Overall Survival and Development of Stage IV Chronic Kidney Disease in Patients Undergoing Partial and Radical Nephrectomy for Benign Renal Tumors

EUROPEAN UROLOGY 64 (2013) 600 606 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Kidney Cancer Editorial by Alexander Kutikov, Marc C. Smaldone and Robert G. Uzzo on pp. 607 609 of this issue Overall Survival and Development of Stage IV Chronic Kidney Disease in Patients Undergoing Partial and Radical Nephrectomy for Benign Renal Tumors Dharam Kaushik a, Simon P. Kim a, M. Adam Childs a, Christine M. Lohse b, Brian A. Costello c, John C. Cheville d, Stephen A. Boorjian a, Bradley C. Leibovich a, R. Houston Thompson a, * a Department of Urology, Mayo Clinic, Rochester, MN, USA; b Health Sciences Research, Mayo Clinic, Rochester, MN, USA; c Department of Oncology, Mayo Clinic, Rochester, MN, USA; d Department of Pathology, Mayo Clinic, Rochester, MN, USA Article info Article history: Accepted December 16, 2012 Published online ahead of print on December 25, 2012 Keywords: Chronic kidney disease Partial nephrectomy Renal cell carcinoma Radical nephrectomy Abstract Background: Although partial nephrectomy (PN) has been associated with improved renal function compared with radical nephrectomy (RN) for renal cell carcinoma, the impact on overall survival (OS) remains controversial. Objective: To evaluate comparative OS and renal function in patients following PN and RN for a renal mass where malignancy was not a confounding factor. Design, setting, and participants: Using the Mayo Clinic Nephrectomy Registry, we retrospectively identified 442 patients with unilateral sporadic benign renal masses treated surgically with PN or RN between 1980 and 2008. Outcome measurements and statistical analysis: The primary outcome measures were OS and the incidence of new-onset stage IV chronic kidney disease (CKD), determined using the Kaplan-Meier method. Cox models were used to test the association of nephrectomy type with these outcomes. Results and limitations: Overall, 206 and 236 patients with benign renal masses were surgically treated with RN and PN, respectively. Patients who underwent RN were older (median age: 67 vs 64 yr; p = 0.02) and had larger tumors (median size: 5.0 vs 2.7 cm; p < 0.001). Median follow-up for patients still alive at last follow-up was 8.3 yr (range: 0.1 27.9 yr). Estimated OS (95% confidence interval [CI]) rates at 10 and 15 yr were 69% (62 76%) and 53% (45 62%) for RN compared with 80% (73 87%) and 74% (65 83%) following PN ( p = 0.032). After adjusting for covariates of interest, patients treated with RN were significantly more likely to die from any cause (hazard ratio [HR]: 1.75; 95% CI, 1.08 2.83; p = 0.023) or develop stage IV CKD (HR: 4.23; 95% CI, 1.80 9.93; p < 0.001) compared with patients who underwent PN. Limitations include the retrospective design, selection bias for surgical approach, and referral bias to a tertiary care facility. Conclusions: Our data suggest that PN may confer a clinical benefit for improved renal function and better OS compared with RN after excluding the confounding effect of malignancy. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel. +1 507 284 9983; Fax: +1 507 284 4951. E-mail address: thompson.robert@mayo.edu (R.H. Thompson). 0302-2838/$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2012.12.023

EUROPEAN UROLOGY 64 (2013) 600 606 601 1. Introduction Due to the growing use of diagnostic imaging studies, the incidence of renal masses has been increasing, along with a concomitant stage migration such that most cases present as ct1 renal tumors (<7 cm) [1]. Although the historical treatment paradigm for management of a renal mass advocated for radical nephrectomy (RN), clinical guidelines currently recommend partial nephrectomy (PN), if technically feasible based on tumor size and location, largely due to a growing number of observational studies suggesting equivalent oncologic outcome, lower risk of adverse renal functional outcomes, and possibly improved overall survival (OS) [2 17]. However, a multi-institutional randomized prospective clinical trial in 2011 comparing PN and RN demonstrated an OS benefit for RN for small renal masses (SRMs), challenging the updated clinical guidelines and suggesting that further investigation is warranted [18]. In this context, it is essential to acknowledge that approximately 16 23% of patients who present with a renal mass are found to have benign tumors at the time of nephrectomy [19,20]. To date, few studies have evaluated whether PN confers a survival benefit for patients who have a benign renal mass at the time of nephrectomy [21]. To that end, the objective of our study was to assess for differences in OS and the development of stage IV chronic kidney disease (CKD) for patients undergoing PN or RN for benign renal masses where the confounding issue of malignancy is negated. 2. Methods 2.1. Patient selection After obtaining institutional review board approval, we queried the Mayo Clinic Nephrectomy Registry and identified 442 patients treated with an elective RN (n = 206) or PN (n = 236) for unilateral sporadic benign solid renal masses between 1980 and 2008. Patients with imperative indications for PN, such as a solitary kidney or elevated preoperative serum creatinine (defined as >1.6 for men and >1.4 for women), were excluded from the study. Clinical features studied included age at surgery, sex, body mass index (BMI), symptoms at presentation, Eastern Cooperative Oncology Group (ECOG) performance status, Charlson score (which includes diabetes) [22], and preoperative estimated glomerular filtration rate (egfr) calculated using the abbreviated Modification of Diet and Renal Disease (MDRD) equation [23]. Patients with a palpable mass, abdominal discomfort, gross hematuria, acute onset varicocele, or constitutional symptoms including rash, sweats, weight loss, fatigue, early satiety, or anorexia were considered symptomatic at presentation. Pathologic features included histologic subtype and tumor size, and all pathology slides were reviewed by one urologic pathologist (JCC). Vital status for patients in the Nephrectomy Registry is updated yearly through a review of medical records and correspondence with patients and their local physicians. National registries such as the Social Security Death Index and Accurint (a health care database of approximately 34 billion public records) are used to obtain follow-up information on each patient in the registry. Follow-up egfrs were calculated using follow-up serum creatinine levels and corresponding patient gender and age according to the abbreviated MDRD equation [23]. 2.2. Statistical methods Comparisons of features between groups of interest were evaluated using Wilcoxon rank sum, chi-square, and Fisher exact tests. OS was estimated using the Kaplan-Meier method. The duration of follow-up was calculated from the date of surgery to the date of death or last follow-up. Four patients who subsequently developed renal cell carcinoma (RCC) were censored at the date of RCC diagnosis. Survival free of new-onset stage IV CKD, defined as an egfr <30 ml/min per 1.73 m 2 during follow-up, was estimated using the Kaplan-Meier method. The duration of follow-up was calculated from the date of surgery to the date of egfr <30 ml/min per 1.73 m 2 or the date of last follow-up egfr. Patients who were missing preoperative egfr or whose last follow-up egfr was within 30 d of surgery were excluded from analyses of this end point. All patients had a preoperative egfr 30 ml/ min per 1.73 m 2, and only follow-up egfrs that were assessed before the date of RCC diagnosis were included for the four patients who subsequently developed RCC. Univariate and multivariable associations with death and new-onset stage IV CKD were evaluated using Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Because the proportion of patients treated with RN versus PN changed dramatically during the time period of interest (eg, 36% and 37% of patients treated in the 1980s and 1990s were treated with PN, respectively, compared with 76% in the 2000s), year group was used as a stratification effect in the Cox models. The year groups were chosen so that they contained approximately the same numbers of patients with the end point of interest. Statistical analyses were performed using the SAS software package (SAS Institute, Cary, NC, USA). All tests were two sided, and p values <0.05 were considered statistically significant. 3. Results Table 1 summarizes comparisons of clinical and pathologic features and early surgical complications between patients treated with RN and PN for benign solid renal masses. Patients treated with RN were significantly older, more likely to have oncocytomas, less likely to have angiomyolipomas, and had larger tumors compared with patients treated with PN. A total of 127 patients died during followup, at a mean of 8.3 yr following surgery (median: 7.4 yr; range: 0.1 24.4 yr). Among the 315 patients still alive at last follow-up, the mean duration of follow-up was 9.0 yr (median: 8.3 yr; range: 0.1 27.9 yr); only 24 patients (8%) had <2 yr of follow-up. Estimated overall survival rates at 5, 10, and 15 yr following surgery for the 206 patients treated with RN were 88% (95% CI, 83 93; number still at risk: 160), 69% (95% CI, 62 76; number still at risk: 96), and 53% (95% CI, 45 62; number still at risk: 42), respectively, compared with 91% (95% CI, 87 95; number still at risk: 141), 80% (95% CI, 73 87; number still at risk: 65), and 74% (95% CI, 65 83; number still at risk: 27), respectively, for the 236 patients treated with PN ( p =0.032;Fig. 1). Table 2 summarizes the univariate and multivariable associations of clinical and pathologic features with death from any cause. Univariately, patients treated with RN were >50% more likely to die compared with patients treated with PN (HR: 1.52; p = 0.032). After adjusting for age, sex, BMI, symptoms at presentation, constitutional symptoms at presentation, ECOG, Charlson score, preoperative egfr, histologic subtype, and tumor size, patients treated with RN

602 EUROPEAN UROLOGY 64 (2013) 600 606 Table 1 Comparison of clinical and pathologic features between patients treated with radical nephrectomy and partial nephrectomy for benign solid renal masses * Feature RN n = 206 PN n = 236 p value Mean (median; range) Age at surgery, yr 64.2 (67; 24 89) 61.4 (64; 26 94) 0.021 BMI, kg/m 2 (n = 416) 27.0 (26.2; 16.8 55.7) 27.9 (27.1; 16.5 49.8) 0.10 Charlson score (n=435) 1.2 (1; 0 9) 1.1 (1; 0 9) 0.80 Preoperative egfr, ml/min per 1.73 m 2 (n = 429) 66.6 (66; 39 171) 67.9 (66; 38 133) 0.49 Tumor size, cm (n = 424) 6.1 (5.0; 0.4 20.0) 3.5 (2.7; 0.8 22.0) <0.001 Sex Female 100 (49) 109 (46) 0.62 Male 106 (51) 127 (54) Symptoms at presentation (n = 439) 87 (43) 92 (39) 0.41 Constitutional symptoms at presentation (n = 439) 25 (12) 22 (9) 0.32 ECOG performance status (n = 436) 0 169 (84) 209 (89) 0.21 >0 31 (16) 27 (11) Preoperative egfr, ml/min per 1.73 m 2 (n = 429) 60 129 (65) 156 (67) 0.53 45 59 62 (31) 65 (28) 30 44 6 (3) 11 (5) Histologic subtype Oncocytoma 155 (75) 154 (65) 0.005 Angiomyolipoma 31 (15) 66 (28) Papillary adenoma 2 (1) 0 Metanephric adenoma 3 (1) 5 (2) Other benign 15 (7) 11 (5) Excluded from analysis of postoperative egfr 41 (20) 42 (18) 0.57 Early surgical complications (within 30 d) Bleeding or hematoma 6 (3) 6 (3) 0.81 Deep vein thrombosis 0 1 (<1) 1.0 Pulmonary embolism 0 1 (<1) 1.0 Myocardial infarction 0 1 (<1) 1.0 Wound infection 1 (<1) 5 (2) 0.22 Abscess 0 2 (1) 0.50 Sepsis 0 1 (<1) 1.0 Acute renal failure 1 (<1) 3 (1) 0.63 Pneumothorax 2 (1) 2 (1) 1.0 Any of the above 9 (4) 19 (8) 0.11 BMI = body mass index; ECOG = Eastern Cooperative Oncology Group; egfr = estimated glomerular filtration rate; PN = partial nephrectomy; RN = radical nephrectomy. * n = 442. n (%) [(Fig._1)TD$FIG] Fig. 1 Kaplan-Meier plot showing association of type of surgery with overall survival. PN = partial nephrectomy; RN = radical nephrectomy. were 75% more likely to die compared with patients treated with PN (HR: 1.75; p = 0.023). No statistically significant two-way interactions with type of surgery were identified. Eighty-three patients were missing preoperative GFR (n = 13) or had a last follow-up GFR that was within 30 d of surgery only (n = 70). No statistically significant differences between the 83 patients who were excluded from the analysis of new-onset stage IV CKD and the 359 who were included were identified (see Table 1 for a comparison of type of surgery; remaining data not shown). Of the 359 patients included in this analysis, 42 developed newonset stage IV CKD, at a mean of 6.1 yr following surgery (median: 5.6 yr; range: 0.2 15.8 yr). Of the 317 patients who did not develop new-onset stage IV CKD, the mean duration of renal function follow-up was 6.7 yr (median: 5.2 yr; range: 0.1 26.9 yr). Of the 165 RN patients, there were 8, 51, 72, and 34 patients with postoperative egfr 60 ml/min per 1.73 m 2, 45 59, 30 44, and <30, respectively. Of the 194

EUROPEAN UROLOGY 64 (2013) 600 606 603 Table 2 Univariate and multivariable associations with death from any cause Univariate Multivariable Feature Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Age at surgery (10-yr increase) 2.34 (1.93 2.84) <0.001 2.05 (1.58 2.65) <0.001 Sex Female 1.0 (reference) 1.0 (reference) Male 1.87 (1.29 2.71) <0.001 1.49 (0.94 2.34) 0.087 BMI (5 kg/m 2 increase) 1.05 (0.91 1.22) 0.51 1.10 (0.89 1.35) 0.40 Symptoms at presentation 0.72 (0.50 1.03) 0.07 0.82 (0.49 1.37) 0.45 Constitutional symptoms at presentation 1.20 (0.74 1.94) 0.46 1.03 (0.51 2.10) 0.93 ECOG performance status 0 1.0 (reference) 1.0 (reference) >0 3.80 (2.58 5.61) <0.001 1.93 (1.14 3.26) 0.014 Charlson comorbidity index (1-unit increase) 1.47 (1.36 1.58) <0.001 1.21 (1.08 1.36) <0.001 Preoperative egfr (10 ml/min per 1.73 m 2 increase) 0.82 (0.71 0.94) 0.006 1.08 (0.92 1.26) 0.34 Histologic subtype Other 1.0 (reference) 1.0 (reference) Oncocytoma 1.93 (1.23 3.04) 0.005 0.81 (0.45 1.45) 0.47 Tumor size (1-cm increase) 0.95 (0.90 1.01) 0.11 0.97 (0.91 1.04) 0.40 Type of surgery PN 1.0 (reference) 1.0 (reference) RN 1.52 (1.04 2.23) 0.032 1.75 (1.08 2.83) 0.023 BMI = body mass index; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; egfr = estimated glomerular filtration rate; PN = partial nephrectomy; RN = radical nephrectomy. PN patients, there were 88, 70, 28, and 8 patients with postoperative egfr 60 ml/min per 1.73 m 2, 45 59, 30 44, and <30, respectively. Estimated rates of survival free of new-onset stage IV CKD at 5, 10, and 15 yr following surgery for the 165 patients treated with RN were 88% (95% CI, 82 94; number still at risk: 94), 76% (95% CI, 68 85; number still at risk: 51), and 66% (95% CI, 56 78; number still at risk: 20), respectively, compared with 97% (95% CI, 95 100; number still at risk: 91), 91% (95% CI, 85 98; number still at risk: 38), and 91% (95% CI, 85 98; number still at risk: 10), respectively, for the 194 patients treated with PN ( p < 0.001; Fig. 2). Table 3 summarizes univariate and multivariable associations of clinical and pathologic features with new-onset stage IV CKD. Univariately, patients treated with RN were more than four times more likely to develop new-onset stage IV CKD compared with patients treated with PN (HR: 4.02; p < 0.001). Because only 42 patients [(Fig._2)TD$FIG] developed new-onset stage IV CKD, a multivariable model could likely not support the inclusion of all 11-candidate predictors without overfitting. As such, the multivariable model presented in Table 3 includes those features that were univariately associated with this outcome at the 0.10 significance level. After adjusting for age, ECOG, Charlson score, preoperative egfr, and histologic subtype, patients treated with RN remained more than four times more likely to develop new-onset stage IV CKD compared with patients treated with PN (HR: 4.23; p < 0.001). Again, no statistically significant two-way interactions with type of surgery were identified. When we evaluated the subset of patients treated in 1990 or later, similar results are obtained. In particular, after adjusting for covariates of interest (Tables 2 and 3) and including year of surgery as a stratification effect, patients treated with RN were more likely to die (HR: 1.88; Fig. 2 Kaplan-Meier plot showing association of type of surgery with survival free of new-onset stage IV chronic kidney disease (CKD). PN = partial nephrectomy; RN = radical nephrectomy.

604 EUROPEAN UROLOGY 64 (2013) 600 606 Table 3 Univariate and multivariable associations with new-onset stage IV chronic kidney disease Univariate Multivariable Feature Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Age at surgery (10-yr increase) 2.41 (1.70 3.40) <0.001 1.66 (1.10 2.50) 0.015 Sex Female 1.0 (reference) Male 1.19 (0.64 2.21) 0.58 BMI (5 kg/m 2 increase) 1.06 (0.83 1.35) 0.65 Symptoms at presentation 0.93 (0.50 1.72) 0.81 Constitutional symptoms at presentation 1.06 (0.44 2.54) 0.89 ECOG performance status 0 1.0 (reference) 1.0 (reference) >0 5.35 (2.66 10.73) <0.001 2.37 (0.95 5.89) 0.065 Charlson comorbidity index (1-unit increase) 1.43 (1.25 1.63) <0.001 1.21 (1.02 1.43) 0.028 Preoperative egfr (10 ml/min per 1.73 m 2 increase) 0.56 (0.42 0.74) <0.001 0.78 (0.60 1.02) 0.074 Histologic subtype Other 1.0 (reference) 1.0 (reference) Oncocytoma 2.34 (0.99 5.57) 0.054 1.27 (0.50 3.20) 0.61 Tumor size (1-cm increase) 1.03 (0.94 1.12) 0.59 Type of surgery PN 1.0 (reference) 1.0 (reference) RN 4.02 (1.81 8.96) <0.001 4.23 (1.80 9.93) <0.001 BMI = body mass index; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; egfr = estimated glomerular filtration rate; PN = partial nephrectomy; RN = radical nephrectomy. 95% CI, 1.06 3.31; p = 0.030) and were more likely to develop new-onset stage IV CKD (HR: 4.16; 95% CI, 1.58 10.99; p = 0.004) compared with patients treated with PN. 4. Discussion In this study, we sought to evaluate comparative OS and the incidence of severe CKD following PN and RN for patients found to have benign renal tumors. A key finding of this study is that PN was associated with a lower incidence of developing stage IV CKD following surgery for a benign renal mass. Although this information supports previous observations [24,25] comparing PN and RN for RCC, the results of our study also suggest improved OS for patients treated with PN compared with RN in a setting where the confounding effect of malignancy is absent. These findings are distinct from a recent prospective randomized trial where RN in the intention-to-treat population had better OS compared with PN (81.1% vs 75.7%) in the setting of SRMs (5 cm). Although limitations of this trial include poor accrual, lack of estimated renal functional outcomes, and patient crossover from a randomized surgical approach, this trial represents the only level 1 data comparing RN and PN and challenges the current clinical guidelines for management of SRM [18]. More recently, a systematic review and meta-analysis of PN and RN for SRMs, which included findings from the Van Poppel trial [18], found that PN had improved OS and renal function compared with RN [3]. This meta-analysis revealed that PN confers 19%, 29%, and 61% risk reduction for OS, cancer-specific mortality, and severe CKD, respectively. Although this meta-analysis was performed on a heterogeneous study population, with only 7 of the 36 studies (19%) providing information on patients lost to follow-up and a lack of multiple clinical trials, the conclusions did suggest better OS, similar to our current study. The systematic review and meta-analysis demonstrated that the improved CSS for PN was due to a single population-based study using Surveillance, Epidemiology and End Results (SEER) Medicare data. Smaldone et al recently used SEER-Medicare data in an elderly administrative cohort suggesting that PN confers a significant OS advantage between 1 and 3 yr postoperatively [26]. The survival experience observed in our cohort was similar, illustrating the notion that when the confounding effect of malignancy is obviated, factors responsible for variation in survival remain poorly understood. It is important to highlight that most of the observational studies assessing the treatment effect of PN for SRMs have limited patients compared with those with RCC only. To date, only one study has examined the clinical effectiveness of PN compared with RN for patients found to have benign SRMs on surgical pathology following surgery. Weight et al reviewed the renal and survival outcomes at the Cleveland Clinic for patients with unanticipated benign tumors by type of nephrectomy with a median follow-up of 4.1 yr [21]. Their results suggested that PN was associated with better renal function and improved OS. Finding similar observations, our data provide longer follow-up duration of 8.3 yr with all pathologic specimens reviewed by one urologic pathologist. Collectively, the results support the current best practice guidelines for the surgical management of SRMs from the European Association of Urology, American Urological Association, and National Comprehensive Cancer Network [6,10,27]. The treatment paradigm of PN for SRM is based on the demonstrated lower risk of developing CKD after surgery, which then, in turn, has been postulated to be associated with a reduced risk of all-cause mortality. The adverse clinical effect of reduced egfr was previously shown in a community-based study of 1 120 295 adults in whom egfr

EUROPEAN UROLOGY 64 (2013) 600 606 605 was calculated between 1996 and 2000 and who did not undergo dialysis or renal transplantation in the same time period. CKD, defined as an egfr <60 ml/min per 1.73 m 2, was found to be an independent risk factor for the development of cardiovascular events, number of hospitalizations, and death [28]. It has also been shown using SEER cancer registry data that, compared with PN, RN is associated with a 38% increased risk of overall mortality and a 1.4-fold greater number of cardiovascular events after surgery [29]. A recent population-based cohort study has shown that patients who undergo PN are less likely to experience adverse renal outcomes such as end-stage renal disease receipt of dialysis services than those who underwent RN [30]. We recognize the limitations of this study. Most important, the inferences from our results are confounded by the selection bias of the retrospective nonrandomized design over a prolonged time period. In addition, we used the MDRD equation to calculate egfr, and we acknowledge that this formula lacks precision, particularly in individuals at the extremes of age or weight. The pathologic feature of a benign tumor was not elucidated until after surgery. Although this study eliminates the confounding factor of malignancy impact on outcome, the histology was not known in the preoperative setting when surgical approach was decided. However, our results highlight important renal functional and survival considerations when deciding on surgical approach for SRM patients, and given the discordant findings in the literature, these results further contribute to the debate. 5. Conclusions Our results suggest that renal preservation with PN can reduce the risk of developing stage IV CKD and may be associated with improved OS in comparison with RN for patients with benign renal masses. Author contributions: R. Houston Thompson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Thompson, Childs. Acquisition of data: Thompson, Lohse, Childs. Analysis and interpretation of data: Thompson, Lohse, Kim, Kaushik. Drafting of the manuscript: Kaushik, Kim, Thompson. Critical revision of the manuscript for important intellectual content: Kim, Kaushik, Thompson, Lohse, Leibovich, Boorjian, Cheville, Costello. Statistical analysis: Lohse, Thompson. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Thompson. Other (specify): None. Financial disclosures: R. Houston Thompson certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Chow WH, Devesa SS, Warren JL, Fraumeni Jr JF. Rising incidence of renal cell cancer in the United States. JAMA 1999;281:1628 31. [2] Tan HJ, Norton EC, Ye Z, Hafez KS, Gore JL, Miller DC. Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. JAMA 2012;307: 1629 35. [3] Kim SP, Thompson RH, Boorjian SA, et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. 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