RCC) accounts for 3-4 of all adultmalignancies and its incidence rate has been steadily increas-ing worldwide [1] In the United States the estimated num-bers of new cases and deaths in 2015 were 61560 and 14080respectively [1] Therefore it is essential to optimize decisionmaking in treatment and prognosis of RCC and to providebetter counseling for each RCC patient Until now manycharacteristics of RCC itself and patients have been suggestedas possible prognostic factors However only a few including

pathological stage and Fuhrman grade are undisputed prog-nostic factors for RCC especially nonmetastatic RCC (non-mRCC) [2]

Inflammation has an impact on tumorigenesis and tumorprogression [3] In addition inflammation has been recentlyshown to predict the prognosis of various operable cancers[4] As inflammation is easily accessible can be measuredreliably and can be incorporated into the tumor stagingsystem [4] its use as a prognostic factor seems promising

Of the many hematological and biochemical markers forsystemic inflammatory response neutrophil-to-lymphocyte



Table 1 Main characteristics of recently published studies on prognostic value of neutrophil-to-lymphocyte ratio in patients withnonmetastatic renal cell carcinoma

Study cohort Studycases

Histologicsubtype TNM stage

NLR

Value Cut-off Prognostic significancelowast AdjustmentvariablesRFS CSS

Lucca et al [15] 430 Clear cell T1ndash3 Median 29 42 Yes NA Stage grade tumorsize necrosis

Pichler et al [16] 678 Clear cell T1ndash4 Mean 351 33 No No Age gender stagegrade necrosis

Viers et al [17] 827 Clear cell M0 Median 351 40 No Yes

Age genderECOG PS tumorsize Sx stagegrade necrosis

Huang et al [18] 218 Papillary T1ndash3Nx Median 31 36 Yes NA

Age gender SxDM HTN stagenode TNM groupgrade necrosisANC ALC

De Martino et al [19] 281 Papillary andchromophobe T1ndash3Nx Median 26 36 Yes NA

Age genderECOG PS stage

TNM group gradeMVI ANC ALC

Wen et al [20] 327 All T1ndash4 Mean 272 17 Yes NA Age gender tumorsize stage subtype

Forget et al [21] 227 All M0 Median 301 50 Yes NA Age gender stagegrade node

Jagdev et al [22] 228 3 majorsubtypes M0 NA NA No NA NA

Present study 1284 3 majorsubtypes T1ndash4 Mean 22 37 Yes Yes

Age gender BMIECOG PS Sx

tumor size stagegrade subtypesarcomatoid

differentiationnecrosis

lowastResults from multivariate analysisRFS stands for disease-free progression-free and metastasis-free survival as well as recurrence-free survivalTNM tumor-node-metastasis NLR neutrophil-to-lymphocyte ratio RFS recurrence-free survival CSS cancer-specific survival necrosis tumor necrosisNA not available ECOG PS Eastern Cooperative Oncology Group performance status MVI microvascular invasion ANC absolute neutrophil count ALCabsolute lymphocyte count Sx symptoms at presentation DM diabetes mellitus HTN hypertension

ratio (NLR) has been introduced relatively recently [5] Neu-trophils represent the inflammatory response whereas lym-phocytes reflect cell-mediated immunity [3] Therefore NLRmay be a better indicator of inflammation compared to exist-ing conventional markers Furthermore NLR is an inexpen-sive easily accessible and widely available marker InitiallyNLR was validated as a prognostic factor of major cardiacevents [6 7] Since then it has been established as a prog-nostic factor in several cancers including hepatocellular car-cinoma and colorectal cancer [8ndash10]

Multiple studies suggested that NLR might be a prognos-tic factor in mRCC irrespective of the treatment method [811ndash13] However the few studies investigating the prognosticsignificance of NLR in non-mRCC have reported conflictingresults [14ndash22] Furthermore previous studies were small-scale and lacked other possible prognostic factors as con-founding variables (Table 1)

We assessed the prognostic significance of NLR in a largemulticenter cohort of non-mRCC patients To our knowl-edge this is the largest scale study conducted in the fieldwhich also included the most widely accepted prognosticfactors


21 Patients Approval for the study was obtained fromthe relevant institutional ethics committee A total of 3410patients with RCC underwent curative partial or radicalnephrectomy at six institutions between 2000 and 2014 Weconsecutively excluded 239 patients with lymph node andordistantmetastasis immediately after surgery 574 patientswhodid not have any of the three major RCC subtypes (clearcell papillary and chromophobe variants) 351 patients withpostoperative follow-up durations within 3 months and 962


patients with unavailable data on at least one of the relevantparameters Only patients with complete absolute neutrophilcount (ANC) and absolute lymphocyte count (ALC) datawithin the 2 weeks before surgery were included in the studyFinally 1284 non-mRCC patients (pathologically TxN0M0)from any of the three major RCC subtypes were included inthis study and retrospectively reviewed

22 Variables The characteristics of RCC and patients aredetailed in Table 2

Formost patients postoperative follow-upwas scheduledevery 3 months for 6 months every 6 months for the next3 years and yearly thereafter NLR was defined as the ANCdivided by theALCThe general health statuswas determinedby the Eastern Cooperative Oncology Group performancestatus (ECOG PS) Tumor size was measured as the greatestdiameter of the pathologic specimen Pathologic staging wasperformed using the 2002 tumor-node-metastasis (TNM)classification system and grading was performed usingFuhrman nuclear grading system The histologic subtypewas determined using the 2004 World Health Organization(WHO) international histological classification of tumorsFor all specimens urologic pathologists of each institutiondetermined the pathologic features of the tumor Recurrence-free survival (RFS) and cancer-specific survival (CSS) werecalculated from the date of surgery to the date of recurrenceand RCC-specific death respectively and were confirmed byimaging studies

23 Statistical Analysis Theprimary endpoints were RFS andCSSThe ideal cut-off level ofNLRwas estimated by testing allpossible cut-off levels that were likely to discriminate betweensurvival and recurrence and RCC-specific death using theCox proportional hazard model The ideal cut-off leveldeterminedwas then rounded to clinically relevant levels [11]To compare the relationship between the characteristics ofRCC and the patients Student t-test Pearson chi-squaredtest or Fisher exact test stratified by NLR was used

The RFS and CSS rates were calculated using the Kaplan-Meier method stratified by NLR and the log-rank test wasused to compare the groups The prognostic significance ofNLR as a continuous and categorical variable was evaluatedusing variables entered into the Cox proportional hazardsmodel The variables analyzed included patient age genderbody mass index (BMI) ECOG PS symptoms at presenta-tion tumor size pathologic T stage Fuhrman grade histo-logic subtype sarcomatoid differentiation and tumor necro-sis The accuracy of NLR in predicting RFS and CSS wasreflected by Harrell concordance index (c-index) calculatedusing the Cox proportional hazard models with and withoutthe incorporation of NLR

All tests were two-sided and 119901 lt 005 was consideredstatistically significant Survival the Cox regression methodin R 322 (R Development Core Team Vienna AustriahttpswwwR-projectorg) was used to calculate the c-index whereas IBM SPSS Statistics forWindows version 210(IBMCorp Armonk NY USA) was used for other statisticalassessments

3 Results

31 The Association between Clinical and Pathologic Charac-teristics and NLR A cut-off NLR level of 37 was estimatedto be the optimal cut-off level for discriminating betweenpatientsrsquo recurrences (hazard ratio (HR) = 3049 95 con-fidence interval (CI) = 2015ndash4614 and 119901 lt 0001)The sameNLR cut-off level was effective for discriminating betweenpatientsrsquo RCC-specific deaths (HR = 4947 95 CI = 2766ndash8849 and 119901 lt 0001) Based on these results the NLR cut-off level of 37 was used in all subsequent analyses (low NLRlt37 high NLR ge37)

The mean follow-up period was 468 months for allpatients (median 39 months interquartile range 19ndash69months) The mean NLRs of patients with low and high NLRwere 18 plusmn 07 and 60 plusmn 32 respectively (119901 lt 0001) Table 1shows the association of NLR with different clinical andpathological characteristics Patients with high NLR differedsignificantly from those with lowNLR in various parametersPatients with high NLR were older (119901 = 0001) and hadhigher ECOG PS (119901 lt 0001) and T stage (119901 lt 0001) andlarger tumors (119901 lt 0001) compared to those with low NLRPatients with high NLR also had greater symptom ratios (119901 =0003) sarcomatoid differentiation ratios (119901 = 0004) andtumor necrosis ratios (119901 lt 0001)

32 Recurrence-Free Survival in relation to NLR Duringfollow-up 142 (111) patients had recurrence (Table 2) The5-year RFS rates were 716 in patients with high NLR and882 in those with low NLR The 5-year RFS rate wassignificantly lower in patients with high NLR than in thosewith low NLR (119901 lt 0001 Figure 1(a))

Multivariate analysis identifiedNLR to be an independentpredictor of RFS (HR of NLR as a continuous variable = 1081119901 = 0028 HR of NLR as a categorical variable = 1788 119901 =0009 Table 3) The predictive accuracy of the multivariatemodel with NLR was 811 whereas that of the multivariatemodel without NLR was 789

33 Cancer-Specific Survival in relation to NLR Duringfollow-up 56 (44) patients died of RCC-related causes(Table 2) The 5-year CSS rates were 842 in patients withhigh NLR and 964 in those with low NLR The 5-year CSSrate was significantly lower in patients with high NLR than inthose with low NLR (119901 lt 0001 Figure 1(b))

Multivariate analysis identifiedNLR to be an independentpredictor of CSS (HR of NLR as a continuous variable = 1156119901 = 0009 HR of NLR as a categorical variable = 2566 119901 =0004 Table 4) The predictive accuracy of the multivariatemodel with NLR was 879 whereas that of the multivariatemodel without NLR was 837

4 Discussion

In this study NLR was identified to be a significant prog-nostic factor of both RFS and CSS in patients with non-mRCC even when the models were adjusted for other well-known prognostic factors The predictive accuracy of the


Table 2 Association of different clinical and pathological characteristics with neutrophil-to-lymphocyte ratio in patients with nonmetastaticrenal cell carcinoma

Variable All Low NLR High NLR 119901 valueNumber of subjects 1284 1168 116NLR mean plusmn SD 22 plusmn 17 18 plusmn 07 60 plusmn 32 lt0001lowast

Age mean plusmn SD year 559 plusmn 129 555 plusmn 128 598 plusmn 129 0001lowast

Gender 0236lowastlowast

Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)

BMI mean plusmn SD kgm2 246 plusmn 33 247 plusmn 32 238 plusmn 34 0006lowast

ECOG PS ge 1 n () 180 (140) 148 (127) 32 (276) lt0001lowastlowast

Symptoms at presentation 0003lowastlowast

No symptom n () 975 (759) 900 (771) 75 (647)Symptom n () 309 (241) 268 (229) 41 (353)

Tumor size(1) mean plusmn SD cm 408 plusmn 268 394 plusmn 254 550 plusmn 355 lt0001lowast

(2) Category lt0001lowastlowast

lt4 cm n () 748 (583) 701 (600) 47 (405)4ndash7 cm n () 351 (273) 321 (275) 30 (259)ge7 cm n () 185 (144) 146 (125) 39 (336)

Side 1000lowastlowastlowast

Unilateral n () 1268 (988) 1153 (987) 115 (991)Bilateral n () 16 (12) 15 (13) 1 (09)

Type of nephrectomy lt0001lowastlowast

Radical n () 634 (494) 552 (473) 82 (707)Partial n () 650 (506) 616 (527) 34 (293)

Method of surgery 0042lowastlowast

Open n () 697 (543) 628 (538) 69 (595)Laparoscopic n () 316 (246) 283 (242) 33 (284)Robot n () 271 (211) 257 (220) 14 (121)

T stage lt0001lowastlowast

T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)

Fuhrmanrsquos grade 0561lowastlowast

G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)

Histologic subtype 0042lowastlowast

Clear cell n () 1114 (868) 1017 (871) 97 (836)Papillary n () 87 (68) 73 (63) 14 (121)Chromophobe n () 83 (65) 78 (67) 5 (43)

Sarcomatoid differentiation yes n () 29 (23) 22 (19) 7 (60) 0004lowastlowast

Tumor necrosis yes n () 208 (162) 174 (149) 34 (293) lt0001lowastlowast

Recurrence n () 142 (111) 114 (98) 28 (241) lt0001lowastlowast

RCC-specific death n () 56 (44) 40 (34) 16 (138) lt0001lowastlowast

NLR neutrophil-to-lymphocyte ratio low NLR lt37 high NLR ge37 BMI body mass index ECOG PS Eastern Cooperative Oncology Group performancestatus RCC renal cell carcinoma n number of subjects SD standard deviationlowastStudent t-testlowastlowastPearsonrsquos chi-square testlowastlowastlowastFisherrsquos exact test


Table 3 Multivariate analyses predicting probability of cancer recurrence in relation to the neutrophil-to-lymphocyte ratio in patients withnonmetastatic renal cell carcinoma

Variables NLR as a continuous variable NLR as a categorical variableHR 95 CI 119901 value HR 95 CI 119901 value

Age 1011 0997ndash1025 0134 1011 0997ndash1026 0123GenderFemale versus male 0873 0588ndash1296 0502 0876 0591ndash1299 0510

BMI 0959 0907ndash1015 0146 0959 0907ndash1014 0146ECOG PSge1 versus 0 1936 1270ndash2950 0002 1900 1244ndash2902 0003

Symptoms at presentation 1185 0811ndash1731 0380 1208 0830ndash1758 0325Tumor size 1011 1005ndash1017 0001 1011 1004ndash1017 0001T stage 0009 0010T2 versus T1 1384 0745ndash2571 0303 1376 0743ndash2550 0310T3-4 versus T1 2068 1281ndash3340 0003 2050 1267ndash3314 0003

Fuhrmanrsquos gradeG3-4 versus G1-2 1974 1352ndash2882 lt0001 1958 1340ndash2863 0001

Histologic subtype 0012 0019pRCC versus cRCC 1044 0582ndash1872 0886 1029 0575ndash1841 0924chRCC versus cRCC 0104 0023ndash0467 0003 0132 0032ndash0545 0005

Sarcomatoid differentiation 2095 1061ndash4137 0033 2004 1010ndash3977 0047Tumor necrosis 1255 0817ndash1927 0300 1265 0825ndash1939 0282NLR(1) Continuous 1081 1009ndash1160 0028(2) High versus low NLR 1788 1153ndash2771 0009

NLR neutrophil-to-lymphocyte ratio low NLR lt37 high NLR ge37 BMI body mass index ECOG PS Eastern Cooperative Oncology Group performancestatus cRCC clear cell renal cell carcinoma pRCC papillary renal cell carcinoma chRCC chromophobe renal cell carcinomaHR hazard ratio CI confidenceinterval

0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10

(Months)Low NLRHigh NLR

p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)

Figure 1 Kaplan-Meier curve for recurrence-free survival (a) and cancer-specific survival (b) for patients with nonmetastatic renal cellcarcinoma according to neutrophil-to-lymphocyte ratio NLR neutrophil-to-lymphocyte ratio


Table 4 Multivariate analyses predicting probability of cancer-specific death in relation to the neutrophil-to-lymphocyte ratio in patientswith nonmetastatic renal cell carcinoma





Fuhrmanrsquos gradeG3-4 versus G1-2 2155 1141ndash4072 0018 2101 1110ndash3977 0023

Histologic subtype 0854 0860pRCC versus cRCC 1268 0551ndash2919 0576 1257 0554ndash2850 0584chRCC versus cRCC 0001 lt0001ndash5496 0959 0001 lt0001ndash6687 0962



multivariate models for RFS and CSS increased by 22 and42 respectively with NLR inclusion

The present study had several strengths compared to theprevious studies in the field (Table 1) Firstly this was thelargest study that included the threemajor histologic subtypesof RCC Secondly while the present study evaluated bothRFS and CSS most of the previous studies did not evaluateCSS The identification of CSS as well as RFS is a cornerstone to prove the prognostic value of NLR Finally thepresent study included themostwidely accepted independentprognostic factors of non-mRCC including age gender andBMI ECOG PS symptoms at presentation tumor size stageand grade histologic subtype sarcomatoid differentiationand tumor necrosis

In terms of clinical and pathologic characteristics at diag-nosis patients with high NLR differed significantly fromthose with low NLR in various parameters Patients withhigh NLR had a larger tumor a higher T stage worse ECOGPS worse symptoms sarcomatoid differentiation and tumornecrosis These results are similar to those reported in pre-vious studies [17 18 20] suggesting that higher NLR may beassociated with worse clinical behavior of non-mRCC

NLR was shown to be a possible prognostic factor formRCC in multiple studies irrespective of the treatmentmethod [8 11ndash13] However studies concerning the prognos-tic significance of NLR for non-mRCC are scarce with con-flicting results Some studies did not show a relationship

between NLR and non-mRCC prognosis [16 22] whileothers did [14 15 18ndash21] Interestingly one study reporteddifferent results for RFS and CSS [17] These conflictingresults may partly be because previous studies were relativelysmall-scale and lacked other possible prognostic factors asconfounding variables (Table 1)

An important point is that most of the previous studiesincorporated NLR as a categorical variable in their modelsThe use of a continuous variable reflects an intrinsic effectwhereas that of a categorical variable seems to adjust itselfand to be created [23] In addition it is difficult to interpretthe prognostic value of NLR using different cut-off levelsalthough most studies including the present one showed thatthe cut-off levels of NLR were in the range 3-4 (Table 1) Inthis respect it is remarkable that NLR was not only usedas a categorical variable but also as a continuous variable inthis study We identified that NLR as a continuous variablewas also an independent prognostic factor Interestingly NLRcut-off level of 37 was estimated for CSS as well as RFS in thisstudy Considering that CSS is in alignment with RFS in non-mRCC these results may strengthen our conclusion

It is well known that inflammation affects tumorigenesisand progression [3 17] Neutrophils represent the inflam-matory response whereas lymphocytes reflect cell-mediatedimmunity [3] Therefore a high NLR reflects both anincreased inflammatory and a decreased antitumor immuneresponse suggesting a possible contribution to aggressive


tumor biology tumor progression and poor survival [17]In various cancers including hepatocellular carcinoma andcolorectal cancer high NLR was associated with poor out-come [9 10] This was also supported by the results of ourclinical study which showed that higher NLR was likely tobe associated with worse clinical behavior and indicated poorprognosis for RFS and CSS

In contrast to our findings some studies did not show arelationship betweenNLR andnon-mRCCprognosis [16 22]In a study of 678 patients with cRCC Pichler et al [16]reported that NLR was not an independent prognostic factorfor CSS or metastasis-free survival However NLR was onlyincluded as a categorical variable in this analysis Certainly aspecified cut-off level may create a false or misleading associ-ation Furthermore they only analyzed patients with cRCCAs RCC is a heterogeneous and complex disease [24 25] itsresults may not be directly applicable to patients with non-cRCC In a study of 228 patients with non-mRCC Jagdev etal [22] reported thatNLRwas not an independent prognosticfactor for disease-free survival However their study involvedonly a small number of patients Furthermore as their studydid not focus on NLR the data on NLR were insufficient andwere logarithmically transformed for analysis

This study also had a few limitations Firstly data wereretrospectively collected Secondly preoperative conditionssuch as chronic infection and chronic disease which mightaffect the level of NLR were not included However it isimpossible to identify all the conditions associated with theNLR level in the clinical setting Therefore this study may bea better representation of the prognostic significance of NLRin actual practice Lastly this study lacked a central review ofpathology although most of the previous large multicenterstudies did Instead urologic pathologists determined allpathologic features at each institution

Despite limitations it is noted that this study is thelargest in the field incorporating the most widely acceptedindependent prognostic factors of non-mRCCand evaluatingboth RFS and CSS

5 Conclusion

This study showed that patients with high NLR differedsignificantly from those with low NLR in various clinicaland pathologic parameters suggesting that higher NLR mayindicate worse clinical behavior of non-mRCC In additionNLR was a significant prognostic factor of both RFS and CSSand incorporation of NLR into conventional prognostic pre-dictors increased the predictive accuracy by 22 and 42respectively This study suggests that the use of preoperativeNLR may be helpful in counseling and clinical trial design inpatients with non-mRCC

Abbreviations

Non-mRCC Nonmetastatic renal cell carcinomaNLR Neutrophil-to-lymphocyte ratioANC Absolute neutrophil countALC Absolute lymphocyte countECOG PS Eastern Cooperative Oncology Group

performance status

TNM Tumor-node-metastasisWHO World Health OrganizationRFS Recurrence-free survivalCSS Cancer-specific survivalBMI Body mass indexHR Hazard ratioCI Confidence interval

Competing Interests

The authors have nothing to disclose


Seok-Soo Byun participated in the studyrsquos design coordina-tion treatment of patients and data collection Eu ChangHwang Seok Ho Kang Sung-Hoo Hong Jinsoo Chung TaeGyun Kwon Hyeon Hoe Kim Cheol Kwak and Yong-JuneKim were members of the research group and participatedin the treatment of patients and data collection Won Ki Leeconceived the study participated in its design performed thestatistical analysis and drafted the manuscript All authorsread and approved the final manuscript

References

[1] R L Siegel K D Miller and A Jemal ldquoCancer statistics 2015rdquoCA Cancer Journal for Clinicians vol 65 no 1 pp 5ndash29 2015

[2] B Ljungberg K Bensalah S Canfield et al ldquoEAU guidelineson renal cell carcinoma 2014 updaterdquo European Urology vol67 no 5 pp 913ndash924 2016

[3] S I Grivennikov F R Greten and M Karin ldquoImmunityInflammation and Cancerrdquo Cell vol 140 no 6 pp 883ndash8992010

[4] C S D Roxburgh and D C McMillan ldquoRole of systemicinflammatory response in predicting survival in patients withprimary operable cancerrdquo Future Oncology vol 6 no 1 pp 149ndash163 2010

[5] R Zahorec ldquoRatio of neutrophil to lymphocyte countsmdashrapidand simple parameter of systemic inflammation and stress incritically illrdquo Bratislavske Lekarske Listy vol 102 no 1 pp 5ndash142001

[6] P H Gibson B L Croal B H Cuthbertson et al ldquoPreopera-tive neutrophil-lymphocyte ratio and outcome from coronaryartery bypass graftingrdquo American Heart Journal vol 154 no 5pp 995ndash1002 2007

[7] B Azab V Chainani N Shah and J T McGinn ldquoNeutrophil-lymphocyte ratio as a predictor of major adverse cardiac eventsamong diabetic population a 4-year follow-up studyrdquo Angio-logy vol 64 no 6 pp 456ndash465 2013

[8] K Hu L Lou J Ye and S Zhang ldquoPrognostic role of theneutrophil-lymphocyte ratio in renal cell carcinoma a meta-analysisrdquo BMJ Open vol 5 no 4 Article ID e006404 2015

[9] M-X Li X-M Liu X-F Zhang et al ldquoPrognostic role ofneutrophil-to-lymphocyte ratio in colorectal cancer a system-atic review and meta-analysisrdquo International Journal of Cancervol 134 no 10 pp 2403ndash2413 2014

[10] W-K Xiao D Chen S-Q Li S-J Fu B-G Peng and L-JLiang ldquoPrognostic significance of neutrophil-lymphocyte ratioin hepatocellular carcinoma ameta-analysisrdquoBMCCancer vol14 no 1 article 117 pp 117ndash126 2014


[11] J Atzpodien P Royston T Wandert and M Reitz ldquoMetastaticrenal carcinoma comprehensive prognostic systemrdquo BritishJournal of Cancer vol 88 no 3 pp 348ndash353 2003

[12] F Donskov and H von der Maase ldquoImpact of immune param-eters on long-term survival in metastatic renal cell carcinomardquoJournal of Clinical Oncology vol 24 no 13 pp 1997ndash2005 2006

[13] D Keizman M Ish-Shalom P Huang et al ldquoThe associationof pre-treatment neutrophil to lymphocyte ratio with responserate progression free survival and overall survival of patientstreatedwith sunitinib formetastatic renal cell carcinomardquoEuro-pean Journal of Cancer vol 48 no 2 pp 202ndash208 2012

[14] Y Ohno J Nakashima M Ohori T Gondo T Hatano and MTachibana ldquoFollowup of neutrophil-to-lymphocyte ratio andrecurrence of clear cell renal cell carcinomardquo Journal of Urologyvol 187 no 2 pp 411ndash417 2012

[15] I LuccaM deMartino S L Hofbauer N Zamani S F Shariatand T Klatte ldquoComparison of the prognostic value of pretreat-ment measurements of systemic inflammatory response inpatients undergoing curative resection of clear cell renal cell car-cinomardquoWorld Journal ofUrology vol 33 no 12 pp 2045ndash20522015

[16] M Pichler G C Hutterer C Stoeckigt et al ldquoValidation of thepre-treatment neutrophil-lymphocyte ratio as a prognostic fac-tor in a large European cohort of renal cell carcinoma patientsrdquoBritish Journal of Cancer vol 108 no 4 pp 901ndash907 2013

[17] B R Viers R H Thompson S A Boorjian C M Lohse B CLeibovich and M K Tollefson ldquoPreoperative neutrophil-lym-phocyte ratio predicts death among patients with localized clearcell renal carcinoma undergoing nephrectomyrdquo Urologic Onco-logy Seminars and Original Investigations vol 32 no 8 pp1277ndash1284 2014

[18] J Huang D M Dahl L Dong et al ldquoPreoperative neutrophil-to-lymphocyte ratio and neutrophilia are independent predic-tors of recurrence in patients with localized papillary renal cellcarcinomardquo BioMed Research International vol 2015 Article ID891045 9 pages 2015

[19] M De Martino A J Pantuck S Hofbauer et al ldquoPrognosticimpact of preoperative neutrophil-to-lymphocyte ratio in local-ized nonclear cell renal cell carcinomardquo Journal of Urology vol190 no 6 pp 1999ndash2004 2013

[20] R-M Wen Y-J Zhang S Ma et al ldquoPreoperative neutrophilto lymphocyte ratio as a prognostic factor in patients with non-metastatic renal cell carcinomardquo Asian Pacific Journal of CancerPrevention vol 16 no 9 pp 3703ndash3708 2015

[21] P Forget J-PMachiels P G Coulie et al ldquoNeutrophil lympho-cyte ratio and intraoperative use of ketorolac or diclofenac areprognostic factors in different cohorts of patients undergoingbreast lung and kidney cancer surgeryrdquo Annals of SurgicalOncology vol 20 no 3 supplement pp S650ndashS660 2013

[22] S P K Jagdev W Gregory N S Vasudev et al ldquoImproving theaccuracy of pre-operative survival prediction in renal cell car-cinoma with C-reactive proteinrdquo British Journal of Cancer vol103 no 11 pp 1649ndash1656 2010

[23] Y Luo D-L She H Xiong S-J Fu and L Yang ldquoPretreatmentneutrophil to lymphocyte ratio as a prognostic predictor of uro-logic tumors a systematic review and meta-analysisrdquoMedicinevol 94 no 40 article e1670 2015

[24] S-S Byun S K Hong S Lee et al ldquoThe establishment ofKORCC (KoreanRenal Cell Carcinoma) databaserdquo Investigativeand Clinical Urology vol 57 no 1 pp 50ndash57 2016

[25] F-M Deng and J Melamed ldquoHistologic variants of renal cellcarcinoma does tumor type influence outcomerdquoUrologic Clin-ics of North America vol 39 no 2 pp 119ndash132 2012

Clinical StudyPretreatment Neutrophil-to-Lymphocyte RatioCan Predict the Prognosis in Bladder Cancer Patients WhoReceive Gemcitabine and Nedaplatin Therapy

Shinji Ohtake1 Takashi Kawahara12 Ryo Kasahara1 Hiroki Ito1 Kimito Osaka1

Yusuke Hattori2 Jun-ichi Teranishi2 Kazuhide Makiyama1 Nobuhiko Mizuno3

Susumu Umemoto4 Yasuhide Miyoshi2 Noboru Nakaigawa1 Hiroshi Miyamoto5

Masahiro Yao1 and Hiroji Uemura2

1Department of Urology Yokohama City University Graduate School of Medicine Yokohama Japan2Departments of Urology and Renal Transplantation Yokohama City University Medical Center Yokohama Japan3Department of Urology Yokohama Sakae Kyosai Hospital Yokohama Japan4Department of Urology Hiratsuka Kyosai Hospital Hiratsuka Japan5Departments of Pathology and Urology Johns Hopkins University School of Medicine Baltimore MD USA

Correspondence should be addressed to Takashi Kawahara takashi tk2001yahoocojp

Received 7 April 2016 Accepted 18 August 2016


Copyright copy 2016 Shinji Ohtake et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Introduction and Objectives Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a simple marker of the systemicinflammatory response in critical care patientsWe previously assessed the utility ofNLR as a biomarker to predict tumor recurrenceand cancer death in bladder cancer patients who underwent radical cystectomy In this study we evaluated the prognostic impactof NLR in bladder cancer patients who received gemcitabine and nedaplatin (GN) chemotherapy Methods A total of 23 patientswho received GN chemotherapy for advanced bladder cancer were enrolled in this study The cut-off point of NLR accordingto the sensitivity and specificity levels was derived from the area under receiver operator characteristics (AUROC) curve plottedfor disease progression or overall mortality Results The NLR cut-off point was determined as 414 for both tumor progressionand overall mortality Median progression-free survival (PFS)overall survival (OS) in the higher NLR group (NLR ge 414) andlower NLR group (NLR lt 414) were 194468 days versus 73237 days respectively Kaplan-Meier analysis showed that higher NLRsignificantly correlated with poorer PFS (119901 = 0011) andOS (119901 = 0045)Conclusions NLRmay serve as a new biomarker to predictresponses to GN-based chemotherapy in advanced bladder cancer patients andor their prognosis

1 Introduction

Cisplatin alone gemcitabine and cisplatin (GC) and metho-trexate vinblastine doxorubicin and cisplatin (M-VAC)have evolved as the standard first-line systemic therapy forrecurrent or metastatic urothelial carcinoma (UC) Howeverits serious dose-limiting adverse effects include consider-able renal toxicity marked emesis and neurotoxicity Itsnephrotoxic properties particularly make it unsuitable forpatients with renal dysfunction Indeed UC is usually seenin the elderly and due to age-associated impairment in the

renal function and performance status approximately 30ndash50 of patients are ineligible for cisplatin-based chemother-apy [1] Instead nedaplatin a second-generation platinumcomplex with lower renal and gastrointestinal toxicities thancisplatin can be used in patients withmarginal renal function[2]

Neutrophil-to-lymphocyte ratio (NLR) has been sug-gested as a simple marker of the systemic inflammatoryresponse in critical care patients [3] NLR can be easily cal-culated from routine complete blood counts in the peripheralblood [4 5] It has also been reported to be an independent



prognosticator for some solidmalignancies including bladdercancer [4ndash13]

We previously assessed the utility of NLR as a biomarkerto predict tumor recurrence and cancer death in bladdercancer patients who underwent radical cystectomy [14]In the current study we investigated whether NLR couldpredict the prognosis of bladder cancer patients who receivedgemcitabine and nedaplatin (GN) chemotherapy


21 Patients A total of 23 patients (17 men and 6 women)with measurable lesions were treated with GN chemotherapyfor their advanced bladder UC at our institutions from 2005to 2014 Of these patients 4 underwent radical cystectomyprior to GN therapyThe mean age was 630 years (range 46ndash74) the mean creatinine clearance was 805mLmin (range43ndash1571) and the mean follow-up period was 115 months(range 23ndash298) Written informed consent was obtainedfrom all patients and the institutional review board approvedthis study

22 Drug Administration and Evaluation of ResponsesPatients received gemcitabine 1000mgm2 on days 1 and8 plus nedaplatin 80 or 100mgm2 on day 1 Dose modi-fication was allowed depending on the patientrsquos conditionrenal function or bone marrow suppression Twelve patientsreceived at least 3 cycles of GN chemotherapy whereas theremaining 10 received 1 or 2 cycles Tumor response wasassessed according to the Response Evaluation Criteria inSolid Tumor (RECIST) Toxicity was evaluated accordingto the Common Terminology Criteria for Adverse Events(CTCAE) ver 30

23 Clinical and Laboratory Assessments Complete bloodcell counts (CBCs) were performed and NLR was calculatedusing the neutrophil and lymphocyte counts obtained onthe same day or a few days before the initial chemotherapyWe determined the cut-off point of the NLR based on thesensitivity and specificity levels derived from the area underreceiver operator characteristics (AUROC) curve plottedusing disease progression or overall mortality

24 Statistical Analysis The patient characteristics and pre-treatment factors were analyzed using the Mann-Whitney 119880test and chi-square test respectivelyTheKaplan-Meier curvewas used to estimate the progression-free survival (PFS) andoverall survival (OS) The survival duration was defined asthe time between the date of installation of GN chemotherapyand the time of tumor progression or deathThe log-rank testwas performed for comparison of two groups All statisticalanalyses were performed using the GraphPad Prism softwareprogram (GraphPad Software La Jolla CA USA) 119901 lt 005was considered to be statistically significant

3 Results

31 Patients Of 23 patients complete response (CR) andpartial response (PR) were obtained in 2 (87) and 3

(130) patients respectively The median PFS and OS were147 days and 396 days respectively Grade 3 or 4 anemiathrombocytopenia and neutropenia were observed in 10(435) 10 (826) and 21 (913) patients respectivelyNone of these patients died of adverse effects of GN therapy

32TheNLRCut-OffValue Based on the AUROC curve theNLR cut-off point was determined to be 414 for both PFS(AUROC 0618) and OS (AUROC 0717) [Figure 1] Clinico-pathological characteristics of the 23 patients are summarizedin Table 1 There were no statistically significant differencesin the baseline characteristics between high (ge414) and low(lt414) NLRs

33 NLR and Patient Outcomes We compared PFS and OSin patients with high versus lowNLRs Kaplan-Meier analysisshowed that higher NLR strongly correlated with the risks ofdisease progression (119901 = 0006 Figure 2(a)) and mortality(119901 = 0045 Figure 2(b))

4 Discussion

Although advances in chemotherapy have improved the sur-vival of patients with recurrent or metastatic UC a portion ofpatients still die within a few months of disease progressionTherefore more useful and reliable biomarkers that provideadditional prognostic information are needed CBCs aretypically examined during the clinical check-up and theNLR can be applied to all patients virtually either beforeor after surgerymedical treatment We previously reportedNLR as an independent prognosticator in men presentingwith metastatic prostate cancer as well as in bladder cancerpatients who received radical cystectomy [14] Indeed NLRhas been shown to be a prognostic factor in patients withbladder cancer [12 15ndash19] On the other hand the associationbetween NLR and tumor progression remains controversial[12 15ndash19] Several studies have shown a higher NLR topredict a worse prognosis in bladder cancer patients [16 18ndash20] whereas others have concluded that NLR is not stronglycorrelated with OS [12 15ndash18] In the current study higherNLR significantly correlated with a poorer prognosis inpatients who received GN chemotherapy for their advancedbladder cancer

In addition to cisplatin various anticancer platinumcomplexes have been developed Carboplatin a cisplatin ana-logue has been shown to exhibit improved toxicity and favor-able antitumor effects resulting in response rates of 184for upper urinary tract UC [20] Additionally nedaplatin wasdeveloped as a second-generation platinum complex withlower renal and gastrointestinal toxicities compared with cis-platin [21] Sasaki et al demonstrated that the pharmacoki-netic behavior of nedaplatin was similar to that of carboplatinbut is strikingly different from that of cisplatin Cisplatineasily binds to serum proteins resulting in a smaller percent-age of platinum excreted into the urine after infusioncompared with nedaplatin or carboplatin [22] Matsumotoet al showed greater activity of GN therapy against lungcancer models than the activity of a combination of gemc-itabine with cisplatin or carboplatin [23] In our institution


Table 1 Clinicopathological characteristics of the patients

Total NLR lt 414 NLR ≧ 414119901 value

(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)

GenderFemale 6 (261) 4 (444) 2 (143) 0131Male 17 (739) 5 (556) 12 (857)

Creatinine clearance (mLmin)lt60 3 (130) 2 (222) 1 (71) 0332ge60 20 (870) 7 (778) 13 (929)

Clinical lymph node metastasisYes 19 (826) 8 (889) 11 (786) 0483No 4 (174) 1 (111) 3 (214)

Neoadjuvant chemotherapyYes 4 (174) 3 (333) 1 (71) 0147No 19 (826) 6 (667) 13 (929)

Clinical T stagele2 6 (261) 2 (222) 4 (286) 0565ge3 17 (739) 7 (778) 10 (714)

02 04 06 08 10False positive fraction

0

02

04

06

08

1

True

pos

itive

frac

tion

(a) Progression-free survival


0

02

04

06

08

1

True

pos

itive

frac

tion

(b) Overall survival

Figure 1 The AUROC for NLR (a) PFS and (b) OS

we have used nedaplatin-based chemotherapy for high-grade UC and have demonstrated good responses with themedian PFS and OS times of 147 and 396 days respectively[2 24]

There are several limitations associated with this studyincluding selection bias and missing data for some of thevariables due to its retrospective nature However this studymay provide supportive data for other studies as well as future

prospective studies Another potential limitation is that wedid not determine the mechanism of NLR for bladder cancerprogression Previous studies showed a correlation betweenNLR as a marker of systemic inflammation in cancer patientsand patient outcomes

In conclusion we demonstrated that NLR might be anew biomarker to predict the prognosis of advanced bladdercancer in patients undergoing GN chemotherapy


200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)

Figure 2 The association between NLR and patient outcomes (a) PFS and (b) OS

Competing Interests


Acknowledgments

Grants from the Uehara Memorial Foundation the TokyoBiochemical Research Foundation and the Japanese Founda-tion for Research and Promotion of Endoscopy and an Inter-national Exchange Grant from Kato Memorial BioscienceFoundationwere provided to Takashi KawaharaThere are noapplicable grant numbers

References

[1] A Dash M D Galsky A J Vickers et al ldquoImpact of renalimpairment on eligibility for adjuvant cisplatin-based chemo-therapy in patients with urothelial carcinoma of the bladderrdquoCancer vol 107 no 3 pp 506ndash513 2006

[2] T Kawahara H Oshiro Z Sekiguchi et al ldquoHigh-gradeinvasive urothelial carcinoma with focal plasmacytoid differen-tiation successfully treated by transurethral resection followedby chemoradiotherapyrdquo International Journal of Urology vol 18no 12 pp 851ndash853 2011


[4] S R Walsh E J Cook F Goulder T A Justin and N JKeeling ldquoNeutrophil-lymphocyte ratio as a prognostic factor incolorectal cancerrdquo Journal of Surgical Oncology vol 91 no 3 pp181ndash184 2005

[5] Y Ohno J NakashimaM Ohori T Hatano andM TachibanaldquoPretreatment neutrophil-to-lymphocyte ratio as an indepen-dent predictor of recurrence in patients with nonmetastaticrenal cell carcinomardquoThe Journal of Urology vol 184 no 3 pp873ndash878 2010

[6] P XueMKanai YMori et al ldquoNeutrophil-to-lymphocyte ratiofor predicting palliative chemotherapy outcomes in advanced

pancreatic cancer patientsrdquo Cancer Medicine vol 3 no 2 pp406ndash415 2014

[7] D Gomez G Morris-Stiff G J Toogood J P A Lodge and KR Prasad ldquoImpact of systemic inflammation on outcome fol-lowing resection for intrahepatic cholangiocarcinomardquo Journalof Surgical Oncology vol 97 no 6 pp 513ndash518 2008

[8] W Chua K A Charles V E Baracos and S J Clarke ldquoNeu-trophillymphocyte ratio predicts chemotherapy outcomes inpatients with advanced colorectal cancerrdquo British Journal ofCancer vol 104 no 8 pp 1288ndash1295 2011

[9] B Azab V R Bhatt J Phookan et al ldquoUsefulness of the neutro-phil-to-lymphocyte ratio in predicting short- and long-termmortality in breast cancer patientsrdquoAnnals of Surgical Oncologyvol 19 no 1 pp 217ndash224 2012

[10] O Dalpiaz M Pichler S Mannweiler et al ldquoValidation ofthe pretreatment derived neutrophil-lymphocyte ratio as aprognostic factor in a European cohort of patients with uppertract urothelial carcinomardquo British Journal of Cancer vol 110no 10 pp 2531ndash2536 2014

[11] M R Jung Y K Park O Jeong et al ldquoElevated preoperativeneutrophil to lymphocyte ratio predicts poor survival followingresection in late stage gastric cancerrdquo Journal of Surgical Oncol-ogy vol 104 no 5 pp 504ndash510 2011

[12] A Demirtas V Sabur E C Aknsal et al ldquoCan neutrophil-lymphocyte ratio and lymph node density be used as prognosticfactors in patients undergoing radical cystectomyrdquo The Scien-tific World Journal vol 2013 Article ID 703579 5 pages 2013

[13] L Rosenberg G O Lawlor T Zenlea et al ldquoPredictors of endo-scopic inflammation in patients with ulcerative colitis in clinicalremissionrdquo Inflammatory Bowel Diseases vol 19 no 4 pp 779ndash784 2013

[14] T Kawahara K Furuya M Nakamura et al ldquoNeutrophil-to-lymphocyte ratio is a prognostic marker in bladder cancerpatients after radical cystectomyrdquo BMC Cancer vol 16 no 1article 185 2016

[15] T Hermanns B Bhindi Y Wei et al ldquoPre-treatment neutro-phil-to-lymphocyte ratio as predictor of adverse outcomes inpatients undergoing radical cystectomy for urothelial carci-noma of the bladderrdquo British Journal of Cancer vol 111 no 3pp 444ndash451 2014


[16] T Gondo J Nakashima Y Ohno et al ldquoPrognostic value ofneutrophil-to-lymphocyte ratio and establishment of novel pre-operative risk stratification model in bladder cancer patientstreated with radical cystectomyrdquo Urology vol 79 no 5 pp1085ndash1091 2012

[17] L S Krane K A Richards A K Kader R Davis K C Balajiand A K Hemal ldquoPreoperative neutrophillymphocyte ratiopredicts overall survival and extravesical disease in patientsundergoing radical cystectomyrdquo Journal of Endourology vol 27no 8 pp 1046ndash1050 2013

[18] S TemrazDMukherji Z A A Farhat et al ldquoPreoperative lym-phocyte-to-monocyte ratio predicts clinical outcome in pa-tients undergoing radical cystectomy for transitional cell car-cinoma of the bladder a retrospective analysisrdquo BMC Urologyvol 14 no 1 article 76 2014

[19] B R Viers S A Boorjian I Frank et al ldquoPretreatment neu-trophil-to-lymphocyte ratio is associated with advanced patho-logic tumor stage and increased cancer-specific mortalityamong patients with urothelial carcinoma of the bladder under-going radical cystectomyrdquo European Urology vol 66 no 6 pp1157ndash1164 2014

[20] H Akaza M Hagiwara N Deguchi et al ldquoPhase II trial of car-boplatin in patients with advanced germ-cell testicular tumorsand transitional cell carcinomas of the urinary tractrdquo Can-cer Chemotherapy and Pharmacology vol 23 no 3 pp 181ndash1851989

[21] W Cao C Xu G Lou et al ldquoA phase II study of paclitaxel andnedaplatin as first-line chemotherapy in patients with advancedesophageal cancerrdquo Japanese Journal of Clinical Oncology vol39 no 9 pp 582ndash587 2009

[22] Y Sasaki T Tamura K Eguchi et al ldquoPharmacokineticsof (glycolato-001015840)-diammine platinum (II) a new platinumderivative in comparison with cisplatin and carboplatinrdquo Can-cer Chemotherapy andPharmacology vol 23 no 4 pp 243ndash2461989

[23] M Matsumoto Y Takeda H Maki et al ldquoPreclinical invivo antitumor efficacy of nedaplatin with gemcitabine againsthuman lung cancerrdquo Japanese Journal of Cancer Research vol92 no 1 pp 51ndash58 2001

[24] S Umemoto Y Miyoshi Y Yokomizo et al ldquoA case of salvagecombination chemotherapy of gemcitabine plus nedaplatin forsquamous cell carcinoma of the ureterrdquoHinyokika Kiyo vol 52no 1 pp 35ndash39 2006







Contents































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References
































Contents































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





























Contents































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



























Contents































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



















































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




































1 Introduction













43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



































43080

403330

2774160

5273860

2463370

113330

96920

806670

3895840

8406140

4846630

226670

le45

yrs

Age groups


0

100

200

300

400

500

600

700

800

900

Patie

nts n

umbe

r

gt85

yrs

76

ndash85

yrs

66

ndash75

yrs

56

ndash65

yrs

46

ndash55

yrs









T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






























T1-T2 1490 (508) 56 (421) 1128 (555) 306 (401)T3-T4 1439 (492) 77 (579) 905 (445) 457 (599)

N0 2021 (689) 90 (677) 1450 (713) 481 (630)1 908 (311) 43 (323) 583 (287) 282 (370)

M0 1976 (675) 86 (647) 1423 (700) 467 (612)1 953 (325) 47 (353) 610 (300) 296 (388)

























4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References








































4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References
































4 Conclusions


Disclosure


Competing Interests




Acknowledgments


References











































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References
























































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




































1 Introduction














3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



































3 Results
















4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






































4 Discussion









Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




























Table1Ch

aracteris

ticso

find

ividualstudies

inclu

dedin

them

eta-analysis

Stud

y(year)

Cou

ntry

Patie

nts

Inclu

dedperio

dAge

(range)(year)

Gender(MF)

Cut-o

ff(m

gdL

)FU

(range)(year)

Cofactors

NOSscore

Duetal2

013

China

286

2000ndash2003

Median

5572(28ndash77)

185101

400

Median

56(346ndash

945)

Hem

oglobin

calcium

LDHpTstageFu

hrman

gradetumor

size

7

Pichlere

tal2013

Austr

ia994

2000ndash2010

Mean(632plusmn119)

599395

466

Mean

481(0ndash132)

AgegenderpT

stage

Fuhrman

gradenecrosis

8

Erdem

etal2

014

Turkey

128

2006ndash2011

Mean(5866plusmn1131

)9137

343

Median

365

GenderagepT

stage

Fuhrman

gradetumor

size

histo

logics

ubtypesplasma

D-dim

er

8

Niedw

orok

etal2

015

Germany

982002ndash2011

Mean

635(18ndash82)

6137

281

Mean

36(20ndash

122)

NA

7SasakiandOnishi 2

015

Japan

126

2003ndash2013

Median

67(37ndash86)

8442

399

Median

308(2ndash125)

PSpTsta

geH

bAlbLDH

8

Obataetal 2

016

Japan

601

1995ndash2010

Median

58(50ndash

67)

467134

420

Median

74(47ndash107)

Fuhrman

gradepT

stage

histo

logics

ubtypes

8

Leee

tal2016

Korea

1511

2006ndash2013

Median

58(49ndash

67)

1077434

328

Median

36(24ndash

57)

AgeB

MIhypertensio

ndiabetes

mellitusE

COG

scoretumor

sizeFu

hrman

gradepT

stagehisto

logic

subtypestum

ornecrosis

sarcom

atoiddifferentiatio

n

8

Albalbum

inB

MIbo

dymassind

exE

COGE

astern

Coo

perativ

eOncolog

yGroup

FUfollow-upLD


PSperform

ance

statusN

An

otavailable



Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





























Hazard ratio


06916076080499

32351090832716

017830519402256301330163512952

33940

21101

40306

1000

200 [141 283]214 [077 592]165 [106 256]

2541 [007 933065]248 [180 342]

1512 [119 19143]

213 [174 261]Total (95 CI)




= 526 df = 5 (p = 038) I2 = 5

(a)


Hazard ratio

81229200490

1000

389 [112 1346]307 [146 643]

514 [233 1134]247 [149 409]

312 [219 444]

06335037770403702579

135841121

1637109042


Total (95 CI)





(b)


Hazard ratio

142 [105 192]252 [110 578]249 [140 444]

167 [130 215]

71593

192

1000

015280423302952

035280924309123


Total (95 CI)





(c)









233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






























233 [170 319]526 [278 997]

683 [139 3351]

369 [181 754]

481373146

1000


6443816

698

130553898

1941

206637

276165

143184








(a)


418195

442

6868714

787

3693715

421

82551491

1430

9235918

1000

193 [157 237]360 [196 662]281 [083 959]





= 391 df = 2 (p = 014) I2 = 49


(b)


074 [057 098]099 [049 197]163 [034 786]

079 [062 101]

86411620

1000

1260

1834

641

704

251

383

146


2 5Favours negative



= 138 df = 2 (p = 050) I2 = 0


4518

48490

112

11715

(c)




4713

604

107746770

1614

24397

259

43413435

603

8956640

1000

080 [064 100]155 [074 326]091 [033 254]

086 [070 105]




= 282 df = 2 (p = 024) I2 = 29

(d)




1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





























1 2 30SE of log HR

minus5

0

5

10lo

gHR

(a)


minus2

0

2

4

6

Stan

dard

ized

effec

t

2 4 60Precision

(b)






Competing Interests




Acknowledgments


References











































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





























































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



































1 Introduction

















3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References







































3 Results
















Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References









































Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




























Table 1 Continued







)Baseline








4 Discussion




mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





























mul

ativ

e pro

babi

lity

inci

denc

e of s

hort

-term

Category disease

p lt 0001

00

02

04

06

08

10

deve

lopm

ent o

f de n

ovo

CKD

000 500 750250 1000 1250




(a)

p lt 0001

Cum

ulat

ive i

ncid

ence

pro

babi

lity

of lo

ng-te

rm

Long-term follow-up



00

02

04

06

08

10

de n

ovo

CKD

dev

elopm

ent

000 500 750250 1000 1250


(b)










Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References































Warm 0076Cold 0026 053 004 699None 0034 077 007 827











5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References































5 Conclusion


Competing Interests




References






































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References


















































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




































1 Introduction










NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References































NLR































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References


































3 Results







4 Discussion







Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References
































Male n () 913 (711) 825 (706) 88 (759)Female n () 371 (289) 343 (294) 28 (241)















T1 n () 1016 (791) 945 (809) 71 (612)T2 n () 89 (69) 75 (64) 14 (121)T3-4 n () 179 (139) 148 (127) 31 (267)


G1-2 n () 664 (517) 607 (520) 57 (491)G3-4 n () 620 (483) 561 (480) 59 (509)


















0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





































0 12 24 36 48 60 72 84 96 108 120

Recu

rren

ce-fr

ee su

rviv

al ra

te

05

06

07

08

09

10


p lt 0001

(a)

0 12 24 36 48 60 72 84 96 108 120

05

06

07

08

09

10

Canc

er-s

peci

fic su

rviv

al ra

te

(Months)

p lt 0001

Low NLRHigh NLR

(b)
























5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References

















































5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References
































5 Conclusion


Abbreviations


performance status


Competing Interests




References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






















































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






































1 Introduction













3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References



































3 Results





4 Discussion






(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References






























(119899 = 23) (119899 = 9) (119899 = 14)Age (years)lt65 11 (476) 4 (444) 7 (500) 0566ge65 12 (524) 5 (556) 7 (500)







0

02

04

06

08

1

True

pos

itive

frac

tion



0

02

04

06

08

1

True

pos

itive

frac

tion








200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References




























200 400 600 8000Follow-up (days)

0

50

100

Prog

ress

ion-

free s

urvi

val (

)

p = 0011

NLR ge 414

NLR lt 415

(a)

0

50

100

Ove

rall

surv

ival

()

200 400 600 800 10000Follow-up (days)

NLR ge 414

NLR lt 415

p = 0045

(b)


Competing Interests


Acknowledgments


References





































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