Nomograms for prostate cancer

Transcription

1 Review Article NOMOGRAMS FOR PROSTATE CANCER STEPHENSON and KATTAN There are several papers in this section on various aspects of prostate cancer: predictive models, robotic radical prostatectomy in large glands, PSA distribution, bicalutamide and PIN, and finally the clinical characteristics of bladder cancer in patients previously treated with irradiation for prostate cancer. There are also several manuscripts on renal, testis and penile cancer. A wide variety of topics, from authors of many nationalities, maintaining the unique internationalism of the BJU International. Nomograms for prostate cancer ANDREW J. STEPHENSON and MICHAEL W. KATTAN* Section of Urologic Oncology, Glickman Urological Institute, Lerner College of Medicine and *Department of Quantitative Health Sciences, The Cleveland Clinic, Cleveland, OH, USA Accepted for publication 24 January 2006 KEYWORDS predictive modelling, prostate cancer, therapy, survival INTRODUCTION Radical prostatectomy (RP), external-beam radiotherapy (EBRT), and transperineal brachytherapy (TrB) are the potential treatment options for patients with clinically localized prostate cancer. The reported overall long-term success rates associated with these treatments are >65% in appropriately selected patients [1 3]. Presently there are no randomized trials showing that one treatment is better than another, although it is apparent that the success of each of these therapies might vary depending on the characteristics on an individual s cancer. For example, brachytherapy as monotherapy is generally not offered to patients with high-risk features. The treatment with the highest probability of oncological success might not represent the best intervention for an individual patient. Long-term cancer control is not the only goal a patient wishes to pursue when choosing among treatment alternatives. He is also interested in minimizing the impact of therapy on his quality of life. He might be unwilling to accept the treatment option with the highest likelihood of cure if it is also associated with unacceptable morbidity. All the treatment options for prostate cancer affect quality of life to varying degrees. For example, RP is associated with a higher incidence of urinary incontinence, while EBRT and TrB are associated with higher rates of bowel dysfunction and irritative bladder symptoms. Each of these therapies also affects sexual function to varying degrees. In the absence of evidence showing that one treatment is better than another in terms of oncological efficacy and treatment-related morbidity, the patient is best suited to decide which treatment, if any, is best for him, by weighing the consequences, both good and bad, for each treatment option under consideration. The relative impact of treatment-related morbidity on quality of life might be highly individualized. Only the patient can gauge how much they are willing to compromise, e.g. urinary continence, for long-term cancer control. As such, the physician is poorly positioned to make treatment decisions for these patients. At the heart of decision-making is patient preference, which the physician is also unable to quantify. Some patients might have an aversion to radical surgery while others will be satisfied only if the prostate cancer has been surgically removed. If patients are not involved in choosing among treatment options for their prostate cancer, they are more likely to regret the treatment choice in the future, especially if they have a bad outcome. Accurate estimates of the likelihood of treatment success, complications and longterm morbidity are essential for patient counselling and informed decision-making. Properly informing the patient of the likelihood of treatment success and morbidity JOURNAL COMPILATION 2006 BJU INTERNATIONAL 98, doi: /j x x 39

2 STEPHENSON and KATTAN will improve his satisfaction after treatment. This rationale is based on the work on regret, where not consulting several specialists is a risk factor [4]. If given an overly optimistic likelihood of success (both oncological and functional), a patient is more likely to be surprised and experience more regret when his treatment fails than is one who is informed by an accurate estimate of treatment success. Likewise, a patient who is given an overly pessimistic prediction of treatment success will regret the decision not to pursue definitive therapy if he learns later that he might have had a reasonable chance for a successful outcome. Accurate estimates of risk are essential for physicians if they are to recommend against treatment for a patient with indolent or incurable disease, or for the rational application of adjuvant treatment strategies for patients at risk of disease progression after definitive local therapy. Accurate risk estimates are also required for clinical trial design, to ensure homogeneous high-risk patient groups for whom new cancer therapeutics will be investigated. RISK ESTIMATION IN MEDICINE Traditionally, clinical judgement has formed the basis for risk estimation, patient counselling and decision making. However, humans have difficulty with predicting outcomes due to the biases that exist at all stages of the prediction process [5,6]. Clinicians do not recall all cases equally; certain cases can stand out and exert an unsuitably large influence when predicting future outcomes. They tend to be inconsistent when processing their mental database and tend to resort to heuristics ( rules of thumb ) when processing becomes difficult [7]. When it is time to make a prediction, they tend to predict the preferred outcome rather than the outcome with the highest probability [5]. Finally, clinicians find it difficult to learn from mistakes during the feedback process. Numerous prognostic variables for prostate cancer progression have been identified, including serum PSA level, clinical stage, biopsy Gleason sum, pathological stage, RP specimen Gleason sum, surgical margin status and tumour volume. Likewise, the recovery of potency after RP is influenced by preoperative erectile function, patient age, comorbid medical conditions, cavernosal nerve preservation, and individual surgeon s technique [8]. Clinicians have difficulty weighing the relative importance of each of FIG. 1. Preoperative nomogram based on 983 patients treated at the Methodist Hospital (Houston, TX, USA) for predicting the 5-year probability of freedom from PSA recurrence after definitive therapy with RP. Reprinted with permission from Kattan et al. [13]. these factors when formulating predictions of outcome. To obtain more accurate predictions, researchers have developed predictive tools based on statistical models [9]. In general, these predictive models have been shown to perform as well as or better than clinical judgement when predicting probabilities of outcome [10]. Statistical models predicting the likelihood of long-term cancer control, urinary continence and potency will be useful for the individual patient when deciding upon RP as the treatment for his prostate cancer. RISK GROUPS VS NOMOGRAMS A popular approach to developing predictive models is to group patients with similar characteristics and to make a prediction for each group. For example, D Amico et al. [11] developed a model that predicts cancer control for patients treated with RP, EBRT or TrB by placing patients into mutually exclusive risk groups based on clinical stage, biopsy Gleason sum, and pretreatment PSA level. While risk grouping is a logical approach, grouping patients is an inefficient use of the data and tends to reduce the predictive accuracy of a prognostic model. When predicting the outcome for a subset of patients, the relative importance of prognostic variables in another patient group is ignored. The method of counting risk factors/variables should also be avoided because this assumes that each variable exerts an equal prognostic weight on the outcome, which is unlikely to represent the true relationship between variables and prognosis [12]. In addition, risk-grouping requires converting continuous variables into categorical variables, which removes information about the actual value. An alternative method to risk groups is to develop continuous multivariable models called nomograms. A nomogram is a graphic representation of a mathematical formula or algorithm that incorporates several predictors modelled as continuous variables to predict a particular endpoint. Nomograms consist of sets of axes; each variable is represented by a scale, with each value of that variable corresponding to a specific number of points according to its prognostic significance. For example, the nomogram shown in Fig. 1 [13] assigns to each PSA level a unique point value that represents its prognostic significance. In a final pair of axes, the total point value from all the variables is converted to the probability of reaching the endpoint. By using scales, nomograms calculate the continuous probability of a particular outcome. By incorporating all relevant continuous predictive factors for individual patients, nomograms provide more accurate predictions than models based on riskgrouping, and they generally surpass clinical experts at predicting outcomes by calculating probabilities in a uniform fashion [5,10,14,15]. Several studies have documented the superior performance of nomograms compared to risk-grouping tools [15 17]. This might stem from the fact that risk groups consist of patients with similar (albeit not identical) characteristics, resulting in heterogeneity within a risk group that reduces the predictive 40 JOURNAL COMPILATION 2006 BJU INTERNATIONAL

3 NOMOGRAMS FOR PROSTATE CANCER FIG. 2. Preoperative nomogram predicting the 5-year PFP after RP Kattan et al. [13] for patients classified as low-, intermediateor high-risk by D Amico et al. [11]. Reprinted with permission from Mitchell et al. [20]. Nomogram value accuracy [18,19]. The heterogeneity inherent in risk groups is illustrated in Fig. 2 [11,13,20], where the 5-year progression-free probability (PFP) after RP was calculated using a continuous, multivariable preoperative nomogram among patients classified as low-, medium- and high-risk, using the criteria of D Amico et al. [11]. While low-risk patients uniformly had a high likelihood of being free of progression by the nomogram, a substantial proportion of intermediate- and even high-risk patients had a calculated 5- year PFP of 90%. A considerable overlap in the nomogram predictions is also evident among intermediate- and high-risk patients. A risk group is composed of a mixture of patients and is only useful for gauging the prognosis for that group of patients. A patient does not care about the outcome of his (heterogeneous) group; he cares about his prognosis; his physician should do the same. In contrast to risk groups, a nomogram makes a tailored predicted probability based on the characteristics of each patient. While nomograms are more complex than risk groups, this added complexity results in a better predictive accuracy for the both patient and physician. Nomograms have been adapted for use on personal digital assistants and personal computers to facilitate their use in the clinic or for research purposes. These nomograms are available in the public domain for free downloading ( The better predictive accuracy of continuous, multivariable nomograms vs risk groups is illustrated by comparing the ability of the Partin tables to predict the pathological Kattan Nomogram Values by Clinical Risk Group Low Intermediate risk group High features of prostate cancer with a suite of nomograms that we have recently developed. The Partin tables combined serum PSA level (four categories), clinical stage (seven categories) and biopsy Gleason sum (five categories) to predict the pathological stage of prostate cancer that is assigned as one of four mutually exclusive groups, i.e. organconfined, established extracapsular extension (ECE), seminal vesicle invasion (SVI), or lymph node involvement (LNI) [21]. These tables underestimate the probability of, e.g. ECE, as a substantial proportion of patients with lymph node metastases and SVI will also have ECE. Among patients with prostate cancer in our institutional database, the predictive accuracy of the Partin tables for predicting organconfined disease, SVI and LNI was 0.71, 0.72 and 0.74, respectively [21,22] (Bianco FJ Jr et al. unpublished data). By contrast, nomograms incorporating PSA level, clinical stage and Gleason sum modelled as continuous variables had a concordance index for predicting organ-confined disease, SVI and LNI of 0.74, 0.84 and 0.76, respectively [21,22] (Bianco FJ Jr et al. unpublished data). EVALUATING THE PERFORMANCE OF PREDICTIVE MODELS Several considerations apply when designing predictive models. A model should accurately predict which patients will and will not reach the endpoint (discrimination), generate predictions that closely approximate actual outcomes (calibration), and perform consistently when applied to different data sets (validation). They should also be based on sufficiently many cases; specifically, they must incorporate a large enough proportion of cases that reach the endpoint of interest. Predictive models should incorporate an appropriate number of variables, including variables that are statistically insignificant. If the model uses only statistically significant variables, they tend to exert an inappropriately large influence, resulting in falsely narrowed CIs that make the nomogram appear more accurate than it is [24,25]. Ideally, a predictive model should be generalizable, i.e. it should repeatedly perform with similar accuracy when applied to heterogeneous novel populations. Prognostic models lose their general applicability when they use small datasets, use datasets with a large proportion of missing information, incorrectly impute or delete missing records, or incorporate an inappropriate number of variables [26]. Further, for greatest utility in the clinical setting, nomograms should incorporate variables that are reliable and used routinely, and they should be easy to use. The nomograms developed by Kattan et al. are based on Cox proportional hazards or logistic regression analysis modified by restricted cubic splines [26]. Unmodified regression models require variables to assume linear relationships, which is not ideal because it assumes that incremental changes represent the same significance across the spectrum of values. For example, a rise in PSA level from 2 ng/ml to 4 ng/ml would represent the same impact as a rise from 302 ng/ml to 304 ng/ ml. The application of cubic splines imparts flexibility to the nomogram by allowing continuous variables to maintain nonlinear relationships. Machine-learning modelling methods such as artificial neural networks offer greater flexibility than traditional statistical methods, and theoretically might lead to enhanced predictive accuracy if datasets contain highly predictive nonlinear or interactive effects. However, traditional statistical methods appear to perform as well as machine-learning methods, and offer the added advantage of reproducibility and interpretability through the generation of hazard ratios and tests of significance for the predictors [27]. These nomograms use data in their most elemental forms to extract the maximum amount of useful information. For example, the primary and secondary Gleason grades are used as independent variables, rather than the Gleason score alone, as several combinations of primary/secondary Gleason grades can result in the same Gleason sum (e.g = 6, = 6, = 6), but these combinations JOURNAL COMPILATION 2006 BJU INTERNATIONAL 41

4 STEPHENSON and KATTAN might reflect quite different disease states with different prognoses [28]. An important approach incorporated into these nomograms is that patients receiving secondary treatment before showing disease progression are classified as treatment failures. This approach is used because the secondary treatment was probably prompted by some evidence of recurrence, so the time of secondary treatment is assumed to be shortly before the recurrence would have been detected [25]. Censoring (or excluding) these patients would bias the nomogram towards improved outcomes, but by designating adjuvant therapy equivalent to disease progression, the efficacy of primary therapy is better evaluated. The discrimination of these nomograms is measured using the concordance index (or c-index), rather than the receiver operator characteristic curve area. While the area under the curve requires binary outcomes (e.g. cure/fail), the c-index functions in the presence of case censoring and is more appropriate for analysing time-to-event data [29]. The concordance index is the probability that, given two randomly drawn patients, the patient who relapses first had a higher probability of disease recurrence. Note that this calculation assumes that the patient with the shorter follow-up relapses. If both patients relapse at the same time or the patients not relapsing has a shorter follow-up, the probability does not apply to that pair of patients. With this measure, a c-index of 0.5 represents no discriminating ability and a value of 1.0 represents perfect discrimination. Lastly, these nomograms are calibrated and validated to evaluate their accuracy. While external validation represents the reference standard for evaluating accuracy and reproducibility, bootstrapping [30] remains a legitimate alternative that can be used alone or in concert with external validation to assess the precision of the nomogram [26]. NOMOGRAMS FOR PROSTATE CANCER RECURRENCE Many nomograms exist for prostate cancer recurrence after definitive local therapy [9]. There is also a critical need for nomograms that estimate the likelihood of treatmentrelated morbidity (e.g. urinary incontinence and erectile dysfunction). However, the present discussion will be restricted to four contemporary models that predict the continuous risk of disease progression after local definitive therapy with RP [13,31], EBRT [17], or TrB [32]. Each of the pretreatment models predicts the 5-year probability of remaining free from disease progression (i.e. the PFP), based on PSA relapse after definitive therapy. The pretreatment nomograms are useful when deciding upon the definitive treatment options for clinically localized prostate cancer. The postoperative model predicts the 7-year PFP after RP; the postoperative nomogram is useful for deciding upon the need for adjuvant local or systemic therapy after RP. RP Both before- and after-treatment nomograms have been developed to predict the continuous probability of disease progression after RP [13,31]. Before RP: Clinical stage, biopsy Gleason score and pretreatment serum PSA level are known variables associated with disease progression after RP [1,33]. These factors have been combined by Partin et al. [21] to predict the pathological stage of the RP specimen. Although this endpoint is useful for surgical planning, it often does not correlate with the risk of disease progression [34]. Indeed, Hull et al. [1] found that half the patients with extraprostatic disease were free from disease recurrence at 10 years after RP, confirming that the presence of extraprostatic disease does not imply definite disease progression. Kattan et al. [13] developed a pretreatment nomogram that predicts the 5-year PFP for patients who choose RP based on clinical stage, biopsy-derived primary and secondary Gleason grades, and pretreatment PSA level. The model was based on 983 patients with clinically localized prostate cancer treated by one surgeon. Disease progression was defined as an initial PSA increase to 0.4 ng/ml followed by any further rise above this level, evidence of clinical recurrence (local, regional, or distant), administration of adjuvant therapy, or death from prostate cancer. In addition, patients with lymph node metastasis in whom RP was aborted were classified as treatment failures at the time of surgery. The overall 5-year PFP for this cohort was 73%. The nomogram is accurate and discriminating with a c-index of 0.75 when applied to an external validation cohort [35]. It was also validated in the African-American population, with a c-index of 0.74 [36]. The 5-year endpoint is insufficient to predict the likelihood of cure after RP, as substantially many patients are at risk of disease progression beyond 5 years. However, after 10 years recurrence is rare. Among patients treated with RP in our series, there was disease progression in three of 284 patients who had an undetectable PSA level at 10 years after RP [37]. Thus, the 10-year PFP would appear to be a sufficient endpoint for estimating the likelihood that a man will be cured of his prostate cancer by RP alone. Several investigators showed that the results of systematic prostate biopsy provide important preoperative prognostic information for prostate cancer recurrence after RP [38]. Including systematic biopsy results in the D Amico risk groups improved the ability of this model to predict biochemical recurrence after RP [38]. We recently developed a new preoperative nomogram incorporating clinical stage, biopsy Gleason grade, PSA level, number of positive and negative prostate biopsy cores to predict the 10-year probability of cancer recurrence after RP. However, including the number of positive and negative cores resulted in only a mild improvement in predictive accuracy over stage, grade and PSA level in an independent validation (c-index 0.79 vs 0.77) [39]. After RP: Kattan et al. [31] also developed a nomogram to identify patients at high risk of having disease progression after RP (Fig. 3). This instrument uses the pretreatment PSA level, Gleason sum of the RP specimen, ECE, margin status, SVI and LNI predict the 7-year probability of disease progression. The model was based on 996 men with clinically localized prostate cancer treated by one surgeon. Treatment failure was defined as an initial PSA increase to 0.4 ng/ml, followed by any further rise above this level, clinical evidence of disease progression (local or distant), initiation of adjuvant therapy, or death from prostate cancer. The 7-year PFP for the cohort was 73%. The nomogram had a c-index of 0.80 when applied to an international validation cohort, and 0.83 when applied to a cohort of African- Americans [36,40]. The postoperative nomogram was recently updated and enhanced to calculate the JOURNAL COMPILATION 2006 BJU INTERNATIONAL

5 NOMOGRAMS FOR PROSTATE CANCER FIG. 3. Postoperative nomogram based on 996 patients treated at the Methodist Hospital (Houston, TX, USA) for predicting freedom from PSA recurrence after RP. For prostatic capsular invasion (Pros. Cap. Inv.) None refers to L0-L1, Inv Capsule refers to L2, Focal refers to L3F, and Established refers to L3E. Preop., preoperative; Ves., vesicle; Prob., probability. Reprinted with permission from Kattan et al. [31]. treatment with three-dimensional conformal EBRT, based on clinical stage, biopsy Gleason sum, pretreatment PSA level, use of neoadjuvant androgen deprivation therapy, and radiation dose (Fig. 4). The model was based on 1042 men treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) between 1988 and PSA failure was based on the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria, with failure defined as three cumulative increases in serum PSA level, with the failure date designated as the midpoint in time between the first rise and the PSA level immediately before this rise [41]. Bootstrap analysis yielded a c-index of 0.73 and external validation with a cohort of 912 men treated at the Cleveland Clinic yielded a c-index of 0.76, that was significantly better than the best risk grouping model available [17]. TrB FIG. 4. Three-dimensional conformal radiation therapy (3D-CRT) nomogram, based on 1042 patients treated at MSKCC, for predicting freedom from PSA recurrence after radiation therapy. Reprinted with permission from Kattan et al. [13]. Kattan et al. [32] developed a pretreatment nomogram that predicts the 5-year PFP after TrB with 125 I-seeds in the absence of adjuvant hormonal therapy, based on pretreatment PSA level, clinical stage, biopsy Gleason sum, and the co-administration of EBRT (Fig. 5). The model was based on 920 men treated for T1 2 prostate cancer at MSKCC, with treatment failure defined by a modified version of the ASTRO criteria, the administration of adjuvant hormonal deprivation therapy, clinical evidence of disease progression (local, regional, or distant), or death from prostate cancer. External validation with 1827 men treated at the Seattle Prostate Institute gave a c-index of 0.61, and further validation with 765 men treated at the Arizona Oncology Services yielded a c-index of year probability of prostate cancer recurrence after RP [37]. Given that a patient s prognosis improves with the disease-free interval maintained after RP, we also enabled the 10-year PFP to be adjusted to reflect this changing prognosis. When applied to two independent validation datasets, the nomogram was accurate and discriminating (c-index 0.81 and 0.79). EBRT Kattan et al. [17] developed a pretreatment nomogram to predict the 5-year PFP after LIMITATIONS OF NOMOGRAMS While clinically useful for counselling patients, nomograms are far from perfect and cannot be applied to all men with prostate cancer. In general, nomograms are constructed and validated using patients treated at academic centres, whose outcomes might differ considerably from those of patients treated at community health centres, as the quality and availability of treatments can vary with the location and level of experience of the treating physician [42,43]. Recently, the preoperative nomogram was validated on a cohort of patients treated at both academic and community centres, and JOURNAL COMPILATION 2006 BJU INTERNATIONAL 43

6 STEPHENSON and KATTAN overestimated the likelihood of cure amongst these patients (particularly for those with probabilities of recurrence of <35%) [44]. All nomograms were developed in populations of patients treated with RP, EBRT or TrB, and thus they are only applicable for patients who otherwise would be candidates for each of these treatments. As a patient and his physician might exert a selection bias for a particular treatment, it would be most appropriate to apply the nomogram as a last step in the decision-making process after the patient has chosen a particular treatment. FIG. 5. Nomogram for predicting 5-year freedom from PSA recurrence after permanent TrB with no neoadjuvant androgen ablative therapy. Reprinted with permission from Kattan et al. [32]. These nomograms use serum PSA relapse as a measure of disease progression. Although PSA universally antedates metastatic progression and cancer-specific mortality, it has not been validated as a surrogate endpoint for diseasespecific mortality [45,46]. At 15 years after biochemical recurrence, patients are as likely to die from prostate cancer as they are from competing causes [47]. As a sensitive marker of disease recurrence, PSA recurrence is a valuable endpoint for counselling patients about the likelihood of treatment success. However, the probability of developing clinical recurrence and death from prostate cancer are more meaningful endpoints to predict. A nomogram was recently developed that predicts the 5-year probability of distant metastases (with or without the use of salvage androgen-deprivation therapy) among patients treated with EBRT [18]. We are currently working to develop nomograms to predict the probability of metastatic progression after RP. The outcome predictions determined by the nomograms for RP, EBRT and TrB should not be used alone to compare treatments. In particular, clinicians and patients should not simply select the treatment with the highest nomogram-based prediction of freedom from recurrence. Although the nomograms all use PSA recurrence as the primary endpoint, the definitions of PSA recurrence are different for each of the nomograms; radiation therapy nomograms use the ASTRO definition, while RP nomograms use a PSA level of 0.4 ng/ml followed by another higher value. Gretzer et al. [48] applied the ASTRO criteria of recurrence to a series of surgically treated patients and produced an apparent improvement in the 15-year PFP from 68% (based on a single PSA increase of 0.2 ng/ ml) to 90%. Even if a similar definition of recurrence is used for patients treated by RP, EBRT and TrB, the PSA outcome might be biased in favour of radiation therapy. The reason for this bias is that, before a patient who is managed with radiotherapy or brachytherapy can be considered a PSA failure, he must first achieve a PSA nadir, which can take several years [49]. Conversely, patients who are managed with RP will reach their PSA nadir within the first few weeks after RP. Consequently, among patients who are destined to fail biochemically, the time to failure will be earlier for surgically treated patients [50]. It is also apparent that biochemical progression after RP and EBRT are not equivalent endpoints to compare. In the absence of salvage androgen-deprivation therapy, the reported median interval from biochemical recurrence to metastatic progression has been estimated to be 8 years after RP, compared to only 3 years after EBRT [46,51]. Thus, it would appear that patients who have a biochemical recurrence after EBRT are at considerably greater risk of early metastatic progression than those who recur after RP. SUMMARY Continuous, multivariable models such as nomograms currently represent the most accurate and discriminating tools for predicting the outcome of patients who undergo definitive therapy for localized prostate cancer. When faced with the difficult decision of choosing among the treatment options for prostate cancer, the nomograms for prostate cancer recurrence after RP, EBRT and TrB provide patients with accurate estimates of treatment success with each of these therapies. Equipped with this information, the patient is more likely to be confident in his treatment decision and less likely to experience regret in the future. However, it should be emphasized that nomogram predictions must be interpreted as such; they do not make treatment recommendations or act as a surrogate for physician patient interactions, nor do they provide definitive information on symptomatic disease progression or complications associated with treatments. Thus, the current nomogram prediction should serve as the initial basis upon which to further explore these issues when selecting a treatment for prostate cancer. Future nomograms that predict the likelihood of metastatic progression, cancer-specific mortality, and long-term urinary and sexual function are likely to have great utility for the patient and physician when exploring treatment alternatives. CONFLICT OF INTEREST M. W. Kattan is the founder of Oncovance Technologies. 44 JOURNAL COMPILATION 2006 BJU INTERNATIONAL

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