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Can we offer additional BCG therapy for three-month BCG refractory high grade/T1, Tis bladder cancer patients? Can we offer additional BCG therapy for three-month BCG refractory high grade/T1, Tis bladder...
Elsawy, Amr A.; Laymon, Mahmoud; Mansour, Islam; Elghareeb, Ahmed; Harraz, Ahmed
2023-03-22 00:00:00
ARAB JOURNAL OF UROLOGY https://doi.org/10.1080/2090598X.2023.2190687 Can we offer additional BCG therapy for three-month BCG refractory high grade/T1, Tis bladder cancer patients? Amr A. Elsawy, Mahmoud Laymon, Islam Mansour, Ahmed Elghareeb and Ahmed Harraz Urology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt ABSTRACT ARTICLE HISTORY Received 20 January 2023 Background: We lack tools to predict treatment and survival outcomes in patients receiving Accepted 8 March 2023 additional BCG therapy as a bladder-preserving therapy in high grade/T1, Tis NMIBC patients who showed persistent/recurrent tumors at three-month follow-up. KEYWORDS Objectives: To assess the predictors of additional BCG response in patients who experienced Bladder cancer; BCG persistent/recurrent tumors at three-month follow-up after BCG induction. refractory; three-month Patients and methods: We retrospectively analyzed database for NMIBC. Between 2000 and cystoscopy; recurrence; 2019, 231 patients with high-grade T1/Tis NMIBC showed persistent/recurrent tumors at progression 3-month after BCG-induction, refused or were unfit to radical cystectomy (RC) and were offered additional intravesical BCG as bladder-preserving treatment. Predictors of the outcome after additional BCG were studied using univariate and multivariate logistic regression analysis. Kaplan Meier curve was utilized to estimate the recurrence-free survival (RFS) and progression- free survival (PFS). COX regression analysis was performed to identify independent predictors or RFS and PFS. Results: During a median (range) of 148 (24–224) months, poor response to additional BCG (tumor recurrence and/or progression) was noted in 112 (48.5%) patients. On multivariate logistic regression analysis, 3-month tumor features (persistent T stage, persistent grade and persistent/new CIS) significantly predicted poor response to additional BCG (OR: 3.4, 95%CI: 1.3–10.8, p = 0.021, OR: 2.1, 95%CI: 1.1–4.1, p = 0.02 and OR: 16.6, 95%CI: 4.5–109, p=<0.001, respectively). The mean RFS was 26 (9–152) months with identified 3-month tumor features (persistent T stage and persistent/new CIS) as independent predictors of RFS (HR = 11.5, 95%CI = 2.7–48.3, p = 0.001 and HR = 2.5, 95%CI = 1.5–4.1, p=<0.001, respectively) on multivariate COX regression analysis. In addition, 3-month tumor features (persistent/new CIS, non- papillary shape and bladder neck involvement) were identified to significantly predict PFS (HR = 6.2, 95%CI = 3.4–11.5, p=<0.001 and HR = 2.3, 95%CI = 1.3–4.3 p = 0.001 and HR = 2.1, 95%CI = 1.2–3.8, p=<0.005, respectively). Conclusions: Three-month tumor features could be utilized as a tool to predict treatment outcomes and survival benefits when additional intravesical BCG is utilized as a bladder- preserving treatment in patients with recurrent/persistent tumors at three-month follow-up. Introduction within 24 months after the initial diagnosis [4]. After complete transurethral resection of bladder Thus, patients’ survival could be augmented by tumor (TURBT), intravesical immunotherapy with early identification of those at high probability of bacillus Calmette-Guérin (BCG) is the most effective BCG failure and direct them to optimal manage- adjuvant treatment in high-risk non-muscle invasive ment; early RC [5]. Even, recurrent non-progressive bladder cancer (NMIBC) [1]. The response to BCG disease exhausts health care systems with financial therapy is widely variable with recurrence and pro- burdens on health care systems and is associated gression rates reported in 32% to 43% and 9.5% to with patients’ morbidity with multiple procedures. 14%, respectively [2]. Noteworthy, half of the patients Despite superior survival benefits of RC in BCG- who received adjuvant BCG therapy will eventually unresponsive patients, patients’ reluctance or unfit - fail to achieve a sustained tumor-free status during ness for surgery constrains the clinicians for more long-term follow-up [3]. exhaustion in bladder-preserving modalities as addi- Currently, early radical cystectomy (RC) is tional intravesical BCG, intravesical/systemic che- offered as the standard of care in patients with motherapy (Valrubicin, Gemcitabine or Docetaxel), BCG failure, several studies have demonstrated sig- intravesical photodynamic therapy (PDT) or intravesi- nificant survival benefits when RC is performed cal immunotherapy with interferon-alpha [6]. CONTACT Amr A. Elsawy amrelsawy.unc@hotmail.com Lecturer of Urology, Urology Department, Urology and Nephrology Center, Mansoura 35516, Egypt © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 A. A. ELSAWY ET AL. Unavailability and lack of evidence for most of these managed by endoscopic assessment with examination therapies make the practitioners obliged to utilize under anesthesia. Complete resection was achieved for additional intravesical BCG (second induction or pro- all visible tumors. Immediate intravesical instillation of ceed to maintenance) for patients who recur after doxuribicin was routinely applied in all cases (unless initial response or those with persistent disease after contraindicated) within 24 hours after resection. High- first induction [7]. Prediction of response to this addi- risk NMIBC patients (T1, G3/high grade or CIS) underwent tional regimen of BCG is considered an important step re-staging biopsy 4–6 weeks from the primary procedure whether in patients’ counseling or in the era of BCG after 2006 (and on case-by-case basis before 2006). shortage at which BCG should be prioritize for those Patients usually started BCG induction 2–4 weeks with expected good response. after TURBT. Thereafter, all patients were evaluated Many previous studies have investigated the differ - by check cystoscopy 6 weeks after the last induction ent predictors of initial BCG response (Clinical/ BCG dose. Patients with persistent/recurrent tumor (as Pathological/Immune/Molecular) [8]. However, clinical- confirmed by inpatient TURBT) were offered different pathological predictors are still the simplest and most treatment options including RC (preferably) or bladder reliable tool in clinical practice to predict BCG response preserving therapy using additional intravesical BCG when compared to the novel exciting biomarkers (second induction followed by maintenance regimen which still lack adequate validation [8]. according to the Southwest Oncology Group regi- Noted tumor at 3-month check cystoscopy after men [13]). BCG induction was shown to be a poor prognostic indicator for BCG response in high-risk NMIBC [9,10]. Patients with 3-month recurrence/persistent Grade 3 T1 recurrence at 3-month cystoscopy was tumors who received additional intravesical BCG; previously evaluated as significant predictors of poor Follow-up BCG response [11,12]. However, the impact of other clinical-pathological features of 3-month recurrence is Patients who showed 3-month recurrence/tumor per- not previously studied. sistence and received additional intravesical BCG In this study, we aimed to study the predictors of (either due to refusing or unfitness to RC) were fol- additional BCG response in high grade/T1, Tis NMIBC lowed-up every three months by cystoscopy and cytol- who experienced primary BCG refractory response ogy with upper tract contrast imaging as clinically (recurrent/persistent tumor at 3-months) and were indicated. offered additional BCG therapy as a bladder- preserving treatment. Study endpoints In our study, further disease recurrence was defined as Patients and methods cystoscopic and pathological evidence of the disease, while, disease progression was defined as develop- Study population and eligibility criteria ment of muscle invasive/nodal disease or distant After approval of Institutional Review Board for this metastasis. The primary endpoint included poor study, database for NMIBC at our institute was response to additional BCG which was defined as BCG- reviewed for patients who underwent TURBT for high- refractory and early BCG-relapsing tumor, i.e. within 6 risk NMIBC and completed 6 weekly doses of BCG months for high-grade papillary tumor and within 12 induction from the period 2000 to 2019 and had months for CIS [14]. experienced tumor recurrence at 3-month check cystoscopy. Statistical analysis We excluded patients with unavailable initial pathology for review and those who did not complete For categorical variables, Chi-square and Fisher’s exact at least two years of follow-up from the 3-month cysto- tests were used for comparison whenever appropriate. scopy. All pathology findings were re-checked by Differences in continuous variables were evaluated expert uro-pathologists to confirm tumor characteris- using the Mann-Whitney U-tests. Kaplan-Meier curve tics (stage according to TNM system and grade accord- with the log-rank test was used to compare recurrence ing to the1973 and 2004 World Health Organization and progression-free survivals (RFS and PFS) between grading classification system). both groups. Univariate and multivariate Cox regres- sion analyses were processed to assess the impact of clinical and pathological data on RFS and PFS. Primary TURBT procedures and post-procedural Statistical analysis was performed using strategy R programming language version 3.6.3 using the During the aforementioned study period, all patients appropriate packages. P-value less 0.05 was consid- presenting for evaluation as bladder cancer were ered statistically significant. ARAB JOURNAL OF UROLOGY 3 T stage, persistent grade, persistent/new CIS and tumors Results with bladder neck involvement-BNI-) were shown to pre- Entire cohort dict the outcome of additional BCG. Only three factors persistent T stage, persistent grade and persistent/new During the study period, 1300 patients were eligible CIS maintained their independent relationship on multi- for evaluation of their 3-month cystoscopy result after variate analysis (OR: 3.4, 95%CI: 1.3–10.8, p = 0.021, OR: BCG induction. Of them, 566 (43.5%) patients showed 2.1, 95%CI: 1.1–4.1, p = 0.02 and OR: 16.6, 95%CI: 4.5–109, recurrence ± progression as illustrated in study flow p=<0.001, respectively) (Table 2). chart (Figure 1). Bladder preservation therapy using additional BCG instillation was decided in 252 patients, those who completed at least 24 months follow-up Predictors of recurrence-free survival (RFS) (231patients) were included in the final analysis. The baseline clinical and pathological criteria of During follow-up, tumor recurrence was observed in 112 patients receiving additional BCG therapy after identi- (48.5%) patients. On multivariate COX regression analysis, fied 3-month recurrence are shown in Table 1. Patients 3-month recurrence features (persistent T stage and persis- were followed-up accordingly for a median (range) of tent/new CIS) were identified to significantly predict RFS 148 (24–224) months. Poor response to additional BCG (HR = 11.5, 95%CI = 2.7–48.3, p = 0.001 and HR = 2.5, 95% was noted in 112 (48.5%) patients (Figure 1) . CI = 1.5–4.1, p=<0.001, respectively) (Table 3). The mean RFS was 26 (9–152) months. Survival curves are shown in Figure 2. Clinico-pathological features of patients receiving additional BCG The baseline clinical and pathological criteria of Predictors of progression-free survival (PFS) patients receiving additional BCG therapy are shown During follow-up, tumor progression was defined as devel- in Table 1. The change pattern of pathological features opment of muscle invasive disease. Tumor progression between the primary tumor and 3-month recurrence was observed in 46 (19.9%) patients. On multivariate was assessed and defined as (persistent or regressed/ Cox regression analysis, 3-month recurrence features (per- regressed or progressed) (Table 1). sistent/new CIS, non-papillary shape and bladder neck involvement) were identified to significantly predict PFS (HR = 6.2, 95%CI = 3.4–11.5, p=<0.001 and HR = 2.3, 95% Predictors of the outcomes after additional BCG CI = 1.3–4.3 p = 0.001 and HR = 2.1, 95%CI = 1.2–3.8, Poor response to additional BCG was identified in 112 p=<0.005, respectively) (Table 3). The mean RFS was 26 (48.5%) patients. Three-month tumor features (persistent (9–152) months. Survival curves are shown in Figure 3. Figure 1. Study flow chart. 4 A. A. ELSAWY ET AL. Table 1. Clinico-pathological characteristics of patients receiving additional BCG therapy after identified 3-month recurrence. Variable Value Age (year) 59.2 ± 10.4 Gender Male 200 (86.6%) Female 31 (13.4%) Denovo vs. recurrent NMIBC Denovo 133 (57.6%) Recurrent 98 (42.4%) Initial tumor/s features Three-month tumor features Change pattern of three-month recurrence Tumor number Single 83 (35.9%) Single 115 (49.8%) Regressed 64 (27.7%) Multiple 148 (64.1%) Multiple 116 (50.2%) Persistent 167 (72.3%) T stage Ta 0 (0%) Ta 37 (16%) Regressed 37 (16%) T1 209 (90.5%) T1 188 (81.4%) Persistent 194 (84%) Tis 22 (9.5%) Tis 6 (2.6%) Grade1973 G1 0 (0%) G1 26 (11.3%) Regressed 55 (23.8%) G2 154 (66.7%) G2 134 (58%) Persistent 176 (76.2%) G3 77 (33.3%) G3 71 (30.7%) Size <3 cm 109 (47.2%) <3 cm 157 (68%) Regressed 80 (34.6%) > 3 cm 122 (52.8%) > 3 cm 74 (32%) Progressed 151 (65.4%) CIS No 209 (90.5%) No 207 (89.6%) No/regressed 207 (89.6%) Yes 22 (9.5%) Yes 24 (10.4%) New/persistent 24 (10.4%) Shape Papillary 184 (79.7%) Non papillary* (flat, nodular, suspicious area) 47 (20.3%) Site Not including BN 165 (71.4%) Including BN 66 (28.6%) Table 2. Univariate and multivariate logistic regression analysis of predictors of additional BCG response. No Yes p-value Univariate Age 58.6 ± 11.2 59.9 ± 9.5 0.347 Gender 0.173 Male 99 (49.5%) 101 (50.5%) Female 20 (64.52%) 11 (35.48%) Denovo vs. recurrent NMIBC 0.793 Denovo 70 (52.63%) 63 (47.37%) Recurrent 49 (50%) 49 (50%) Three-month tumor change pattern compared to initial tumor CIS 0.003 No/regressed 114 (55.07%) 93 (44.93%) New/persistent 5 (20.83%) 19 (79.17%) Grade 0.002 Regressed 39 (70.91%) 16 (29.09%) Persistent 80 (45.45%) 96 (54.55%) No 0.307 Regressed1 29 (45.31%) 35 (54.69%) Persistent 90 (53.89%) 77 (46.11%) Size 0.527 Regressed 44 (55%) 36 (45%) Progressed 75 (49.67%) 76 (50.33%) T stage <0.001 Regressed3 35 (94.59%) 2 (5.41%) Persistent1 84 (43.3%) 110 (56.7%) Three-month tumor shape 0.375 Papillary 98 (53.26%) 86 (46.74%) Non papillary (flat, nodular, suspicious area) 21 (44.68%) 26 (55.32%) Three-month tumor site 0.013 Outside BN 94 (56.97%) 71 (43.03%) BN involvement 25 (37.88%) 41 (62.12%) MULTIVARIATE OR 95%CI CIS: New/persistent 16.6 (4.5–109.2) <0.001 Grade: Persistent 2.1 (1.1–4.1) 0.021 T stage ‘Persistent 3.4 (1.3–10.8) 0.021 Three-month tumor site;` BN involvement 1.3 (0.6–3) 0.498 ARAB JOURNAL OF UROLOGY 5 Table 3. Univariate and multivariate Cox regression analysis of recurrence and progression-free survivals. Recurrence-free survival Progression-free survival Univariate Hazards ratio 95%CI p-value Hazards ratio 95%CI p-value Age 1 (1–1) 0.529 1 (1–1) 0.525 Gender; female 0.6 (0.3–1.1) 0.107 0.6 (0.2–1.6) 0.266 Denovo vs. recurrent NMIBC; recurrent 1.1 (0.7–1.5) 0.742 1.3 (0.7–2.3) 0.424 Three-month recurrence change pattern compared to initial tumor CIS; New/persistent 3.4 (2.1–5.6) <0.001 8.5 (4.7–15.6) <0.001 Grade; Persistent 2.1 (1.3–3.6) 0.005 1.6 (0.7–3.4) 0.237 Number; Persistent 0.7 (0.5–1.1) 0.143 0.7 (0.4–1.4) 0.315 Size; Progressed 1.1 (0.7–1.6) 0.695 0.7 (0.4–1.3) 0.261 T stage; Persistent 15 (3.7–60.6) <0.001 0.9 (0.8–1.5) 0.345 Three-month tumor shape; non papillary (flat, nodular, suspicious area) 1.4 (0.9–2.2) 0.109 3.2 (1.8–5.8) <0.001 Three-month tumor site; BN involvement 1.6 (1.1–2.4) 0.014 2.2 (1.3–4) 0.006 MULTIVARIATE CIS; New/persistent 2.5 (1.5–4.1) <0.001 6.2 (3.4–11.5) <0.001 Grade; Persistent 1.1 (0.6–1.9) 0.712 T stage;` Persistent 11.5 (2.7–48.3) 0.001 Three-month tumor site; `BN involvement 1.4 (1–2.1) 0.061 2.1 (1.2–3.8) 0.005 Three-month tumor shape; non papillary (flat, nodular, suspicious area) 2.3 (1.3–4.3) 0.001 Figure 2. Kaplan-Meyer survival curves; Recurrence-free survival . Figure 3. Kaplan-Meyer survival curves; Progression-free survival . 6 A. A. ELSAWY ET AL. (RC vs. BCG) [24]. This discrepancy in the acceptance Discussion rate could be justified by the nature of our institute as Intravesical BCG has been established as a standard adju- a tertiary referral center for bladder cancer patients vant treatment after TURBT for high-risk NMIBC [15–17]. with initial diagnosis made at our hospital excluding Treatment response to intravesical BCG is primarily eval- the multiple distracting opinions for the patients. uated after completing the 6 weeks induction regimen In our study, we hypothesized that both clinico- by 3-month check cystoscopy and cytology [18]. In pathological features of three-month recurrence and approximately 50% of cases, BCG treatment eventually its pattern when compared to primary tumor charac- fails, and half of them experience recurrence in the first 6 teristics can be utilized as an indicator of disease sever- months after complete induction with/out one mainte- ity and provide a predictive instrument not only of nance course of BCG (BCG refractory) [3]. additional BCG-unresponsive, but also the survival fea- Treatment options for patients with identified early tures (RFS and PFS). recurrence (at 3-month cystoscopy) is still a matter of In the study cohort, new/persistent CIS at 3-month discussion around either early RC, additional BCG (re- cystoscopy recurrence was identified as an indepen- induction or proceed to maintenance), other intravesi- dent predictor of additional-BCG unresponsiveness. cal/systemic therapeutic agents, radiation therapy or Moreover, these pathological features adversely com- a clinical trial [19]. Many previous reports have shown promise the survival outcomes. Our finding copes with that early RC was the standard treatment in patients what have been previously reported by Tang and col- with T1 or high grade recurrent tumors at 3-month leagues who concluded that presence of CIS at 3–6 cystoscopy [20]. Nevertheless, in patients who refuse/ month after induction BCG can adversely affect the are unfit to RC due to co-morbidities, bladder- treatment and survival outcomes [25]. Additionally, preserving strategies should be counseled [20]. Herr et al. had demonstrated the compromised PFS in It is worthy to note that the only FDA-approved patient with CIS at 3-month recurrence when received therapeutic option for primary BCG failure are intrave- additional BCG [26]. sical pembrolizumab and valrubicin. However, this has As regard to T stage of 3-month recurrence, persis- conveyed minor modification in practice as valrubicin tence T stage was noted to inversely predict the addi- effectiveness has been argued by many professionals tional BCG response. Furthermore, persistent T stage as the registration trial was questionable and significantly compromised RFS. In the same way, Pembrolizumab remains a costly, difficult to access a previous study by Chinedu and colleagues, T stage with a role yet to be determined [21]. of 3-month recurrence (Ta versus T1), was shown to Despite its proven inferiority to RC in patients who influence treatment response after additional BCG experienced initial BCG-unresponsiveness, there is lack therapy for BCG refractory patients [12], 5-year disease in the literature about the precise survival benefits of progression was identified in only 5% of patients with additional BCG therapy in such patients. Moreover, the Ta recurrence. Similarly, Solsona et al. demonstrated current dilemma of BCG shortage has obliged the the impact of Ta stage in 3-month recurrence on dis- health care providers to prioritize the patients with ease progression when additional BCG was utilized favorable response of BCG. Therefore, prompt charac- (5-year disease progression; 10%) [11]. terization of patients with anticipated additional BCG- Moreover, persistent grade of 3-month recurrence unresponsiveness is warranted for optimal counseling was identified as another major predictor of response and saving of health care costs [22]. to additional BCG therapy. Low-grade tumor at With respect to BCG-failure, most of the definitions 3-month recurrence did not demonstrate noteworthy are either anecdotal or through a panel consensus with events when associated with Ta stage; in agreement lack of a data-driven evaluation. In the real practice, findings previously shown by Chinedu et al [12] and 3-month cystoscopy recurrence after completed BCG Herr et al [27]. On the other hand, persistent grade did induction course is usually defined by practitioners as not maintain its significance (observed in the univari- a surrogate marker of initial BCG-unresponsiveness ate analysis) in the multivariate analysis of RFS. and critical distinction to do in the patients’ manage- BNI at 3-month cystoscopy recurrence was identi- ment either by RC or different bladder-preserving fied in our cohort to significantly compromise the options [23]. PFS. This comes in hand with what has been pre- In our cohort, among patients who experienced viously concluded by Kobayashi and associates 3-month recurrent/persistent tumors, approximately about the prognostic impact of BNI on disease pro- half of them chose RC. The other group was managed gression in primary NMIBC [28]. Additionally, non- by additional BCG intravesical therapy (being the only papillary shape of 3-month recurrence indepen- adapted bladder-preserving option after initial BCG dently associated with disease progression. Non- unresponsiveness at our institute). Catto et al. had papillary morphology of NMIBC was previously reported an acceptance rate; 25% for RC in high-risk demonstrated by Park et al. as a predictor of cancer NMIBC when they were offered allocated treatment progression [29]. ARAB JOURNAL OF UROLOGY 7 Although the noted implications of 3-month recur- Abbreviations rence features (T stage, CIS, grade, shape and BNI) on BNI Bladder neck involvement treatment response and survival outcomes of additional BCG Bacillus Calmette-Guérin BCG therapy after primary BCG-unresponsiveness, we CIS Carcinoma in situ did not observe a significant impact of 3-month recur- NMIBC Non muscle invasive bladder cancer PFS Progression-free survival rence number. On the contrary, tumor number has RC Radical cystectomy been previously studied as predictor of BCG response. RFS Recurrence-free survival Steinberg et al have shown that patients with≥2 prior TURBT Transurethral resection of bladder tumor BCG courses revealed worse outcomes with multifocal tumor, while those with≤1 prior BCG course showed equivalent outcomes [23]. Given the influence of tumor Authors contribution number on treatment outcomes, it can be argued that Concept and design: Amr Elsawy, Ahmed Harraz some of these tumors may be overlooked from the Administrative support: Amr Elsawy, Mahmoud Laymon primary TURBT and not a true recurrence, as well as Data collection: Mahmoud Laymon, Islam Mansour, Ahmed the specific stage, grade and size of each tumor, Elghareeb remains incompletely evaluated. Statistical analysis: Amr Elsawy, Ahmed Harraz Manuscript writing: Amr Elsawy, Mahmoud Laymon, Ahmed In this study, we provide the clinicians with Harraz a useful predictive tool for treatment responsiveness and survival outcomes of additional BCG therapy after initial BCG-unresponsiveness. The findings of Clinical trials registration our analysis should be cautiously interpreted due to clinicaltrials.gov ID: NCT04319263 several limitations. Above all, there might be inher- ent bias resulting from its retrospective nature. Other potential prognostic factors that we did not include Descriptive key message in our data, such as preoperative urine cytology, repeat biopsy, and detrusor muscle inclusion, variant The current study aimed at investigating the predictors of additional intravesical BCG therapy as a bladder-preserving histology and lympho-vascular invasion (LVI) which treatment in high grade/T1, Tis NMIBC with three-month were suggested as significant predictor of BCG ther- persistent/recurrent tumors. apy in the different studies [24,25,26], could be further studied to augment their utilization in clinical practice. References Given that our study consisted of TURBT proce- [1] Cambier S, Sylvester RJ, Collette L, et al. EORTC dures done by multiple surgeons, the outcome Nomograms and risk groups for predicting recurrence, could be confounded by the surgeons’ experience progression, and disease-specific and overall survival with TURBT. 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