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Association between urine 6-sulfatoxy-melatonin level and intravesical Bacillus Calmette-Guerin treatment–induced sleep quality deterioration in patients with non-muscle invasive bladder cancer

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Abstract

Purpose

The level of 6-sulfatoxy-melatonin (SaMT), a metabolite of melatonin, in first-void morning urine reflects blood melatonin levels from the previous night. We investigated the association between urine SaMT and sleep quality deterioration in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin induction therapy (iBCG).

Methods

We enrolled 51 patients who received iBCG once weekly for 6 or 8 weeks. Patient-reported outcomes were assessed with questionnaires including the International Prostate Symptom Score (IPSS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQC30). Questionnaires were completed before (baseline), during, at completion, and 1 and 3 months after iBCG. Melatonin and SaMT levels at baseline were measured in serum and first-void morning urine samples, respectively.

Results

Based on changes in the QLQC30 insomnia subscale, 28 (55%) patients experienced sleep quality deterioration (deterioration group). Urine SaMT values in the deterioration group were lower than those in the non-deterioration group (P = 0.0015; 7.5 vs 15.4 ng/mg creatinine, respectively). Nocturia scores in the non-deterioration group decreased over time, while those of the deterioration group remained high after completion of iBCG. A binary logistic regression analysis revealed that low urine SaMT levels (≤ 9.6 ng/mg creatinine), high IPSS nocturia scores at baseline, and high IPSS storage subscores at baseline were associated with BCG-induced sleep quality deterioration.

Conclusions

This study confirmed the association among urine SaMT levels, nocturia, and sleep disturbance in patients with NMIBC who receive iBCG. We should be aware of treatment-induced impairments to aid in appropriate decision-making.

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Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

The statistical software EZR version based on the open-source R statistical software (v.3.6.1) and PRISM software version 9.3.1 (GraphPad Software, Inc., San Diego, CA, USA). Serum melatonin level: MT ELISA Kit (OKEH02566; Aviva Systems Biology, San Diego, CA, USA). Urine 6-sulfatoxy-melatonin level: Melatonin-sulfate urine ELISA Kit (RE54031; IBL International GmbH®, Hamburg, Germany).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  Google Scholar 

  2. Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL et al (2022) European Association of Urology Guidelines on non-muscle-invasive bladder cancer (Ta, T1, and Carcinoma in Situ). Eur Urol 81:75–94

    Article  Google Scholar 

  3. Matsumoto H, Shiraishi K, Azuma H, Inoue K, Uemura H, Eto M et al (2020) Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: revision working position paper. Int J Urol 27:362–368

  4. Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK et al (2020) Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 18:329–354

    Article  Google Scholar 

  5. Blazeby JM, Hall E, Aaronson NK, Lloyd L, Waters R, Kelly JD et al (2014) Validation and reliability testing of the EORTC QLQ-NMIBC24 questionnaire module to assess patient-reported outcomes in non-muscle-invasive bladder cancer. Eur Urol 66:1148–1156

    Article  Google Scholar 

  6. Gontero P, Oderda M, Mehnert A, Gurioli A, Marson F, Lucca I et al (2013) The impact of intravesical gemcitabine and 1/3 dose Bacillus Calmette-Guerin instillation therapy on the quality of life in patients with nonmuscle invasive bladder cancer: results of a prospective, randomized, phase II trial. J Urol 190:857–862

    Article  Google Scholar 

  7. Siracusano S, Silvestri T, Bassi S, Porcaro AB, Cerruto MA, Talamini R et al (2018) Health-related quality of life after BCG or MMC induction for non-muscle invasive bladder cancer. Can J Urol 25:9480–9485

    PubMed  Google Scholar 

  8. Miyake M, Nishimura N, Oda Y, Owari T, Hori S, Morizawa Y et al (2022) Intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer: functional outcome assessment based on a questionnaire survey and actigraphy. Support Care Cancer 30:887–895

    Article  Google Scholar 

  9. Pesonen JS, Cartwright R, Vernooij RWM, Aoki Y, Agarwal A, Mangera A et al (2020) The impact of nocturia on mortality: a systematic review and meta-analysis. J Urol 203:486–495

    Article  Google Scholar 

  10. Arendt J (1998) Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod 3:13–22

    Article  CAS  Google Scholar 

  11. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP (2008) Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther 7:189–203

    Article  CAS  Google Scholar 

  12. Mehrzadi MH, Hosseinzadeh A, Juybari KB, Mehrzadi S (2020) Melatonin and urological cancers: a new therapeutic approach. Cancer Cell Int 20:444

    Article  CAS  Google Scholar 

  13. Chen YT, Yang CC, Shao PL, Huang CR, Yip HK (2019) Melatonin-mediated downregulation of ZNF746 suppresses bladder tumorigenesis mainly through inhibiting the AKT-MMP-9 signaling pathway. J Pineal Res 66:e12536

    Article  Google Scholar 

  14. Liu S, Liang B, Jia H, Jiao Y, Pang Z, Huang Y (2017) Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells. FEBS Open Bio 7:798–810

    Article  CAS  Google Scholar 

  15. Cheng TC, Lee YH, Chang YP, Lee DC (2020) Improved urinary melatonin level as the perspective indicator that leads to better slee** quality in bladder cancer patients. Ther Adv Urol 12:1756287220940870

    Article  CAS  Google Scholar 

  16. Miyake M, Iida K, Nishimura N, Miyamoto T, Fujimoto K, Tomida R et al (2021) Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study. BMC Cancer 21:266

    Article  CAS  Google Scholar 

  17. Degboe A, Ivanescu C, Rohay JM, Turner RR, Cella D (2019) Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients. Support Care Cancer 27:4189–4198

    Article  Google Scholar 

  18. Kobayashi K, Takeda F, Teramukai S, Gotoh I, Sakai H, Yoneda S et al (1998) A cross-validation of the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) for Japanese with lung cancer. Eur J Cancer 34:810–815

    Article  CAS  Google Scholar 

  19. Tokuda Y, Okubo T, Ohde S, Jacobs J, Takahashi O, Omata F et al (2009) Assessing items on the SF-8 Japanese version for health-related quality of life: a psychometric analysis based on the nominal categories model of item response theory. Value Health 12:568–573

    Article  Google Scholar 

  20. Schernhammer ES, Berrino F, Krogh V, Secreto G, Micheli A, Venturelli E et al (2008) Urinary 6-sulfatoxymelatonin levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 100:898–905

    Article  CAS  Google Scholar 

  21. Xu J, Huang L, Sun GP (2017) Urinary 6-sulfatoxymelatonin level and breast cancer risk: systematic review and meta-analysis. Sci Rep 7:5353

    Article  Google Scholar 

  22. Pinheiro JC, Bates DM (2002) Mixed-Effects Models in S and S-PLUS. Springer, New York

    Google Scholar 

  23. Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP (2011) Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov 5:109–123

    Article  CAS  Google Scholar 

  24. Olesen T, Paul J, Gramme P, Drake MJ, Vandewalle J, Everaert K (2020) Assessment of the most impactful combination of factors associated with nocturia and to define nocturnal polyuria by multivariate modelling. J Clin Med 9:2262

    Article  Google Scholar 

  25. Nowak R, McMillen IC, Redman J, Short RV (1987) The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: two non-invasive techniques for monitoring human circadian rhythmicity. Clin Endocrinol (Oxf) 27:445–452

    Article  CAS  Google Scholar 

  26. Rzepka-Migut B, Paprocka J (2020) Melatonin-measurement methods and the factors modifying the results. a systematic review of the literature. Int J Environ Res Public Health 17:1916

    Article  CAS  Google Scholar 

  27. Liu S, Madu CO, Lu Y (2018) The role of melatonin in cancer development. Oncomedicine 3:37–47

    Article  Google Scholar 

  28. Alonso-Gonzalez C, Menendez-Menendez J, Gonzalez-Gonzalez A, Gonzalez A, Cos S, Martinez-Campa C (2018) Melatonin enhances the apoptotic effects and modulates the changes in gene expression induced by docetaxel in MCF7 human breast cancer cells. Int J Oncol 52:560–570

    CAS  PubMed  Google Scholar 

  29. Pandi-Perumal SR, Sirinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006) Melatonin: Nature’s most versatile biological signal? FEBS J 273:2813–2838

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to their patients and the staff of our institution.

Funding

This research was supported by JSPS KAKENHI grant numbers 21592057 (Kiyohide Fujimoto), 16K20159 (Makito Miyake) and 26861290 (Kiyohide Fujimoto).

Author information

Authors and Affiliations

  1. Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan

    Makito Miyake, Nobutaka Nishimura, Yuki Oda, Tatsuki Miyamoto, Takuto Shimizu, Shunta Hori, Yosuke Morizawa, Daisuke Gotoh, Yasushi Nakai, Satoshi Anai, Kazumasa Torimoto, Katsuya Aoki, Nobumichi Tanaka & Kiyohide Fujimoto

  2. Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, 634-8522, Japan

    Tomomi Fujii

  3. Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, 634-8522, Japan

    Nobumichi Tanaka

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  1. Makito Miyake
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Contributions

Study conceptualization and design: Makito Miyake and Kazumasa Torimoto. Formal analysis and investigation: Nobutaka Nishimura and Sayuri Ohnishi. Funding acquisition: Makito Miyake and Kiyohide Fujimoto. Material preparation and data collection: Yuki Oda, Shunta Hori, Yosuke Morizawa, Daisuke Gotoh, Yasushi Nakai, Satoshi Anai, and Tomomi Fujii. Writing – original draft: Makito Miyake. Writing – review & editing: Nobumichi Tanaka, Kiyohide Fujimoto. All authors contributed substantially and helped revise previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Makito Miyake or Kiyohide Fujimoto.

Ethics declarations

Ethics approval and consent to participate

The study protocol complied with the provisions of the Declaration of Helsinki. This study was conducted according to the Declaration of Helsinki (2013) and was approved by the Ethics Committee of the Nara Medical University (protocol ID: NMU-1719). Each enrolled patient provided written informed consent.

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The authors declare no competing interests.

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Miyake, M., Nishimura, N., Ohnishi, S. et al. Association between urine 6-sulfatoxy-melatonin level and intravesical Bacillus Calmette-Guerin treatment–induced sleep quality deterioration in patients with non-muscle invasive bladder cancer. Support Care Cancer 30, 6145–6153 (2022). https://doi.org/10.1007/s00520-022-07043-0

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