Printer Friendly

Systemic inflammatory response based on neutrophil-to-lymphocyte ratio as a prognostic marker in bladder cancer.

1. Introduction

Cancer is a leading cause of morbidity and mortality presenting multifactorial features affected by a variety of factors, including tumor-related and host (patient)-related factors. Until recently, predicting outcomes in cancer patients have mainly depended upon tumor characteristics, such as pathologic tumor stage and tumor grade. However, various hostrelated factors, including weight loss (cachexia), performance status, and systemic inflammatory response (SIR), have been suggested as potential prognostic indicators in cancer patients.

Since Virchow first described a possible connection between inflammation and cancer in 1876 after observing the presence of leukocytes within neoplastic tissues [1], clear evidence now supports the crucial role played by SIR in the development, progression, metastasis, and survival of malignant cells in most cancers [2]. Most solid malignancies trigger an intrinsic inflammatory response that builds up a protumorigenic microenvironment. Inflammation in the tumor microenvironment may promote angiogenesis, invasion, and metastasis via the signaling of tumor-promoting chemokines and cytokines (i.e., IL-1, IL-6, tumor necrosis factor- [TNF-] a, and IL-23), which are produced by innate immune cells (macrophages, neutrophils, mast cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) and adaptive ones (T and B lymphocytes) [1, 2]. Based on this background, in recent years many clinical studies have supported SIR as a meaningful predictor of survival outcomes in various types of cancers, including cancers of the lung [3-5], colorectum [6-11], gastrointestinal tract [12,13], liver [14,15], esophagus [16-18], breast [19-21], ovaries [22-24], cervix [25, 26], and pancreas [27]. In addition, the prognostic value of SIR has been vigorously assessed in urologic cancers, including prostate cancer [28-31], kidney cancer [32-34], and urothelial carcinoma (UC) (cancers of the bladder [35-48] and upper urinary tract (UUT) [49-60]).

UC is the second-most frequently diagnosed urologic malignancy. Clinical outcomes vary. A majority of UCs (90~ 95%) originate in the bladder, and UC of the UUT only accounts for 5~10% of all UCs. Radical cystectomy (RC) and radical nephroureterectomy (RNU), respectively, are applied as the gold standard local treatment for muscle-invasive or high-risk, non-muscle-invasive UC of the bladder and UUT. However, in spite of these aggressive local approaches, longterm prognosis remains poor due to disease recurrence accompanied by local and/or distant metastasis [61-63]. These poor outcomes suggest a need for ongoing risk stratification and proper selection of multimodal treatment approaches, such as chemotherapy in the neoadjuvant or adjuvant setting. To address these issues, a number of studies have explored SIR-related biomarkers as potential predictors of oncologic outcomes in UC. Among these, NLR, defined as the ratio of absolute neutrophils to absolute lymphocytes, has recently gained considerable attention as a biomarker in urothelial carcinoma (UC) arising from the bladder or upper urinary tract (UUT).

In this paper, we reviewed the clinical studies dealing with SIR-related biomarkers in association with oncologic outcomes in UC, with a special focus on NLR.

2. SIR-Based Prognostic Scoring System

Potential hematological biomarkers representing SIR in cancer patients include C-reactive protein (CRP), albumin, Glasgow Prognostic Score (GPS), modified GPS (mGPS), and neutrophil-to-lymphocyte ratio (NLR). The association of these SIR-related biomarkers with oncological outcomes has been extensively studied by many investigators in many types of nonurologic cancers (Table 1). Because hematological tests are routinely performed in most cancer patients, these biomarkers may be used as easily measurable, objective, reproducible, robust, and inexpensive parameters able to express the severity of SIR in cancer patients.

CRP is a nonspecific but sensitive marker of the acute phase response and is expressed in selected tumor cells [64]. The biological basis for the correlation between expression of this marker, cancer risk, outcome, and survival is not completely understood. Several proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and TNF-a, expressed by the tumor environment induce CRP synthesis from the liver and other tissues [1, 2]. Based on many recent studies, it is now widely accepted that an elevated CRP value is a reliable indicator of poor prognosis in a variety of types of cancers [4, 8, 14, 16, 23, 28, 29, 31, 32, 65, 66].

Serum albumin, another marker of acute phase response to an inflammatory state, is generally used to assess nutritional status, severity of disease, disease progression, and prognosis [64]. Malnutrition and inflammation suppress albumin synthesis. In an adult, the normal range of serum albumin level is 3.5-5.0 g/dL. When levels drop below 3.5 g/dL, the condition is called hypoalbuminemia. The lower serum albumin concentration may be due to the production of cytokines such as IL-6, which modulate the production of albumin by hepatocytes [64]. Alternatively, TNF-a may increase the permeability of the microvasculature, thus allowing an increased transcapillary passage of albumin. Presence of micrometastatic tumor cells in the liver may induce the Kupffer cells to produce a variety of cytokines (IL-1, IL-6, and TNF-a), which may modulate albumin synthesis by hepatocytes [1, 2]. Thus, hypoalbuminemia is uncommon in earlystage cancer but as the disease progresses, albumin levels drop significantly and serve as good prognostic indicators in patients with various cancers [7, 19, 22, 67].

GPS and mGPS are inflammation-based prognostic scores developed by combining CRP and albumin to predict the clinical outcomes in cancer patients [68, 69]. GPS and mGPS, as routinely available, easily measured, and well standardized worldwide hematologic biomarkers, have subsequently been the subject of prognostic studies in wide variety of operable [13, 15, 18, 25, 27, 34] and inoperable [9, 10, 17, 20, 33] cancers. Indeed, these scoring systems have been extensively validated in various clinical scenarios and are now recognized to have prognostic value independent of tumor-based factors, such as pathologic tumor stage, tumor grade, lymphovascular invasion, and lymph node involvement.

It is also well recognized that SIR is related to changes in circulating white blood cells, especially an abnormal increase in neutrophils (neutrophilia) along with an abnormal decrease in lymphocytes (lymphocytopenia) [2, 64]. In light of this phenomenon under inflammatory conditions, NLR, being the ratio of neutrophils to lymphocytes, has gained considerable interest over the past decade not only as a potential prognostic factor associated with outcomes in a variety of cancers but also as a means of refining risk stratification of patients to treatment and predicting survival rates. Currently, NLR has been demonstrated to have significant prognostic value in urologic cancers, such as prostate [70] and renal cancer [71, 72], and also in cancers outside the urinary system [5, 11, 21, 24, 26].

3. SIR in Bladder Cancer

Prognosis in bladder cancer utilizes the same factors utilized for other types of cancers, including tumor-related factors, such as tumor stage, grade, lymphovascular invasion (LVI), and lymph node involvement (LNI) [61, 63]. However, all of these factors feature postoperative parameters. Given that SIR-related hematological biomarkers are easily obtained through pretreatment routine blood examination and have provided reliable prognostic information in other types of cancers, these biomarkers have been investigated in risk stratification for recurrence and mortality of patients with bladder cancer in both pre- and posttreatment settings. Several clinical studies have found an association between SIR-related hematological biomarkers, including CRP, albumin, and GPS, and oncologic outcomes of UC of the bladder (Table 3). In each different treatment setting, elevated CRP, defined as different cut-off (1.0 or 0.5mg/dL),was significantly related to worse cancer-specific-survival (CSS) [35, 36]. One study demonstrated that in muscle-invasive bladder cancer (MIBC) patients with elevated CRP levels showed significantly more adverse pathologic features, such as extravesical disease ([greater than or equal to] pT3), larger tumor size, lymph node involvement, and positive surgical margin prior to undergoing RC compared to patients with normal CRP levels. In addition, one-unit elevation in pre-RC CRP levels was significantly associated with a 20% increased risk of cancer-related death after RC [37]. In inoperable advanced bladder cancer, hypoalbuminemia and GPS 2 measured prior to chemotherapy were independently associated with shortened progression-free survival (PFS) and overall survival (OS), respectively [39]. Recently, Ku et al. developed a nomogram incorporating albumin, lymphocyte count, and platelet count to predict the probability of 5-year OS and disease-specific survival (DSS) after RC that demonstrated higher predictive accuracy than the existing staging system [46].

4. NLR in Non-Muscle-Invasive Bladder Cancer (NMIBC)

To date, few studies have assessed the association between NLR and the prognosis of NMIBC initially treated with transurethral resection of the bladder tumor (TURBT). Indeed, the evaluation of the prognostic role of NLR has been conducted with focus on MIBC patients undergoing RC or a mixed cohort of muscle-invasive and non-muscle-invasive tumors (Table 2). One recent study assessed the predictive value of preoperative NLR in 107 patients initially diagnosed with NMIBC following TURBT [47]. When applying each different cut-off point for NLR using the standardized cutoff finder algorithm, NLR > 2.41 and NLR > 2.43 were significantly associated with unfavorable disease progression and recurrence. Owing to the limited sample size of this study, further studies will be required to validate the role of NLR as a predictor for recurrence and progression in NMIBC.

5. NLR in Muscle-Invasive Bladder Cancer (MIBC)

In the past five years, the prognostic role of NLR in MIBC has been actively investigated in association with various oncological outcomes, including pathologic outcome, post-RC recurrence, and survival (Table 2). Several studies evaluated the association between NLR and post-RC survival outcomes [38, 40, 41, 44]. The cut-off point chosen to define an elevated NLR differed across studies, ranging from 2.5 to 3. Although one study reported no significant association between elevated NLR and OS [40], elevated NLR has been regarded as an independent predictor of RFS (recurrence-free survival), OS, and CSS in most studies [38, 41, 44]. One study reported that higher NLR values were observed in MIBC patients compared with NMIBC patients [42]. In addition, several studies demonstrated a significant correlation between a higher NLR and adverse pathologic outcomes, such as larger tumor size, pathological upstaging to locally advanced disease (pT3), and LNI after RC [41-44]. In locally advanced MIBC treated with neoadjuvant chemotherapy (NACH) prior to RC, continuous NLR decrease from before NACH to before RC was observed only in patients showing a pathological response after RC; therefore, sustained NLR decrease during NACH was suggested as a potential surrogate marker reflecting the effect of NACH [48]. The aforementioned studies mainly dealt with the prognostic value of NLR in the pretreatment setting. Interestingly, one recent study elucidated the influence of posttreatment NLR measured in the early post-RC period on oncologic outcomes [45]. The cut-off point of pre- and post-RC NLR (2.1 and 2.0, resp.) was differently determined according to each receiver operating characteristics (ROC) curve analysis. Similar to the aforementioned study results, elevated NLR after RC was also significantly associated with adverse pathologic outcomes, such as pT3/T4 disease, LVI, and LNI, and was an independent predictor of OS and CSS. Moreover, patients with perioperative continuous elevated NLR (2.1 ->2.0) showed worse OS and CSS compared with other change groups. Therefore, pre- and posttreatment NLR might have prognostic value in predicting postoperative survival outcome in patients with MIBC.

6. NLR in Upper Urinary Tract Urothelial Carcinoma (UTUC)

Similar to bladder cancer, the prognostic significance of other SIR-related hematological biomarkers, including CRP, albumin, and neutrophil count, has been proven to be reliable in terms of predicting adverse pathologic and survival outcomes following definitive surgery in UTUC [49, 51, 52, 55, 58]. In recent years, the prognostic role of NLR has also been vigorously assessed in UTUC [50, 53, 56, 57, 60] (Table 3). Although all of the studies involved cohorts of patients with operable UTUC, the threshold to determine elevated NLR levels was not uniform, ranging from 2.5 to 3. However, irrespective of the choice of NLR threshold, elevated NLR over the threshold was consistently correlated with adverse postoperative pathologic findings (high tumor grade, advanced tumor stage, LVI, and LNI) and worse survival outcomes following RNU.

7. Clinical Implications of SIR in Bladder Cancer

NMIBC can primarily be treated with TURBT. However, frequent recurrence (50~70%) and progression (10~20%) rates after TURBT are a major concern [61,73]. Management of NMIBC might involve lifelong surveillance and place a considerable economic burden on patients. Currently, cystoscopy is the standard of care during the surveillance period. It is, however, invasive, and repeated cystoscopic examinations can cause substantial discomfort and pain to patients. Although investigators have developed various models to predict recurrence and progression after TURBT for NMIBC including nomogram, scoring systems, and risk tables [74-77], these models mainly incorporated tumor-related factors, such as tumors number, tumor diameter, T category, World Health Organization (WHO) tumor grade, and carcinoma in situ (CIS). Considering the significant correlation of elevated NLR with disease recurrence and progression in NMIBC [47], the addition of NLR to the existing prediction model may contribute to more accurate stratification of patients with NMIBC according to risk of recurrence and progression. Also, according to risk stratification based on pretreatment NLR values, selective cystoscopic examination and additional treatment, including intravesical Bacillus Calmette-Guerin (BCG) immunotherapy or chemotherapy, will be possible in patients with high-risk NMIBC, thereby reducing their economic burden and the potential discomfort caused by repeated cystoscopy.

In terms of MIBC, one significant challenge has been the limited, pretreatment, risk-stratification data that exists for patients undergoing RC. The well-established risk factors for recurrence and survival in MIBC included tumor-related factors, including pathologic tumor stage, pathologic tumor grade, CIS, LVI, and LNI [78-80]. Moreover, most predictive models (nomogram) predicting recurrence and survival in bladder cancer have been heavily based on postoperative pathologic factors, such as pathologic tumor stage, pathological grade, LVI, and LNI [81-83], with minimal consideration for associated host-related factors. Meanwhile, the accuracy of clinical staging in bladder cancer remains poor, reporting upstaging rate of 50% at RC specimen [84]. Thus, not enough data exists to facilitate appropriate patient counseling and guide clinical trial enrollment. As such, it is required to identify biomarkers that can assist with preoperative patient risk stratification and counseling. To achieve these goals, SIR-related hematological biomarkers can be a potential and promising factor. Assessment of SIR-related biomarkers in bladder cancer may be particularly relevant, because the inflammatory process seems to play an important role in the genesis and progression of, as well as mortality from, bladder cancer [1,2]. Based on the previous study result [43], demonstrating a significant association between pretreatment elevated NLR and pathologic upstaging after RC, the performance of early cystectomy or NACH prior to RC might be considered in patients with pretreatment high NLR to attain tumor downstaging and improve postoperative survival. In addition, the pattern of change in NLR during NACH will be a valuable surrogate marker for monitoring and predicting pathological response to NACH [48]. Several studies reported the incorporation of SIR-related hematological biomarkers, such as CRP, NLR, albumin, and lymphocyte and platelet count, with a predictive model for survival outcomes in MIBC [37, 38, 46] or UTUC [50, 55, 57], improved predictive accuracy of the model, and consequently discriminated patients well according to risk stratification. It follows that pretreatment evaluation of NLR will be helpful in counseling patients about their prognosis.

A recent studyrevealed that the NLRvalue measured during the early postoperative period (from 1 to 3 months) after RC had a significant correlation with adverse oncological and survival outcomes [45]. Thus, postoperative NLR and the pattern of NLR change in the perioperative period may also provide valuable information in determining which patients should be referred for additional multimodal treatment, such as radiation and adjuvant chemotherapy.

The limitations of current NLR-associated studies in cancer are as follows. First, as mentioned earlier, there was no uniform cut-off point for NLR; each threshold was adopted according to a variety of statistical methodologies. Unlike tumor-related prognostic factors, including pathologic tumor stage and grade, NLR as a host-related factor can be affected by a variety of physiologic conditions, such as patients' comorbidities (hypertension and diabetes mellitus) and type of cancer, which can trigger immune response to cancer so that the establishment of definite NLR threshold may be difficult in consideration of these changeable physiologic conditions among cancer patients. Second, nearly all of the studies were both clinical and retrospective. Further large-scale prospective clinical or experimental animal (preclinical) research using a unified and robust statistical methodology will be required to determine the definite cut-off value of NLR and to discover the biological mechanisms supporting the correlation between NLR and oncologic outcomes in cancer patients.

8. Conclusion

Elevated NLR has shown a significant association with adverse oncologic and survival outcomes in patients with UC. Thus, NLR as a potential marker of SIR may become a promising tool in the management of patients with UC of the bladder and UUT, in terms of improved risk assessment for prognosis and guidance for treatment. Moreover, the ease and convenience of routine blood examinations in the clinical setting mean that NLR can be an objective, inexpensive, reproducible, and cost-effective measurement for the prediction of prognosis in UC. However, current NLR-related studies have not applied uniform NLR thresholds and thus require cautious interpretation because of many statistical methodological limitations. For the introduction of NLR into the clinical practice, rigorous attempts should be made in proper prospective study design.

http://dx.doi.org/ 10.1155/2016/8345286

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

[1] F. Balkwill and A. Mantovani, "Inflammation and cancer: back to virchow?" The Lancet, vol. 357, no. 9255, pp. 539-545, 2001.

[2] S. I. Grivennikov, F. R. Greten, and M. Karin, "Immunity, inflammation, and cancer," Cell, vol. 140, no. 6, pp. 883-899, 2010.

[3] E. Espinosa, J. Feliu, P. Zamora et al., "Serum albumin and other prognostic factors related to response and survival in patients with advanced non-small cell lung cancer," Lung Cancer, vol. 12, no. 1-2, pp. 67-76, 1995.

[4] J. M. Jones, N. C. McGonigle, M. McAnespie, G. W. Cran, and A. N. Graham, "Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer," Lung Cancer, vol. 53, no. 1, pp. 97-101, 2006.

[5] Y. Yao, D. Yuan, H. Liu, X. Gu, and Y. Song, "Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy," Cancer Immunology, Immunotherapy, vol. 62, no. 3, pp. 471-479, 2013.

[6] S. D. Heys, L. G. Walker, D. J. Deehan, and O. E. Eremin, "Serum albumin: a prognostic indicator in patients with colorectal cancer," Journal of the Royal College of Surgeons of Edinburgh, vol. 43, no. 3, pp. 163-168, 1998.

[7] C.-C. Lai, J.-F. You, C.-Y. Yeh et al., "Low preoperative serum albumin in colon cancer: a risk factor for poor outcome," International Journal of Colorectal Disease, vol. 26, no. 4, pp. 473-481, 2011.

[8] Y.-C. Shiu, J.-K. Lin, C.-J. Huang et al., "Is C-reactive protein a prognostic factor of colorectal cancer?" Diseases of the Colon and Rectum, vol. 51, no. 4, pp. 443-449, 2008.

[9] E. F. Leitch, M. Chakrabarti, J. E. M. Crozier et al., "Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer," British Journal of Cancer, vol. 97, no. 9, pp. 1266-1270, 2007.

[10] M. Ishizuka, H. Nagata, K. Takagi, and K. Kubota, "Influence of inflammation-based prognostic score on mortality of patients undergoing chemotherapy for far advanced or recurrent unresectable colorectal cancer," Annals of Surgery, vol. 250, no. 2, pp. 268-272, 2009.

[11] W. Chua, K. A. Charles, V. E. Baracos, and S. J. Clarke, "Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer," British Journal of Cancer, vol. 104, no. 8, pp. 1288-1295, 2011.

[12] S. Dutta, A. B. C. Crumley, G. M. Fullarton, P. G. Horgan, and D. C. McMillan, "Comparison of the prognostic value of tumour and patient related factors in patients undergoing potentially curative resection of gastric cancer," The American Journal of Surgery, vol. 204, no. 3, pp. 294-299, 2012.

[13] X. Jiang, N. Hiki, S. Nunobe et al., "Prognostic importance of the inflammation-based Glasgow prognostic score in patients with gastric cancer," British Journal of Cancer, vol. 107, no. 2, pp. 275-279, 2012.

[14] K. Hashimoto, Y. Ikeda, D. Korenaga et al., "The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma," Cancer, vol. 103, no. 9, pp. 1856-1864, 2005.

[15] A. Kinoshita, H. Onoda, N. Imai et al., "Comparison of the prognostic value of inflammation-based prognostic scores in patients with hepatocellular carcinoma," British Journal of Cancer, vol. 107, no. 6, pp. 988-993, 2012.

[16] A. B. C. Crumley, D. C. McMillan, M. McKernan, J. J. Going, C. J. Shearer, and R. C. Stuart, "An elevated C-reactive protein concentration, prior to surgery, predicts poor cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer," British Journal of Cancer, vol. 94, no. 11, pp. 1568-1571, 2006.

[17] A. B. C. Crumley, D. C. McMillan, M. McKernan, A. C. McDonald, and R. C. Stuart, "Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer," British Journal of Cancer, vol. 94, no. 5, pp. 637-641, 2006.

[18] Y. K. Vashist, J. Loos, J. Dedow et al., "Glasgow prognostic score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer," Annals ofSurgical Oncology, vol. 18, no. 4, pp. 1130-1138, 2011.

[19] C. G. Lis, J. F. Grutsch, P. G. Vashi, and C. A. Lammersfeld, "Is serum albumin an independent predictor of survival in patients with breast cancer?" Journal of Parenteral and Enteral Nutrition, vol. 27, no. 1, pp. 10-15, 2003.

[20] A. M. Al Murri, J. M. S. Bartlett, P. A. Canney, J. C. Doughty, C. Wilson, and D. C. McMillan, "Evaluation of an inflammationbased prognostic score (GPS) in patients with metastatic breast cancer," British Journal of Cancer, vol. 94, no. 2, pp. 227-230, 2006.

[21] B. Azab, V. R. Bhatt, J. Phookan et al., "Usefulness of the neutrophil-to- lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients," Annals of Surgical Oncology, vol. 19, no. 1, pp. 217-224, 2012.

[22] D. Parker, C. Bradley, S. M. Bogle et al., "Serum albumin and CA125 are powerful predictors of survival in epithelial ovarian cancer," BJOG, vol. 101, no. 10, pp. 888-893, 1994.

[23] L. A. Hefler, N. Concin, G. Hofstetter et al., "Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer," Clinical Cancer Research, vol. 14, no. 3, pp. 710-714, 2008.

[24] H. Cho, H. W. Hur, S. W. Kim et al., "Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment," Cancer Immunology, Immunotherapy, vol. 58, no. 1, pp. 15-23, 2009.

[25] S. Polterauer, C. Grimm, V. Seebacher et al., "The inflammation-based glasgow prognostic score predicts survival in patients with cervical cancer," International Journal of Gynecological Cancer, vol. 20, no. 6, pp. 1052-1057, 2010.

[26] Y.-Y. Lee, C. H. Choi, H.-J. Kim et al., "Pretreatment neutrophil: lymphocyte ratio as a prognostic factor in cervical carcinoma," Anticancer Research, vol. 32, no. 4, pp. 1555-1561, 2012.

[27] M. La Torre, G. Nigri, M. Cavallini, P. Mercantini, V. Ziparo, and G. Ramacciato, "The glasgow prognostic score as a predictor of survival in patients with potentially resectable pancreatic adenocarcinoma," Annals of Surgical Oncology, vol. 19, no. 9, pp. 2917-2923, 2012.

[28] S. Lehrer, E. J. Diamond, B. Mamkine, M. J. Droller, N. N. Stone, and R. G. Stock, "C-reactive protein is significantly associated with prostate-specific antigen and metastatic disease in prostate cancer," BJUInternational, vol. 95, no. 7, pp. 961-962, 2005.

[29] T. M. Beer, A. S. Lalani, S. Lee et al., "C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer," Cancer, vol. 112, no. 11, pp. 2377-2383, 2008.

[30] P. A. McArdle, T. Qayyum, and D. C. McMillan, "Systemic inflammatory response and survival in patients with localised prostate cancer: 10-year follow-up," Urologia Internationalis, vol. 84, no. 4, pp. 430-435, 2010.

[31] Z.-Q. Liu, L. Chu, J.-M. Fanget al., "Prognostic role of C-reactive protein in prostate cancer: a systematic review and metaanalysis," Asian Journal of Andrology, vol. 16, no. 3, pp. 467-471, 2014.

[32] P. I. Karakiewicz, G. C. Hutterer, Q.-D. Trinh et al., "C-reactive protein is an informative predictor of renal cell carcinoma-specific mortality: a European study of 313 patients," Cancer, vol. 110, no. 6, pp. 1241-1247, 2007.

[33] S. Ramsey, G. W. A. Lamb, M. Aitchison, J. Graham, and D. C. McMillan, "Evaluation of an inflammation-based prognostic score in patients with metastatic renal cancer," Cancer, vol. 109, no. 2, pp. 205-212, 2007.

[34] G. W. A. Lamb, M. Aitchison, S. Ramsey, S. L. Housley, and D. C. McMillan, "Clinical utility of the glasgow prognostic score in patients undergoing curative nephrectomy for renal clear cell cancer: basis of new prognostic scoring systems," British Journal of Cancer, vol. 106, no. 2, pp. 279-283, 2012.

[35] M. Hilmy, J. M. S. Bartlett, M. A. Underwood, and D. C. McMillan, "The relationship between the systemic inflammatory response and survival in patients with transitional cell carcinoma of the urinary bladder," British Journal of Cancer, vol. 92, no. 4, pp. 625-627, 2005.

[36] S. Yoshida, K. Saito, F. Koga et al., "C-reactive protein level predicts prognosis in patients with muscle-invasive bladder cancer treated with chemoradiotherapy," BJU International, vol. 101, no. 8, pp. 978-981, 2008.

[37] G. Gakis, T. Todenhofer, M. Renninger et al., "Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score," BJU International, vol. 108, no. 11, pp. 1800-1805, 2011.

[38] T. Gondo, J. Nakashima, Y. Ohno et al., "Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy," Urology, vol. 79, no. 5, pp. 1085-1091, 2012.

[39] E. C. Hwang, I. S. Hwang, H. S. Yu et al., "Utility of inflammation-based prognostic scoring in patients given systemic chemotherapy first-line for advanced inoperable bladder cancer," Japanese Journal of Clinical Oncology, vol. 42, no. 10, pp. 955-960, 2012.

[40] A. Demirtac, V. Sabur, E. C. Aknsal et al., "Can neutrophil-lymphocyte ratio and lymph node density be used as prognostic factors in patients undergoing radical cystectomy?" The Scientific World Journal, vol. 2013, Article ID 703579, 5 pages, 2013.

[41] T. Hermanns, B. Bhindi, Y. Wei et al., "Pre-treatment neutrophil-to- lymphocyte ratio as predictor of adverse outcomes in patients undergoing radical cystectomy for urothelial carcinoma of the bladder," British Journal of Cancer, vol. 111, no. 3, pp. 444-451, 2014.

[42] M. Kaynar, M. E. Yildirim, H. Badem et al., "Bladder cancer invasion predictability based on preoperative neutrophil-lymphocyte ratio," Tumor Biology, vol. 35, no. 7, pp. 6601-6605, 2014.

[43] A. Potretzke, L. Hillman, K. Wong et al., "NLR is predictive of upstaging at the time of radical cystectomy for patients with urothelial carcinoma of the bladder," Urologic Oncology: Seminars and Original Investigations, vol. 32, no. 5, pp. 631-636, 2014.

[44] B. R. Viers, S. A. Boorjian, I. Frank et al., "Pretreatment neutrophil-to- lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer-specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy," European Urology, vol. 66, no. 6, pp. 1157-1164, 2014.

[45] M. Kang, C. W. Jeong, C. Kwak, H. H. Kim, and J. H. Ku, "The prognostic significance of the early postoperative neutrophilto-lymphocyte ratio in patients with urothelial carcinoma of the bladder undergoing radical cystectomy," Annals of Surgical Oncology, pp. 1-8, 2015.

[46] J. H. Ku, M. Kang, H. S. Kim, C. W. Jeong, C. Kwak, and H. H. Kim, "The prognostic value of pretreatment of systemic inflammatory responses in patients with urothelial carcinoma undergoing radical cystectomy," British Journal of Cancer, vol. 112, no. 3, pp. 461-467, 2015.

[47] R. Mano, J. Baniel, O. Shoshany et al., "Neutrophil-to-lymphocyte ratio predicts progression and recurrence of non-muscle-invasive bladder cancer," Urologic Oncology: Seminars and Original Investigations, vol. 33, pp. 67. e1-67.e7, 2015.

[48] J.-A. Seah, R. Leibowitz-Amit, E. G. Atenafu et al., "Neutrophil-lymphocyte ratio and pathological response to neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer," Clinical Genitourinary Cancer, vol. 13, no. 4, pp. e229-e233, 2015.

[49] K. Saito, S. Kawakami, Y. Ohtsuka et al., "The impact of preoperative serum C-reactive protein on the prognosis of patients with upper urinary tract urothelial carcinoma treated surgically," BJU International, vol. 100, no. 2, pp. 269-273, 2007.

[50] T. Azuma, Y. Matayoshi, K. Odani et al., "Preoperative neutrophil- lymphocyte ratio as an independent prognostic marker for patients with upper urinary tract urothelial carcinoma," Clinical Genitourinary Cancer, vol. 11, no. 3, pp. 337-341, 2013.

[51] T. Hashimoto, Y. Ohno, J. Nakashima, T. Gondo, M. Ohori, and M. Tachibana, "Clinical significance of preoperative peripheral blood neutrophil count in patients with non-metastatic upper urinary tract carcinoma," World Journal of Urology, vol. 31, no. 4, pp. 953-958, 2013.

[52] J. Obata, E. Kikuchi, N. Tanaka et al., "C-reactive protein: a biomarker of survival in patients with localized upper tract urothelial carcinoma treated with radical nephroureterectomy," Urologic Oncology, vol. 31, no. 8, pp. 1725-1730, 2013.

[53] O. Dalpiaz, G. C. Ehrlich, S. Mannweiler et al., "Validation of pretreatment neutrophil-lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma," BJU International, vol. 114, no. 3, pp. 334-339, 2014.

[54] O. Dalpiaz, M. Pichler, S. Mannweiler et al., "Validation of the pretreatment derived neutrophil-lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma," British Journal of Cancer, vol. 110, no. 10, pp. 2531-2536, 2014.

[55] J. H. Ku, M. Kim, W. S. Choi, C. Kwak, and H. H. Kim, "Preoperative serum albumin as a prognostic factor in patients with upper urinary tract urothelial carcinoma," International Brazilian Journal of Urology, vol. 40, no. 6, pp. 753-762, 2014.

[56] H.-L. Luo, Y.-T. Chen, Y.-C. Chuang et al., "Sub-classification of upper urinary tract urothelial carcinoma by the neutrophil-to-lymphocyte ratio (NLR) improves prediction of oncological outcome," BJU International, vol. 113, no. 5, pp. E144-E149, 2014.

[57] N. Tanaka, E. Kikuchi, K. Kanao et al., "A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy," Annals of Surgical Oncology, vol. 21, no. 12, pp. 4041-4048, 2014.

[58] N. Tanaka, E. Kikuchi, S. Shirotake et al., "The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: a multi-institutional study," European Urology, vol. 65, no. 1, pp. 227-234, 2014.

[59] M. Kim, K. C. Moon, W. S. Choi et al., "Prognostic value of systemic inflammatory responses in patients with upper urinary tract urothelial carcinoma," World Journal of Urology, vol. 33, no. 10, pp. 1439-1457, 2015.

[60] H. H. Sung, H. Gyun Jeon, B. C. Jeong et al., "Clinical significance of prognosis using the neutrophil-lymphocyte ratio and erythrocyte sedimentation rate in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma," BJU International, vol. 115, pp. 587-594, 2015.

[61] M. Babjuk, M. Burger, R. Zigeuner et al., "EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013," European Urology, vol. 64, no. 4, pp. 639-653, 2013.

[62] M. Roupret, M. Babjuk, E. Comperat et al., "European guidelines on upper tract urothelial carcinomas: 2013 update," European Urology, vol. 63, no. 6, pp. 1059-1071, 2013.

[63] J. A. Witjes, E. Comperat, N. C. Cowan et al., "EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines," European Urology, vol. 65, no. 4, pp. 778-792, 2014.

[64] C. Gabay and I. Kushner, "Acute-phase proteins and other systemic responses to inflammation," The New England Journal of Medicine, vol. 340, no. 6, pp. 448-454, 1999.

[65] F. A. Mahmoud and N. I. Rivera, "The role of C-reactive protein as a prognostic indicator in advanced cancer," Current Oncology Reports, vol. 4, no. 3, pp. 250-255, 2002.

[66] K. H. Allin and B. G. Nordestgaard, "Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer," Critical Reviews in Clinical Laboratory Sciences, vol. 48, no. 4, pp. 155-170, 2011.

[67] V. Seebacher, C. Grimm, A. Reinthaller et al., "The value of serum albumin as a novel independent marker for prognosis in patients with endometrial cancer," European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 171, no. 1, pp. 101106, 2013.

[68] D. C. McMillan, "The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer," Cancer Treatment Reviews, vol. 39, no. 5, pp. 534-540, 2013.

[69] M. J. Proctor, D. S. Morrison, D. Talwar et al., "A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome study," European Journal of Cancer, vol. 47, no. 17, pp. 2633-2641, 2011.

[70] D. Keizman, M. Gottfried, M. Ish-Shalom et al., "Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram," Oncologist, vol. 17, no. 12, pp. 1508-1514, 2012.

[71] D. Keizman, M. Ish-Shalom, P. Huang et al., "The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma," European Journal of Cancer, vol. 48, no. 2, pp. 202-208, 2012.

[72] Y. Wu, X. Fu, X. Zhu et al., "Prognostic role of systemic inflammatory response in renal cell carcinoma: a systematic review and meta-analysis," Journal of Cancer Research and Clinical Oncology, vol. 137, no. 5, pp. 887-896, 2011.

[73] S. S. Chang, "Non-muscle invasive bladder cancer," Urologic Clinics of North America, vol. 40, no. 2, 2013.

[74] K. W. Seo, B. H. Kim, C. H. Park, C. I. Kim, and H. S. Chang, "The efficacy of the EORTC scoring system and risk tables for the prediction of recurrence and progression of non-muscle-invasive bladder cancer after intravesical bacillus calmette-guerin instillation," Korean Journal of Urology, vol. 51, no. 3, pp. 165-170, 2010.

[75] V. Hernandez, E. De La Pena, M. D. Martin, C. Blazquez, F. J. Diaz, and C. Llorente, "External validation and applicability of the EORTC risk tables for non-muscle-invasive bladder cancer," World Journal of Urology, vol. 29, no. 4, pp. 409-414, 2011.

[76] S. J. Hong, K. S. Cho, M. Han et al., "Nomograms for prediction of disease recurrence in patients with primary Ta, T1 transitional cell carcinoma of the bladder," Journal of Korean Medical Science, vol. 23, no. 3, pp. 428-433, 2008.

[77] J. Fernandez-Gomez, R. Madero, E. Solsona et al., "Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus calmette-guerin: the CUETO scoring model," The Journal of Urology, vol. 182, no. 5, pp. 2195-2203, 2009.

[78] P. Bassi, G. D. Ferrante, N. Piazza et al., "Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort," The Journal of Urology, vol. 161, no. 5, pp. 1494-1497, 1999.

[79] I. Honma, N. Masumori, E. Sato et al., "Local recurrence after radical cystectomy for invasive bladder cancer: an analysis of predictive factors," Urology, vol. 64, no. 4, pp. 744-748, 2004.

[80] K. Turkolmez, H. Tokgoz, B. Resorlu, K. Kose, and Y. Beduk, "Muscle-invasive bladder cancer: predictive factors and prognostic difference between primary and progressive tumors," Urology, vol. 70, no. 3, pp. 477-481, 2007.

[81] International Bladder Cancer Nomogram Consortium, "Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer," Journal of Clinical Oncology, vol. 24, no. 24, pp. 3967-3972, 2006.

[82] P. I. Karakiewicz, S. F. Shariat, G. S. Palapattu et al., "Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder," Journal of Urology, vol. 176, no. 4, pp. 1354-1362, 2006.

[83] S. F. Shariat, P. I. Karakiewicz, G. S. Palapattu et al., "Nomograms provide improved accuracy for predicting survival after radical cystectomy," Clinical Cancer Research, vol. 12, no. 22, pp. 6663-6676, 2006.

[84] R. S. Svatek, S. F. Shariat, G. Novara et al., "Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort," BJU International, vol. 107, no. 6, pp. 898-904, 2011.

Hyung Suk Kim and Ja Hyeon Ku

Department of Urology, Seoul National University College of Medicine, Seoul 110-

744, Republic of Korea

Correspondence should be addressed to Ja Hyeon Ku; kuuro70@snu.ac.kr

Received 4 September 2015; Accepted 4 November 2015

Academic Editor: Shih-Ping Hsu
TABLE 1: Clinical studies on the prognostic value of SIR-related
hematological biomarkers in various types of cancers other than U(

Study         Marker     Type of cancer     Threshold      Assessment
                                                             period

Parker et     Albumin    Ovarian cancer     3.5 & 4.1        Before
al. [22]                                       g/dL        operation

Lis et al.    Albumin    Breast cancer       3.5 g/dL        Before
[19]                                                       operation

Lai et al.    Albumin     Colon cancer       3.5 g/dL        Before
[7]                                                        operation

Seebacher     Albumin     Endometrial       4.21 g/dL        Before
et al. [67]                  cancer             or         operation
                                            continuous

Hashimoto       CRP           HCC            1.0mg/dL        Before
et al. [14]                                                operation

Lehrer et       CRP         Prostate            NA           Before
al. [28]                     cancer        (continuous)    radiation

Crumley et      CRP     Gastroesophageal    1.0 mg/dL        Before
al. [16]                     cancer                        operation

Jones et        CRP       Lung cancer        0.4mg/dL        Before
al. [4]                                                    operation

Karakiewicz     CRP           RCC           0.4 & 2.3        Before
et al. [32]                                   mg/dL       nephrectomy

Beer et al.     CRP        Metastatic       0.8 mg/dL        Before
[29]                    prostate cancer                    docetaxel
                                                             based
                                                          chemotherapy

Hefler et       CRP      Ovarian cancer     1.0 mg/dL        Before
al. [23]                                                    surgery

Shiu et al.     CRP        Colorectal       0.5 mg/dL        Before
[8]                          cancer                         surgery

Crumley et      GPS        Inoperable       1.0 mg/dL        Before
al. [17]                gastroesophageal    (CRP) 3.5     nonsurgical
                             cancer            g/dL        treatment
                                            (Albumin)

AI Murri et     GPS        Metastatic       1.0 mg/dL     Before non-
al. [20]                 breast cancer      (CRP) 3.5       surgical
                                               g/dL        treatment
                                            (Albumin)

Ramsey et       GPS      Metastatic RCC     1.0 mg/dL        Before
al. [33]                                    (CRP) 3.5      treatment
                                               g/dL
                                            (Albumin)

Polterauer      GPS     Cervical cancer     1.0 mg/dL        Before
et al. [25]                                 (CRP) 3.5       surgery
                                               g/dL
                                            (Albumin)

Vashist et      GPS        Esophageal       1.0 mg/dL        Before
al. [18]                     cancer         (CRP) 3.5       surgery
                                               g/dL
                                            (Albumin)

Kinoshita       GPS           HCC           1.0 mg/dL        Before
et al. [15]                                 (CRP) 3.5      treatment
                                               g/dL
                                            (Albumin)

Leitch et      mGPS        Colorectal       1.0 mg/dL        Before
al. [9]                 cancer (operable    (CRP) 3.5      treatment
                        or unresectable)       g/dL
                                            (Albumin)

Jiang et       mGPS      Gastric cancer     1.0 mg/dL        Before
al. [13]                                    (CRP) 3.5       surgery
                                               g/dL
                                            (Albumin)

Ishizuka et    mGPS       Unresectable      1.0 mg/dL        Before
al. [10]                   colorectal       (CRP) 3.5     chemotherapy
                             cancer            g/dL
                                            (Albumin)

La Torre et    mGPS        Pancreatic       1.0 mg/dL        Before
al. [27]                     cancer         (CRP) 3.5       surgery
                                               g/dL
                                            (Albumin)

Lamb et al.    mGPS           RCC           1.0 mg/dL        Before
[34]                                        (CRP) 3.5       surgery
                                               g/dL
                                            (Albumin)

Cho et al.      NLR      Ovarian cancer        2.6           Before
[24]                                                        surgery

Chua et al.     NLR        Metastatic           5            Before
[11]                       colorectal                     chemotherapy
                             cancer

Azab et al.     NLR      Breast cancer       Multiple        Before
[21]                                         cut-offs     chemotherapy
                                           (1.8, 2, 45,
                                              3, 33)

Keizman et      NLR     Metastatic CRPC         3            Before
al. [70]                                                  ketoconazole

Keizman et      NLR      Metastatic RCC         3            Before
al. [71]                                                   sunitinib

Lee et al.      NLR     Cervical cancer        1.9           Before
[26]                                                       treatment

Yao et al.      NLR      Advanced lung         2.63          Before
[5]                          cancer                       chemotherapy

Study         Results

Parker et     Low-albumin level (continuous value) was associated
al. [22]      with worse OS

Lis et al.    Low-albumin level (<3.5 g/dL) was related to higher
[19]          death rate

Lai et al.    Hypoalbuminemia (<3.5 g/dL) was associated with
[7]           increased morbidity and mortality

Seebacher     Increased albumin level (continuous) was related to
et al. [67]   better DFS and PFS

Hashimoto     Elevated CRP (>1) was significant predictor of worse OS
et al. [14]   and RFS

Lehrer et     There was a significant correlation of CRP level with
al. [28]      PSA

Crumley et    Elevated CRP (>1) was independent predictor of CSS
al. [16]

Jones et      Elevated CRP (>0.4) was related to larger tumor size,
al. [4]       advanced tumor stage, and incomplete resection

Karakiewicz   Elevated CRP (>2.3) was an informative predictor of
et al. [32]   worse CSS

Beer et al.   Elevated CRP (>0.8) was a strong predictor of poor OS
[29]          and lower PSA response to chemotherapy

Hefler et     Elevated CRP (>1.0 & continuous) was associated with
al. [23]      postoperative residual tumor and worse OS

Shiu et al.   Elevated CRP (>0.5) was correlated with larger tumor
[8]           size, higher stage, and poorer CSS

Crumley et    High GPS was significant predictor of worse CSS
al. [17]

AI Murri et   High GPS was significant predictor of worse CSS
al. [20]

Ramsey et     High GPS was significant predictor of worse CSS
al. [33]

Polterauer    High GPS was significant predictor of worse OS and DFS
et al. [25]

Vashist et    High GPS was a strong prognosticator of perioperative
al. [18]      morbidity and worse DFS and OS

Kinoshita     High GPS was independently associated with worse CSS
et al. [15]

Leitch et     High mGPS was independently associated with worse CSS
al. [9]       in patients with either operable or unresectable
              colorectal cancer

Jiang et      High mGPS was independently associated with worse OS
al. [13]      irrespective of cancer stage

Ishizuka et   High mGPS (1/2) was an independent risk factor of poor
al. [10]      CSS

La Torre et   High mGPS was independently associated with worse OS
al. [27]      irrespective of cancer stage

Lamb et al.   High mGPS was significantly independent predictors of
[34]          worse OS and CSS

Cho et al.    Positive NLR (>2.6) showed worse OS and DFS than
[24]          negative NLR (<2.6)

Chua et al.   Elevated NLR (>5) was independently associated with
[11]          less clinical response to chemotherapy and worse OS and
              PFS

Azab et al.   High NLR (>3.3) was an independent significant
[21]          predictor of all-cause mortality

Keizman et    Low NLR (<3.0) was significantly associated with better
al. [70]      PFS

Keizman et    Low NLR ([less than or equal to] 3.0) was independent
al. [71]      predictor of better response to sunitinib and favorable
              PFS and OS

Lee et al.    High NLR ([greater than or equal to] 1.9) was related
[26]          to more advanced stage and increased NLR (continuous)
              was an independent predictor of worse PFS and OS

Yao et al.    Low NLR ([less than or equal to] 2.63) was
[5]           independently associated with better clinical response
              to chemotherapy and favorable OS and PFS

RCC: renal cell carcinoma, HCC: hepatocellular carcinoma, CRP: C-
reactive protein, GPS: Glasgow Prognostic Score, mGPS: modified
Glasgow Prognostic Score, NLR: neutrophil-to-lymphocyte ratio, OS:
overall survival, DPS: disease-free survival, PPS: progression-free
survival, and CSS: cancer specific survival.

TABLE 2: Clinical studies on the prognostic value of SIR-related
hematological biomarkers in UC of the bladder.

Study           Marker     Publication    (NMIBC/MIBC)
                               year

Hilmy et         CRP           2005       105 (76/29)
al. [35]

Yoshida et       CRP           2008        88 (0/88)
al. [36]

Gakis et         CRP           2011       246 (0/246)
al. [37]

Hwang et         GPS,          2012        67 (0/67)
al. [39]       Albumin

Ku et al.      Albumin         2015           419
[46]          Neutrophil                   (173/246)
                count
               Platelet
                count

Condo et         NLR           2012       189 (62/127)
al. [38]

Demirtac et      NLR           2013       201 (35/166)
al. [40]

Hermanns et      NLR           2014           424
al. [41]

Kaynar et        NLR           2014       291 (192/99)
al. [42]

Potretzke        NLR           2014       102 (31/71)
et al. [43]

Viers et         NLR           2014           899
al. [44]                                   (392/507)

Mano et al.      NLR           2015       107 (107/0)
[47]

Seah et al.      NLR           2015        26 (0/26)
[48]

Kang et al.      NLR           2015           385
[45]

Study            Threshold         Assessment
                                     period

Hilmy et         1.0 mg/dL       Before surgery
al. [35]                             (TURBT)

Yoshida et       0.5 mg/dL           Before
al. [36]                        radiochemotherapy

Gakis et          0.5 mg/           1-3 days
al. [37]           dL or            before RC
                continuous

Hwang et         1.0 mg/dL        1 day before
al. [39]         (CRP) 3.5            first
                   g/dL           chemotherapy
                 (Albumin)            cycle

Ku et al.        3.5 g/dL           Before RC
[46]             (Albumin)
                  7500/uL
               (Neutrophil)
                   400 X
                [10.sup.5]/
               ul (Platelet)

Condo et            2.5             Before RC
al. [38]

Demirtac et         2.5             Before RC
al. [40]

Hermanns et          3              Before RC
al. [41]

Kaynar et           NA            1 day before
al. [42]       (continuous)     surgery (TURBT or
                                       RC)

Potretzke           NA              Before RC
et al. [43]    (continuous)

Viers et            2.7          Within 90 days
al. [44]                            before RC

Mano et al.      2.41 (for        Before TURBT
[47]           progression)
                 2.43 (for
                recurrence)

Seah et al.         NA            Before NACH,
[48]                            during NACH, and
                                    after RC

Kang et al.         2.0          Within 1 month
[45]          (postoperative)     before RC and
                    2.1          within 3 months
              (preoperative)        after RC

Study         Main findings

Hilmy et      Elevated preoperative CRP (>1) was
al. [35]      independently associated with worse
              CSS

Yoshida et    Elevated preoperative CRP ([greater
al. [36]      than or equal to] 0.5) was
              independent predictor of worse CSS

Gakis et      Patients with elevated CRP (>0.5)
al. [37]      showed advanced age, more
              extravesical disease, larger tumor
              size, node positive disease, and
              positive surgical margin and
              increased CRP (continuous) was
              independent predictor of worse CSS

Hwang et      Hypoalbuminemia (<3.5) and GPS 2
al. [39]      was independently associated with
              reduced PFS and OS, respectively

Ku et al.     Low albumin, high lymphocyte count,
[46]          and high platelet count were
              significantly associated with worse
              OS and CSS

Condo et      Elevated NLR ([greater than or
al. [38]      equal to] 2.5) was an independent
              predictor of worse DSS

Demirtac et   Elevated NLR (>2.5) was not
al. [40]      associated with overall survival

Hermanns et   Patients with elevated NLR
al. [41]      ([greater than or equal to] 3)
              significantly showed more advanced
              pathologic tumor stage Elevated NLR
              ([greater than or equal to]3) was
              significantly associated with RFS,
              OS, and CSS

Kaynar et     Patients with MIBC showed
al. [42]      significantly higher NLR value than
              those with NMIBC Also, higher NLR
              significantly correlated with
              advanced age, larger tumor size,
              and aggressive tumor invasiveness

Potretzke     NLR was significant predictor of
et al. [43]   pathological upstaging after RC;
              also, patients with pathological
              upstaging to [greater than or equal
              to] pT3 had a significantly greater
              NLR compared to patents who
              remained at [less than or equal to]
              pT2

Viers et      Elevated NLR ([greater than or
al. [44]      equal to] 2.7) was significantly
              associated with adverse pathologic
              finding (higher pathologic tumor
              stage, node positive, and larger
              tumor size); increased NLR
              (continuous) was independently
              associated with worse RFS, OS, and
              CSS

Mano et al.   Elevated NLR (>2.41) showed more
[47]          pTl tumors and was significantly
              associated with disease
              progression; elevated NLR (>2.43)
              was independent predictor of
              disease recurrence

Seah et al.   Significant NLR decrease from
[48]          before NACH to before RC was
              observed in patients with
              pathological response after NACH
              and RC

Kang et al.   Patients with elevated
[45]          postoperative NLR ([greater than or
              equal to] 2.0) had higher rates of
              [greater than or equal to] pT3,
              LVI, and positive lymph node and
              elevated postoperative NLR
              ([greater than or equal to] 2.0)
              was an independent predictor of OS
              and CSS; also, patients with
              perioperative continuous elevated
              NLR (2.1-->2.0) showed worse OS and
              CSS compared with other change
              groups

CRP: C-reactive protein, GPS: Glasgow Prognostic Score, mGPS:
modified Glasgow Prognostic Score, NLR: neutrophil-to-lymphocyte
ratio, TURBT: transurethral resection ofbladder tumor, RC: radical
cystectomy, NACH: neoadjuvant chemotherapy, NMIBC: nonmuscle invasive
bladder cancer, OS: overall survival, DSS: disease-specific survival,
RFS: recurrence-free survival, and CSS: cancer specific survival.

TABLE 3: Clinical studies on the prognostic value of SIR-related
hematological biomarkers in upper urinary tract urothelial carcinoma.

Study           Marker      Publication     Number    Threshold
                                year          of
                                           patients

Saito et          CRP           2007         130      0.5 mg/dL
al. [49]

Obata et          CRP           2013         183      0.5 mg/dL
al. [52]

Tanaka et         CRP           2014         564      Multiple
al. [58]                                              cut/offs
                                                      (0.5, 2.0
                                                       mg/dL)

Ku et al.       Albumin         2014         181      3.5 g/dL
[55]

Hashimoto     Neutrophil        2013          84       4000/uL
et al. [51]      count

Azuma et          NLR           2013         137         2.5
al. [50]

Dalpiaz et        NLR           2014         202         2.7
al. [53]

Luo et al.        NLR           2014         234          3
[56]

Tanaka et         NLR           2014         665          3
al. [57]

Sung et al.       NLR           2015         410         2.5
[60]

Study         Assessment   Main findings
                period

Saito et        Before     Patients with elevated (>0.5) CRP showed
al. [49]       surgery     higher hemoglobin, advanced tumor stage
                           (>pT3), positive lymph node, high grade,
                           and LVI; moreover, elevated (>0.5) CRP was
                           significant prognostic factor for DSS and
                           RFS

Obata et        Before     Patients with elevated (>0.5) CRP showed
al. [52]       surgery     advanced tumor stage ([greater than or
                           equal to] pT3), LVI, and higher number of
                           metastases; moreover, elevated (>0.5) CRP
                           was significant prognostic factor for worse
                           RFS and CSS

Tanaka et       Before     Elevated CRP (0.5-2.0 or >2.0) level was an
al. [58]       surgery     independent predictor of worse RFS and CSS
                           relative to normal CRP ([less than or equal
                           to] 0.5); in elevated pre-CRP (>0.5) group,
                           postoperative normalization of CRP ([less
                           than or equal to] 0.5) was an independent
                           predictor of better CSS

Ku et al.       Before     Hypoalbuminemia (<3.5) was a significant
[55]           surgery     predictor of worse DSS and OS; also,
                           scoring model incorporated albumin
                           discriminated patients well according to
                           risk of DSS and OS

Hashimoto       Before     Elevated neutrophil count ([greater than or
et al. [51]    surgery     equal to] 4000/uL) was an independent
                           prognostic factor for worse RFS

Azuma et        Before     Elevated ([greater than or equal to] 2.5)
al. [50]       surgery     NLR was significantly associated with worse
                           RFS and CSS; also, scoring model
                           incorporated NLR discriminated patients
                           well according to risk of RFS and CSS

Dalpiaz et      Before     Elevated ([greater than or equal to] 2.7)
al. [53]       surgery     NLR was significantly associated with worse
                           OS and CSS

Luo et al.      Before     Elevated ([greater than or equal to] 3) NLR
[56]           surgery     was significantly associated with worse MFS
                           and CSS; also, the use of a NLR of >3
                           further identified a poor prognostic group,
                           especially in patients with pT3 for MFS and
                           CSS

Tanaka et       Before     Patients with elevated (>3) NLR
al. [57]       surgery     significantly showed high tumor grade (Gr
                           3), advanced tumor stage, positive lymph
                           node, and LVI; elevated ([greater than or
                           equal to] 3) NLR was an independent risk
                           factor for worse RFS and CSS; furthermore,
                           addition of pre-NLR slightly improved the
                           accuracies of the base model for predicting
                           both RFS and CSS

Sung et al.     Before     Elevated NLR ([greater than or equal to]
[60]           surgery     2.5) was independent predictor of worse
                           PFS, OS, and CSS, along with elevated ESR

CRP: C-reactive protein, NLR: neutrophil-to-lymphocyte ratio, LVI:
lymphovascular invasion, OS: overall survival, DSS: disease-specific
survival, RFS: recurrence-free survival, MPS: metastasis-free
survival, and CSS: cancer specific survival.
COPYRIGHT 2016 Hindawi Limited
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2016 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Kim, Hyung Suk; Ku, Ja Hyeon
Publication:Disease Markers
Article Type:Report
Date:Jan 1, 2016
Words:8416
Previous Article:Immunohistochemical expression of VEGF and podoplanin in uterine cervical squamous intraepithelial lesions.
Next Article:Skin autofluorescence in systemic sclerosis is related to the disease and vascular damage: a cross-sectional analytic study of comparative groups.
Topics:

Terms of use | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters