scholarly journals Improvement of Outcomes in Patients with Lupus Nephritis: Management Evolution in Chinese Patients from 1994 to 2010

2019 ◽  
Vol 46 (8) ◽  
pp. 912-919 ◽  
Author(s):  
Si-Jia Shao ◽  
Jin-Hua Hou ◽  
Guo-Tong Xie ◽  
Wen Sun ◽  
Dan-Dan Liang ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Activity Index ◽  
Survival Rates ◽  
Standard Of Care ◽  
Chinese Patients ◽  
Renal Outcome ◽  
Therapeutic Effects ◽  
Endstage Renal Disease ◽  
Renal Relapse ◽  
Chronicity Index

Objective.To assess how the longterm outcomes have changed over the past decades in Chinese patients with lupus nephritis (LN). The trends in patient manifestation at presentation, treatment pattern, and therapeutic effects were evaluated.Methods.A cohort of biopsy-proven patients with LN (n = 1945) from January 1994 to December 2010 was analyzed. Treatment regimens, treatment response, renal relapse, and renal outcome were compared at different time periods (1994–1998, 1999–2004, and 2005–2010).Results.Patients in the later periods had shorter duration of disease, lower serum creatinine value and chronicity at biopsy, and more frequent followup. They were more likely to receive standard-of-care therapies, which included cyclophosphamide, mycophenolate mofetil, and combination therapy. Patients in the later periods had higher probabilities of achieving remission (p < 0.001) and lower probabilities of experiencing renal flare (p = 0.007). The 5-year renal survival rates were 92.6%, 90.6%, and 94.3% in 1994–1998, 1999–2004, and 2005–2010, respectively. The 5-year risk of endstage renal disease (ESRD) did not differ between 1994–1998 and 1999–2004, but was significantly lower in 2005–2010 (HR 0.40, 95% CI 0.19–0.85 vs 1999–2004). In multivariable Cox analysis, standard therapy was independently associated with lower risk of ESRD (adjusted HR 0.72, 95% CI 0.52–0.98, p = 0.04). Variables of renal damage at biopsy (renal function, activity index, and chronicity index) were independently associated with poor outcome.Conclusion.The outcomes of Chinese patients with LN have improved from 1994 to 2010. With the increased use of standard therapies, the remission rates have increased and renal relapse has decreased.

Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis

2020 ◽  
Vol 79 (8) ◽  
pp. 1077-1083 ◽  
Author(s):  
Gabriella Moroni ◽  
Mariele Gatto ◽  
Francesco Tamborini ◽  
Silvana Quaglini ◽  
Francesca Radice ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Cox Regression ◽  
Characteristic Curve ◽  
Survival Rates ◽  
Multivariable Analysis ◽  
Response To Therapy ◽  
Renal Outcome ◽  
Free Survival ◽  
European League Against Rheumatism ◽  
Chronicity Index

ObjectivesShort-term predictive endpoints of chronic kidney disease (CKD) are needed in lupus nephritis (LN). We tested response to therapy at 1 year.MethodsWe considered patients with LN who underwent renal biopsy followed by induction therapy between January 1970 and December 2016. LN was assessed using the International Society of Nephrology/Renal Pathology Society (2003) criteria and the National Institute of Health (NIH) activity and chronicity index. The renal outcome was CKD. Response was defined according to EULAR/European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations: complete: proteinuria <0.5 g/24 hours, (near) normal estimated glomerular filtration rate (eGFR); partial: ≥50% proteinuria reduction to subnephrotic levels, (near) normal eGFR; and no response: all the other cases. Logistic regression analysis was employed for 12-month response and Cox regression for CKD prediction.ResultsWe studied 381 patients (90.5% Caucasians). After 12-month therapy, 58%, 26% and 16% of patients achieved complete, partial and no response, respectively, according to EULAR/ERA-EDTA. During a median follow-up of 10.7 (IQR: 4.97–18.80) years, 53 patients developed CKD. At 15 years, CKD-free survival rate was 95.2%, 87.6% and 55.4% in patients with complete, partial and no response at 12 months, respectively (p<0.0001). CKD-free survival rates did not differ between complete and partial responders (p=0.067). Serum creatinine (HR: 1.485, 95% CI 1.276 to 1.625), eGFR (HR 0.967, 95% CI 0.957 to 0.977) and proteinuria at 12 months (HR 1.234, 95% CI 1.111 to 1.379) were associated with CKD, yet no reliable cut-offs were identified on the receiver operating characteristic curve. In multivariable analysis, no EULAR/ERA-EDTA response at 12 months (HR 5.165, 95% CI 2.770 to 7.628), low C4 (HR 1.053, 95% CI 1.019 to 1.089) and persistent arterial hypertension (HR 3.154, 95% CI 1.500 to 4.547) independently predicted CKD.ConclusionsLack of EULAR/ERA-EDTA response at 12 months predicts CKD.

scholarly journals Changing patterns in clinical–histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis

2018 ◽  
Vol 77 (9) ◽  
pp. 1318-1325 ◽  
Author(s):  
Gabriella Moroni ◽  
Paolo Gilles Vercelloni ◽  
Silvana Quaglini ◽  
Mariele Gatto ◽  
Davide Gianfreda ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Activity Index ◽  
Progressive Increase ◽  
Renal Outcome ◽  
Rank Test ◽  
Renal Survival ◽  
Chronicity Index

ObjectivesTo evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time.Patients and methodsWe studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970–1985, P2 1986–2001 and P3 2002–2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test.ResultsA progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD.ConclusionsClinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.

scholarly journals Comparison of the 2018 and 2003 International Society of Nephrology/Renal Pathology Society classification in terms of renal prognosis in patients of lupus nephritis: a retrospective cohort study

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Ryosuke Umeda ◽  
Soshiro Ogata ◽  
Shigeo Hara ◽  
Kazuo Takahashi ◽  
Daijo Inaguma ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Biopsy ◽  
International Society ◽  
Activity Index ◽  
Renal Pathology ◽  
Renal Outcome ◽  
Rank Test ◽  
Class Iii ◽  
Renal Prognosis ◽  
Chronicity Index

Abstract Background Although the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between the 2018 revised ISN/RPS classification and the 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised ISN/RPS classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003. Methods We retrospectively collected medical records of 170 LN patients from the database of renal biopsy at Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as a 30% decline of estimated glomerular filtration rate (eGFR). Results A total of 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). The mean age was 42 years, 88% were female, and the median observation period was 50.5 months. Renal prognosis was significantly different among the classes and significantly poor in the patients with higher modified National Institute of Health (mNIH) chronicity index (C index, ≥ 4) by a log-rank test (p = 0.05 and p = 0.02, respectively). By Cox proportional hazard models, only the C index was significantly associated with renal outcome (hazard ratio 1.32, 95% CI 1.11–1.56, p ≤ 0.01), while the classes, the 2003 activity and chronicity subdivision, and the mNIH activity index had no significant association with renal outcome. Each component of the C index was significantly associated with renal outcome in different models. Conclusion This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification.

scholarly journals Comparison of 2018 and 2003 International Society of Nephrology/Renal Pathology Society classification in terms of renal prognosis in patients of lupus nephritis: a retrospective cohort study.

2020 ◽  
Author(s):  
Ryosuke Umeda ◽  
Soshiro Ogata ◽  
Shigeo Hara ◽  
Kazuo Takahashi ◽  
Daijo Inaguma ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Biopsy ◽  
International Society ◽  
Activity Index ◽  
Renal Pathology ◽  
Renal Outcome ◽  
Rank Test ◽  
Class Iii ◽  
Renal Prognosis ◽  
Chronicity Index

Abstract Background: Although 2018 revised ISN/RPS classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between 2018 revised ISN/RPS classification and 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003.Methods: We retrospectively collected medical records of 170 LN patients from the database of renal biopsy in Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as 30% decline of estimated glomerular filtration rate (eGFR). Results: A total 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). Mean age was 42 years, 88% were female, and median observation period was 50.5 months. Renal prognosis was significantly different among the classes, and significantly poor in the patients with higher modified National Institute of Health (mNIH) Chronicity index (C index, ≥4) by a log-rank test (p=0.05, p=0.02 respectively). By Cox proportional hazard models, only C index was significantly associated with renal outcome (Hazard Ratio; 1.32, 95% CI; 1.11-1.56, p≤0.01), while the classes, the 2003 activity and chronicity subdivision, and mNIH activity index had no significant association with renal outcome. Each component of C index was significantly associated with renal outcome in different models. Conclusion: This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification

scholarly journals Renal Remission Status and Longterm Renal Survival in Patients with Lupus Nephritis: A Retrospective Cohort Analysis

2018 ◽  
Vol 45 (5) ◽  
pp. 671-677 ◽  
Author(s):  
Julie E. Davidson ◽  
Qinggong Fu ◽  
Beulah Ji ◽  
Sapna Rao ◽  
David Roth ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Cox Regression ◽  
Cohort Analysis ◽  
Standard Of Care ◽  
Renal Survival ◽  
Endstage Renal Disease ◽  
American College Of Rheumatology ◽  
Remission Status ◽  
Kaplan Meier ◽  
Remission Criteria

Objective.This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy.Methods.Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death].Results.In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan–Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082–0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063–0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission.Conclusion.Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.

Urinary sediment suggests lupus nephritis histology

Lupus ◽  
2016 ◽  
Vol 26 (6) ◽  
pp. 580-587 ◽  
Author(s):  
M U Martínez-Martínez ◽  
L M de G Llamazares-Azuara ◽  
D Martínez-Galla ◽  
P B Mandeville ◽  
F Valadez-Castillo ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Kidney Biopsy ◽  
Activity Index ◽  
Classification Tree ◽  
Area Under The Curve ◽  
Roc Curves ◽  
Urine Sediment ◽  
Urinary Sediment ◽  
Secondary Objective ◽  
Chronicity Index

Objectives The objective of this paper was to evaluate correlations between kidney biopsy indexes (activity and chronicity) and urinary sediment findings; the secondary objective was to find which components of urinary sediment can discriminate proliferative from other classes of lupus nephritis. Methods Lupus nephritis patients scheduled for a kidney biopsy were included in our study. The morning before the kidney biopsy, we took urine samples from each patient. Receiver operating characteristic (ROC) curves were plotted to determine the area under the curve (AUC) of each test for detecting proliferative lupus nephritis; a classification tree was calculated to select a set of values that best-predicted lupus nephritis classes. Results We included 51 patients, 36 of whom were women (70.6%). Correlations of lupus nephritis activity index with the counts in the urinary sediment of erythrocytes (isomorphic and dysmorphic), acanthocytes, and leukocytes were 0.65 ( p < 0.0001) 0.62 ( p < 0.0001) and 0.22 ( p = 0.1228), respectively. Correlations of lupus nephritis chronicity index with the counts of erythrocytes, acanthocytes, and leukocytes were 0.60 ( p ≤ 0.0001), 0.52 ( p = 0.0001) and 0.17 ( p = 0.2300), respectively. Our classification tree had an accuracy of 84.3%. Conclusions Evaluation of urine sediment reflects lupus nephritis histology.

scholarly journals The Value of a Panel of Autoantibodies for Predicting the Activity of Lupus Nephritis at Time of Renal Biopsy

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Gabriella Moroni ◽  
Silvana Quaglini ◽  
Antonella Radice ◽  
Barbara Trezzi ◽  
Francesca Raffiotta ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Biopsy ◽  
Kidney Biopsy ◽  
Clinical Presentation ◽  
Activity Index ◽  
Serum Biomarkers ◽  
Immunological Parameters ◽  
Renal Histology ◽  
Chronicity Index ◽  
Dsdna Antibodies

Few studies have correlated serum biomarkers with renal histology, the gold standard for renal activity, in lupus nephritis (LN). We tested a panel of autoantibodies and complement at the time of kidney biopsy and after treatment. Anti-dsDNA, anti-nucleosome, anti-ribosome P, and anti-C1q antibodies and C3/C4 were measured in 107 patients with LN at the time of renal biopsy and after 6–12 months and were correlated with clinical/histological parameters. At multivariate analysis, high titers of anti-C1q antibodies or of anti-dsDNA antibodies (P=0.005, OR = 8.67, CI: 2.03–37.3) were the independent predictors that discriminate proliferative from nonproliferative LN. All the immunological parameters, except anti-ribosome, showed a significant correlation with activity index but not with chronicity index. Only anti-C1q showed a significant correlation with the amount of proteinuria (R=0.2,P=0.03). None of the immunological parameters were predictive of remission at 6 and 12 months. We found that anti-C1q alone or in combination with anti-dsDNA emerged as the most reliable test in differentiating proliferative and nonproliferative LN. Anti-C1q was the only test correlated with the clinical presentation of LN. After treatment, the titre of the autoantibodies was significantly reduced, but none was predictive of remission.

Differences in clinico-pathological characteristics and outcomes between proteinase 3-ANCA positivity and myeloperoxidase-ANCA positivity in lupus nephritis

Lupus ◽  
2019 ◽  
Vol 28 (9) ◽  
pp. 1111-1119 ◽  
Author(s):  
C Li ◽  
J -J Wang ◽  
M -L Zhou ◽  
D -D Liang ◽  
J Yang ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Interstitial Fibrosis ◽  
Survival Rates ◽  
Proteinase 3 ◽  
Tubular Atrophy ◽  
Positive Group ◽  
Renal Outcomes ◽  
Pathological Characteristics ◽  
Chronicity Index ◽  
Low Prevalence

Background Owing to the low prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in lupus nephritis (LN), there is no study about the differences between proteinase 3 (PR3)-ANCA positivity and myeloperoxidase (MPO)-ANCA positivity in LN until now. Methods Here we perform a retrospective study to determine whether there are differences in clinic-pathological characteristics and renal outcomes between PR3-ANCA-positive LN patients and MPO-ANCA-positive LN patients. Results A total of 26 (27.4%) PR3-ANCA-positive LN patients and 69 (72.6%) MPO-ANCA-positive LN patients ( p < 0.001) were eligible for this study. Compared with PR3-ANCA-positive LN patients, MPO-ANCA-positive LN patients had significantly higher levels of serum creatinine (109.6 µmol/l vs. 74.3 µmol/l, p = 0.02), lower titers of antinuclear antibodies (ANA) (128 vs. 256, p = 0.01), and higher serum concentrations of C3 and C4 (0.54 g/l vs. 0.36 g/l, p = 0.002; 0.12 g/l vs. 0.06 g/l, p < 0.001; respectively). Furthermore, the MPO-ANCA-positive group had higher scores for chronicity index ( p = 0.007), including interstitial fibrosis ( p = 0.001) and tubular atrophy ( p = 0.03) on biopsy specimens. The renal survival rates for MPO-ANCA-positive LN patients were 94.1% at 1 year, 83.2% at 5 years and 79.6% at 10 years; these values were worse when compared with those of the PR3-ANCA-positive group, which were 100%, 100% and 100%, respectively. Conclusion MPO-ANCA-positive LN patients had more severely impaired baseline renal function and less active lupus serology. More severely chronic pathological changes, including interstitial fibrosis and tubular atrophy on renal specimens, occurred in MPO-ANCA-positive LN patients. We found that MPO-ANCA-positive LN patients had worse renal outcomes.

The relationship between the modified National Institute of Health activity and chronicity scoring system, and the long-term prognosis for lupus nephritis: A retrospective single-center study

Lupus ◽  
2021 ◽  
pp. 096120332110342
Author(s):  
Shiori Nakagawa ◽  
Tadashi Toyama ◽  
Yasunori Iwata ◽  
Megumi Oshima ◽  
Hisayuki Ogura ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Scoring System ◽  
Primary Outcome ◽  
Activity Index ◽  
Secondary Outcome ◽  
Long Term Prognosis ◽  
Moderate Hazard ◽  
Chronicity Index ◽  
End Stage

Background The revision of International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification guidelines for lupus nephritis (LN) was suggested by a working group, who recommended a modified National Institute of Health (NIH) activity and chronicity scoring system to evaluate active and chronic LN lesions. However, whether this approach was useful for estimating long-term prognosis for LN patients is unclear. Methods We conducted a retrospective cohort study in Japanese subjects with biopsy-proven LN, between 1977 and 2018. Pathologic lesions were evaluated based on ISN/RPS 2003 classifications and the modified NIH scoring system. Patients were grouped by activity index (low, 0–5; moderate, 6–11; high, 12–24), and chronicity index (low, 0–2; moderate, 3–5; high, 6–12). The primary outcome was a composite of end-stage kidney disease (ESKD) or all-cause death, and the secondary outcome was ESKD alone. Results Sixty-six subjects with a median age of 31 years were included. During median follow-up (11.5 years), 15 patients reached the primary outcome: 10 had ESKD, four had died, and one had ESKD and died. Kaplan–Meier analysis showed that the cumulative primary outcome incidence increased with a higher chronicity index (log-rank trend p < 0.001). From multivariable survival analysis, moderate (hazard ratio [HR] 6.17, 95% confidence interval [CI] 1.14 to 33.20; p = 0.034) and high chronicity indices (HR 20.20, 95% CI 1.13 to 359.82; p = 0.041) were risk factors for the primary outcome. Conclusion Moderate and high chronicity indices were associated with an increased ESKD risk for LN.

scholarly journals Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

2020 ◽  
Vol 9 (2) ◽  
pp. e14-e14
Author(s):  
Eman Hassan Abdelbary ◽  
Noha Farouk Ahmed ◽  
Adel Abdelmohsen Ghorab
Keyword(s):  
Lupus Nephritis ◽  
Serum Creatinine ◽  
Lupus Erythematosus ◽  
Kidney Diseases ◽  
Activity Index ◽  
Kidney Injury ◽  
Class Iii ◽  
Clinicopathologic Characteristics ◽  
Chronicity Index

Introduction: Lupus nephritis (LN) is a substantial manifestation of systemic lupus erythematosus (SLE). HDAC6 is overexpressed in various kidney diseases, and its inhibition slows kidney injury progression. Urinary TFF3 increases in chronic kidney diseases (CKDs) and may be associated with patient’s outcome. Objectives: This study aimed to examine the relationship between renal HDAC6 and TFF3 proteins expression and with clinicopathologic characteristics and outcome of LN. Patients and Methods: HDAC6 and TFF3 proteins’ expression was immunohistochemically detected in 56 cases of LN. They were correlated to patients’ age, gender, urinary 24 hours protein and serum creatinine levels at baseline and during follow up. Additionally, they were correlated to LN classes, activity index (AI) and chronicity index (CI) and relapse free survival (RFS). Results: HDAC6 overexpression was significantly associated with serum creatinine and 24 hours proteinuria levels at baseline (P = 0.041 and P =0.026 respectively) and during follow up (P < 0.001). It was associated with AI and CI of class III and IV LN (P = 0.047 and 0.003 respectively). TFF3 overexpression was associated with higher serum creatinine and more proteinuria at baseline (P = 0.015 and 0.001 respectively) and during follow up (P < 0.001). It was significantly associated with higher CI (P = 0.001). Both markers were associated with shorter RFS (P < 0.001). Conclusion: HDAC6 and TFF3 proteins are associated with clinicopathologic features of renal damage in LN. They are reliable predictors of patients’ RFS, which makes them good candidates for risk stratification of patients and targeted therapy.

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