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1.  Can the Tumor Deposits Be Counted as Metastatic Lymph Nodes in the UICC TNM Staging System for Colorectal Cancer? 
PLoS ONE  2012;7(3):e34087.
Objective
The 7th edition of AJCC staging manual implicitly states that only T1 and T2 lesions that lack regional lymph node metastasis but have tumor deposit(s) will be classified in addition as N1c, though it is not consistent in that pN1c is also an option for pT3/T4a tumors in the staging table. Nevertheless, in this TNM classification, how to classify tumor deposits (TDs) in colorectal cancer patients with lymph node metastasis (LNM) and TDs simultaneously is still not clear. The aim of this study is to investigate the possibility of counting TDs as metastatic lymph nodes in TNM classification and to indentify its prognostic value for colorectal cancer patients.
Methods and Results
In this retrospective study, 513 cases of colorectal cancer with LNM were reviewed. We proposed a novel pN (npN) category in which TDs were counted as metastatic lymph nodes in the TNM classification. Cancer-specific survival according to the npN or pN category was analyzed using Kaplan-Meier survival curves. Univariate and multivariate analyses were performed to indentify significant prognostic factors. Harrell's C statistic was used to test the predictive capacity of the prognostic models. The results revealed that the TD was a significant prognostic factor in colorectal cancer. Univariate and multivariate analyses uniformly indicated that the npN category was significantly correlated with prognosis. The results of Harrell's C statistical analysis demonstrated that the npN category exhibited a superior predictive capacity compared to the pN category of the 7th edition TNM classification. Moreover, we also found no significant prognostic differences in patients with or without TD in the same npN categories.
Conclusions
The counting of TDs as metastatic lymph nodes in the TNM classification system is potentially superior to the classification in the 7th edition of the TNM staging system to assess prognosis and survival for colorectal cancer patients.
doi:10.1371/journal.pone.0034087
PMCID: PMC3312887  PMID: 22461900
2.  The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study 
BMC Urology  2014;14:72.
Background
The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry.
Methods
Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival.
Results
The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM.
Conclusion
Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.
doi:10.1186/1471-2490-14-72
PMCID: PMC4159381  PMID: 25174263
Renal cell carcinoma; Size; Metastasis; Survival
3.  Application of the revised Tumour Node Metastasis (TNM) staging system of clear cell renal cell carcinoma in eastern China: advantages and limitations 
Asian Journal of Andrology  2013;15(4):550-557.
This study was designed to evaluate whether the revised 2010 Tumour Node Metastasis (TNM) staging system could lead to a more accurate prediction of the prognosis of renal cell carcinoma (RCC) patients. A total of 1216 patients who had undergone radical nephrectomy or partial nephrectomy for RCC from 2003 to 2011 were enrolled. All of the patients had pathologically confirmed clear cell RCC (ccRCC). All cases were staged by both the 2002 and 2010 TNM staging systems after pathological review, and survival data were collected. Univariate and multivariate Cox regression models were used to evaluate cancer-specific survival (CSS) and progression-free survival (PFS) after surgery. Continuous variables, such as age and tumour diameter, were calculated as mean values and standard deviations (s.d.) or as median values. Survival was calculated by the Kaplan–Meier method, and the log-rank test assessed differences between groups. Statistically significant differences in CSS and PFS were noted among patients in T3 subgroups using the new 2010 staging system. Therefore, the revised 2010 TNM staging system can lead to a more accurate prediction of the prognosis of ccRCC patients. However, when using the revised 2010 staging system, we found that more than 92% of patients (288/313) with T3 tumours were staged in the T3a subgroup, and their survival data were not significantly different from those of patients with T2b tumours. In addition, T2 subclassification failed to independently predict survival in RCC patients.
doi:10.1038/aja.2012.161
PMCID: PMC3739222  PMID: 23564046
kidney neoplasm; prognosis; renal cell carcinoma; TNM stage
4.  Increased expression of colony stimulating factor-1 is a predictor of poor prognosis in patients with clear-cell renal cell carcinoma 
BMC Cancer  2015;15:67.
Background
This study aims to evaluate the impact of colony stimulating factor-1 (CSF-1) expression on recurrence and survival of patients with clear-cell renal cell carcinoma (ccRCC) following surgery.
Methods
We retrospectively enrolled 267 patients (195 in the training cohort and 72 in the validation cohort) with ccRCC undergoing nephrectomy at a single institution. Clinicopathologic features, cancer-specific survival (CSS) and recurrence-free survival (RFS) were recorded. CSF-1 levels were assessed by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on CSS and RFS. Concordance index (C-index) was calculated to assess predictive accuracy.
Results
In both cohorts, CSF-1 expression positively correlated with advanced Fuhrman grade and necrosis. High CSF-1 expression indicated poor survival and early recurrence of ccRCC patients after surgery, especially those with advanced TNM stage disease. Multivariate Cox regression analysis showed CSF-1 expression was an independent unfavorable prognostic factor for recurrence and survival. The predictive accuracy of the University of California Los Angeles Integrated Staging System (UISS) was significantly improved when CSF-1 expression was incorporated.
Conclusions
High CSF-1 expression is a potential adverse prognostic biomarker for recurrence and survival of ccRCC patients after nephrectomy.
doi:10.1186/s12885-015-1076-5
PMCID: PMC4339479  PMID: 25886010
Clear-cell renal cell carcinoma; Colony stimulating factor-1; Prognostic biomarker; Recurrence-free survival; Cancer-specific survival
5.  Stage T1N0M0 renal cell carcinoma: the prognosis in Asian patients 
Chinese Journal of Cancer  2011;30(11):772-778.
The prognostic features of T1N0M0 renal cell carcinoma (RCC) in Asian patients have not been well explored in large sample studies. In this study, we retrospectively analyzed the records of 713 patients undergoing nephrectomy for T1N0M0 RCC between 1991 and 2009 in three Asian hospitals. Univariate and multivariate analysis were performed to identify the independent predictive factors for T1N0M0 RCC prognosis among a series of Clinicopathological parameters, including age, gender, tumor size, Fuhrman grade, and histological classification. Our results showed that 388 of 713 patients had tumors 4.0 cm or smaller (stage T1a) and 325 of 713 patients had tumors 4.0–7.0 cm in size (stage T1b). Five-year cancer-specific survival (CSS) and recurrence-free survival (RFS) rates for this group of patients were 96.0% and 93.5%, respectively. The patients with T1b RCC had a significantly lower 5-year CSS and RFS rates than did those with T1a RCC (CSS, 93.1% vs. 98.6%, P = 0.026; RFS, 90.0% vs. 96.5%, P < 0.001). Patients with low grade (grades I–II) tumors had a higher 5-year CSS (97.8% vs. 91.2%, P = 0.001) and RFS (95.5% vs. 85.5%, P < 0.001) rate than did those with high grade (grades I–II) tumors. More interestingly, when stratifying patients to T1a and T1b groups, the role of grade in distinguishing prognosis could be only observed in patients with T1b disease. Cox regression showed tumor size and Fuhrman grade were significant in predicting CSS and RFS. Our study suggests that the prognosis of patients with T1N0M0 RCC is excellent, and these results are comparable to previously reported studies in Western patients. Furthermore, our data indicates that patients with T1b disease and high Fuhrman grade have high risk of tumor recurrence and death, thus requiring more frequent follow-up.
doi:10.5732/cjc.011.10085
PMCID: PMC4013300  PMID: 22035858
Renal cell carcinoma; tumor size; Fuhrman grade; prognosis
6.  Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma 
Oncology Letters  2015;9(6):2485-2494.
Renal cell carcinoma (RCC) is a common tissue tumor that occurs across all age groups and has become one of the types of cancer with the fastest increasing incidence. Due to the resistance of RCC chemo- and radiotherapy, surgery is the only currently effective treatment. Therefore, specific markers for the diagnosis and prognosis of RCC are expected to result in novel methods of treatment. Ecto-5′-nucleotidase, also termed cluster of differentiation (CD)73, is a protein that is activated in several types of aggressive cancer and may promote cancer progression. CD73 was examined in the present study to determine the association between the protein and RCC. The expression levels of CD73 in 159 RCC tissue sections and 30 paratumorous normal renal tissue samples obtained from 235 patients that underwent nephrectomy were examined by immunohistochemical staining. By contrast, the expression level of P-glycoprotein (P-gp), a potential prognostic factor in RCC, was also examined in 85 RCC and 13 normal tissue samples. Intense CD73 expression was identified in 75 out of 159 RCC cell membranes compared with normal renal tissues. In contrast, there was high P-gp expression in the blood vessels of 42 out of 85 RCC tissues and there was no significant difference between the P-gp expression identified in RCC cells (34 out of 85) and the cell membrane of normal renal cells (2 out of 13). The expression level of CD73 in RCC cells was significantly associated with tumor type, tumor node metastasis (TNM) stage, and tumor grade. However, the expression of P-gp in RCC cells was only associated with the TNM stage and tumor grade. Using a multivariable Cox regression analysis, it was found that the median survival rate of RCC patients with intense CD73 expression in RCC cells was 62.06±5.35 months, which was drastically shorter compared with rare CD73 expression (103.72±3.67 months). In conclusion, the expression level of CD73 is significantly associated with RCC tumor progression and may serve as a favorable marker for the diagnosis and prognosis of RCC, in addition to being a therapeutic target for the treatment of RCC.
doi:10.3892/ol.2015.3138
PMCID: PMC4473655  PMID: 26137095
renal cell carcinoma; CD73; P-glycoprotein; tumor progression; prognosis
7.  Prognostic Value of Tumor Size in Patients with Remnant Gastric Cancer: Is the Seventh UICC Stage Sufficient for Predicting Prognosis? 
PLoS ONE  2014;9(12):e115776.
Background
The 7th UICC N stage may be unsuitable for remnant gastric cancer (RGC) because the original disease and previous operation usually cause abnormal lymphatic drainage. However, the prognostic significance of the current TNM staging system in RGC has not been studied.
Methods
Prospective data from 153 RGC patients who underwent curative gastrectomy from Jan 1995 to Aug 2009 were reviewed. All patients were classified according to tumor size (<3 cm as N0;>3&≤5 cm as N1;>5&≤7 cm as N2; and>7 cm as N3). The overall survival was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using the Cox proportional hazard model.
Results
Tumor sizes ranged from 1.0 to 15.0 cm (median 5.0 cm). Tumor size, depth of invasion and lymph node (LN) metastasis were significant prognostic factors based on both the univariate and multivariate analyses (P<0.05). In the survival analysis, the seventh edition UICC-TNM classification provided a detailed classification; however, some subgroups of the UICC-TNM classification did not have significantly different survival rates. The combination of the seventh edition T classification and the suggested N classification, with ideal relative risk (RR) results and P value, was distinctive for subgrouping the survival rates except for the IA versus IB and II A versus IIB. A modified staging system based on tumor size, predicted survival more accurately than the conventional TNM staging system.
Conclusions
In RGCs, tumor size is an independent prognostic factor and a modified TNM system based on tumor size accurately predicts survival.
doi:10.1371/journal.pone.0115776
PMCID: PMC4280110  PMID: 25549339
8.  Association of Abnormal Preoperative Laboratory Values with Survival After Radical Nephrectomy for Clinically Confined Clear Cell Renal Cell Carcinoma 
Urology  2008;71(2):278-282.
Objectives
To determine whether preoperative laboratory values are independently associated with death from clinically confined clear cell renal cell carcinoma (RCC) after radical nephrectomy.
Methods
We identified 1707 patients with clinically confined (pNx/pN0, pM0), unilateral, sporadic clear cell RCC treated with radical nephrectomy between 1970 and 2002. Associations of abnormal preoperative laboratory values including hypercalcemia, anemia, elevated erythrocyte sedimentation rate (ESR), and elevated alkaline phosphatase with death from RCC were evaluated using Cox proportional hazards regression models, both univariately and multivariately by adjusting for known prognostic features of the 2002 primary tumor classification, tumor size, nuclear grade, and coagulative tumor necrosis.
Results
At last follow-up, 1009 patients had died, including 425 who died from RCC at a median of 3.0 years after surgery (range, 0 to 26 years). Even after adjusting for known prognostic features, 9% of patients with preoperative hypercalcemia exhibited significantly increased likelihood of dying from RCC compared with patients with normal or lower levels of serum calcium (relative ration [RR] 1.64; P = 0.002). Similarly, preoperative anemia (35% of patients; RR 1.27; P = 0.026) and elevated ESR (44% of patients; RR 1.66; P = 0.003) portended an increased risk of death from RCC even after multivariate adjustment.
Conclusions
Abnormal preoperative laboratory values including hypercalcemia, anemia, and elevated ESR are independently associated with increased risk of cancer-specific death from clinically confined clear cell RCC. Consideration of these variables in future models may improve prognostic accuracy. We believe these factors should be routinely assessed and included in prospective studies of outcome in RCC patients.
doi:10.1016/j.urology.2007.08.048
PMCID: PMC2789389  PMID: 18308103
9.  External validation of nomograms for predicting cancer-specific mortality in penile cancer patients treated with definitive surgery 
Chinese Journal of Cancer  2014;33(5):249-255.
Using a population-based cancer registry, Thuret et al. developed 3 nomograms for estimating cancer-specific mortality in men with penile squamous cell carcinoma. In the initial cohort, only 23.0% of the patients were treated with inguinal lymphadenectomy and had pN stage. To generalize the prediction models in clinical practice, we evaluated the performance of the 3 nomograms in a series of penile cancer patients who were treated with definitive surgery. Clinicopathologic information was obtained from 160 M0 penile cancer patients who underwent primary tumor excision and regional lymphadenectomy between 1990 and 2008. The predicted probabilities of cancer-specific mortality were calculated from 3 nomograms that were based on different disease stage definitions and tumor grade. Discrimination, calibration, and clinical usefulness were assessed to compare model performance. The discrimination ability was similar in nomograms using the TNM classification or American Joint Committee on Cancer staging (Harrell's concordance index = 0.817 and 0.832, respectively), whereas it was inferior for the Surveillance, Epidemiology and End Results staging (Harrell's concordance index = 0.728). Better agreement with the observed cancer-specific mortality was shown for the model consisting of TNM classification and tumor grade, which also achieved favorable clinical net benefit, with a threshold probability in the range of 0 to 42%. The nomogram consisting of TNM classification and tumor grading was shown to have better performance for predicting cancer-specific mortality in penile cancer patients who underwent definitive surgery. Our data support the integration of this model in decision-making and trial design.
doi:10.5732/cjc.013.10176
PMCID: PMC4026545  PMID: 24559854
Penile neoplasms; neoplasm staging; prognosis; mortality
10.  The 2002 AJCC TNM classification is a better predictor of primary small cell esophageal carcinoma outcome than the VALSG staging system 
Chinese Journal of Cancer  2013;32(6):342-352.
Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive malignant tumor with a poor prognosis. The optimal disease staging system and treatment approaches have not yet been defined. This study aimed to evaluate the prediction of different staging systems for prognosis and treatment options of SCCE. We retrospectively accessed the clinicopathologic characteristics, treatment strategy, and prognosis of 76 patients diagnosed with primary SCCE between 2001 and 2011. The 1-, 2-, 3-, and 5-year overall survival rates were 58%, 31%, 19%, and 13%, respectively. Univariate analysis showed that the 2002 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification (P = 0.002), Veterans Administration Lung Study Group (VALSG) stage (P = 0.001), predisposing factors (P < 0.001), T category (P = 0.023), and M category (P < 0.001) were prognostic factors for overall survival. Multivariate analysis showed that the 2002 AJCC TNM stage (P < 0.001) was the only independent prognostic factor for survival. The value of the area under the receiver operator characteristic (ROC) curve (AUC) of the 2002 AJCC TNM staging system was larger than that of VALSG staging system with regard to predicting overall survival (0.774 vs. 0.620). None of the single treatment regimens showed any benefit for survival by Cox regression analysis. Thus, the 2002 AJCC TMN staging system improved the prediction of SCCE prognosis; however, the optimal treatment regimen for SCCE remains unclear.
doi:10.5732/cjc.012.10161
PMCID: PMC3845624  PMID: 23114087
Small cell carcinoma; esophagus; TNM staging; chemotherapy; radiotherapy; esophagectomy
11.  Comparison of the 6th and 7th editions of the AJCC/UICC TNM staging system for gastric cancer focusing on the “N” parameter-related survival: the monoinstitutional NodUs Italian study 
Background
A large number of Asian population studies examined the difference between the 6th and the 7th tumor, node, metastasis (TNM) while it is still poorly validated among Caucasian populations. This is a retrospective study aimed at investigating the efficacy of the 7th edition American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system for gastric cancer focusing on the “N” parameter-related survival for prognostic assessment in gastric cancer patients of a single Western high-volume institution.
Methods
From January 2002 to December 2009, the data of 274 patients with gastric cancer who underwent gastric surgery at the 8th General and Gastrointestinal Surgical Centre of the Second University of Naples were analyzed retrospectively. We collected data for patient demographics, tumor characteristics, surgical characteristics, and TNM stage. Particularly, the nodal status, with the number of dissected nodes and metastatic nodes, was reviewed from the pathology records. The same patient dataset was used to stage patients according to both the 6th and 7th edition criteria.
Results
Age at surgery, tumor location, histological grade, Lauren’s classification subtypes, and 6th and 7th AJCC/UICC N categories were found to have statistically significant associations with overall survival on univariate analysis. In the 6th edition staging system, the Kaplan–Meier plot did not show significant overlapped survival curves: significant differences were found between N0 and N1, P < .001; N1 and N2, P = .04; and N2 and N3, P < .001. On the contrary, in the 7th edition, among all five substages, there were similar survival curves between N categories 2 and 3a (P = .98) with a statistically significant discriminatory ability only between N1 versus N3b and N2 versus N3b (P = .02 and .04, respectively).
Conclusions
Based on analysis, we found that several clinicopathological variables, especially histological grade and Lauren’s classification, were significant prognostic factors in our database. The 6th and 7th AJCC/UICC N classifications represent significantly independent prognostic factors, and the 6th AJCC/UICC N classification seems to be superior to the 7th AJCC/UICC N classification in terms of uniformity, differentiation, and monotonicity of gradients.
doi:10.1186/s12957-015-0633-3
PMCID: PMC4504099  PMID: 26179492
Gastric cancer; Staging system; Lymph node status; 7th TNM; 6th TNM
12.  Systematic classification and prediction of complications after nephrectomy in patients with metastatic renal cell carcinoma (RCC) 
BJU international  2012;110(9):1276-1282.
Objective
To evaluate and identify factors predictive for morbidity after radical nephrectomy in patients with metastatic renal cell carcinoma (mRCC).
Patients and methods
We identified patients with mRCC who underwent nephrectomy at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1989 and 2009.
Postoperative complications were characterised using a modified version of the Clavien-Dindo classification system.
Patient and disease characteristics, including a previously validated MSKCC risk-stratification system using calcium, haemoglobin (Hb), lactate dehydrogenase, and Karnofsky Performance Status (KPS), were evaluated as predictors of postoperative complications using univariate and multivariable logistic regression models.
The area under the receiver operating characteristic curve (AUC) was calculated for each model to assess predictive accuracy and corrected for overfit using 10-fold cross validation.
Results
Over the study period, 195 patients with mRCC underwent nephrectomy; 53 (27%) developed grade ≥2 complications within 8 weeks of surgery.
Pulmonary, thromboembolic events and anaemia requiring transfusion were the most common types of complications after nephrectomy in the metastatic setting.
In univariate analysis, age, low albumin, low KPS, high corrected serum calcium, low serum Hb, and unfavourable MSKCC risk score were predictive of complications.
Patients who sustained postoperative complications were less likely to receive systemic therapy within 56 days (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.12–0.86; P = 0.024).
A multivariable model containing KPS (OR 14.5; 95%CI 4.34–48.6; P < 0.001) and age (OR 1.04; 95%CI 1.01–1.08; P = 0.014) showed the greatest predictive accuracy (corrected AUC 0.72; 95%CI 0.63–0.80) for postoperative complications.
Conclusion
Postoperative complications after radical nephrectomy in the setting of mRCC are common and occur frequently in older patients and those with worse KPS.
These complications are important because they may delay or deny receipt of subsequent systemic therapy.
doi:10.1111/j.1464-410X.2012.11103.x
PMCID: PMC3985128  PMID: 22554107
renal cell carcinoma; metastatic; nephrectomy; sunitinib; complications; Clavien
13.  Age at diagnosis is a determinant factor of renal cell carcinoma–specific survival in patients treated with nephrectomy 
Objective
Based on combined data for 4880 patients, 2 previous studies reported that advanced age is a predictor of increased renal cell carcinoma–specific mortality (RCC-SM). We explored the effect of age in cubic spline analyses to identify the age groups with the most elevated risk for renal cell carcinoma (RCC).
Methods
Our study included 3595 patients from 14 European centres who had partial or radical nephrectomies. We used the Kaplan–Meier method to compile life tables, and we performed Cox regression analyses to assess RCC-SM. Covariates included age at diagnosis, sex, TNM (tumour, node, metastasis) stage, tumour size, Fuhrman grade, symptom classification and histological subtype.
Results
Age ranged from 10 to 89 (mean 63, median 67) years. The median duration of follow-up was 2.9 years. The median survival for the cohort was 13.4 years. Stage distribution was as follows: 1915 patients (53.3%) had stage I disease, 388 (10.8%) had stage II, 895 (24.9%) had stage III and 397 (11.0%) had stage IV disease. In multivariate analyses, we coded age at diagnosis as a cubic spline, and it achieved independent predictor status (p < 0.001). The risk of RCC-SM was lowest among patients younger than 50 years. We observed an increase in RCC-SM until the age of 50, at which point the level of risk reached a plateau. We observed a second increase among patients aged 75–89 years. We found similar patterns when we stratified patients according to the 2002 American Joint Committee on Cancer (AJCC) stages.
Conclusion
The effect of age shows prognostic significance and indicates that follow-up and possibly secondary treatments might need to be adjusted according to the age of the patient.
PMCID: PMC2593600  PMID: 19066680
14.  Prognostic value of the seventh AJCC/UICC TNM classification of non-cardia gastric cancer 
Background
The TNM staging criteria for gastric carcinoma have seen numerous revisions, the most recent of which are reflected in the seventh edition AJCC TNM cancer staging manual.
Methods
A retrospective evaluation of the sixth and seventh TNM classification of gastric cancer on a prospective database, regarding patients operated on for primary gastric cancer, was conducted. The end point of the study was prognosis evaluation in terms of overall survival.
Patients operated on for primary gastric cancer between September 2003 and March 2012 at our Department of Emergency and General Surgery, were consecutively retrieved in this study; a total of 114 patients were considered. Cardia gastric cancers, gastric lymphomas and gastrointestinal stromal tumors (GIST) were excluded. Median and mean follow-up periods were 22.5 and 27.7 months (range 15 days to 5 years). Both TNM6 and TNM7 were used to evaluate our patients. Overall survival and survival rates at different stages were analyzed using the Kaplan-Meier method and differences were determined using a log-rank test. Cox’s proportional hazard model was used to identify significant factors related to prognosis in a multivariate analysis.
Results
Overall survival between the sixth and seventh TNM classification was not significantly different. Both the Kaplan-Meier analysis and the multivariate analysis showed that the major negative prognostic factor was lymphovascular invasion (P < 0.001 in the univariate analysis and P = 0.035 to 0.048 in the multivariate analysis). Stage distribution and stage-related survival changed from the sixth to the seventh edition, especially in T3 stage where median survival for the sixth edition was 720 days versus 1,200 days for the seventh edition. Moreover, differences were shown in the survival rate of N1 versus N2 stages within the seventh TNM.
Conclusions
Even though further studies are needed in order to increase the number of patients studied, the seventh edition seems to provide a more accurate prognosis, especially regarding N1 and N2 tumors, showing that the most important prognostic factor is lymphovascular invasion.
doi:10.1186/1477-7819-11-103
PMCID: PMC3686645  PMID: 23687939
Gastric cancer; Seventh TNM classification; Sixth TNM classification; Overall survival
15.  Evaluation of Argonaute protein as a predictive marker for human clear cell renal cell carcinoma 
Argonaute subfamily proteins are involved in human organ growth and development. Recent studies found its association with human breast cancer, however, its expression profile and its prognostic value in clear cell renal cancer (ccRCC) have not been investigated. Methods: Expression of the Argonaute proteins were assessed by immunohistochemistry (IHC) in tissue microarrays (TMA), containing paired tumor tissue and adjacent non-cancer tissue from 176 patients who had undergone surgery in hospital for histologically proven ccRCC. Prognostic value and correlation with other clinico-pathologic factors were evaluated in two classifications. Results: Data showed a significant higher expression of Argonaute 1 and Argonaute 2 present in neoplastic tissues compared with that in adjacent tissue; A significant correlation existed between the higher expression of Argonaute 1 protein with the T stage, lymph node metastasis and clinical TNM (cTNM); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that elevated Argonaute 1 and Argonaute 2 expression in cancer tissue predicted poorer overall survival (OS) compared with group in lower expression (36.3% VS 67.1%; 37.3% VS 53.9%; respectively). Notably, multivariate analyses by Cox’s proportional hazard model revealed that expression of Argonaute 2 was an independent prognostic factor in renal cancer. Conclusions: In summary, our present study clarify that the aberrant expression of Argonaute in human RCC is possibly involved with tumorigenesis and development, and the Argonaute protein could act as a potential biomarker for prognosis assessment of renal cancer. Related mechanism is worthy of further investigation.
PMCID: PMC3657361  PMID: 23696926
Renal cancer; Argonaute protein; immunohistochemistry; tissue microarray
16.  Correlation between nasopharyngeal carcinoma tumor volume and the 2002 International Union Against Cancer tumor classification system 
Background
The correlation between primary tumor volume and nasopharyngeal carcinoma (NPC) UICC 2002 T classification, N classification and distant metastasis after radiation therapy was discussed to provide further evidence for the inclusion of tumor volume into the TNM classification staging system.
Methods
Between February 2001 and December 2008, 666 patients with NPC treated with intensity-modulated radiation therapy (IMRT) were analyzed retrospectively. Primary gross tumor volume was calculated from treatment planning computed tomography scans. The Kruskal-Wallis and Mann–Whitney tests were used for comparison of continuous variables and the chi-square test was used for categorical variables. A logistic regression model was used for multivariate analysis.
Results
Median primary tumor volume of the 666 patients was 20.35 ml (range, 0.44 − 192.63 ml), and it gradually increased with T classification. Statistically significant differences in tumor volume were observed between patients with different T classifications (p < 0.001). The cervical lymph node metastasis rate was 64.7% (430/666); the differences in primary tumor volume between patients with or without lymph node metastasis were statistically significant (p < 0.001). Posttreatment distant metastasis occurred in 100 NPC patients, and the five-year distant metastasis-free survival was 84.2%. Univariate and multivariate analyses showed that N classification (p < 0.001) and tumor volume (p = 0.007) were the main factors influencing distant metastasis.
Conclusion
Tumor volume was correlated with T classification, cervical lymph node mestastasis and distant metastasis after radiation therapy in nasopharyngeal carcinoma, suggesting that tumor volume should be included into the TNM staging system.
doi:10.1186/1748-717X-8-87
PMCID: PMC3642025  PMID: 23578324
Nasopharyngeal carcinoma; Primary tumor volume; TNM classification; Intensity-modulated radiation therapy
17.  Effect of complication grade on survival following curative gastrectomy for carcinoma 
AIM: To elucidate the potential impact of the grade of complications on long-term survival of gastric cancer patients after curative surgery.
METHODS: A total of 751 gastric cancer patients who underwent curative gastrectomy between January 2002 and December 2006 in our center were enrolled in this study. Patients were divided into four groups: no complications, Grade I, Grade II and Grade III complications, according to the following classification systems: T92 (Toronto 1992 or Clavien), Accordion Classification, and Revised Accordion Classification. Clinicopathological features were compared among the four groups and potential prognostic factors were analyzed. The Log-rank test was used to assess statistical differences between the groups. Independent prognostic factors were identified using the Cox proportional hazards regression model. Stratified analysis was used to investigate the impact of complications of each grade on survival.
RESULTS: Significant differences were found among the four groups in age, sex, other diseases (including hypertension, diabetes and chronic obstructive pulmonary disease), body mass index (BMI), intraoperative blood loss, tumor location, extranodal metastasis, lymph node metastasis, tumor-node-metastasis (TNM) stage, and chemotherapy. Overall survival (OS) was significantly influenced by the complication grade. The 5-year OS rates were 43.0%, 42.5%, 25.5% and 9.6% for no complications, and Grade I, Grade II and Grade III complications, respectively (P < 0.001). Age, tumor size, intraoperative blood loss, lymph node metastasis, TNM stage and complication grade were independent prognostic factors in multivariate analysis. With stratified analysis, lymph node metastasis, tumor size, and intraoperative blood loss were independent prognostic factors for Grade I complications (P < 0.001, P = 0.031, P = 0.030). Age and lymph node metastasis were found to be independent prognostic factors for OS of gastric cancer patients with Grade II complications (P = 0.034, P = 0.001). Intraoperative blood loss, TNM stage, and chemotherapy were independent prognostic factors for OS of gastric cancer patients with Grade III complications (P = 0.003, P = 0.005, P < 0.001). There were significant differences among patients with Grade I, Grade II and Grade III complications in TNM stage II and III cancer (P < 0.001, P = 0.001).
CONCLUSION: Complication grade may be an independent prognostic factor for gastric cancer following curative resection. Treatment of complications can improve the long-term outcome of gastric cancer patients.
doi:10.3748/wjg.v20.i25.8244
PMCID: PMC4081699  PMID: 25009399
Gastric cancer; Complication grade; Gastrectomy; Overall survival; Prognosis
18.  THE IMPACT OF COMORBIDITY ON OVERALL SURVIVAL IN PATIENTS SURGICALLY TREATED FOR RENAL CELL CARCINOMA 
Urology  2008;72(2):359-363.
Objectives
While the classification of cancer has traditionally focused on gross and microscopic characteristics of the tumor, overall health of a patient can impact survival. Since patients with renal cell carcinoma (RCC) often have other medical conditions, we explored the impact of preexisting medical disease on survival following radical and partial nephrectomy.
Methods
Between January 1995 and August 2003, comorbidity status of 697 nonmetastatic RCC patients who underwent radical or partial nephrectomy was prospectively coded using the Adult Comorbidity Evaluation-27. Histopathologic review of all slides was performed according to the 2004 World Health Organization scheme. Other variables analyzed include age, gender, ethnicity, pathologic stage, Fuhrman grade, and tumor size. The effect of these factors on overall survival (OS) was analyzed using Cox Proportional Hazards Regression.
Results
The median follow-up was 32.2 months for survivors and 36.5 months for all patients. OS rate at 1, 3, and 5 years was 92.0% (641 patients), 75.3% (525 patients) and 52.7% (367 patients). Univariate analyses demonstrated that age, comorbidity, tumor size, Fuhrman grade, and pathologic stage were significant predictors of OS. Multivariate analysis revealed that age (HR 1.42, 95% CI 1.10–1.82, p=0.0067), comorbidity (HR 1.37, 95% CI 1.16–1.63, p=0.0002), pathologic stage (HR 1.97, 95% CI 1.60–2.41, p<0.0001) and grade (HR 1.83, 95% CI 1.28–2.59, p=0.0008) predicted OS.
Conclusions
This study demonstrates that comorbidity is an independent prognostic factor for OS in RCC patients. Capturing comorbidity information using validated instruments can improve the preoperative evaluation of patients by providing more accurate prognostic information.
doi:10.1016/j.urology.2008.02.061
PMCID: PMC2570477  PMID: 18468663
19.  Negative Node Count Improvement Prognostic Prediction of the Seventh Edition of the TNM Classification for Gastric Cancer 
PLoS ONE  2013;8(11):e80082.
Objective
To demonstrate that the seventh edition of the tumor-node-metastasis (TNM) classification for gastric cancer (GC) should be updated with the number of negative lymph nodes for the improvement of its prognostic prediction accuracy.
Methods
Clinicopathological data of 769 GC patients who underwent curative gastrectomy with lymphadenectomy between 1997 and 2006 were retrospectively analyzed to demonstrate the superiority of prognostic efficiency of the seventh edition of the TNM classification, which can be improved by combining the number of negative lymph nodes.
Results
With the Cox regression multivariate analysis, the seventh edition of the TNM classification, the number of negative nodes, the type of gastrectomy, and the depth of tumor invasion (T stage) were identified as independent factors for predicting the overall survival of GC patients. Furthermore, we confirmed that the T stage-N stage–number of negative lymph nodes–metastasis (TNnM) classification is the most appropriate prognostic predictor of GC patients by using case-control matched fashion and multinominal logistic regression. Finally, we were able to clarify that TNnM classification may provide more precise survival differences among the different TNM sub-stages of GC by using the measure of agreement (Kappa coefficient), the McNemar value, the Akaike information criterion, and the Bayesian Information Criterion compared with the seventh edition of the TNM classification.
Conclusion
The number of negative nodes, as an important prognostic predictor of GC, can improve the prognostic prediction efficiency of the seventh edition of the TNM classification for GC, which should be recommended for conventional clinical applications.
doi:10.1371/journal.pone.0080082
PMCID: PMC3857491  PMID: 24348906
20.  Foxl1 inhibits tumor invasion and predicts outcome in human renal cancer 
The Forkhead Box L1 (Foxl1) transcription factor regulates epithelial proliferation and development of gastrointestinal tract, and has been implicated in gastrointestinal and pancreatic tumorigenesis. However, the role of Foxl1 in renal cancer development and progression remains to be elucidated. The study was conducted to investigate the expression of Foxl1 and its prognostic significance in clear cell renal cell carcinoma (ccRCC). Meanwhile, the function of Foxl1 in human ccRCC was further investigated in cell culture models. Methods: Real-time quantitative PCR, western-blot, immunohistochemistry were used to explore Foxl1 expression in primary ccRCC clinical specimens and ccRCC cell lines. Foxl1 expression was up-regulated by over-expression vector in 786-O and ACHN cells, proliferation, cell cycle, migration and invasion were assayed. Results: Foxl1 expression was down-regulated in the majority of the ccRCC clinical tissue specimens at both mRNA and protein levels. Clinic pathological analysis showed that Foxl1 expression was significantly correlated with tumor stage, lymph node metastasis, distant metastasis, clinical TNM stage (cTNM) and histological grade of renal cancer. The Kaplan-Meier survival curves revealed that low Foxl1 expression was associated with poor prognosis in ccRCC patients. Foxl1 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis. Mechanistic analyses demonstrated that over-expression of Foxl1 inhibits tumor cell growth, migration and invasion in renal cancer cells. Conclusions: These results suggest that Foxl1 expression is a candidate predictor of clinical outcome in patients with resected ccRCC and it plays an inhibitory role in renal tumor progression.
PMCID: PMC3885465  PMID: 24427331
Foxl1; clear cell renal cell carcinoma; prognosis
21.  Analysis of new N-category on prognosis of oesophageal cancer with positive lymph nodes in a Chinese population 
Radiology and Oncology  2013;47(1):63-70.
Background
The 7th edition of the new TNM classification system for oesophageal cancer (EC) has been published. N-category is now divided into N0, N1, N2 and N3. In this study, we aimed to validate the prognostic ability of the new N classification system in EC with positive lymph nodes in a Chinese population, and evaluate whether the new N classification system can help the decision-making for postoperative adjuvant therapy.
Patients and methods
From 2002 to 2008, thoracic EC who underwent oesophagectomy were retrospectively analysed. Patients pathological stage 6th edition of the American Joint Committee on Cancer / Union International Against Cancer (AJCC/UICC) TNM classification were switched to pathological stage 7th edition for this analysis. Patients with pathological stage T1-4N1-3M0 EC were selected. Kaplan-Meier method and Cox regression analysis were employed to compare overall survival (OS).
Results
A total of 545 patients met the inclusion criteria: 346 (63.5%) received oesophagectomy alone, 199 (36.5%) received oesophagectomy and adjuvant radiotherapy, and 36.1% (197/545) received oesophagectomy and adjuvant chemotherapy. Univariate analysis and multivariate analysis revealed significant difference in OS among patients at different postoperative pN-category (p<0.001). This was also present in patients receiving postoperative radiotherapy (p<0.001) and those undergoing postoperative chemotherapy (p<0.001). There was no marked difference in OS between patients receiving postoperative adjuvant therapy and surgery alone at the same postoperative pN-category, except that postoperative radiotherapy marginally improved OS in patients with pN2 and pN3 disease.
Conclusions
Our results validated the prognostic ability of new N classification system. The N-category is an independent prognostic factor in patients with resectable thoracic EC who were positive for lymph nodes in a Chinese population. Further studies are required to clarify the role of new N classification system in the decision-making for postoperative adjuvant therapy.
doi:10.2478/v10019-012-0039-6
PMCID: PMC3573836  PMID: 23450452
oesophageal cancer; prognostic factor; radiotherapy; oesophagectomy; chemotherapy
22.  Nomogram predicted survival of patients with adenocarcinoma of esophagogastric junction 
Background
The aim of this study is to develop a prognostic nomogram for patients with adenocarcinoma of esophagogastric junction and compare its predictive accuracy with the traditional tumor-node-metastasis (TNM) malignant staging system.
Methods
Patients from the Surveillance, Epidemiology, and End Results Program (from 1988 to 2011) and the First Affiliated Hospital of Xi’an Jiaotong University (from 2005 to 2010) were collected retrospectively. Preselected multiple potential interactions were tested irrespective of significance as nomogram parameters. And the Harrell’s C-index was used to estimate the accuracy of the nomogram system. Model validation was performed using bootstrap to quantify our modeling strategy.
Results
In our study, six clinical associated factors (age, sex, depth of invasion, metastasized lymph nodes, examined lymph nodes, histological grade) were evaluated in the nomogram. In the training set, the nomogram exhibited superior discrimination power compared with the American Joint Committee on Cancer (AJCC) TNM classification (Harrell’s C-index, 0.69 and 0.63, respectively). Calibration of the nomogram predicted survival was similar to the actual overall survival. In the validation set, the discrimination of nomogram was also better than the AJCC TNM staging system (C-index, 0.75 and 0.65, respectively), and the calibration of nomogram predicted survival was within a 10 % margin of actual overall survival.
Conclusions
Based on the patients with adenocarcinoma of esophagogastric junction from a Western and an Eastern database, the nomogram provided significantly improved discrimination than the traditional AJCC TNM classification and also provided an accurate individualized prediction of the survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12957-015-0613-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12957-015-0613-7
PMCID: PMC4465317  PMID: 26055624
Adenocarcinoma of esophagogastric junction; Nomogram; Predictor; Survival
23.  DIFFERENTIAL EXPRESSION IN CLEAR CELL RENAL CELL CARCINOMA IDENTIFIED BY GENE EXPRESSION PROFILING 
The Journal of urology  2008;181(2):849-860.
Objective
Gene expression profiling has been shown to provide prognostic information regarding patients with a solitary, sporadic RCC. There is no reliable way to differentiate synchronous renal metastases from bilateral primary tumors in patients with bilateral RCC. We present data using a custom kidney cancer cDNA array that can predict outcomes in patients with unilateral and bilateral RCC.
Methods
Fresh frozen tissue from 38 clear cell RCC (cRCC) was analyzed using a cancer cDNA array containing 3966 genes relevant to cancer or kidney development. Median follow-up was 5.3 years; cancer had recurred in 12 (43%) patients and 11 (39%) patients were deceased at last follow-up.
Results
Using a training dataset of 8 tumors, a 44-gene expression profile (GEP) distinguishing aggressive and indolent cRCC was identified. Of 29 single cRCC, 16 were predicted to be indolent and 13 aggressive by GEP. Recurrence-free survival at 5 years was 68% and 42% in these 2 groups (P=.032). cRCC classified as indolent or aggressive according to SSIGN score had 5-year recurrence-free survival of 78% and 42%, respectively (P=.021). In a cox proportional hazards analysis, GEP was not an independent predictor of recurrence-free survival after accounting for SSIGN score. GEP classification correlated with cancer-specific survival at 5 years in 4 of 4 patients with metachronous cRCC, but only 2 of 4 patients with bilateral synchronous cRCC.
Conclusions
GEP using a kidney cancer-relevant cDNA array can differentiate between aggressive and indolent cRCC. GEP results may be most useful in unilateral cRCC when results are discordant with predictions of tumor behavior based on standard clinicopathologic features. In addition, GEP can provide prognostic information that may help characterize tumors of unknown clinical stage, such as bilateral metachronous cRCC.
doi:10.1016/j.juro.2008.10.069
PMCID: PMC2706314  PMID: 19095258
Carcinoma; Renal Cell; Microarray; Prognostic algorithm (nomogram); Gene expression profile
24.  Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava 
PLoS ONE  2014;9(10):e109877.
Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.
doi:10.1371/journal.pone.0109877
PMCID: PMC4184907  PMID: 25279769
25.  Tumor necrosis is a strong predictor for recurrence in patients with pathological T1a renal cell carcinoma 
Oncology Letters  2014;9(1):125-130.
Patients with pT1aN0M0 renal cell carcinoma (RCC) generally have good prognosis, and recurrence is rare. However, metastasis develops postoperatively in a small number of patients with pT1aN0M0 RCC. The present study was undertaken to identify predictors for recurrence in patients with pT1aN0M0 RCC. We reviewed the clinicopathological factors of 133 patients with pT1aN0M0 RCC who underwent radical or partial nephrectomy at the Department of Urology, National Defense Medical College (Saitama, Japan). Clinicopathological factors, including age, gender, tumor size, histological subtype, tumor grade, microvascular invasion, histological tumor necrosis, C-reactive protein levels and performance status were reviewed. These factors were compared between patients with and without postoperative recurrence. Recurrence-free survival (RFS) and cause-specific survival (CSS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent factors predicting recurrence in patients with pT1aN0M0 RCC. The 5-year RFS and CSS rates were 97.2 and 99.1%, respectively. When clinicopathological factors were compared between patients with and without recurrence, tumor size (P=0.0390) and percentage of tumor necrosis (P<0.0001) were significantly different between groups. All patients with recurrence had primary lesions ≥3 cm. By univariate analysis, tumor size (P=0.0379) and the presence of tumor necrosis (P=0.0319) were significant predictors for recurrence; tumor necrosis was also an independent predictor for recurrence (P=0.0143). In patients with pT1b tumors ≤5 cm (recurrence rate, 16.8%; n=48), the percentage of tumor necrosis was significantly higher in patients with recurrence compared with those without (P=0.0261). This suggests that tumor necrosis may be an important predictor for recurrence in small RCCs. Although recurrence is rare in pT1a RCC, the presence of tumor necrosis may be an important predictor for recurrence. Particularly, patients presenting with pT1a RCC with histological tumor necrosis should undergo careful follow-up.
doi:10.3892/ol.2014.2670
PMCID: PMC4246637  PMID: 25435945
renal cell carcinoma; pathological T1a; recurrence; predictor; tumor necrosis

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