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Treatment Paradigms in Bladder Cancer: Clinical Implications of Histological and Molecular Analysis

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Precision Molecular Pathology of Bladder Cancer

Part of the book series: Molecular Pathology Library ((MPLB))

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Abstract

Despite significant recent advances in characterization of the molecular pathogenesis of bladder cancer, incorporation of these new discoveries into current standard clinical treatment paradigms remains limited. As a result, the treatment of bladder cancer continues to rely heavily on clinical and pathological classifiers of disease that dictate current therapeutic algorithms. Although risk stratification methods for both non-muscle invasive and muscle-invasive bladder cancer can potentially assist in categorizing patients into different treatment groups, there is an urgent need for rapid translation of recent advances in the molecular biology of bladder cancer into standard of care. We review the current clinical treatment paradigms in bladder cancer and discuss opportunities for integration of precision molecular therapy into existing algorithms.

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Abbreviations

BCG:

Bacillus Calmette Guerin

CIS:

Carcinoma in situ

CTLA 4:

Cytotoxic T-lymphocyte associated protein 4

EORTC:

European Organization for Research and Treatment of Cancer

FDG:

18F–fluorodeoxyglucose

FGFR:

Fibroblast growth factor receptor

IFN:

Interferon alpha

MIBC:

Muscle-invasive bladder cancer

MMR:

Mismatch repair

MVAC:

Methotrexate, vinblastine, adriamycin, and cisplatin

NAC:

Neoadjuvant chemotherapy

NBI:

Narrow band imaging

NMIBC:

Non-muscle invasive bladder cancer

PD-1:

Programmed cell death receptor 1

PD-L1:

Programmed cell death receptor ligand 1

SWOG:

Southwestern Oncology Group

TCGA:

The cancer genome atlas

TURBT:

Transurethral resection of bladder tumor

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur Urol. 2016;70:106–19.

    Article  PubMed  Google Scholar 

  3. McConkey DJ, Choi W, Ochoa A, Siefker-Radtke A, Czerniak B, Dinney CP. Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer. Hematol Oncol Clin North Am. 2015;29:377–94. x-xi

    Article  PubMed  Google Scholar 

  4. Svatek RS, Hollenbeck BK, Holmang S, Lee R, Kim SP, Stenzl A, et al. The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol. 2014;66:253–62.

    Article  PubMed  Google Scholar 

  5. Chamie K, Saigal CS, Lai J, Hanley JM, Setodji CM, Konety BR, et al. Compliance with guidelines for patients with bladder cancer: variation in the delivery of care. Cancer. 2011;117:5392–401.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  Google Scholar 

  7. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in Tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lee JK, Terdiman JP, Corley DA. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;371:186.

    CAS  PubMed  Google Scholar 

  9. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Carel RS, Silverberg DS, Kaminsky R, Aviram A. Routine urinalysis (dipstick) findings in mass screening of healthy adults. Clin Chem. 1987;33:2106–8.

    CAS  PubMed  Google Scholar 

  11. Edwards TJ, Dickinson AJ, Natale S, Gosling J, McGrath JS. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocol-driven haematuria clinic. BJU Int. 2006;97:301–5. discussion 5

    Article  PubMed  Google Scholar 

  12. Loo RK, Lieberman SF, Slezak JM, Landa HM, Mariani AJ, Nicolaisen G, et al. Stratifying risk of urinary tract malignant tumors in patients with asymptomatic microscopic hematuria. Mayo Clin Proc. 2013;88:129–38.

    Article  PubMed  Google Scholar 

  13. Jung H, Gleason JM, Loo RK, Patel HS, Slezak JM, Jacobsen SJ. Association of hematuria on microscopic urinalysis and risk of urinary tract cancer. J Urol. 2011;185:1698–703.

    Article  PubMed  Google Scholar 

  14. Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A. The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol. 1989;141:350–5.

    Article  CAS  PubMed  Google Scholar 

  15. Khadra MH, Pickard RS, Charlton M, Powell PH, Neal DE. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163:524–7.

    Article  CAS  PubMed  Google Scholar 

  16. Turney BW, Willatt JM, Nixon D, Crew JP, Cowan NC. Computed tomography urography for diagnosing bladder cancer. BJU Int. 2006;98:345–8.

    Article  PubMed  Google Scholar 

  17. Kundra V, Silverman PM. Imaging in oncology from the University of Texas M. D. Anderson cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am J Roentgenol. 2003;180:1045–54.

    Article  PubMed  Google Scholar 

  18. Barentsz JO, Jager GJ, Witjes JA, Ruijs JH. Primary staging of urinary bladder carcinoma: the role of MRI and a comparison with CT. Eur Radiol. 1996;6:129–33.

    Article  CAS  PubMed  Google Scholar 

  19. Dorfman RE, Alpern MB, Gross BH, Sandler MA. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology. 1991;180:319–22.

    Article  CAS  PubMed  Google Scholar 

  20. Watanabe H, Kanematsu M, Kondo H, Goshima S, Tsuge Y, Onozuka M, et al. Preoperative T staging of urinary bladder cancer: does diffusion-weighted MRI have supplementary value? AJR Am J Roentgenol. 2009;192:1361–6.

    Article  PubMed  Google Scholar 

  21. Picchio M, Treiber U, Beer AJ, Metz S, Bossner P, van Randenborgh H, et al. Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings. J Nucl Med. 2006;47:938–44.

    CAS  PubMed  Google Scholar 

  22. Ahlstrom H, Malmstrom PU, Letocha H, Andersson J, Langstrom B, Nilsson S. Positron emission tomography in the diagnosis and staging of urinary bladder cancer. Acta Radiol. 1996;37:180–5.

    Article  CAS  PubMed  Google Scholar 

  23. Burger M, Grossman HB, Droller M, Schmidbauer J, Hermann G, Dragoescu O, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64:846–54.

    Article  PubMed  Google Scholar 

  24. Lee JY, Cho KS, Kang DH, Jung HD, Kwon JK, CK O, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer. 2015;15:566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Herr HW. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol. 2000;163:60–1. discussion 1-2

    Article  CAS  PubMed  Google Scholar 

  26. Shariat SF, Zippe C, Ludecke G, Boman H, Sanchez-Carbayo M, Casella R, et al. Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with ta, T1 or CIS transitional cell carcinoma of the bladder. J Urol. 2005;173:1518–25.

    Article  CAS  PubMed  Google Scholar 

  27. Hong SJ, Cho KS, Han M, Rhew HY, Kim CS, Ryu SB, et al. Nomograms for prediction of disease recurrence in patients with primary ta, T1 transitional cell carcinoma of the bladder. J Korean Med Sci. 2008;23:428–33.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ali-El-Dein B, Sooriakumaran P, Trinh QD, Barakat TS, Nabeeh A, Ibrahiem el HI. Construction of predictive models for recurrence and progression in >1000 patients with non-muscle-invasive bladder cancer (NMIBC) from a single centre. BJU Int. 2013;111:E331–41.

    Article  PubMed  Google Scholar 

  29. Catto JW, Abbod MF, Linkens DA, Hamdy FC. Neuro-fuzzy modeling: an accurate and interpretable method for predicting bladder cancer progression. J Urol. 2006;175:474–9.

    Article  PubMed  Google Scholar 

  30. Kamat AM, Witjes JA, Brausi M, Soloway M, Lamm D, Persad R, et al. Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer. J Urol. 2014;192:305–15.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Burger M, Oosterlinck W, Konety B, Chang S, Gudjonsson S, Pruthi R, et al. ICUD-EAU international consultation on bladder cancer 2012: non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2013;63:36–44.

    Article  PubMed  Google Scholar 

  32. Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2016;71(3):447–61.

    Article  PubMed  Google Scholar 

  33. Hall MC, Chang SS, Dalbagni G, Pruthi RS, Seigne JD, Skinner EC, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages ta, T1, and tis): 2007 update. J Urol. 2007;178:2314–30.

    Article  PubMed  Google Scholar 

  34. Brausi M, Witjes JA, Lamm D, Persad R, Palou J, Colombel M, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the international bladder cancer group. J Urol. 2011;186:2158–67.

    Article  PubMed  Google Scholar 

  35. Abdollah F, Sun M, Shariat SF, Schmitges J, Djahangirian O, Tian Z, et al. The importance of pelvic lymph node dissection in the elderly population: implications for interpreting the 2010 National Comprehensive Cancer Network practice guidelines for bladder cancer treatment. J Urol. 2011;185:2078–84.

    Article  PubMed  Google Scholar 

  36. Martin-Doyle W, Leow JJ, Orsola A, Chang SL, Bellmunt J. Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol. 2015;33:643–50.

    Article  PubMed  Google Scholar 

  37. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466–5. discussion 75–7

    Article  PubMed  Google Scholar 

  38. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.

    Article  Google Scholar 

  39. Acquaviva J, He S, Zhang C, Jimenez JP, Nagai M, Sang J, et al. FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. Mol Cancer Res. 2014;12:1042–54.

    Article  CAS  PubMed  Google Scholar 

  40. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011;43:875–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim PH, Cha EK, Sfakianos JP, Iyer G, Zabor EC, Scott SN, et al. Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol. 2015;67:198–201.

    Article  PubMed  Google Scholar 

  42. Pouessel D, Neuzillet Y, Mertens LS, van der Heijden MS, de Jong J, Sanders J, et al. Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment. Ann Oncol. 2016;27:1311–6.

    Article  CAS  PubMed  Google Scholar 

  43. Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2:1118–33.

    Article  CAS  PubMed  Google Scholar 

  44. Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, et al. Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2015;33:3401–8.

    Article  CAS  PubMed  Google Scholar 

  45. Rodriguez-Vida A, Saggese M, Hughes S, Rudman S, Chowdhury S, Smith NR, et al. Complexity of FGFR signalling in metastatic urothelial cancer. J Hematol Oncol. 2015;8:119.

    Article  PubMed  PubMed Central  Google Scholar 

  46. di Martino E, Tomlinson DC, Knowles MAA. Decade of FGF receptor research in bladder cancer: past, present, and future challenges. Ther Adv Urol. 2012;2012:429213.

    Google Scholar 

  47. di Martino E, Tomlinson DC, Williams SV, Knowles MA. A place for precision medicine in bladder cancer: targeting the FGFRs. Future Oncol. 2016;12(9):2243–63.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Herr HW, Morales A. History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol. 2008;179:53–6.

    Article  PubMed  Google Scholar 

  49. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Joudi FN, Smith BJ, O'Donnell MA. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Urol Oncol. 2006;24:344–8.

    Article  CAS  PubMed  Google Scholar 

  51. Nagabhushan TL, Maneval DC, Benedict WF, Wen SF, Ihnat PM, Engler H, et al. Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer. Cytokine Growth Factor Rev. 2007;18:389–94.

    Article  CAS  PubMed  Google Scholar 

  52. Dinney CP, Fisher MB, Navai N, O'Donnell MA, Cutler D, Abraham A, et al. Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. J Urol. 2013;190:850–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.

    Article  CAS  PubMed  Google Scholar 

  57. Lee R, Droller MJ. The natural history of bladder cancer. Implications for therapy. Urol Clin North Am. 2000;27:1–13. vii

    Article  CAS  PubMed  Google Scholar 

  58. Marshall VF, Whitmore WF Jr. The present position of radical cystectomy in the surgical management of carcinoma of the urinary bladder. J Urol. 1956;76:387–91.

    Article  CAS  PubMed  Google Scholar 

  59. Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol. 2006;176:486–92. discussion 91–2

    Article  PubMed  Google Scholar 

  60. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19:666–75.

    Article  CAS  PubMed  Google Scholar 

  61. Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29:2171–7.

    Article  CAS  PubMed  Google Scholar 

  62. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859–66.

    Article  CAS  PubMed  Google Scholar 

  63. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48:202–5. discussion 5–6

    Article  Google Scholar 

  64. Culp SH, Dickstein RJ, Grossman HB, Pretzsch SM, Porten S, Daneshmand S, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol. 2014;191:40–7.

    Article  PubMed  Google Scholar 

  65. Moschini M, Soria F, Klatte T, Wirth GJ, Ozsoy M, Gust K, et al. Validation of preoperative risk grouping of the selection of patients most likely to benefit from neoadjuvant chemotherapy before radical cystectomy. Clin Genitourin Cancer. 2016;15(2):e267–73.

    Article  PubMed  Google Scholar 

  66. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A. 2014;111:3110–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18:3377–86.

    Article  PubMed  Google Scholar 

  70. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4:1140–53.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Groenendijk FH, de Jong J, Fransen van de Putte EE, Michaut M, Schlicker A, Peters D, et al. ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol. 2016;69:384–8.

    Article  CAS  PubMed  Google Scholar 

  72. Sonpavde G, Goldman BH, Speights VO, Lerner SP, Wood DP, Vogelzang NJ, et al. Quality of pathologic response and surgery correlate with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. Cancer. 2009;115:4104–9.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe–Unit 1373, Houston, TX, 77030, USA

    Mehrad Adibi & Colin P. Dinney

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  1. Mehrad Adibi
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  2. Colin P. Dinney
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Correspondence to Mehrad Adibi .

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Editors and Affiliations

  1. Department of Pathology, University of California San Diego, San Diego, California, USA

    Donna E. Hansel

  2. Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA

    Seth P. Lerner

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Adibi, M., Dinney, C.P. (2018). Treatment Paradigms in Bladder Cancer: Clinical Implications of Histological and Molecular Analysis. In: Hansel, D., Lerner, S. (eds) Precision Molecular Pathology of Bladder Cancer. Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-64769-2_5

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